2006 Gout

Rheum Dis Clin N Am 32 (2006) ix
Erratum
Erratum to ‘‘New Therapeutics in

Rheumatoid Arthritis’’
[Rheum Dis Clin N Am 32 (1) (2006) 57-74]
Christine Savage, MD, E. William St. Clair, MDT
Duke University Medical Center, Durham, NC, USA
In the February 2006 issue of Rheumatic Disease Clinics of North America,

an incorrect drug dosage was printed. On page 66 in the article ‘‘New Thera-
peutics in Rheumatoid Arthritis,’’ the correct dosage for rituximab should be
1000 mg intravenously once on days 1 and 15.
DOI of original article title 10.1016/j.rdc.2005.10.004.

* Corresponding author.
E-mail address: stcla003@mc.duke.edu (E.W. St. Clair).
0889-857X/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.rdc.2006.05.009 rheumatic.theclinics.com
Rheum Dis Clin N Am 32 (2006) xi – xii
Preface
Gout
Hyon Choi, MD, DrPH, FRCPC

Guest Editor
Crystal deposition arthropathy continues to be one of the most common in-

flammatory rheumatic disorders that constitutes significant public health prob-
lems. These problems are anticipated to grow in scope in view of the growing
elderly population worldwide and increasing prevalence of risk factors for these
disorders. There have been many exciting recent developments in crystal ar-
thropathy research, and the current issue of Rheumatic Disease Clinics of North
America intends to summarize these data and put them into context.
First, recent epidemiologic data are reviewed, including the overall disease
burden and modifiable risk factors of gout, which have implications for the pre-
vention and management of this painful condition. An article discusses the ma-
jor chronic disorders associated with hyperuricemia or gout and acknowledges
the ongoing research and debate on their independent pathogenetic links. Recent
elucidation of molecular mechanisms of urate crystal–induced inflammation and
renal urate transport mechanisms is reviewed in two articles, both of which rep-
resent substantial advancement in our pathogenetic understanding with potential
therapeutic implications. Two articles review therapeutic approaches for crystal
deposition arthropathy: one for overall therapeutic modalities, including history
and recent advances, and the other for all relevant human clinical trials, including
trials of the new potent agents in development.
Specific to calcium deposition diseases, one article updates their overall patho-
genesis and clinical manifestations. Two separate articles review the potential
pathogenetic roles of calcium deposition on other major disorders in a balanced
xii preface
manner: one for osteoarthritis and the other for nonrheumatic disorders. Finally,
another article reviews radiographic modalities that are used for crystal ar-
thropathy. Special thanks are owed to Anthony Reginato, MD, PhD, for assisting
reviews of these last four articles. It is hoped that putting these articles together
will help disseminate these important recent developments among clinicians and
researchers in the field and stimulate research that will elucidate further the
pathogenesis of these disorders and their associated conditions and lead to im-
proved methods of prevention, diagnosis, and treatment.
Hyon Choi, MD, DrPH, FRCPC

Division of Rheumatology
Vancouver General Hospital
The University of British Columbia
Arthritis Research Centre of Canada
Vancouver, BC, Canada
Channing Laboratory
Department of Medicine
Brigham and Women’s Hospital
Boston, MA, USA
E-mail address: hchoi@partners.org
Rheum Dis Clin N Am 32 (2006) 255 – 273
Epidemiology of Crystal Arthropathy

Hyon Choi, MD, DrPHa,b,T
a
Division of Rheumatology, Vancouver General Hospital,
The University of British Columbia, Arthritis Research Centre of Canada, Suite 300,
895 West 10th Avenue, Vancouver, BC V5Z 1L7, Canada
b
Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital,
181 Longwood Avenue, Boston, MA 02115, USA
Gout is an inflammatory arthritis mediated by the crystallization of uric acid

within the joints and often is associated with hyperuricemia. Epidemiologic data
suggest that the overall disease burden of gout remains substantial and may be
increasing. Identifying and characterizing important modifiable risk factors for
gout is a major step in the prevention and management of this painful condition.
As more scientific data on these modifiable risk factors and comorbidities of gout
become available, integration of these factors into gout prevention and care
strategies may become essential [1]. This article reviews the relevant epidemio-
logic data on gout, with a focus on recent progress and available data on other
crystal arthropathies, although existing data on the latter are limited.
Prevalence of gout
Definitive diagnosis of gout requires either the presence of monosodium urate

monohydrate crystals in joint fluid or a tophus [2]. In population surveys de-
signed to estimate the prevalence of gout, however, this method of identification
is impractical. For this reason, several criteria for gout case definition have been
developed, including the Rome criteria [3], the New York criteria [4], and the
American College of Rheumatology (ACR) criteria [2]. Although the ACR cri-
T Division of Rheumatology, Vancouver General Hospital, The University of British Co-

lumbia, Arthritis Research Centre of Canada, Suite 300, 895 West 10th Avenue, Vancouver,
BC V5Z 1L7, Canada.
E-mail address: hchoi@partners.org
256 choi
teria are applicable in clinical and population-based research [2], the ACR sur-
vey criteria, in particular, have been used widely in recent epidemiologic studies
of gout [5,6].
The National Arthritis Data Workgroup reviewed earlier population-based
studies that estimated the prevalence of gout [7]—the Tecumseh Community
Health Study [8], the Framingham Heart Study [9], and the Sudbury study [10].
These data are summarized in Table 1. These studies were conducted in con-
fined geographic regions and were relatively small (total participants: 7207,
5127, and 4626, respectively). Furthermore, these studies were done before the
ACR criteria were developed [2]. Overall, the age distribution of the Framingham
study population was older, resulting in a higher prevalence than in the other two
(see Table 1).
The United States national prevalence of gout has been estimated using self-
reported data from various years of the National Health Interview Survey (NHIS)
and the Third National Health and Nutrition Examination Survey (NHANES III,
1988–1994). In the NHIS, the presence of gout during a 1-year period was
recorded if a respondent answered ‘‘yes’’ to the question, ‘‘Have you or any
member of your household had gout within the past year?’’ In contrast, during
the home interview of the NHANES, all subjects were asked, ‘‘Has a doctor ever
told you that you had gout?’’ Interviewers were instructed to emphasize the word,
doctor. If the respondent stated that it was another health professional who gave
the diagnosis of gout to him or her, then the answer was coded as ‘‘no’’ [11].
Although the accuracy of these self-reported data has not been studied spe-
cifically in these surveys, validation data from other studies may help understand
the general accuracy of self-reported gout. Data from the Sudbury study shows
that 44% of self-reported cases could be validated according to Rome or New
York criteria [10]. The validation rate from a physician cohort (Johns Hopkins
Precursor Study) was much higher, however—80% according to the ACR survey
criteria applied by mail and 100% by mail combined with medical record review
[6]. Similarly, the validation rate of self-reported gout in a recent large pro-
Table 1
Prevalence of gout in the United States in regional population studies
Prevalence (per 1000)
Source (year) Gout definition Age Total Male Female
Tecumseh Community ‘‘Rome’’a 20 7.2 4.8
Health Study (1960)
Framingham Heart Arbitraryb 42 (mean, 58) 14.8 28.5 3.9
Study (1964)
Sudbury study (1972) Romec and NYd 15 3.7 6.6 1.0
a
‘‘Rome’’: ‘‘insofar as possible’’ on the Rome criteria.
b
Arbitrary: at least 2 of the following 3 features — a typical attack of arthritis, an attack of
arthritis with a prompt response to colchicine therapy, and hyperuricemia.
c
Rome: Rome criteria for gout.
d
NY: New York criteria for gout.
epidemiology of crystal arthropathy 257
Table 2
Annual prevalence of gout per 1000 in the United States by age, sex, race, and income, 1996
Age, year
b 45 45–64 65
Sex
Male 3.4 33.5 46.4
Female 0.2 12.0 19.5
Race
White 1.9 21.0 31.0
Black 0.7 35.6 35.2
Income
b $10,000 — 54.9 36.6
$10,000–$19,999 — 23.9 34.9
$20,000–$34,999 1.4 29.8 21.5
$35,000 2.8 18.3 28.5
spective cohort of male health professionals (Health Professionals Follow-Up

Study [HPFS]) was approximately 70% according to the ACR survey criteria
assessed by a mailed survey [5]. The difference in the validation rate of self-
reported gout between these studies likely reflects differences in level of health
knowledge in the study populations, although the contribution of the differ-
ences in the criteria used cannot be eliminated.
The most recent available NHIS data on self-reported gout are from the 1996
survey (Table 2) [12]. The overall prevalence for the 1-year period was 9.4 cases
per 1000 persons in the United States. The prevalence increased with age, from
1.8 per 1000 in persons aged 18 to 44 to 33.5 per 1000 in persons aged 45 to 64,
and to 46.4 per 1000 in persons aged 65 and older. The prevalence was higher in
men at all ages and higher in blacks aged 45 and older than in whites in the same
age group (see Table 2) [12]. In addition, the prevalence tended to be higher with
lower family income levels (see Table 2).
In the NHANES III, the lifetime prevalence of gout was lowest (0.4%) in
subjects aged 20 to 29 and highest (8%) in those aged 70 to 79 (Table 3). Among
men, the prevalence of gout increased from 0.2% in subjects aged 20 to 29 to
Table 3
Life-time prevalence of gout per 1000 in the United States (Third National Health and Nutrition
Examination Survey, 1988–1994)T
Age, year Total Male Female
20 26 38 16
20–29 4 2 5
30–39 11 21 1
40–49 17 26 9
50–59 39 56 23
60–69 61 94 32
70–79 80 116 52
80 59 71 53
T Lifetime prevalence of gout obtained by the question, ‘‘Has a doctor ever told you that you
had gout?’’
258 choi
Table 4
Annual prevalence of gout per 1000 in the United States by survey year (National Health Inter-
view Survey)T
Age group, year
All ages 17/18–44 45–64 65
1969 4.8 3.1 12.0 12.7
1976 7.8 3.8 18.4 24.1
1988 8.5 3.1 21.0 27.0
1996 9.4 1.8 22.4 30.8
T 1-Year prevalence of gout obtained by the question, ‘‘Have you or any member of your
household had gout within the past year?’’
11.6% in those aged 70 to 79. Although gout was reported more often in men
than in women overall, the prevalence in women approached that of men after
menopause (see Table 3). The prevalence of gout was 3.2% in women aged 60 to
69 and increased to 5.2% in women aged 70 to 79 and 5.3% in women 80 years
and older [11]. These national data suggest that the prevalence of gout is
approximately 2.7% in the United States. This corresponds to an estimated
5.9 million persons who have gout: 4.0 million men and 1.9 million women.
Despite the emphasis on physician diagnosis of gout, however, these estimates
may be overestimated, because they were based on self-reported data.
Available data suggest that the prevalence of gout is increasing. Prevalence
estimates derived from the NHIS over time can be compared directly (Table 4),
because the survey instrument has not changed. The prevalence more than
doubled, and the steepest increase occurred between 1969 and 1976 [13]. More
recent NHIS data from the 1992 to 1996 surveys suggest the increasing trend
seemed to slow substantially between 1992 and 1996 (8.4 and 9.4 per 1000) (see
Table 4). Similarly, a multicenter study of general practices in the United
Kingdom reports that the prevalence of gout in 1991 increased threefold com-
pared with the estimates from the 1970s [14]. An increasing trend between the
1960s and 1992 also was observed in Maori Indians and in European descendants
in New Zealand [15]. More recently, a study based on a United States managed
care population recently reported that the overall prevalence of gout or hyper-
uricemia requiring a gout or serum urate-lowering medication in 1999 increased
by 80% compared with that in 1990 [16]. A similar increasing trend was observed
in Chinese population surveys performed in the 1990s [17].
Incidence of gout
Data on the incidence of gout are limited. The Rochester Epidemiology

Project identified 39 new cases of acute gout meeting the ACR criteria [2] during
the 2-year interval, 1977 to 1978, resulting in an age- and sex-adjusted annual
incidence rate of 45.0 per 100,000 (95% confidence interval [CI], 30.7–59.3)
[18]. In comparison, for the interval 1995 to 1996, 81 cases were diagnosed,
Table 5
Annual incidence of gout per 1000 (Rochester County residents)
(1977–1978) (1995–1996)
Age Male Female Male Female
20–29 0.2 0.0 0.1 0.0
30–39 0.6 0.0 0.8 0.1
40–49 1.1 0.2 1.0 0.1
50–59 1.6 0.4 1.6 0.0
60–69 1.3 0.5 2.5 0.6
70–79 2.3 0.6 4.6 1.3
80 2.6 0.9 3.4 1.6
providing an annual incidence rate of 62.3 per 100,000 (95% CI, 48.4–76.2).
These rates resulted in a greater than twofold increase in the rate of primary gout
(ie, no history of diuretic exposure) during the 20-year period. In contrast, the
incidence of secondary, diuretic-associated gout did not increase over time [18].
The age-specific incidence rates stratified by sex are summarized in Table 5.
The Johns Hopkins Precursor Study documents 60 cases of incident gout that
developed in 1216 male physicians during a median follow-up of 29 years
(34,729 person-years of observation) [19]. These figures indicated an annual inci-
dence rate of 1.7 per 1000 (95% CI, 1.3–2.2). Recently, the HPFS documented
a comparable incidence rate (1.5 per 1000).
Risk factors for gout
Demographic factors
Age
Prevalence and incidence of gout increase with age in men and women [5,7,
11,18]. Serum urate rate levels also tend to increase with aging in women, but
the trend is less clear in men [8]. For example, the Normative Aging Study finds
no independent association between normal aging and serum uric acid levels in
healthy men [20]. Age-associated risk factors for hyperuricemia and gout might
explain some portion of the increasing incidence of gout with older age, includ-
ing increased prevalence of chronic medical conditions and medication use and
deterioration of renal function.
Gender
Although the prevalence and incidence of gout are substantially higher in
men than in women before menopause, the disease burden in women tends to
approach that of men after menopause. For example, the prevalence of gout in
NHANES III (discussed previously) may be overestimated given that they were
based on self-reports of physician-diagnosed gout; however, even if the true age-
specific prevalences were 50% lower, they still would be substantial, with the
260 choi
prevalence of gout in this population approaching that of rheumatoid arthritis

(2% in the NHANES III) [21]. Furthermore, the Rochester Epidemiology Proj-
ect data indicate that the incidence of primary gout has doubled in women during
the past 20 years [18].
Gender also may alter the magnitude of the effect of certain risk factors. For
example, case series of gout comparing distributions of risk factors between men
and women suggest that risk factors for gout in women may be different from
those for men [22,23]. A higher proportion of female than male patients who had
gout had hypertension and renal insufficiency and were treated with diuretics
[22–24]. Conversely, more males than female patients reported heavy lcohol in-
take (especially beer), suggesting that alcohol intake may not be a major factor
contributing to the development of gout in female patients [22–24]. Although
these data are intriguing, these differences may reflect the difference in back-
ground prevalence of these factors between men and women, and these hospital-
based case series are open to a referral bias. These data call for gender-specific
epidemiology studies to quantify the magnitudes of associations in the differ-
ent sexes.
Race
A study based on two cohorts of former medical students, 352 black men in
the Meharry Cohort Study and 571 white men in the Johns Hopkins Precursor
Study, showed that the relative risk (RR) for gout in the black men was 1.69 (95%
CI, 1.02–2.80) compared with the white men [25]. The excess risk for gout in
black men was explained by a greater risk for incident hypertension among
them [25].
Modifiable risk factors
Serum uric acid and gout

Although hyperuricemia is considered the precursor of gout, only a few
epidemiologic studies have prospectively investigated the relation between prior
uric acid levels and risk for incident gout in men [26,27]. The Normative Aging
Study evaluated incidence of gout stratified by prior uric acid levels [26]. Based
on 84 incident cases of gout during a 15-year period, the all-male study found
that annual incidence of gout was less than 0.1% for men who had serum uric
acid level less than 7.0 mg/dL, 0.4% for 7.0 to 7.9 mg/dL, 0.8% for 8.0 to
8.9 mg/dL, 4.3% for 9.0 to 9.9 mg/dL, and 7.0% for greater than 10.0 mg/dL.
A Chinese population study followed men who had hyperuricemia (defined by
7.0 mg/dL) during a 5-year period and documented 42 cases of incident gout
[27]. Annual incidence rates of gout in this study were 2.2% for 7.0 to 7.9 mg/dL,
5.5% for 8.0 to 8.9 mg/dL, and 12.2% for greater than or equal to 9.0 mg/dL
(Fig. 1) [27]. No data on the impact of prior uric acid levels on incident gout
specifically in women are available.
It remains unclear if dietary and other risk factors predict the risk for incident
gout independent of prior uric acid levels. The Normative Aging Study reported
9%
8%
Annual Incidence of Gout

7%
6%
5%
4%
3%
2%
1%
0%
<6 6-6.9 7-7.9 8-8.9 9-9.9 >10
Serum Uric Acid (mg/dL)
Fig. 1. Relation between prior serum uric acid levels and incidence of gout. Annual incidence of gout
was less than 0.1% for men who had serum uric acid level less than 7 mg/dL, 0.4% for 7 to 7.9 mg/dL,
0.8% for 8 to 8.9 mg/dL, 4.3% for 9 to 9.9 mg/dL, and 7.0% for greater than 10 mg/dL. Solid line
denotes these data points and dotted line shows an exponential projection of the data points. (From
Campion EW, Glynn RJ, De Labry LO. Asymptomatic hyperuricemia. Risks and consequences in
the Normative Aging Study. Am J Med 1987;82:421–6; with permission.)
that age, body mass index (BMI), and hypertension no longer were associated
significantly with the risk for incident gout after adjusting for baseline serum
uric acid levels [26]. The Chinese study, however, restricted to men who had
hyperuricemia, showed significant associations with obesity, alcohol consump-
tion, and diuretic use (for hypertension) independent of uric acid levels [27].
Furthermore, the same study found a significant interaction between persistent
alcohol consumption and baseline uric acid levels in the hyperuricemic range
[27]. These data suggest that certain risk factors may be associated more strongly
in men who have hyperuricemia. For example, because renal urate clearance
is impaired in those who have hyperuricemia (such as gouty patients), the ab-
sorption of dietary purines causes a steeper increase in the blood uric acid level
than do equivalent quantities in persons who have normouricemia [28,29].
Adiposity
Adiposity has been noted to be associated with serum uric acid levels and
proposed to increase the risk for gout. Several prospective cohort studies have
evaluated the association between obesity and gout [19,25,26,30]. The Johns
Hopkins Precursor Study reported that increased BMI at age 35, but not at
baseline (mean age, 22), was associated with the risk for gout (RR 1.12 for 1 unit
increase in BMI; P = .02) [19]. The Normative Aging Study showed BMI at
baseline (mean age, 52) significantly associated with hyperuricemia or gout, al-
though the study had similar limitations [26]. The Framingham study found a
262 choi
significantly higher BMI in patients who had gout after adjusting for age [30].
In these studies, a small number of gout cases or the lack of data limited the
comprehensive adjustment of relevant covariates. Specifically, no prospective
information had been available about the relation between obesity and incident
gout after adjusting for dietary factors, which themselves may be risk factors for
gout and vary with adiposity.
In a recent prospective analysis in the HPFS, BMI and waist-to-hip ratio were
strongly associated with the risk for incident gout after adjusting for various
confounders including dietary factors [31]. Compared with men who had BMI
21 to 22.9 kg/m2, the multivariate RRs of gout were 1.95 (1.44–2.65) for men
who had BMI 25 to 29.9 kg/m2, 2.33 (1.62–3.36) for 30 to 34.9 kg/m2, and
2.97 (1.73–5.10) for greater than 35 kg/m2 ( P for trend b .001) (Fig. 2). The multi-
variate RR for gout in men in the highest waist-to-hip ratio quintile (0.98–1.39)
compared with those in the lowest (0.70–0.88) was 1.82 (95% CI, 1.39–2.39;
P for trend b .001). The HPFS data showed a substantial attenuation of RR af-
ter adjustment for confounders, emphasizing the importance of multivariate
models. Further, compared with men who maintained their weight ( 4 to +4 lb)
since age 21, the multivariate RR of gout for men who gained 30 pounds or
more was 1.99 (1.49–2.66). In contrast, the multivariate RR for men who lost
10 pounds or more since the study baseline was 0.61 (95% CI, 0.40–0.92) [31].
Increased adiposity may lead to hyperuricemia via increased production and de-
creased renal excretion of urate [32,33]. Factors not related to uric acid, such as
chronic joint trauma resulting from excess weight, are proposed as an additional
explanation for the association between obesity and gout [6,33].
The impact of adiposity on gout adds to the already substantial hazards asso-
ciated with the obesity epidemic in the United States. The 1999 to 2000 National
Health and Nutrition Examination Survey estimated that the age-adjusted preva-
lence of obesity (BMI N 30) in United States adults is 30.5% [34]. The prevalence
of class 3 obesity (BMI index 40) in adults has more than doubled in 10 years,
6
Multivariate Relative Risk
4 P for trend = < 0.001
0 <21 21-22.9 23-24.9 25-29.9 30-35 >=35
BMI (kg/m2)
Fig. 2. Relation between BMI and incidence of gout in men.

with an estimated prevalence of 2.2% in the year 2000 [35]. Obesity is associated
with at least as much morbidity as poverty, smoking, and problem drinking [36]
and leads to approximately 300,000 deaths per year in the United States [37]. For
example, weight gain is linked to increased risks of coronary heart disease (CHD)
[38,39], hypertension [40], type 2 diabetes [41,42], kidney stone [43], and gall-
stones [44]. A new Healthy Eating Pyramid strongly recommends daily exercise
and weight control, placing them at the foundation of the pyramid (Fig. 3) [1,45].
Comprehensive persistent efforts to reduce adiposity could contribute to reducing
the disease burden from gout and associated morbidities [46].
Diet
Purine-rich foods and high protein intake long had been believed risk factors
for gout [32,33]; however, the associations had not confirmed prospectively.
Metabolic experiments in animals and humans demonstrated the urate-raising
effect of artificial short-term loading of purified purine [47–50]. Small-scale case-
Fig. 3. Dietary influences on the risk for gout and their implications within the Healthy Eating
Pyramid. Data on the relationship between diet and the risk for gout are derived primarily from the
recent HPFS. Upward solid arrows denote an increased risk for gout, downward solid arrows denote a
decreased risk, and horizontal arrows denote no influence on risk. Broken arrows denote potential
effect but without prospective evidence for the outcome of gout. (Adapted from Choi HK, Mount DB,
Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499–516; with permission.)
264 choi
control studies that assessed dietary intake retrospectively in confirmed cases of

gout and controls, however, failed to find an association between purine intake
and gout [51,52]. In addition, the possibility that the consumption of dairy
products has a role in protecting against gout has been raised by previous studies
[53,54]. In a recent study (HPFS), the relation between these purported dietary
risk factors and incident gout during a 12-year period in 47,150 male participants
(730 incident gout cases), who had no history of gout at baseline, was examined
prospectively [5]. Men in the highest quintile of meat intake had a 41% higher
risk for gout compared with those in the lowest quintile, and men in the highest
quintile of seafood intake had a 51% higher risk compared with the lowest
quintile (Fig. 4). Purine-rich vegetable consumption, however, was not associated
with an increased risk for gout. Further, men in the highest quintile of dairy intake
had a 44% lower risk for gout compared with those in the lowest and the inverse
association was limited to low-fat dairy consumption (Fig. 5). Although total and
animal protein intake were not associated significantly with risk for gout, men in
the highest quintile of vegetable protein had a 27% lower risk for gout compared
with those in the lowest quintile, and men in the highest quintile of dairy protein
intake had a 48% lower risk for gout compared with those in the lowest quintile.
Dairy protein may exert its urate-lowering effect without the concomitant purine
load contained in other animal protein sources, such as meat and seafood, given
that dairy products have a low purine content [54,55]. It also is possible, however,
that other factors in dairy products may be responsible for the inverse association.
The absence of the inverse association with high-fat dairy products could result
from the counteracting effect of saturated fats contained in high-fat dairy prod-
ucts. These fats are associated positively with insulin resistance [56,57], which
reduces renal excretion of urate, thus raising serum uric acid levels [46,58–60].
A recent Taiwanese case-control study (91 gout cases and 91 controls) suggested
Total Meat Seafood Purine-rich Vegetables

2.0
1.5
1.0
P for trend = 0.016
P for trend = 0.016 P for trend = 0.779
0.5
0.0
Q1 Q3 Q5 Q1 Q3 Q5 Q1 Q3 Q5
(0.6) (1.3) (2.3) (0.1) (0.3) (0.7) (0.2) (0.6) (1.4)
Purine-rich Food Group Quintile (serving/d)
Fig. 4. Relative risk for incident gout according to intake of purine-rich food groups in men. The
reference group for comparisons is the men who have the lowest intake quintile in each food group.
Q1 to Q5 denote first quintile (lowest) to 5th quintile (highest).
1.5 Low-Fat Dairy Intake High-Fat Dairy Intake

1.0
0.5
P for trend < 0.001 P for trend = 0.648
0.0
Q1 Q2 Q3 Q4 Q5 Q1 Q2 Q3 Q4 Q5
(0.1) (0.4) (0.8) (1.2) (2.6) (0.2) (0.5) (0.8) (1.2) (2.5)
Dairy Intake Quintiles (serving/d)
Fig. 5. Relative risk for incident gout according to dairy intake in men. The reference group for
comparisons is the men who have the lowest quintile of dairy intake. Q1 to Q5 denote first quintile
(lowest) to 5th quintile (highest).
a protective effect of folate and dietary fiber against gout (odds ratios, 0.43 and
0.37 between the extreme tertiles, respectively) [52]. These interesting findings
call for prospective confirmation.
Implications of these findings for dietary recommendation for patients who
have hyperuricemia or gout generally are consistent with the new Healthy Eating
Pyramid (see Fig. 3), except for fish intake [1]. The use of plant-derived omega-3
fatty acids or supplements of eicosapentaenoic acid and docosahexaenoic acid in
place of fish consumption could be considered to provide the benefit of these
fatty acids without increasing the risk for gout. Omega-3 fatty acids also may
have anti-inflammatory effect against gouty flares [1].
Alcohol
The association between alcohol consumption and risk for gout has been
suspected since ancient times; however, the association had not been confirmed
prospectively. Several cohort studies previously evaluated the association be-
tween alcohol intake and gout but were limited by small sample size and lack of
comprehensive adjustment of relevant variables [19,25,26,30,61] In the recent
HPFS, increasing alcohol intake was associated with increasing risk for gout
(a dose-response relationship) [62]. Compared with men who did not drink al-
cohol, the multivariate RR of gout increased from 1.25 (95% CI, 0.95–1.64) for
alcohol consumption (5 to 9.9 g per day) to 2.53 (1.73–3.70) (50 g per day)
( P for trend b.001). This risk varied substantially according to type of alcoholic
beverage: beer conferred a larger risk than liquor, whereas moderate wine drink-
ing did not increase the risk (Fig. 6) [62]. These findings confirmed the long-
held belief of relation between alcohol intake and risk for gout. In addition, they
suggest that certain nonalcoholic components that vary among these alcoholic
beverages play a role in the incidence of gout. Beer is the only alcoholic beverage
266 choi
4
Beer Liquor Wine

3
1
P for trend < 0.001 P for trend = 0.01 P for trend = 0.68
0
< 1/m 5-7/w >1/d < 1/m 5-7/w >1/d < 1/m 5-7/w >1/d
Alcohol Types (serving/time)
Fig. 6. Relative risk for incident gout according to individual alcoholic beverage intake in men. The
reference group for comparisons in the lower panel is the men who have the lowest intake category,
less than 1 serving per month.
acknowledged to have a large purine content, which is predominantly guanosine,

a readily absorbable nucleoside [51,63]. The effect of ingested purine in beer on
blood uric acid may be sufficient to augment the hyperuricemic effect of alcohol
itself, producing a greater risk for gout than liquor or wine. It remains unclear
whether or not there are other nonalcoholic offending factors, particularly in beer,
or perhaps protective factors in wine mitigating the alcohol effect on the risk for
gout [62].
Medications, supplements, and toxins
Many medications and substances affect serum urate levels, potentially

affecting the risk for gout (Table 6). Among these, diuretics are shown to
independently increase the actual risk for gout in a prospective population-based
study [31]. During the HPFS 12 years of follow-up of men who had no previous
history of gout, diuretic use was associated independently with an increased risk
for incident gout independent of hypertension (RR 1.77; 95% CI, 1.42–2.20)
[31]. Because the indications for these urate-raising medications may pose an
increased risk for gout by themselves, it is important to adjust appropriately for
these indications in determining the independent impact of these medications.
Several studies suggest that high doses of vitamin C show a uricosuric effect
[64–68]. For example, ingestion of ascorbic acid (4 g) led to a twofold in-
crease in fractional clearance of uric acid up to 6 hours after the ingestion, and
ingestion of ascorbic acid (8 g for 3 to 7 days) reduced the serum uric acid by up
to 3.1 mg/dL as a result of a sustained uricosuria [67]. A recent trial showed that
supplementation with vitamin C (500 mg per day for 2 months) reduces serum
uric acid by 0.5 mg/dL [68]. Because vitamin C generally is considered safe, its
uricosuric effect may provide a useful option for the prevention and management
of hyperuricemia and gout.
Table 6
Substances affecting urate levels
Substances Implicated mechanisms and comments
Urate-raising agents
Diuretics zRenal tubular reabsorption associated with
volume depletion [71,72], may stimulate
URAT1 [73]
Salicylate (low dose) A Renal urate excretion [74]
b-blockers Unknown (no change in renal urate excretion [75]
Lactate, b-hydroxybutyrate, acetoacetate Trans-stimulation of URAT1 [73]
Pyrazinamide, nicotinate Trans-stimulation of URAT1 [73]
Ethambutol A Renal urate excretion
Cyclosporin, tacrolimus zRenal tubular reabsorption associated with
A glomerular filtration [76–80], hypertension [81],
interstitial nephropathy [82,83]
Insulin Higher insulin levels are known to reduce renal
excretion of urate [46,58–60]. May stimulate
URAT1 [73] or the Na+-dependent anion
cotransporter in brush border membranes of the
renal proximal tubule [1]
Lead A Renal urate excretion from chronic lead
nephropathy [84]
Urate-lowering agents
Probenecid, sulfinpyrazone, benzbromarone Inhibition of URAT1 [73]
Losartan Inhibition of URAT1 [73]
Salicylate (high dose) Inhibition of URAT1 [73]
Fenofibrate May inhibit URAT1
Amlodipine zRenal urate excretion [81]
Vitamin C Via uricosuric effect due to a competition for
renal reabsorption
via an anion-exchange transport system at the
proximal tubules
Allopurinol, febuxostat Inhibition of xanthine oxidase
Uricase Oxidation of urate to allantoin
Abbreviation: URAT1, urate transporter-1.
Although toxic levels of lead (ie, blood lead levels N60 mg/dL) clearly are
associated with gouty arthritis [69], no such relation was found with bone or
blood lead levels arising from community exposure in the Normative Aging
Study [61]. A clinical study based on 111 Taiwanese adults, including 27 who
had gout [70], however, suggested that chronic low-level environmental lead
exposure may inhibit urate excretion and that lead chelation therapy reduces this
inhibition [70]. Further research on large populations with variable lead exposure
levels would be helpful in determining the threshold for saturnine gout and the
importance of this variable in relation to other known risk factors for gout [61].
Associated medical conditions
Various medical conditions have been suspected of being associated with hy-
peruricemia and gout, including the metabolic syndrome, obesity, hypertension,
268 choi
renal insufficiency, kidney stone, type 2 diabetes, and cardiovascular disorders.

Available data on the link between hyperuricemia and these disorders are re-
viewed in detail in the article by Becker and Meenakshi elsewhere in this issue;
this section discusses the relation with the risk for gout. Hypertension and renal
insufficiency have been shown in the HPFS to be associated independently with
the risk for incident gout (RR 2.31 [95% CI, 1.96–2.72] and 4.60; [1.88–11.25],
respectively) [31]. A history of kidney stone, however, was not associated with
the risk for incident gout (RR 1.05 [95% CI, 0.54–2.07]), whereas a confirmed
diagnosis of gout increased the risk for kidney stone (2.12 [1.22–3.68]) [85]. In
the Framingham study, gout was associated with a 60% increased risk for CHD in
men (95% CI, 1.1–2.2) [24]. The small number of women who had gout, how-
ever, limited a meaningful analysis (three cases of CHD in 19 women) [24]. The
potential independent link with other disorders remains to be clarified.
Calcium pyrophosphate dihydrate deposition and pseudogout
A definitive diagnosis of calcium pyrophosphate dihydrate (CPPD) deposition

disease would require unequivocal identification of CPPD crystals in joint fluid
or articular tissue [86,87]. It has been proposed that the presence of synovial fluid
crystal identification using polarized light microscopy and radiographic cal-
cification of the cartilage would make a definitive diagnosis and either one
would make a probable diagnosis [86,87]. Because joint aspiration or biopsy is
impractical in population studies, presence of radiographic chondrocalcinosis
often has been used in epidemiologic and clinical investigations to study CPPD
disease [86–91].
Studies have suggested that the prevalence of radiographic chondrocalcinosis
increases with age [88–90]. The Framingham Knee Osteoarthritis Study, based on
1402 elderly adults, reported that the prevalence of radiographic chondrocalci-
nosis in the knee joints increased from less than 4% in those under age 70 to 27%
in those over 85. The same study also reported a modest cross-sectional asso-
ciation between radiographic chondrocalcinosis and knee osteoarthritis (RR 1.52)
and females tending to have a slightly increased age-adjusted prevalence, although
the estimate was not statistically significant (RR 1.33 [95% CI, 0.93–1.92]). No
population epidemiologic data exist for pyrophosphate arthropathy or ‘‘pseudo-
gout’’ per se [87]. Most of available cases series suggest that mean age at
presentation of between seventh and eighth decades of life with a female pre-
dominance (2–3:1) [87,92].
Although many metabolic and endocrine diseases are reported to predispose to
CPPD deposition, the validity of many of these associations remains unclear [93].
A critical review reported that there were better evidences for the association with
hyperparathyroidism, hemochromatosis, hypophosphatasia, hypomagnesemia,
and hypothyroidism than with other suspected conditions [93].
Hereditary CPPD deposition diseases are reported in several ethnic popula-
tions, usually with autosomal dominance inheritance pattern [87,94,95]. Two
main clinical types are reported, the first characterized by early-onset, florid,
polyarticular chondrocalcinosis and the second by late-onset oligoarticular with
arthritis resembling sporadic pyrophospate arthropathy [87]. An abstract of a
Spanish familial study reported a comparison between 21 kindreds with definite
CPPD of ‘‘sporadic cases’’ and 15 kindreds of patients who had other rheumatic
disease (controls) [87,96]. The familial aggregation rate for chondrocalcinosis in
these kindreds was 38.8% compared with 0% in the controls.
Basic calcium phosphate deposition arthropathy
Basic calcium phosphate (BCP) crystal deposition is associated with several

clinical manifestations, ranging from asymptomatic status to destructive arthropa-
thy, called Milwaukee shoulder syndrome. Population data on these conditions
are scarce; there is only one large-scale study, reported in 1941 [97]. From 1937
through 1939, 6061 office workers and candidates underwent physical and fluo-
roscopic examination of both shoulders in connection with an insurance com-
pany. The prevalence of calcium deposition was 2.7% (3.6% in males and 2.5%
in females). Thirty-five percent of shoulders with calcium deposition were
associated with some degree of pain or discomfort before or during the time of
the study. Recent clinical studies indicate that the prevalence of intra-articular
BCP crystals in joints with osteoarthritis may be high (67%) [98]; these and
other related data are reviewed in detail in the article by Rosenthal elsewhere in
this issue.
References
[1] Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499 – 516.
[2] Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute
arthritis of primary gout. Arthritis Rheum 1977;20:895 – 900.
[3] Criteria CIOMS. Rome. Appendix 1. Proposed diagnostic criteria for use in population studies.
In: Kellgren JH, Jeffrey MR, Ball J, editors. The epidemiology of chronic rheumatism. Oxford7
Blackwell Scientific; 1963. p. 324 – 6.
[4] Bennett PH, Wood PHN, editors. Population studies of the rheumatic diseases. Proceedings of
the 3rd International Symposium, New York, June 5–10, 1966. Amsterdam7 Excerpta Medica
Foundation; 1968. p. 457 – 8.
[5] Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake, and the risk
of gout in men. N Engl J Med 2004;350:1093 – 103.
[6] Roubenoff R. Gout and hyperuricemia. Rheum Dis Clin North Am 1990;16:539 – 50.
[7] Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and se-
lected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778 – 99.
[8] Mikkelsen WM, Dodge HJ, Duff IF, et al. Estimates of the prevalence of rheumatic diseases in
the population of Tecumseh, Michigan, 1959–60. J Chronic Dis 1967;20:351 – 69.
[9] Hall AP, Barry PE, Dawber TR, et al. Epidemiology of gout and hyperuricemia. A long-term
population study. Am J Med 1967;42:27 – 37.
[10] O’Sullivan JB. Gout in a New England town. A prevalence study in Sudbury, Massachusetts.
Ann Rheum Dis 1972;31:166 – 9.
270 choi
[11] Kramer HM, Curhan G. The association between gout and nephrolithiasis: the National Health
and Nutrition Examination Survey III, 1988–1994. Am J Kidney Dis 2002;40:37 – 42.
[12] Centers for Disease Control and Prevention, National Center for Health Statistics. Vital and
health statistics: current estimates from the National Health Interview Survey, 1996. Series 10.
No. 200. Atlanta: Department of Health and Human Services (US). Available at: http://www.cdc.
gov/nchs/data/series/sr_10/sr10_200.pdf. Accessed March 1, 2006.
[13] Lawrence RC, Hochberg MC, Kelsey JL, et al. Estimates of the prevalence of selected arthritic
and musculoskeletal diseases in the United States. J Rheumatol 1989;16:427 – 41.
[14] Harris CM, Lloyd DC, Lewis J. The prevalence and prophylaxis of gout in England. J Clin
Epidemiol 1995;48:1153 – 8.
[15] Klemp P, Stansfield SA, Castle B, et al. Gout is on the increase in New Zealand. Ann Rheum Dis
1997;56:22 – 6.
[16] Wallace KL, Riedel AA, Joseph-Ridge N, et al. Increasing prevalence of gout and hyperuricemia
over 10 years among older adults in a managed care population. J Rheumatol 2004;31:1582 – 7.
[17] Zeng Q, Wang Q, Chen R, et al. Primary gout in Shantou: a clinical and epidemiological study.
Chin Med J (Engl) 2003;116:66 – 9.
[18] Arromdee E, Michet CJ, Crowson CS, et al. Epidemiology of gout: is the incidence rising?
J Rheumatol 2002;29:2403 – 6.
[19] Roubenoff R, Klag MJ, Mead LA, et al. Incidence and risk factors for gout in white men. JAMA
1991;266:3004 – 7.
[20] Glynn RJ, Campion EW, Silbert JE. Trends in serum uric acid levels 1961–1980. Arthritis
Rheum 1983;26:87 – 93.
[21] Rasch EK, Hirsch R, Paulose-Ram R, et al. Prevalence of rheumatoid arthritis in persons
60 years of age and older in the United States: effect of different methods of case classification.
Arthritis Rheum 2003;48:917 – 26.
[22] Lally EV, Ho Jr G, Kaplan SR. The clinical spectrum of gouty arthritis in women. Arch Intern
Med 1986;146:2221 – 5.
[23] Puig JG, Michan AD, Jimenez ML, et al. Female gout. Clinical spectrum and uric acid me-
tabolism. Arch Intern Med 1991;151:726 – 32.
[24] Macfarlane DG, Dieppe PA. Diuretic-induced gout in elderly women. Br J Rheumatol 1985;
24:155 – 7.
[25] Hochberg MC, Thomas J, Thomas DJ, et al. Racial differences in the incidence of gout. The
role of hypertension. Arthritis Rheum 1995;38:628 – 32.
[26] Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences
in the Normative Aging Study. Am J Med 1987;82:421 – 6.
[27] Lin KC, Lin HY, Chou P. The interaction between uric acid level and other risk factors on
the development of gout among asymptomatic hyperuricemic men in a prospective study.
J Rheumatol 2000;27:1501 – 5.
[28] Nugent CA. Renal urate excretion in gout studied by feeding ribonucleic acid. Arthritis Rheum
1965;8:671 – 85.
[29] Gibson T, Highton J, Potter C, et al. Renal impairment and gout. Ann Rheum Dis 1980;39:
417 – 23.
[30] Abbott RD, Brand FN, Kannel WB, et al. Gout and coronary heart disease: the Framingham
Study. J Clin Epidemiol 1988;41:237 – 42.
[31] Choi HK, Atkinson K, Karlson EW, et al. Obesity, weight change, hypertension, diuretic use, and risk
of gout in men—The Health Professionals Follow-Up Study. Arch Intern Med 2005;165:742 – 8.
[32] Emmerson BT. The management of gout. N Engl J Med 1996;334:445 – 51.
[33] Fam AG. Gout, diet, and the insulin resistance syndrome. J Rheumatol 2002;29:1350 – 5.
[34] Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults,
1999–2000. JAMA 2002;288:1723 – 7.
[35] Freedman DS, Khan LK, Serdula MK, et al. Trends and correlates of class 3 obesity in the
United States from 1990 through 2000. JAMA 2002;288:1758 – 61.
[36] Sturm R, Wells KB. Does obesity contribute as much to morbidity as poverty or smoking? Public
Health 2001;115:229 – 35.
[37] Allison DB, Fontaine KR, Manson JE, et al. Annual deaths attributable to obesity in the United
States. JAMA 1999;282:1530 – 8.
[38] Willett WC, Manson JE, Stampfer MJ, et al. Weight, weight change, and coronary heart disease
in women. Risk within the dnormalT weight range. JAMA 1995;273:461 – 5.
[39] Rimm EB, Stampfer MJ, Giovannucci E, et al. Body size and fat distribution as predictors
of coronary heart disease among middle-aged and older US men. Am J Epidemiol 1995;141:
1117 – 27.
[40] Huang Z, Willett WC, Manson JE, et al. Body weight, weight change, and risk for hypertension
in women. Ann Intern Med 1998;128:81 – 8.
[41] Colditz GA, Willett WC, Rotnitzky A, et al. Weight gain as a risk factor for clinical diabetes
mellitus in women. Ann Intern Med 1995;122:481 – 6.
[42] Conigrave KM, Hu BF, Camargo Jr CA, et al. A prospective study of drinking patterns in
relation to risk of type 2 diabetes among men. Diabetes 2001;50:2390 – 5.
[43] Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA
2005;293:455 – 62.
[44] Maclure KM, Hayes KC, Colditz GA, et al. Weight, diet, and the risk of symptomatic gallstones
in middle-aged women. N Engl J Med 1989;321:563 – 9.
[45] Willett WC, Stampfer MJ. Rebuilding the food pyramid. Sci Am 2003;288:64 – 71.
[46] Dessein PH, Shipton EA, Stanwix AE, et al. Beneficial effects of weight loss associated with
moderate calorie/carbohydrate restriction, and increased proportional intake of protein and
unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis 2000;
59:539 – 43.
[47] Clifford AJ, Riumallo JA, Young VR, et al. Effects of oral purines on serum and urinary uric acid
of normal, hyperuricaemic and gouty humans. J Nutr 1976;106:428 – 50.
[48] Clifford AJ, Story DL. Levels of purines in foods and their metabolic effects in rats. J Nutr
1976;106:435 – 42.
[49] Zollner N. Influence of various purines on uric acid metabolism. Bibl Nutr Dieta 1973;34 – 43.
[50] Zollner N, Griebsch A. Diet and gout. Adv Exp Med Biol 1974;41:435 – 42.
[51] Gibson T, Rodgers AV, Simmonds HA, et al. A controlled study of diet in patients with gout.
Ann Rheum Dis 1983;42:123 – 7.
[52] Lyu LC, Hsu CY, Yeh CY, et al. A case-control study of the association of diet and obesity with
gout in Taiwan. Am J Clin Nutr 2003;78:690 – 701.
[53] Loenen HM, Eshuis H, Lowik MR, et al. Serum uric acid correlates in elderly men and women
with special reference to body composition and dietary intake (Dutch Nutrition Surveillance
System). J Clin Epidemiol 1990;43:1297 – 303.
[54] Garrel DR, Verdy M, PetitClerc C, et al. Milk- and soy-protein ingestion: acute effect on serum
uric acid concentration. Am J Clin Nutr 1991;53:665 – 9.
[55] Ghadirian P, Shatenstein B, Verdy M, et al. The influence of dairy products on plasma uric acid
in women. Eur J Epidemiol 1995;11:275 – 81.
[56] Christiansen E, Schnider S, Palmvig B, et al. Intake of a diet high in trans monounsaturated fatty
acids or saturated fatty acids. Effects on postprandial insulinemia and glycemia in obese patients
with NIDDM. Diabetes Care 1997;20:881 – 7.
[57] Feskens EJ, Kromhout D. Habitual dietary intake and glucose tolerance in euglycaemic men: the
Zutphen Study. Int J Epidemiol 1990;19:953 – 9.
[58] Ter Maaten JC, Voorburg A, Heine RJ, et al. Renal handling of urate and sodium during acute
physiological hyperinsulinaemia in healthy subjects. Clin Sci (Lond) 1997;92:51 – 8.
[59] Muscelli E, Natali A, Bianchi S, et al. Effect of insulin on renal sodium and uric acid handling in
essential hypertension. Am J Hypertens 1996;9:746 – 52.
[60] Facchini F, Chen YD, Hollenbeck CB, et al. Relationship between resistance to insulin-mediated
glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 1991;
266:3008 – 11.
[61] Shadick NA, Kim R, Weiss S, et al. Effect of low level lead exposure on hyperuricemia and
gout among middle aged and elderly men: the Normative Aging Study. J Rheumatol 2000;27:
1708 – 12.
272 choi
[62] Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake and risk of incident gout in men—
a prospective study. Lancet 2004;363:1277 – 81.
[63] Gibson T, Rodgers AV, Simmonds HA, et al. Beer drinking and its effect on uric acid. Br J
Rheumatol 1984;23:203 – 9.
[64] Mitch WE, Johnson MW, Kirshenbaum JM, et al. Effect of large oral doses of ascorbic acid on
uric acid excretion by normal subjects. Clin Pharmacol Ther 1981;29:318 – 21.
[65] Berger L, Gerson CD, Yu TF. The effect of ascorbic acid on uric acid excretion with a com-
mentary on the renal handling of ascorbic acid. Am J Med 1977;62:71 – 6.
[66] Sutton JL, Basu TK, Dickerson JW. Effect of large doses of ascorbic acid in man on some
nitrogenous components of urine. Hum Nutr Appl Nutr 1983;37:136 – 40.
[67] Stein HB, Hasan A, Fox IH. Ascorbic acid-induced uricosuria. A consequency of megavitamin
therapy. Ann Intern Med 1976;84:385 – 8.
[68] Huang HY, Appel LJ, Choi MJ, et al. The effects of vitamin C supplementation on serum
concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum 2005;52:
1843 – 7.
[69] Reynolds PP, Knapp MJ, Baraf HS, et al. Moonshine and lead. Relationship to the pathogenesis
of hyperuricemia in gout. Arthritis Rheum 1983;26:1057 – 64.
[70] Lin JL, Tan DT, Ho HH, et al. Environmental lead exposure and urate excretion in the general
population. Am J Med 2002;113:563 – 8.
[71] Steele TH. Evidence for altered renal urate reabsorption during changes in volume of the
extracellular fluid. J Lab Clin Med 1969;74:288 – 99.
[72] Steele TH, Oppenheimer S. Factors affecting urate excretion following diuretic administration in
man. Am J Med 1969;47:564 – 74.
[73] Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion
exchanger that regulates blood urate levels. Nature 2002;417:447 – 52.
[74] Caspi D, Lubart E, Graff E, et al. The effect of mini-dose aspirin on renal function and uric acid
handling in elderly patients. Arthritis Rheum 2000;43:103 – 8.
[75] Reyes AJ. Cardiovascular drugs and serum uric acid. Cardiovasc Drugs Ther 2003;17:397 – 414.
[76] Lin HY, Rocher LL, McQuillan MA, et al. Cyclosporine-induced hyperuricemia and gout.
N Engl J Med 1989;321:287 – 92.
[77] Gupta AK, Rocher LL, Schmaltz SP, et al. Short-term changes in renal function, blood pressure,
and electrolyte levels in patients receiving cyclosporine for dermatologic disorders. Arch Intern
Med 1991;151:356 – 62.
[78] Hansen JM, Fogh-Andersen N, Leyssac PP, et al. Glomerular and tubular function in renal
transplant patients treated with and without ciclosporin A. Nephron 1998;80:450 – 7.
[79] Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol 2000;11:
974 – 9.
[80] Ahn KJ, Kim YS, Lee HC, et al. Cyclosporine-induced hyperuricemia after renal transplant:
clinical characteristics and mechanisms. Transplant Proc 1992;24:1391 – 2.
[81] Chanard J, Toupance O, Lavaud S, et al. Amlodipine reduces cyclosporin-induced hyper-
uricaemia in hypertensive renal transplant recipients. Nephrol Dial Transplant 2003;18:2147 – 53.
[82] Starzl TE, Fung J, Jordan M, et al. Kidney transplantation under FK 506. JAMA 1990;264:
63 – 7.
[83] Boots JM, van Duijnhoven EM, Christiaans MH, et al. Single-center experience with tacrolimus
versus cyclosporine-Neoral in renal transplant recipients. Transpl Int 2001;14:370 – 83.
[84] Ball GV, Sorensen LB. Pathogenesis of hyperuricemia in saturinine gout. N Engl J Med 1969;
280:1199 – 202.
[85] Kramer HJ, Choi HK, Atkinson K, et al. The association between gout and nephrolithiasis in
men: The Health Professionals’ Follow-Up Study. Kidney Int 2003;64:1022 – 6.
[86] McCarty DJ. Crystals and arthritis. Dis Mon 1994;40:255 – 99.
[87] Hochberg MC, Silman AJ, Smolen JS, et al. Rheumatology. 3rd ed. New York7 Mosby; 2003.
[88] Wilkins E, Dieppe P, Maddison P, et al. Osteoarthritis and articular chondrocalcinosis in the
elderly. Ann Rheum Dis 1983;42:280 – 4.
[89] Felson DT, Anderson JJ, Naimark A, et al. The prevalence of chondrocalcinosis in the elderly and
its association with knee osteoarthritis: the Framingham Study. J Rheumatol 1989;16:1241 – 5.
[90] Sanmarti R, Kanterewicz E, Pladevall M, et al. Analysis of the association between chon-
drocalcinosis and osteoarthritis: a community based study. Ann Rheum Dis 1996;55:30 – 3.
[91] Doherty M, Dieppe P. Crystal deposition disease in the elderly. Clin Rheum Dis 1986;12:
97 – 116.
[92] Doherty M, Dieppe P. Clinical aspects of calcium pyrophosphate dihydrate crystal deposition.
Rheum Dis Clin North Am 1988;14:395 – 414.
[93] Jones AC, Chuck AJ, Arie EA, et al. Diseases associated with calcium pyrophosphate deposition
disease. Semin Arthritis Rheum 1992;22:188 – 202.
[94] Riestra JL, Sanchez A, Rodriguez-Valverde V, et al. Radiographic features of hereditary articular
chondrocalcinosis. A comparative study with the sporadic type. Clin Exp Rheumatol 1988;6:
369 – 72.
[95] Doherty M, Hamilton E, Henderson J, et al. Familial chondrocalcinosis due to calcium pyro-
phosphate dihydrate crystal deposition in English families. Br J Rheumatol 1991;30:10 – 5.
[96] Fernandez-Dapica MP, Reginato AJ. Familial chondrocalcinosis in Spain. Arthritis Rheum 1992;
35:S45.
[97] Bosworth BM. Calcium deposits in the shoulder and subacromial bursitis. A survey of
12,222 shoulders. JAMA 1941;116:2477 – 82.
[98] Derfus BA, Kurian JB, Butler JJ, et al. The high prevalence of pathologic calcium crystals in
pre-operative knees. J Rheumatol 2002;29:570 – 4.
Hyperuricemia and Associated Diseases

Michael A. Becker, MDa,T, Meenakshi Jolly, MDb
a
Rheumatology Section, The University of Chicago Pritzker School of Medicine, Chicago, IL, USA
b
Department of Medicine, Rush University Medical Center, Chicago, IL, USA
In the years after introduction of effective urate-lowering therapy, many

persons who had hyperuricemia but no symptoms of gout were treated with
allopurinol or uricosuric agents in the belief that the previously demonstrated
association of gout with chronic structural and functional renal abnormalities
denoted a causal relationship. Epidemiologic studies in the late 1970s [1,2],
however, seemed to allay the concern that hyperuricemia and gout were in-
dependent risk factors for chronic kidney disease. These studies prompted the
current conservatism in the management of asymptomatic hyperuricemia. Never-
theless, the association of hyperuricemia and gout with other important disorders
continues to be documented and, combined with experimental data derived from
studies in rats, has led to reconsideration of a pathogenetic role for hyperurice-
mia independent of crystal deposition in hypertension, chronic kidney disease,
cardiovascular disease (coronary heart disease, stroke and peripheral artery dis-
ease, and congestive heart failure), and aberrant metabolic states, such as hyper-
triglyceridemia, obesity, insulin resistance, and metabolic syndrrome. Whether
or not hyperuricemia (or even ‘‘high normal’’ serum urate levels) plays a causal
role or simply is a marker arising in the course of each related disorder remains
unresolved. This article reviews the current status of the relationship between
hyperuricemia and associated disorders.
T Corresponding author. Rheumatology Section, MC 0930, University of Chicago Medical

Center, 5841 Maryland Avenue, Chicago, IL 60637.
E-mail address: mbecker@medicine.bsd.uchicago.edu (M.A. Becker).
276 becker & jolly
Definition of hyperuricemia
Physicochemical and population definitions of hyperuricemia exist [3]. The

physicochemical definition (serum urate concentration in excess of 6.8 mg/dL,
the limit of urate solubility in serum) is preferable in the context of gout, to stress
that the risk for crystal deposition disease imparted by urate supersaturation of
extracellular fluids begins at approximately this concentration and probably is
equivalent in comparably affected men and women. Hyperuricemia without
gout (asymptomatic hyperuricemia) is more common with this definition, with
prevalence rates of 5% to 8% in men in the United States [4–6] and up to 25% in
adult men of Polynesian derivation [7], than with a definition of hyperuricemia
based on serum urate values 2 standard deviations or more above the mean
population value.
With respect to the issue of crystal deposition and independent roles of
hyperuricemia, however, it is important to acknowledge the results of popu-
lation studies of serum urate, showing that values are higher in men than
in women before menopause and are more comparable thereafter. Furthermore,
children have lower serum urate levels, with adult male levels reached at the
time of puberty and female levels changing little before menopause. In fact, as
exemplified by the studies of juvenile-onset hypertension and cardiovascular
disease (discussed later), it may become necessary to frame new definitions
of ‘‘high’’ serum urate levels as distinct from physicochemical or population-
based hyperuricemia.
Hyperuricemia and hypertension
An association of hyperuricemia and hypertension [8–12] long has been rec-

ognized and is supported by the following observations:
1. Prevalences of hyperuricemia of approximately 20% to 40% in untreated

hypertensive patients and approximately 50% to 70% in treated or renally
impaired hypertensive patients
2. Gout prevalences of 2% to 12% in hypertensive patients
3. 25% to 50% hypertension prevalences in groups of patients who have
documented gout
4. Increasing prevalence of hyperuricemia with increasing blood pressure in
the general population
5. Increasing risk for development of hypertension with increasing baseline
serum urate levels
Despite these findings, conflicting results of epidemiologic studies and

the existence of multiple potentially confounding variables preclude establish-
hyperuricemia & associated diseases 277
ment of a cause-effect relationship in either direction. For example, the high

prevalence of hypertension in patients who have classical gout is related more
closely to obesity than to the duration of gout [13,14]. Moreover, only 1% of
blood pressure variation could be accounted for by serum urate values in
the Israel Ischemic Heart Disease Study of 10,000 men ages 40 or older [15].
These findings contrast with longitudinal studies in which the risk for future
hypertension is correlated with serum urate levels [9,10,12] and a trial of in-
dividuals, who initially were normotensive, in whom serum urate levels re-
mained positively and significantly associated with systolic and diastolic blood
pressures for 12 years and, when high, predicted the development of hyperten-
sion [8].
Because of difficulty in distinguishing epidemiologically between causal and
epiphenomenologic bases for the hyperuricemia-hypertension association, in-
creasing attention is devoted to mechanistic and experimental studies. Renal uric
acid clearances depend on tubular secretory and postsecretory reabsorption rates,
which are reported to be inappropriately low relative to glomerular filtration
rates in adult and childhood essential hypertension [3,16], and may be regu-
lated, in part, by renal blood flow. In fact, selectively increased renal vascular
resistance and total peripheral resistance are documented in subjects who have
essential hypertension and hyperuricemia, raising the possibility that hyper-
uricemia is a consequence of early nephrosclerosis in patients who have essential
hypertension [17]. A similar argument is made for the early appearance of
hyperuricemia in patients who have familial juvenile hyperuricemic nephropathy
(FJHN) [18].
In contrast, a causal role for hyperuricemia in hypertension is suggested by
the results of other experimental and clinical studies. Urate is reported to ac-
tivate critical proinflammatory pathways in vascular smooth muscle cells and,
hence, may have a role in the vascular changes associated with hypertension and
vascular disease [19,20]. Urate stimulates monocyte chemoattractant protein-1
production in vascular smooth muscle cells via mitogen-activated protein kinase
and cyclooxygenase 2. In Sprague-Dawley rats with serum urate levels raised
by oxonate inhibition of uricase activity, a direct correlation is observed between
serum urate level and the development of salt-resistant, allopurinol-reversible
high blood pressure [21]. Also demonstrated is increased juxtaglomerular renin
content and decreased macula densa neuronal nitric oxide synthase content,
implicating the respective mediator systems in the dysregulation of blood pres-
sure. Preglomerular arteriolopathy [22] accompanying these changes may ac-
count for the subsequent development of a salt-sensitive hypertensive state, not
reversible by lowering of serum urate levels [23]. Feig and Johnson recently
demonstrated a linear relationship between serum urate levels and systolic blood
pressure (r = 0.8, P b 0.001) in adolescents who have new-onset hyperten-
sion [24]. Furthermore, in a pilot study of such individuals, allopurinol admin-
istration results in urate lowering and normalization of blood pressure [25].
Johnson and colleagues [26–29] review in detail the evidence for a role of urate in
human hypertension.
278 becker & jolly
Hyperuricemia and chronic kidney disease
Despite the nearly invariable occurrence of hyperuricemia in chronic kidney

disease in humans and the high frequency of chronic renal impairment in patients
who have gout, evidence for a pathogenetic role of hyperuricemia in the initiation
or progression of chronic renal impairment comes mainly from animal studies
[30]. Mild oxonate-induced increases in serum urate levels in Sprague-Dawley
rats result in glomerular hypertension, hypertrophy, and, ultimately, sclerosis;
renin-dependent systemic hypertension and afferent arteriolosclerosis; and
interstitial renal inflammation, terminating in fibrosis [21,22,31–35]. All of these
changes occur at high but subsaturating urate levels and are independent of urate
crystal deposition. A role for increased urate levels in worsening structural and
functional renal disease also is demonstrated in the cyclosporine-induced [36]
and remnant kidney [33] models of chronic kidney disease in rats. Few studies in
humans are available to support the potential implications of the rat studies.
As discussed previously, earlier studies [1,2] in subjects who have gout and
hyperuricemia failed to corroborate a renal risk of hyperuricemia or gout, at least
at serum urate levels (b13 mg/dL in men; b10 mg/dL in women) commonly
encountered in clinical practice. Although a pathologically demonstrable in-
terstitial urate crystal deposition nephropathy (called urate nephropathy) does
exist, this entity only rarely is of clinical consequence [37]. The shift of in-
vestigative focus to crystal-unrelated effects of urate on the kidney holds more
promise for resolution of the question of a causal role of hyperuricemia in pro-
gressive renal disease.
FJHN is an autosomal dominantly inherited hyperuricemic disorder, commonly
progressing to end-stage renal disease, and allopurinol treatment is reported by
some investigators [38,39], but not all [18], to retard or prevent progression.
Although gout occurs in some patients who have FJHN, there is little evidence
for crystal deposition as a mediator of renal impairment [18], so that confirmation
of a benefical effect of allopurinol in this process is important in assessing the
role of hyperuricemia in the renal disease, for which alternative mechanisms are
proposed [40]. Most families who have the FJHN phenotype have mutations in
the UMOD gene encoding uromodulin (Tamm-Horsfall protein) [41], a fact that
should allow early identification of at-risk family members in whom the benefits
of early urate-lowering therapy can be assessed.
In epidemiologic studies, urate levels are reported to correlate with develop-
ment of chronic renal insufficiency in patients who have hypertension [42,43],
and patients who have impaired renal function have higher serum urate levels
[44–46]. Recently, a reciprocol relationship between serum urate levels and renal
vascular responsiveness to angiotensin II administration was reported [47], sug-
gesting that increased urate levels may, as in rats, activate the renin-angiotensin
system. Finally, the incidence of end-stage renal disease developing over 7 years
in Okinawan women who had serum urate levels greater than or equal to
6.0 mg/dL at baseline was significantly higher than in their counterparts who had
lower urate levels [48].
Hyperuricemia and cardiovascular disease
Coronary heart disease
The weight of recent evidence supports the view that hyperuricemia is an

important risk factor for ischemic heart disease and probably other forms of
cardiovascular disease [49,50]. Whether or not hyperuricemia is only a marker or
is a pathogenetic factor in cardiovascular diseases remains uncertain (Table 1),
and resolution of this issue will likely require large interventional trials assessing
the proposition that prevention or reversal of hyperuricemia has beneficial effects
on the course of cardiovascular disorders in at-risk patients.
The issue of hyperuricemia as an independent risk factor for atheroscle-
rotic cardiovascular disease is controversial [49]. Multivariate analysis of cardiac
risk factors in the original Framingham cohort did not identify an independent
predictive role for serum urate values in coronary heart disease [51] but did
show a 60% excess of coronary disease in gouty men never treated with di-
uretics [52]. Additional study of the Framingham cohort [53] supports the con-
tention that risk factors other than hyperuricemia are causal in atherosclerotic
heart disease. In 6763 subjects who had baseline serum urate levels established
from 1971 to 1976, hyperuricemia was not associated (by 1994) with an increased
risk for adverse outcome (coronary heart disease, death from cardiovascular
disease, or death from all causes) in men or, after adjustment for other cardiovas-
cular risk factors, in women. Similarly, Wannamethee and coworkers did not find
hyperuricemia a risk factor for coronary heart disease in men, independent of pre-
existing myocardial infarction, atherosclerosis, and the cluster of risk factors
associated with the insulin resistance syndrome [54]. Clustering of hyperuricemia
with cardiovascular risk factors also is reported by others [55].
Other published studies, however, favor a more direct role for hyperuricemia
in cardiovascular events or mortality [26,27,50,56–68]. In the National Health
and Nutrition Examination Survey (NHANES) I study, increasing serum urate
concentration was related to increasing cardiovascular mortality in both sexes and
in blacks and whites [56]. Death rates resulting from ischemic heart disease
increased in relation to serum urate quartile (relative risk 1.77 in men and 3.00 in
women), and cardiac and overall cardiovascular mortality risks of hyperuricemia
persisted even after adjustment for age, race, body mass index (BMI), smoking
status, alcohol intake, cholesterol, hypertension, and diabetes. In the NHANES III
study, serum urate levels greater than or equal to 6 mg/dL were found to be an
independent predictor of coronary heart disease [61]. Also, in two studies in-
cluding more than 2600 patients who had angiographically confirmed coronary
artery disease [57,62], overall mortality rates in patients either whose serum urate
was greater than 7.1 mg/dL (compared with those whose had serum urate was
b 5.1) [57] or who were in the highest quintile for serum urate ( N6.4 mg/dL) were
increased substantially and independently. Finally, the Losartan Intervention for
Endpoint Reduction in Hypertension (LIFE) study reported a significant
association between baseline serum urate level and risk for a morbid or fatal
280
Table 1
Studies relating serum urate concentrations and cardiovascular disease
Serum urate as independent
Author, year [ref.] Subjects/study name Longitudinal study Outcome variables predictor of CVD
Brand, 1985 [51] Framingham cohort Yes CHD No
Culleton, 1999 [53] Framingham cohort Yes Incident CHD, all cause and No
6763 Participants CVD mortality
Wannamethee, 1997 [54] 7688 Men, 40–59 years Yes Fatal/nonfatal CHD events No
Moriarity, 2000 [63] ARIC cohort; 13,504 healthy subjects Yes CHD events (fatal/nonfatal) No
Lin, 2004 [139] 391 Men with hyperuricemia Yes CVD
Abbott, 1988 [52] 5209, Framingham cohort with gout CHD Yes, in men
Freedman, 1995 [64] 5,421 (NHANES 1) 25–74 years Yes Mortality (all cause, ischemic Yes, in women
heart disease)
becker
Alderman, 1999 [50] 7978 Mild–moderate HTN subjects Yes CV events Yes
&
Liese, 1999 [65] MONICA cohort, 1044 subjects, 45–64 years Yes CHD, all cause/CV mortality Yes
Fang, 2000 [56] 5926, Subjects 25–74 years (NHANES 1 Yes CHD, all cause/CV mortality Yes
follow-up)
jolly
Franse, 2000 [66] 4327 Systolic HTN subjects 60 years (SHEP) Yes CV events, all cause mortality Yes
Verdecchia, 2000 [67] 1720 Subjects with untreated HTN Yes CV events, all cause/CV mortality Yes
Tuttle, 2001 [60] 277 Patients undergoing cardiac catheterization Yes SUA and CHD Yes, in women
Bickel, 2002 [57] 1,017 CHD (angiographic) Yes Mortality Yes
Athyros, 2004 [71] GREACE study, 1600 with CHD Yes All vascular events Yes
Niskanen, 2004 [68] 1423 Middle-aged, healthy Finnish men Yes CV/all cause mortality Yes
Hoieggen, 2004 [69] 9193 Subjects, 55–80 years old with untreated Yes Fatal/nonfatal MI, CV mortality, Yes
HTN and LVH (LIFE study) fatal/nonfatal stroke
Tomita, 2000 [45] 49,413 Healthy Japanese 25–60 years Yes CHD and stroke events, all Yes
cause mortality
Madsen, 2005 [62] 1,595 Angiographically defined CAD patients Yes Mortality Yes
Abbreviations: CAD, coronary artery disease; CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; HTN, hypertension.
cardiovascular event (hazard ratio 1.024 per 10 mmol/L increment in baseline

serum urate) [69].
Data supporting a role for serum urate as a determinant of coronary heart
disease also have emerged from two cardiovascular disease interventional stud-
ies. In the LIFE study [69], which compares losartan-based and atenolol-based
therapy in high-risk hypertensive patients who had left ventricular hypertrophy,
losartan therapy is associated with lower rates of cardiovascular morbidity and
death [70]. Analysis of baseline and in-trial serum urate levels indicates that
29% of the cardiovascular benefit of losartan-based therapy could be ascribed
to the urate-lowering (uricosuric) effect of losartan (not shared by atenolol)
therapy, which prevented increases in serum urate levels during the 4.8 years
of the trial. Similarly, in the Greek Atorvastatin and Coronary-Heart-Disease
Evaluation (GREACE) study [71], patients who had coronary heart disease
treated with atorvastatin showed an in-trial 8.2% reduction in serum urate levels
compared with a 3.3% mean increase in urate in patients who were untreated. The
risks of recurrent coronary disease events were correlated significantly with the
serum urate levels, such that serum urate was regarded an independent predictor
of recurrent coronary heart disease events.
Mechanisms by which hyperuricemia may promote vascular occlusive dis-
ease are under study. A direct relationship between plasma homocysteine
and serum urate levels is reported in patients who have atherosclerosis [72]. A
mutation in the methyl tetrahydrofolate reductase (MTHFR) gene is correlated
with hyperuricemia and hyperhomocysteinemia, the latter a state associated with
thrombotic disease [73]. In a recent study [74], flow-mediated arterial dilation
(FMD) in healthy hyperuricemic and normouricemic control patients who hade
high cardiovascular risk was determined before and after 3 months of allopurinol
treatment. Allopurinol (300 mg daily) reduced serum urate levels in both groups
of subjects, and the significantly lower baseline FMD in the hyperuricemic
group was normalized, suggesting that restoration of normal serum urate levels
improved this measure of vascular function [74]. Other possible mechanisms
relating hyperuricemia and cardiovascular disease are reviewed by Gavin and
Struthers [75].
Stroke and peripheral artery disease
Uric acid administration is protective against experimental ischemic stroke in

rats [76]. In humans, however, there is only one report of a more favorable
outcome of stroke in individuals who are hyperuricemic [77]. In fact, higher
serum urate levels are associated with poorer outcomes in stroke, and serum urate
greater than or equal to 7 mg/dL is described as an independent risk factor for
stroke [61]. Lehto and coworkers [78] found hyperuricemia a predictor (hazard
ratio 1.93) of nonfatal and fatal stroke in a population-based study of middle
aged, non–insulin-dependent diabetics. Similar findings are reported by others
[79,80]. In the Cardiovascular Study in the Elderly (CASTEL) study [79], serum
282 becker & jolly
urate also was an independent predictor of stroke mortality [79,59], poor out-
come, and subsequent vascular events, especially in diabetics [81]. Even though
levels of antioxidants, such as ascorbate, are reduced immediately after acute
ischemic stroke, patients who have the worst early outcome are those who have
higher plasma urate levels [82], raising the speculation that under circumstances
of alternative antioxidant depletion, urate may become prooxidant [82,83].
In patients in the LIFE study who were hyperuricemic [69], the cardiovascular
benefits of losartan extended to a reduced incidence of cerebrovascular events.
Whether or not the increased risk of stroke in individuals who are hyperuricemic
is mediated by increased predilection for the development of hypertension or
through a urate effect on the vascular endothelium is unclear, but these potential
mechanisms are under investigation [84].
Hyperuricemia also is a significant and independent risk factor for peripheral
arterial disease in Taiwanese men who have type 2 diabetes [84] and for carotid
artery atherosclerosis. Nieto and coworkers, in their prospective case control
study [85], find baseline serum urate levels associated significantly and in-
dependently with increased carotid artery atherosclerosis 13 years later. The
serum antioxidant capacity, however, was elevated unexpectedly in individuals
who had atherosclerosis, suggesting that hyperuricemia may be a compensatory
rather than a causative factor.
Congestive heart failure
Hyperuricemia is a common finding in congestive heart failure [86], and

higher serum urate levels are associated with increasing severity and poorer
outcomes in heart failure [87,88]. Anker and colleages [87] found high serum
urate levels an independent marker for impaired prognosis in patients who have
moderate to severe congestive heart failure. Urate also may contribute to more
severe heart failure via its role in hypertension [89]. Thus, there is evidence for
direct and indirect pathophysiologic roles of abnormal urate metabolism in con-
gestive heart failure [90].
In animal models, allopurinol decreases myocardial oxygen consumption [91]
and improves systolic function [92]. Endothelial damage resulting from local
xanthine oxidase-generated oxygen free radicals is proposed as a basis of cardiac
dysfunction in hyperuricemic states, and allopurinol inhibition of xanthine oxi-
dase is reported to improve endothelial dysfunction in patients who have heart
failure [86,93]. Ongoing interventional trials [89] assessing cardiovascular out-
comes resulting from inhibition of urate production with allopurinol and oxypuri-
nol should provide useful information relative to these proposed relationships.
Overall, a causal role for hyperuricemia in cardiovascular disease events and
mortality is not established unequivocally [26,58]. There seem to be more than
sufficient grounds, however, to support new clinical (interventional) and ex-
perimental initiatives for studying the potential causal mechanisms by which
hyperuricemia may promote cardiovascular disease [27].
Hyperuricemia, metabolic syndrome, and its components
Metabolic syndrome
Complexity in defining the role of hyperuricemia in chronic diseases, such

as hypertension and atherosclerotic cardiovascular disease, is underlined by
additional associations of hyperuricemia with the clinical and biochemical ab-
normalities of the metabolic syndrome: obesity, hyperlipidemia, and insulin re-
sistance. Included in the diagnostic criteria for the metabolic syndrome are waist
circumference, triglyceride levels, high-density lipoprotein (HDL) cholesterol
levels, blood pressure, and fasting blood glucose levels. Emmerson [94] has
reviewed evidence supporting inclusion of hyperuricemia resulting from impaired
renal uric acid clearance [95,96] as an intrinsic component of the metabolic
syndrome of hyperinsulinemia and resistance to insulin action [97]. The fact that
acute elevations of serum triglycerides, plasma free fatty acids, or serum insulin
do not effect serum urate levels in health volunteers supports this view [96].
Serum urate levels contribute significantly to levels of HDL cholesterol and
total cholesterol, BMI, and systolic blood pressure in children and adolescents
who are obese and may be a reliable marker of ‘‘premetabolic syndrome’’ [98].
The inverse correlation of serum urate and insulin sensitivity and the positive
correlation of urate and triglyceride levels may explain up to 50% of urate var-
iation [96]. It also is suggested that hyperuricemia may be used as a simple
marker of insulin resistance [96]. In addition, studies of weight loss-inducing
medications, such as sibutramine and orlistat, confirm reductions in BMI, fasting
and postprandial glucose levels, waist circumference, insulin resistance, blood
pressure, and serum levels of cholesterol, triglycerides, lipoprotein a, apolipo-
protein B, and urate uric acid [99] (ie, all the features of metabolic syndrome).
A corollary of these observations is that individuals who are hyperuricemic
and hyperlipidemic, in particular those who have abdominal obesity, may be a
high-risk group for the cardiovascular correlates of insulin resistance.
Obesity
Epidemiologic studies have established a strong positive correlation between

body weight and serum urate concentration, but the basis of the relationship is
complex and multifactorial [100–108]. Obesity is associated with decreased renal
uric acid clearance and increased urate production [109,110]. Direct and indi-
rect evidence for excessive body weight promoting hyperuricemia and gout is
presented in many studies [56,111–115], but a role of hyperuricemia influencing
development of obesity emerges from a few other studies (Table 2).
In interventional studies, weight reduction is associated with a modest low-
ering of serum urate concentration and a decrease in the rate of de novo pu-
rine synthesis [109]. In addition, the weight loss associated with moderate calorie
and carbohydrate restriction and increased proportional intake of protein and
unsaturated fat (as recommended for insulin-resistant states) is accompanied by a
284
Table 2
Characteristics of selected studies on relationship of hyperuricemia and obesity
Author, year [ref.] Study design Subjects Question addressed Observations Remarks
Loenen, 1990 [107] Cross sectional 460 Healthy Dutch Demographic correlates Average 7-kg difference An association between body
ages 65–79 of obesity between lowest and highest weight and SUA present
tertiles of SUA for men, Study included whites only,
and 5 kg for women diabetics were excluded, and
30% participants were on
becker
prescribed dietary restrictions

&
Fang, 2000 [56] Longitudinal 5926 Subjects Cardiovascular and all BMI and BP increased with Independent risk factor status
ages 25–74 cause mortality increasing quartiles of SUA in not evaluated
men and women at baseline
jolly
Masuo, 2003 [114] Longitudinal 433 Young, nonobese, Relation between serum SUA predicts subsequent SUA was an independent risk
normotensive men urate, weight gain, and weight gain and BP elevation factor for weight gain and BP
blood pressure elevation
Ogura, 2004 [113] Longitudinal 17,155 Students SUA and obesity or Serum uric acid levels Independent association
related factors tightly related to BMI between SUA and BMI not
clear. Study included only men
Abbreviations: BMI, body mass index; BP, blood pressure; SUA, serum urate.
decrease in serum urate levels and dyslipidemia in patients who have gout [116].
Furthermore, amelioration of insulin resistance by a low-energy diet decreases
serum urate levels in individuals who are overweight and hypertensive [117].
Finally, the weight-reduction agents, sibutramine and orlistat, lower serum urate
levels [99,118,119], and, in the prospective Swedish Obese Subjects Study [120],
2- and 10-year hyperuricemia and hypertriglyceridemia incidence rates were
lower in patients who had undergone bariatric surgery than in unoperated obese
control subjects.
Leptin, the hormone product of the obese (ob) gene, is expressed in adipo-
cytes and acts through the hypothalamus to regulate food intake and energy
expenditure. Most persons who are obese show leptin resistance, and increased
leptin levels are associated with insulin resistance in individuals who are non-
diabetic [121]. Insulin response, triglyceride levels, and BMI are associated in-
dependently and significantly with leptin concentrations [122].
Serum urate and leptin levels correlate in healthy male adolescents [123] and
in women who are moderately obese [124], and an independent relation between
serum leptin and urate was found in 822 Japanese women, even after adjust-
ing for BMI and percent body fat [125]. Women have a higher mean leptin
and lower mean urate and triglyceride concentrations than men even after adjust-
ment for BMI [126]. Similar findings are observed in children who are obese
[127]. Creatinine, leptin, insulin, and triglyceride levels account for significant
variability in serum urate in men and women [126]. These studies suggest that the
association of serum urate, obesity, and insulin resistance may be mediated, at
least in part, by leptin expression and that leptin levels may prove to be a link
between obesity and hyperuricemia.
Hyperlipidemia
The issue of hypertriglyceridemia and hyperuricemia is addressed in many

studies [56,98,128–131]. Hyperuricemia is observed in up to 80% of patients
who have hypertriglyceridemia. Furthermore, hypertriglyceridemia also may
be seen in 50% to 75% of patients who have gout. In humans, fasting serum
triglyceride levels may be the most important determinant of serum urate levels
[132]. Obesity and excessive alcohol intake confound these issues. Reductions in
serum HDL-C and HDL2-C concentrations also are observed in individuals who
are hyperuricemic [125,133]. By regression analysis, no association between
gout and HDL levels or BMI index was seen, suggesting that reduced HDL
levels are attributable to altered triglyceride metabolism [133]. Concentrations of
serum Lp(a) lipoprotein, triglycerides, and apolipoproteins AII, B, CII, CIII, and
E reportedly were increased, and HDL-C was decreased in patients who had gout
[134]. The prevalence of apolipoprotein E2 allele was greater in patients who had
gout, and its presence was associated with higher triglyceride levels in very low-
density and intermediate-density lipoproteins and with reduced renal uric acid
excretion [135].
286 becker & jolly
In the prospective GREACE study, addition of atorvastatin to the standard

treatment of coronary heart disease patients resulted in serum urate reduction
averaging 8.2% compared with an average 3.3% increase in patients receiving
standard care without atorvastatin [71]. In the atorvastatin treatment group, tri-
glyceride levels fell by 31%, HDL-C rose by 7%, and the LDL-C/HDL-C ratio
decreased by 50%. Similarly, in another prospective study [120], lower 2- and
10-year incidence rates of hypertriglyceridemia and hyperuricemia were observed
in obese patients who underwent bariatric surgery.
Insulin resistance
The relationship between hyperuricemia and insulin resistance may be indi-

rect and mediated through increased fasting plasma triglyceride levels or BMI
[96,136]. In experimental animals, urate suppresses basal insulin release in iso-
lated rat pancreatic islets and inhibits glucose-stimulated insulin secretion [137].
In a study of the relationship of insulin-mediated glucose disposal and serum
urate in 36 healthy nondiabetic volunteers [95], renal uric acid clearance de-
creased in proportion to increased insulin resistance, resulting in increased se-
rum urate concentration. An association between hyperinsulinemia and decreased
renal uric acid clearance also is reported in another study [96].
Increased serum urate concentration is among the significant risk factors as-
sociated with non–insulin-dependent diabetes mellitus in Japanese Americans
living in Hawaii and Los Angeles [138]. Persistent hyperuricemia in postmeno-
pausal women in the Kinmen study also is associated with subsequent devel-
opment of diabetes [139,140]. In a longitudinal study of Japanese male office
workers, a strong association between serum urate and subsequent development
of hypertension or type 2 diabetes was found [141]. The relationship with dia-
betes was stronger in men who had BMI less than 24.2 kg/m2 compared with
higher BMI, but the absolute risk was greater in more men who were obese.
In another prospective study, however, hyperuricemia is associated with the
development of hypertension but not type 2 diabetes [10]. Finally, metformin
administration not only reduces postprandial and fasting blood glucose levels but
also serum urate levels [99].
Summary
It is the authors’ belief that the literature to date has not established a causal
link between hyperuricemia and the previously discussed disorders that justify
the use in clinical practice of urate-lowering treatment in aymptomatic hyper-
uricemia to avoid or modify the course of the associated diseases. Relationships
between hyperuricemia and each of these morbid states do, however, exist and
may, in one or more of these disorders, prove causal and, thus, exploitable by
urate-lowering intervention. Although experimental studies performed in animals
have limitations set by differences between humans and other mammals in purine
metabolism and in renal uric acid handling, and an entirely suitable mammalian
model for hyperuricemia remains to be created, additional experimental studies
and, especially, interventional clinical studies aimed at evaluating the effects of
urate-lowering on the courses of these disorders are warranted.
References
[1] Fessel JW. Renal outcomes of gout and hyperuricemia. Am J Med 1979;67:74 – 82.
[2] Liang MH, Fries JF. Asymptomatic hyperuricemia: the case for conservative management. Ann
Intern Med 1978;88:666 – 70.
[3] Wyngaarden JB, Kelley WN. Gout and hyperuricemia. New York7 Grune & Stratton; 1976.
[4] Gibson T, Waterworth R, Hatfield P, et al. Hyperuricemia, gout and kidney function in New
Zealand Maori men. Br J Rheumatol 1984;23:276 – 82.
[5] Darmavan J, Valkenburg HA, Muirden KD, et al. The epidemiology of gout and hyperuri-
cemia in a rural population of Java. J Rheumatol 1992;19:1595 – 9.
[6] Ko YC, Wang TN, Tsai LY, et al. High prevalence of hyperuricemia in adolescent Taiwan
aborigenes. J Rheumatol 2002;29:837 – 42.
[7] Klemp P, Stansfield SA, Castle B, et al. Gout is on the increase in New Zealand. Ann Rheum
Dis 1997;56:22 – 6.
[8] Jossa F, Farinaro E, Panico S, et al. Serum uric acid and hypertension: the Olivetti heart study.
J Hum Hypertens 1994;8:677 – 81.
[9] Masuo K, Kawaguchi H, Mikami H, et al. Serum uric acid and plasma norepinephrine
concentrations predict subsequent weight gain and blood pressure elevation. Hypertension
2003;42:474 – 80.
[10] Taniguchi Y, Hayashi T, Tsumura K, et al. Serum uric acid and the risk of hypertension and
type 2 diabetes in Japanese men. The Osaka health study. J Hypertens 2001;19:1209 – 15.
[11] Nakanishi N, Okamato M, Yoshida H, et al. Serum uric acid and risk for development of
hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers.
Eur J Epidemiol 2003;18:523 – 30.
[12] Hunt SC, Stephenson SH, Hopkins PN, et al. Predictors of an increased risk of future hyper-
tension in Utah. A screening analysis. Hypertension 1991;17:969 – 76.
[13] Grahame R, Scott JT. Clinical survey of 354 patients with gout. Ann Rheum Dis 1970;29:
461 – 8.
[14] Rapado A. Relationship between gout and arterial hypertension. Adv Exp Med Biol 1974;41B:
451 – 9.
[15] Kahn HA, Medalie JH, Neufeld HN, et al. The incidence of hypertension and associated
factors: the Israel ischemic heart disease study. Am Heart J 1972;84:171 – 82.
[16] Prebis JW, Gruskin AB, Polinsky MS, et al. Uric acid in childhood essential hypertension.
J Pediatr 1981;98:702 – 7.
[17] Messerli FH, Frohlich ED, Dreslinski GR, et al. Serum uric acid in essential hypertension:
an indicator of renal vascular involvement. Ann Intern Med 1980;93:817 – 21.
[18] Puig JG, Miranda ME, Mateos FA, et al. Hereditary nephropathy associated with hyperuri-
cemia and gout. Arch Intern Med 1993;153:357 – 65.
[19] Kanellis J, Watanabe S, Li JH, et al. Uric acid stimulates monocyte chemoattractant protein-1
production in vascular smooth muscle cells via mitogen activated protein kinase and cyclooxy-
genase-2. Hypertension 2003;41:1287 – 93.
[20] Kanellis J, Kang DH. Uric acid as a mediator of endothelial dysfunction, inflammation, and vas-
cular disease. Semin Nephrol 2005;25:39 – 42.
[21] Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by
a novel crystal independent mechanism. Hypertension 2001;38:1101 – 6.
288 becker & jolly
[22] Mazzali M, Kanellis J, Han L, et al. Hyperuricemia induces a primary renal arteriolopathy
in rats by a blood pressure independent mechanism. Am J Physiol Renal Physiol 2002;282:
F991–7.
[23] Watanabe S, Kang DH, Feng L, et al. Uric acid, hominoid evolution and the pathogenesis
of salt- sensitivity. Hypertension 2002;40:355 – 60.
[24] Feig DI, Johnson RJ. Hyperuricemia in childhood essential hypertension. Hypertension 2003;
42:247 – 52.
[25] Feig DI, Nakagawa T, Karumanchi SA, et al. Hypothesis: uric acid, nephron number, and the
pathogenesis of essential hypertension. Kidney Int 2004;66:1 – 8.
[26] Johnson RJ, Tuttle KR. Much ado about nothing, or much to do about something? The
continuing controversy over the role of uric acid in cardiovascular disease. Hypertension 2000;
35:E10.
[27] Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension
and cardiovascular and renal disease? Hypertension 2003;41:1183 – 90.
[28] Johnson RJ, Rodriguez-Iturbe B, Kang DH, et al. A unifying pathway for essential hyper-
tension. AJH 2005;18:431 – 40.
[29] Feig DI. Uric acid and hypertension in adoloscents. Semin Nephrol 2005;25:32 – 8.
[30] Kang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyperuri-
cemia on progression of renal disease. Semin Nephrol 2005;25:43 – 9.
[31] Sanchez-Lozada LG, Tapia E, Avila-Casado C, et al. Mild hyperuricemia induces glomerular
hypertension in normal rats. Am J Physiol Renal Physiol 2002;283:F1105–10.
[32] Nakagawa T, Mazzali M, Kang DH, et al. Hyperuricemia causes glomerular hypertrophy in the
rat. Am J Nephrol 2003;23:2 – 7.
[33] Kang DH, Nakawaga T, Feng L, et al. A role of uric acid in the progression of renal disease.
J Am Soc Nephrol 2002;13:2888 – 97.
[34] Kang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyper-
uricemia on progression of renal disease. Semin Nephrol 2005;25:43 – 9.
[35] Sanchez-Lozada L, Tapia E, Rodriguez-Iturbe B, et al. Hemodynamics of hyperuricemia.
Semin Nephrol 2005;25:19 – 24.
[36] Mazzali M, Kim Y-G, Suga S, et al. Hyperuricemia exacerbates chronic cyclosporine ne-
phropathy. Transplantation 2001;71:900 – 5.
[37] Reif MC, Constantiner A, Levitt MF. Chronic gouty nephropathy: a vanishing syndrome.
N Engl J Med 1981;304:535 – 6.
[38] Fairbanks LD, Cameron JS, Venkat-Raman G, et al. Early treatment with allopurinol in familial
juvenile hyerpuricaemic nephropathy (FJHN) ameliorates the long-term progression of renal
disease. Q J Med 2002;95:597 – 607.
[39] McBride MB, Simmonds HA, Ogg CS, et al. Efficacy of allopurinol in ameliorating the pro-
gressive renal disease in familial juvenile hyperuricaemic nephropathy (FJHN). A six-year
update. Adv Exp Med Biol 1998;431:7 – 11.
[40] Cameron JS, Simmonds HA. Hereditary hyperuricemia and renal disease. Semin Nephrol
2005;25:9 – 18.
[41] Dahan K, Vuyst D, Smaers M, et al. A cluster of mutations in the UMOD gene causes familial
juvenile hyperuricemic nephropathy with anornal expression of uromodulin. J Am Soc Nephrol
2003;14:2883 – 93.
[42] Segura J, Campo C, Ruilope LM. How relevant and frequent is the presence of mild renal
insufficiency in essential hypertension? J Clin Hypertens 2002;4:332 – 6.
[43] Leoncini G, Viazzi F, Parodi D, et al. Mild renal dysfunction and subclinical cardiovascular
damage in primary hypertension. Hypertension 2003;42:14 – 8.
[44] Staessen J for members of the European working party on high blood pressure in the elderly.
The determinants and prognostic significance of serum uric acid in elderly patients of the
European working party on high blood pressure in the elderly trial. Am J Med 1991;90:50s – 4s.
[45] Tomita M, Mizuno S, Yamanaka H, et al. Does hyperuricemia affect mortality? A prospective
cohort study of Japanese male workers. J Epidemiol 2000;10:403 – 9.
[46] Iseki K, Oshiro S, Tozawa M, et al. Significance of hyperuricemia on the early detection of
renal failure in a cohort of screened subjects. Hyprtens Res 2001;24:691 – 7.
[47] Perlstein TS, Gumieniak O, Hopkins PN, et al. Uric acid and the state of the intrarenal renin
angiotensin system in humans. Kidney Int 2004;66:1465 – 70.
[48] Iseki K, Ikemiya Y, Inoue T, et al. Significance of hyperuricemia as a risk factor for developing
ESRD in a screened cohort. Am J Kidney Dis 2004;44:642 – 50.
[49] Johnson RJ, Kivlighn SD, Kim YG, et al. Reappraisal of the pathogenesis and consequences
of hyperuricemia in hypertension, cardiovascular, and renal disease. Am J Kidney Dis 1999;
33:225 – 34.
[50] Alderman MH, Cohen H, Madhavan S, et al. Serum uric acid and cardiovascular events in
successfully treated hypertensive patients. Hypertension 1999;34:144 – 50.
[51] Brand FN, McGee DL, Kannel WB, et al. Hyperuricemia as a risk factor of coronary heart
disease: the Framingham study. Am J Epidemiol 1985;121:11 – 8.
[52] Abbott RD, Brand FN, Kannel WB, et al. Gout and coronary heart disease: the Framingham
study. J Clin Epidemiol 1988;41:237 – 42.
[53] Culleton BF, Larson M, Kannel WB, et al. Serum uric acid and risk for cardiovascular disease
and death: the Framingham heart study. Ann Intern Med 1999;131:7 – 13.
[54] Wannamethee SG, Shaper AG, Whincup PH. Serum urate and the risk of major coronary heart
disaese events. Heart 1997;78:147 – 53.
[55] Nagahama K, Iseki K, Inoue T, et al. Hyperuricemia and cardiovascular risk factor clustering in
a screened cohort in Okinawa, Japan. Hypertens Res 2004;27:227 – 33.
[56] Fang J, Alderman MH. Serum uric acid and cardiovascular mortality. The NHANES I epide-
miologic follow up study, 1971–1992. JAMA 2000;283:2404 – 10.
[57] Bickel C, Rupprecht HJ, Blankenberg S, et al. Serum uric acid as an independent predictor
of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol
2002;89:12 – 7.
[58] Yusuf S, Bosch J. Urate levels as predictor of cardiac deaths: causal relation or mere asso-
ciation? Eur Heart J 2002;23:760 – 1.
[59] Wong KY, MacWalter RS, Fraser HW, et al. Urate predicts subsequent cardiac death in stroke
survivors. Eur Heart J 2002;23:788 – 93.
[60] Tuttle KR, Short RA, Johnson RJ. Sex differences in uric acid and risk factors for coronary
artery disease. Am J Cardiol 2001;87:1411 – 4.
[61] Rich MW. Uric acid: is it a risk factor for cardiovascular disease? Am J Cardiol 2000;1018 – 21.
[62] Madsen TE, Muhlestein JB, Carlquist JF, et al. Serum uric acid independently predicts mor-
tality in patients with significant, angiographically defined coronary disease. Am J Nephrol
2005;25:45 – 9.
[63] Moriarity JT, Folsom AR, Iribarren C, et al. Serum uric acid and risk of coronary heart disease:
Atherosclerosis Risk In Communities (ARIC) Study. Ann Epidemiol 2000;10:136 – 43.
[64] Freedman DS, Williamson DF, Gunter EW, et al. Relation of serum uric acid to mortality and
Ischemic heart disease. The NHANES 1 Epidemiologic Follow-up study. Am J Epidemiol
1995;141:637 – 44.
[65] Liese AD, Hense HW, Lowel H, et al. Association of serum uric acid with all- cause and
cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg
Cohort. Epidemiology 1999;10:391 – 7.
[66] Franse LV, Pahor M, Bari MD, et al. Serum uric acid, diuretic treatment and risk of cardio-
vascular events in the Systolic Hypertension in the Elderly Program (SHEP). J Hypertens
2000;18:1149 – 54.
[67] Verdecchia P, Schillaci G, Reboldi G, et al. Relation between serum uric acid and risk of car-
diovascular disease in essential hypertension. The PIUMA study. Hypertension 2000;36:1072 – 8.
[68] Niskanen LK, Laaksonen DE, Nyyssonen K, et al. Uric acid level as a risk factor for cardio-
vascular and all-cause mortality in middle aged men. Arch Intern Med 2004;164:1546 – 51.
[69] Hoieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardio-
vascular outcomes in the LIFE study. Kidney Int 2004;65:1041 – 9.
290 becker & jolly
[70] Dahlof B, Devereux R, de Faire U, et al. The Losartan Intervention For Endpoint reduction
(LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group. Am J
Hypertens 1997;10:705 – 13.
[71] Athyros VG, Elisaf M, Papageorgiou AA, et al. Effect of statins versus untreated dyslipidemia
on serum uric acid levels in patients with coronary artery disease: a subgroup analysis of the
Greek atorvastatin and coronary heart disease evaluation (GREACE) study. Am J Kidney Dis
2004;43:589 – 99.
[72] Malinow MR, Levenson J, Giral P, et al. Role of blood pressure, uric acid, and hemorheo-
logical parameters on plasma homocyteine concentration. Atherosclerosis 1995;114:175 – 83.
[73] Hong YS, Lee MJ, Kim KH, et al. The C677 mutation in methylene tetrahydrofolate reductase
gene: Correlation with uric acid and cardiovascular risk factors in elderly korean men. J Korean
Med Sci 2004;19:209 – 13.
[74] Mercuro G, Vitale C, Cerquetani E, et al. Effect of hyperuricemia upon endothelial function in
patients with increased cardio vascular risk. Am J Cardiol 2004;94:932 – 5.
[75] Gavin AR, Struthers AD. Hyperuricemia and adverse outcomes in cardiovascular disease. Am J
Cardiovasc Drugs 2005;3:309 – 14.
[76] Yu ZF, Bruce-Keller AJ, Goodman Y, et al. Uric acid protects neurons against excitotoxic and
metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res
1998;53:613 – 25.
[77] Chamorro A, Obach V, Cervera A, et al. Prognostic significance of uric acid serum con-
centration in patients with acute ischemic stroke. Stroke 2002;33:1048 – 52.
[78] Lehto S, Niskanen L, Ronnemaa T, et al. Serum uric acid is a strong predictor of stroke in
patients with non-insulin dependent diabetes mellitus. Stroke 1998;29:635 – 9.
[79] Mazza A, Pessina AC, Pavei A, et al. Predictors of stroke mortality in elderly people from the
general population. Eur J Epidemiol 2001;17:1097 – 104.
[80] Wang JG, Staessen JA, Fagard RH, et al. Prognostic significance of serum creatinine and
uric acid in older chinese patients with isolated systolic hypertension. Hypertension 2001;37:
1069 – 74.
[81] Weir CJ, Muir SW, Walters MR, et al. Serum urate as an independent predictor of poor outome
and future vascular events after acute stroke. Stroke 2003;34:1951 – 6.
[82] Abuja PM. Ascorbate prevents pro oxidant effects of urate in oxidation of human low density
lipoprotein. FEBS Lett 1999;446:305 – 8.
[83] Cherubini A, Polidori MC, Bregnocchi M, et al. Antioxidant profile and early outcome in stroke
patients. Stroke 2000;31:2295 – 300.
[84] Tseng CH. Independent association of uric acid levels with peripheral arterial disease in
Taiwanese patients with Type 2 diabetes. Diabet Med 2004;21:724 – 9.
[85] Nieto FJ, Iribarren C, Gross MD, et al. Uric acid and serum antioxidant capacity: a reaction to
atherosclerosis? Atherosclerosis 2000;148:131 – 9.
[86] Doehner W, Schoene N, Rauchhaus M, et al. Effects of xanthine oxidase inhibition with
allopurinol on endothelialfunction and peripheral blood flow in hyperuricemic patients with
chronic heart failure: results from 2 placebo controlled studies. Circulation 2002;105:2619 – 24.
[87] Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure.
Circulation 2003;107:1991 – 7.
[88] Cicoira M, Zanolla L, Rossi A, et al. Elevated serum uric acid levels are associated with
diastolic dysfunction in patients with dilated cardiomyopathy. Am Heart J 2002;143:1107 – 11.
[89] Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure. Insights regard-
ing the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 2003;
107:1951 – 3.
[90] Cappola TP, Kass DA, Nelson GS, et al. Allopurinol improves myocardial efficiency in pa-
tients with idiopathic dilated cardiomyopathy. Circulation 2001;104:2407 – 11.
[91] Ekelund UE, Harrison RW, Shokek O, et al. Intravenous allopurinol decreases myocardial
oxygen consumption and increases mechanical efficiency in dogs with pacing induced heart
failure. Circ Res 1999;85:437 – 45.
[92] Ukai T, Cheng CP, Tachibana H, et al. Allopurinol enhances the contractile response to dobu-
tamine and exercise in dogs with pacing induced heart failure. Circulation 2001;103:750 – 5.
[93] Struthers AD, Donnan PT, Lindsay P, et al. Effect of allopurinol on mortality and hos-
pitalisations in chronic heart failure: a retrospcetive cohort study. Heart 2002;87:229 – 34.
[94] Emmerson B. Hyperlipidaemia in hyperuricaemia and gout. Ann Rheum Dis 1998;58:509 – 10.
[95] Facchini F, Chen Y-D, Hollenbeck CB, et al. Relationship between resistance to insulin-
mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA
1991;266:3008 – 11.
[96] Vuorin-Markkola H, Yki-Jarvonen H. Hyperuricemia and insulin-resistance. J Clin Endocrinol
Metab 1994;78:25 – 9.
[97] Reaven GM. Role of insulin-resistance in human disease. Diabetes 1988;37:1596 – 607.
[98] Denzer C, Muche R, Mayer H, et al. Serum uric acid levels in obese children and ado-
lscents:linkage to testosterone levels and pre metabolic syndome. J Pediatr Endocrinol 2003;
16:1225 – 32.
[99] Gokcel A, Gumurdulu Y, Karakose H, et al. Evaluation of the safety and efficacy of sibutramine,
orlistat and metformin in the treatment of obesity. Diabetes Obes Metab 2002;4:49 – 55.
[100] Brauer GW, Prior IAM. A prospective study of gout in New Zealand Maoris. Ann Rheum Dis
1978;37:466 – 72.
[101] Fessel WJ, Bar GD. Uric acid, lean body weight and creatine interactions: results from re-
gression analysis of 78 variables. Semin Arthritis Rheum 1977;7:115 – 21.
[102] Glynn RJ, Campion EW, Silbert JE. Trends in serum uric acid levels 1961–1980. Arthritis
Rheum 1983;26:87 – 93.
[103] Scott JT. Obesity and hyperuricaemia. Clin Rheum Dis 1977;3:25 – 35.
[104] Sturge RA, Scott JT, Kennedy AC, et al. Serum uric acid in England and Scotland. Ann Rheum
Dis 1977;36:420 – 7.
[105] Seidell JC, Bakx KC, Deurenberg P, et al. Overweight and chronic illness: a retrospective
cohort study with a follow-up of 6–17 years, in men and women of initially 20–50 years of age.
J Chronic Dis 1986;39:585 – 93.
[106] Must A, Jacques PF, Dallal GE, et al. Long term morbidity and mortality of overweight
adolescents. A follow up of the Harvard Growth Study of 1922 to 1935. N Engl J Med 1992;
327:1379 – 80.
[107] Loenen HM, Eshuis H, Lowik MR, et al. Serum uric acid correlates in elderly men and women
with special reference to body composition and dietary intake (Dutch Nutrition Surveillance
System). J Clin Epidemiol 1990;43:1297 – 303.
[108] Bray GA. Complications of obesity. Ann Intern Med 1985;103:1052 – 62.
[109] Emmerson BT. Alteration of urate metabolism by weight reduction. Aust N Z J Med 1973;3:
410 – 2.
[110] Gibson T, Waterworth R, Hatfield P, et al. Hyperuricaemia, gout and kidney function in New
Zealand Maori men. Br J Rheumatol 1984;23:276 – 82.
[111] Kannel WB, Gordon T. Physiological and medical concomittants of obesity: the Framingham
study. In: Bray GA, editor. Obesity in America. Bethesda (MD)7 DHEW (PHS) Publication
79-359; 1979. p. 125 – 63.
[112] Roubenoff R, Klag MJ, Mead LA, et al. Incidence and risk factors for gout in white men.
JAMA 1991;266:3004 – 7.
[113] Ogura T, Matsuura K, Matsumoto Y, et al. Recent trends of hyperuricemia and obseity in
Japanese male adolescents, 1991 through 2002. Metabolism 2004;53:448 – 53.
[114] Masuo K, Kawaguchi H, Mikami H, et al. Serum uric acid and plasma norepinephrine con-
centrations predict subsequent weight gain and blood pressure elevation. Hypertension 2003;
42:474 – 80.
[115] Reynolds PP, Knapp MJ, Baraf HSB, et al. Moonshine and lead. Relationship to the patho-
genesis and hyperuricemia in gout. Arthritis Rheum 1983;26:1057 – 64.
[116] Dessein PH, Shipton EA, Stanwix AE, et al. Beneficial effects of weight loss associated with
moderate calorie/carbohydrate restriction, and increased proportional intake of protein and
292 becker & jolly
unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis
2000;59:539 – 43.
[117] Tsunoda S, Kamide K, Minami J, et al. Decreases in serum uric acid by amelioration of insulin
resistance in overweight hypertensive patients: Effect of a low energy diet and an insulin
sensitizing agent. Am J Hypertens 2002;15:697 – 701.
[118] Tambascia MA, Geloneze B, Repetto EM, et al. Sibutramine enhances insulin sensitivity ame-
liorating metabolic parameters in a double blind, randomised controlled trial. Diabetes Obes
Metab 2003;5:338 – 44.
[119] Krejs GJ. Metabolic benefits associated with sibutramine therapy. Int J Obes Relat Metab
Disord 2002;26:S34 – 7.
[120] Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors
10 years after bariatric surgery. N Engl J Med 2004;351:2683 – 93.
[121] Donahue RP, Prineas R, Donahue DC, et al. Is fasting leptin associated with insulin resistance
among nondiabetic individuals? The Miami community health study. Diabetes Care 1999;22:
1092 – 6.
[122] Ruige JB, Dekker J, Blum WF, et al. Leptin and variables of body adiposity, energy balance,
and Insulin resistance in a population based study: the Hoorn study. Diabetes Care 1999;22:
1097 – 104.
[123] Ogura T, Matsura K, Otsuka F, et al. Serum leptin correlates with serum uric acid but not with
serum testosterone in non obese male adolescents. Res Commun Mol Pathol Pharm 2000;
107:55 – 63.
[124] Garcia-Lorda P, Bullo M, Vila R, et al. Leptin concentrations do not correlate with fat mass nor
with metabolic risk factors in morbidly obese females. Diab Nutr Metab 2001;14:329 – 36.
[125] Matsubara M, Chiba H, Maruoka S, et al. Elevated serum leptin concentrations in women with
hyperurecemia. J Atheroscler Thromb 2002;9:28 – 34.
[126] Bedir A, Topbas M, Tanyeri F, et al. Leptin might be a regulator of serum uric acid concen-
trations in humans. Jpn Heart J 2002;44:527 – 36.
[127] Moreno LA, Pineda I, Rodriguez G, et al. Leptin and metabolic syndrome in obese and non
obese children. Horm Metab Res 2002;34:394 – 9.
[128] Barlow KA. Hyperlipidemia in primary gout. Metabolism 1968;17:289 – 99.
[129] Gibson JT, Grahame R. Gout, hypertriglyceridemia, and alcohol consumption. Ann Rheum Dis
1974;33:109 – 10.
[130] Naito HK, Mackenzie AH. Secondary hypertriglyceridemia and hyperlipoproteinemia in pa-
tients with primary asymptomatic gout. Clin Chem 1979;25:371 – 5.
[131] Jiao S, Kameda K, Matsuzawa Y, et al. Hyperlipoproteinemia in primary gout: hyper-
lipoproteinemic phenotype and influence of alcohol intake and obesity in Japan. Ann Rheum
Dis 1986;45:308 – 13.
[132] Daskalopoulou SS, Mikhailidis DP, Elisaf M. Prevention and treatment of the metabolic
syndrome. Angiology 2004;55:589 – 612.
[133] Takahashi S, Yamamoto T, Moriwaki Y, et al. Impaired lipoprotein metabolism in patients with
primary gout: influence of alcohol intake and body weight. Br J Rheumatol 1994;33:731 – 4.
[134] Takahashi S, Yamamoto T, Moriwaki Y, et al. Increased concentrations of serum Lp(a)
lipoprotein in patients with primary gout. Ann Rheum Dis 1995;54:90 – 3.
[135] Cardona F, Tinahones FJ, Collantes E, et al. The elevated prevalence of apolipoprotein E2 in
patients with gout is associated with reduced renal excretion of urates. Rheumatol 2003;
42:468 – 72.
[136] Clausen JO, Borch-Johnsen K, Ibsen H, et al. Analysis of the relationship between fasting seum
uric acid and the insulin sensitivity index in a population based sample of 380 young healthy
caucasians. Eur J Endocrinol 1998;138:63 – 9.
[137] Rocic B, Vucic-Lovrencic M, Poje N, et al. Uric acid may inhibit glucose induced insulin
secretion via binding to an arginine residue in rat pancreatic beta cells. Bioorg Med Chem Lett
2005;15:1181 – 4.
[138] Hara H, Egusa G, Yamakido M. Incidence of non insulin dependent diabetes mellitus and its
risk factors in Japanese Americans living in Hawaii and Los Angeles. Diabet Med 1996;
13:S133– 42.
[139] Lin KC, Tsai ST, Lin HY, et al. Different progressions of hyperglycemia and diabetes among
hyperuricemic men and women in the Kinmen study. J Rheumatol 2004;31:1159 – 65.
[140] Chou P, Lin-Chia L, Wu GS, et al. Progression of type 2 diabetes among high risk groups in
Kin-Chen kinmen. Diabetes Care 1998;21:1183 – 7.
[141] Nakanishi N, Okamato M, Yoshida H, et al. Serum uric acid and risk for development of
hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers.
Eur J Epidemiol 2003;18:523 – 30.
Gout: Update on Some Pathogenic and

Clinical Aspects
Frédéric Lioté, MD, PhDa,b,c,T, Hang-Korng Ea, MDa,b
a
Fédération de Rhumatologie, Pôle Appareil Locomoteur (Centre Viggo Petersen),
Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
b
INSERM U606 (IFR139), Hôpital Lariboisière, Paris, France
c
Université Médecine Paris 7, Denis Diderot, Paris, France
Gout nowadays is under the scope of fame, thousands of years after its
description by Hippocrates. New pathogenic mechanisms (including autolimita-
tion of acute attacks), new clinical complications, new imaging aspects, and
(as described by Choi elsewhere in this issue) new epidemiologic insights and
therapeutic advances recently have been reported in the English literature. The
genetics of primary gout and hyperuricemia, however, a frequent metabolic
disorder, remain to be elucidated.
The pathogenesis of hyperuricemia is not addressed in this article, but
pathogenesis of gout inflammation is reviewed. New preliminary insights are
beginning to be available from MRI and ultrasound studies, providing possible
tools for evaluation of tophi in clinical trials.
Pathogenesis of urate crystal deposition and tophus
Uric acid is a weak acid (pKa 5,8) that is present mainly as urate, the ionized
form, at physiologic pH. As urate concentrations increase in physiologic fluids,
urate can crystallize as a monosodium salt in oversaturated tissues, mainly within
and around joints, but also in the skin or other structures, such as spinal ligaments
This work was supported by grants from the INSERM, the ARPS, and the ART.
T Corresponding author. Fédération de Rhumatologie (Centre Viggo Petersen), Hôpital Lari-
boisière, AP-HP, 2, rue Ambroise Paré, F-75475 PARIS CEDEX 10, France.
E-mail address: frederic.liote@lrb.aphp.fr (F. Lioté).
296 liotÉ & ea
and fibrous tissues [1]. The physiochemical properties of monosodium urate

(MSU) cause crystals to precipitate in body fluids if the concentration is greater
than 6.8 mg/dL. The solubility of urate is modulated by temperature (lower
temperature at the foot), intra-articular fluid dehydration (onset at night), and
cation concentration. MSU crystallization is dependent on nucleating agents,
such as insoluble collagens, chondroitin sulfate, proteoglycans, cartilage frag-
ments, and other crystals [1].
Tophus can grow from urate crystals depending on urate sursaturation and on
increased promoters or loss of inhibitors of crystallization.
Pathogenesis of urate crystal-induced inf lammation
MSU crystals are capable of directly triggering, amplifying, and sustaining an

intense inflammatory response, a so-called ‘‘acute attack,’’ because of their abil-
ity to activate humoral and cellular inflammatory components. The pathogenic
inflammatory pathways of MSU crystal-induced inflammation recently have been
reviewed [1–3]. Sequential cellular activation is postulated from in vivo studies
focusing on tissue pathology analysis [4,5]: MSU crystals first are released in the
joint cavity, activating synovial lining cells, followed by the recruitment and
activation of mastocytes and peripheral blood monocytes through endothelial
cell activation. Neutrophils are recruited and egress into the joint cavity, leading
to further MSU crystal phagocytosis and cell activation. Autolimitation of
acute inflammation is driven by macrophages, neutrophil necrosis, and apopto-
sis, followed in some cases by low-grade residual synovitis or by restitution
ad integrum.
Initiation
As discussed recently by Liu-Bryan and Terkeltaub, free crystals or even

naked crystals with no protein coating are released from a remodelling tophus [6].
Once released within the joint cavity, under specific local and systemic circum-
stances (temperature, pH variations, local articular traumatism, infection, or sur-
gery), MSU crystals should interact with the synovial lining cells. These cells
are fibroblast-like synoviocytes and macrophage-derived cells, with phagocytic
properties. They can be opsonized by proteins and phagocytosed as particles,
triggering a typical phagocytic inflammatory response [7]. At the onset of crystal-
induced arthritis (CIA), however, synovial fluid contains low protein content,
especially regarding immunoglobulins.
The putative initial mechanism involves the physicochemical surface proper-
ties of MSU particles interacting directly within minutes [8] with membrane
proteins [6] and lipids, either physically or through electrostatic bounds, because
MSU crystals are negatively charged. This direct crystal-cell membrane inter-
action is reported in several studies: within minutes, the crystal contact can
trigger signal transduction, for instance in chondrocytes [6,8]. Recently, toll-like
pathogenic & clinical aspects of gout 297
receptors (TLR) 2 and 4 present at the cell surface have been implicated in
the chondrocyte and macrophage signaling, as shown in vivo using the air-
pouch model developed in TLR-2, TLR-4, and myeloid differentiation factor 88
(MyD88) knockout mice and in vitro in cultured cells [9,10]. In February 2006,
a new cell surface molecule was reported that triggering receptors expressed on
myeloid cells 1 (TREM-1), present on monocytes and neutrophils, which could
be induced rapidly on neutrophils and resident peritoneal macrophages by MSU
crystals in vivo [11]. Maximal expression of TREM-1 messenger RNA (mRNA)
and protein occurs early after MSU crystal exposure. In the murine air-pouch
model, MSU crystals also induce TREM-1 rapidly. It is speculated that cell
membrane modulation leads to cross-linking and clustering of membrane as an
initial event for activation of several and redundant signal signaling pathways,
including G proteins, phospholipase C and D, tyrosine kinases associated with
the FAK complex, and the three mitogen-activated protein kinases. Factors, such
as the myeloid related proteins [12] and the complement membrane attack
complex [13], recently have been identified as other mediators of acute MSU
crystal-induced inflammation.
Crystal-induced cellular activation and recruitment
Neutrophils are the hallmark of inflammatory cells recruited into the synovial
fluid (SF) in gouty attack, but several studies clearly show that other cells play a
central role in the early phase of CIA. Studies of cellular kinetics using animal
models of MSU crystal-induced inflammation demonstrate that monocytes re-
cruited from the blood and resident mastocytes are the first cells to infiltrate or
be activated [5]. Mast cells are proposed as playing a role in innate immunity [14]
and can be an important cell component of MSU CIA because they contain
preformed granules with cytokines and also histamine, an acute phase reagent
[15]. Histamine is well documented as having multiple effects leading to in-
creased vascular permeability and enhanced adhesion molecule expression, such
as upregulating P-selectin, which mediates neutrophil adhesion and recruitment.
Mast cell activation and histamine release are observed in CIA inflammation
model in vivo [5]. Other preformed and stored mastocyte mediators (eg, platelet
activating factor [PAF], vascular endothelial growth factor, tumor necrosis factor
[TNF]-a, and interleukin [IL]-1b) can activate endothelial cells, cell recruitment,
and increase vascular permeability. Finally, therapeutic issues can be raised,
because in MSU crystal-induced murine peritonitis, a role for endogenous mast
cells is suggested, as histamine1 antagonist and PAF antagonist reduce neutrophil
influx into the peritoneal cavity [16].
Monocytes also are implicated in the early onset of MSU CIA. They infiltrate
the tissues of animal models of MSU CIA at a rate 10 times higher than neutro-
phils [5]. As discussed earlier, rapid induction of TREM-1 can trigger inflam-
mation, because costimulation of peritoneal macrophages with MSU crystals and
an anti–TREM-1 agonist antibody increase the production of IL-1b and monocyte
chemotactic protein [11]. MSU crystals actually have the ability to trigger an
298 liotÉ & ea
inflammatory response by freshly isolated monocytes and THP-1 monocytic cells

[7,17–21], including TNF-a, IL-1b, IL-6, and IL-8 (but not IL-10) secretion,
which in turn promote endothelial cell E-selectin expression and secondary neu-
trophil adhesion under dynamic conditions. Similar results are achieved in MSU
crystal-induced rabbit arthritis [22,23]. Nishimura and colleagues show that
MSU CIA in rabbits is attenuated by a neutralizing antibody against IL-8 [24].
As a ‘‘newcomer,’’ IL-18, a member of IL-1 family, is reported to be increased
in plasma from patients who have gout arthritis and secreted by monocytes after
MSU crystal stimulation along with an activation of caspase-1, the processing
enzyme for IL-18 activation [25]. These cytokines and chemokines also are
able to activate endothelial cells and promote monocyte and neutrophil adhesion,
stimulate chemotaxis, and tissue infiltration. Reduced cytokine response by
monocytes to MSU crystals could be an explanation for reduced gout attack in
patients who have chronic renal failure [26].
Angiogenic factors also have cytokine properties and are expressed in gout.
For example, high levels of angiogenin, an angiogenic factor with anti-
inflammatory properties, are measured in SF from patients who have gout [27].
Monocytes play a central role in the regulation of acute attack, because they also
are implicated in the self-limitation of inflammation.
Amplification
Neutrophils are recruited into synovium and migrate within the synovial
cavity along with serum proteins. Their roles were distinguished early by
Schumacher and coworkers in gouty arthritis in dogs [4]. Activated endothelium
allows neutrophil adhesion dependent on E-selection and P-selectin upregulation
and migration into the synovium. This is supposed to be determined by effects of
cytokines (TNF-a and IL-1b) and chemokines (IL-8 and macrophage inflamma-
tory protein-1a) [22,28]. Neutrophils follow concentration gradients of chemo-
attractants, such as C5a and IL-8. IL-8 is a central player, as demonstrated in in
vivo models (air-pouch in mice and arthritis in rabbits) by Terkeltaub and col-
leagues [29] and Nishimura and colleagues [24], using knockout mice for IL-8
receptor, CXCR-2, or neutralizing anti–IL-8 antibody, respectively. By contrast,
IL-18 is not a player in neutrophil recruitment in in vivo MSU crystal-induced
inflammation model [25].
Spontaneous resolution of acute attack
In spite of the intensity and sudden onset of an acute bout of gout, the self-
limitation of joint inflammation that results in an apparent return of the joint
apparently ad integrum is puzzling. Crystal properties can be modified and
represent a first target: crystal size reduction and crystal clearance. Protein and
lipoprotein crystal-coating changes [30–32] have been discussed by several in-
vestigators, but these processes are not considered major players. Macrophages
(eg, resident and differentiated monocytes) could represent the major cell in this
regulatory process. Recently, Landis and Haskard have promoted the idea that the
mononuclear phagocyte may play a key role within the synovial compartment,
tipping the balance from the asymptomatic state to acute inflammation, or vice
versa, depending on the state of monocyte to macrophage differentiation [33].
They demonstrate that a switch from homologous monocytes to macrophages
leads to the loss of ability to produce proinflammatory cytokines (IL-1, Il-6, and
TNF-a) and, conversely, to stimulate anti-inflammatory cytokine secretion (IL-10
and transforming growth factor [TGF]-b1) when stimulated by phagocytosed
MSU crystals [34,35]. Under MSU crystal stimulation, macrophages produce
IL-10 and, mainly, TGF-b1, a pivotal cytokine in the anti-inflammatory process
[36]. TGF-b1 can lower endothelial activation, reduce monocyte and neutrophil
adhesion and recruitment [37], and reduce IL-1 expression and IL-1 receptor
expression. TGF-b1 secretion also can be triggered by ingestion of apoptotic
cells [38,39].
Other anti-inflammatory cytokines, such as IL-10, are shown to reduce in vivo
MSU crystal inflammation. Retrovirally transfected IL-10 cells injected in murine
air-pouch model significantly inhibited MSU crystal-induced cellular infiltration
and production of the mouse CXC chemokine KC. These findings are consistent
with results obtained by the injection of recombinant human IL-10 into air
pouches [40]. Relevance for humans is debated, however, because no IL-10 is
detected in any of the 17 sera tested from patients with gout [41], and lower IL-10
(and normal IL-4) mRNA levels are determined in SF mononuclears from pa-
tients who have gout compared with those who have rheumatoid arthritis [42].
This monocyte-macrophage switch and its ability to control inflammation is
a well-known mechanism not related specifically to MSU crystals. The intrinsic
mechanisms underlying the anti-inflammatory switch are understood poorly
but it seems, for example, that the production of pro- and anti-inflammatory
cytokines by phagocytic monocytes is regulated delicately during the ingestion of
apoptotic cells as part of an intrinsic mechanism to prevent inflammatory auto-
immune reactions [43].
Binding or phagocytosis of apoptotic cells, but not necrotic or lysed cells
[44,45], induces active anti-inflammatory or suppressive properties in human
macrophages [44]. It is observed in SF from various diseases, such as reactive
arthritis and CIA, but not rheumatoid arthritis [46]. Therefore, it is likely that
resolution of inflammation depends not only on the removal of apoptotic cells but
also on active suppression of inflammatory mediator production (Fig. 1).
Other anti-inflammatory compounds also are released by MSU crystal-
stimulated macrophages, namely nitric oxide (NO) and peroxisome proliferator-
activated receptor (PPAR)-g. NO synthase 2 or inducible NO synthase is induced
in vitro by freshly isolated human monocytes by MSU crystals [47]. NO also is
detected in vivo in rat air-pouch fluids after MSU crystal activation [2]. NO
donor can inhibit MSU-crystal inflammation when administered either before
or at the onset of acute inflammation in the rat air-pouch model. Conversely,
NO inhibition maintains the inflammatory cellular reaction evidenced in vivo
[2]. Therefore, in MSU-crystal inflammation, NO seems to act as an anti-
300 liotÉ & ea
Fig. 1. Schematic representation of monocyte-macrophage switch in the installation and resolution

of acute MSU crystal-induced inflammation. (A) Monocytes are recruited from the blood, yet
immature macrophages (MAC) can be stimulated by MSU crystals. In turn, they produce various
cytokines and chemokines, leading to endothelium activation, leukocyte migration, and further cell
activation. Recruited neutrophils (PNN) migrate into the joint cavity and further phagocytize MSU
crystals and release mediators. They undergo various processes: death process from within, necrosis,
and apoptosis. (B) Differentiation of monocytes to MAC seems to be a paradigm in inflammation,
innate and adaptative immunity. A role for apoptotic neutrophil bodies to trigger the MAC ability to
secrete TGF-b1 is demonstrated in various situations but not yet in acute gout. TGF-b1 is a pivotal
anti-inflammatory cytokine, with the ability to block endothelial cell activation, leukocyte adhesion
and recruitment, reduce proinflammatory cytokine production, and increase IL-1ra production. MSU
crystals are unable to stimulate mature and differentiated MAC to produce proinflammatory cytokines.
Apoptotic bodies from neutrophils are demonstrated to enhance MAC differentiation and TGF-b1
production, suggesting a regulatory mechanism for monocyte-MAC switch in acute gout attack.
inflammatory compound. PPAR-g is a member of the nuclear hormone super-

family, which can act as a transcriptional regulator of certain genes; it inhibits the
gene expression of cytokines, such as cyclooxygenase. Early PPAR-g stimula-
tion and production by adherent monocytes by MSU crystals is achieved in vitro.
Similarly, PPAR-g production is achieved in vivo in the rat air-pouch model as
early as 12 hours after crystal stimulation.
Neutrophil apotosis also is advocated as a possible mechanism for resolution.
In vitro experiments, however, suggest that MSU crystals can delay neutrophil
apoptosis [48,49], suggesting a direct role for crystals to avoid resolution of at-
tack. Conversely, apoptotic cell recognition and clearance, via exposure of phos-
phatidyl serine and ligation of its receptor, induce TGF-b1 secretion [38,39,45],
resulting in accelerated resolution of inflammation (Fig. 1).
Intercritical gout
Although MSU crystals are the hallmark of gouty arthritis, they can be found
even during the resolution phase but have lost their ability to stimulate further
inflammation, and also between attacks, because they remain in the joint. Two
studies from Pascual and coworkers [50,51] clearly identify MSU crystals in SF
taken from up to 70% of asymptomatic first metatarsal or knee joint of patients
who had proven gout during the so-called ‘‘intercritical period.’’ Treatment with
colchicine decreases white cell counts in synovial fluid of asymptomatic knees
that contain MSU crystals [52]. A preclinical phase of gout is ascertained, be-
cause MSU crystals also are detected in joints from some patients who had
asymptomatic hyperuricemia and hyperuricemic patients who had chronic renal
failure. Low-grade asymptomatic synovitis and associated intra-articular dormant
tophi can be postulated but await evidence.
Chronic tophaceous gout
After years of chronic and untreated hyperuricemia, gouty arthritis can de-
velop with its hallmark, intrarticular and periarticular tophi. Gout tophi are
characterized by foreign body granulomas consisting of mono- and multinu-
cleated macrophages surrounding deposits of MSU microcrystals. After primary
formation, granulomas grow associated with degradation of the extracellular
matrix. Once developed in situ in cartilage or in synovium, it is assumed that
MSU crystals may contribute to chronic synovitis and associated joint damage.
Tophi can grow at the cartilage surface and within the synovium, leading to low-
grade synovitis, even subsiding after clinical resolution of gout attacks or to
foreign body synovitis around crystals, as evidenced by histologic studies. Direct
cartilage-tophi contact is demonstrated by arthroscopy.
In contrast to acute inflammation, experimental studies related to tophi patho-
genesis are lacking. Immunohistochemistry studies performed on tophi show that
perivascular localized mononuclear cells are CD68+, S100A8+, S100A9+, and
25F9 , representing freshly migrated monocytes/macrophages. In contrast, al-
most all CD68+ mono- and multinucleated cells arranged within granulomas are
S100A8 , S100A9 , and 25F9+, representing mature (nonmigrating) macro-
phages. These macrophages coexpress TNF-a and matrix metalloproteinases
(MMPs) 2 and 9. In parallel, macrophages undergo apoptosis, a phenomenon that
may restrict the destructive potential of inflammatory macrophages [53]. Corti-
costeroids could enhance tophus formation, as shown in the air-pouch model by
Rull and colleagues [54] and in clinical reports.
In vitro chondrocytes can phagocytize particles, such as latex beads [55], and
in vitro nonadherent chondrocytes also can produce active MMPs after MSU
[8] or even calcium crystal stimulation [56]. Direct chondrocyte cell membrane
crystal can trigger cell activation, NO synthase expression and NO production,
IL-1b activation, and MMP expression [8], which can contribute to cartilage
degradation and further tophus breaking [6]. In addition, MSU crystals can con-
302 liotÉ & ea
tribute to bone lesions; Bouchard’s group shows that MSU crystals reduce
the activity of osteoblasts in vitro [57], thereby limiting the healing process
of erosions.
Based on the anti-inflammatory effects of macrophages triggered by either
MSU crystals or apoptotic cells, it can be speculated that a defect in anti-
inflammatory properties of macrophages, as observed in other chronic diseases
[58], could contribute to low-grade inflammation by residual MSU crystals.
Diagnosis of gout
Diagnosis of gout relies on the association of acute attacks, presence of

tophus, hyperuricemia, and, in some advanced diseases, chronic and destructive
arthropathies. Classification of gout is a different issue that is approached partly
with the (former) American Rheumatism Association preliminary criteria [59]. To
date, however, there are no diagnostic recommendations or evidenced-based
medicine recommendations for gout. This gap will be filled by a task force of
the European League Against Rheumatism (EULAR) Standing Committee on
International Clinical Studies Including Therapeutic Trials (ESCISIT), on gout
diagnosis and management. Preliminary diagnostic recommendations were re-
ported at the 2005 EULAR meeting in Vienna (Box 1) and currently are under
review [60]. Based on a systematic literature search and expert consensus
achieved through Delphi procedures, 10 recommendations have been sorted out
and validated. Only clinical issues are discussed briefly.
Clinical issues discussed by the EULAR task force relate mainly to the clini-
cal characteristics of crystal inflammation, namely rapid onset of severe pain,
joint swelling and local tenderness, and overlying erythema, with a peak in
symptoms occurring within 6 to 12 hours. This is typical for crystal acute attack
but can be related to another crystal type, such as calcium pyrophosphate or
apatite or other rarer inflammatory conditions.
Overall, there is a large consensus on the diagnostic value of MSU crystal iden-
tification in SF and tophus. This examination should be done routinely (but always
carefully), because MSU crystal detection can be considered a gold standard for
gout. Suspected tophus can be sampled carefully for MSU crystal to ascertain diag-
nosis. As discussed previously, a retrospective diagnosis of gout can be achieved
when asymptomatic metatarsophalangeal (MTP) or knee joints are tapped and
MSU crystals are detected easily at first look in the polarizing microscope, because
MSU crystals are strongly birefringent. Forty-three joints in gouty patients were
positive for MSU before any hypouricemic drug was started, and 34 out of 48
after treatment was begun [51]. Therefore, standard quality for crystal examination,
identification training should be better defined [61,62]. Before proper studies are
done, it should be recalled that proper conservation of SF has to be achieved,
because room temperature can modify crystals and cells can be lysed. Microscopic
analysis should be performed as soon as possible with a polarizing microscope, but
SF can be kept at 208C before analysis: in these conditions, there is a smaller risk
Box 1. Ten key recommendations for the diagnosis of gout from the
European League Against Rheumatism Standing Committee for
International Clinical Studies Including Therapeutic Trials
1. In acute attacks, the rapid development of severe pain, swell-

ing, and tenderness that reaches its maximum within just 6 to
12 hours, especially with overlying erythema, is highly sugges-
tive of crystal inflammation, although not specific for gout.
2. For typical presentations of gout (such as recurrent podagra
with hyperuricemia), a clinical diagnosis alone is reasonably
accurate but not definitive without crystal confirmation.
3. Demonstration of MSU crystals in synovial fluid or tophus
aspirates permits a definitive diagnosis of gout.
4. A routine search for MSU crystals is recommended in all syno-
vial fluid samples obtained from undiagnosed inflamed joints.
5. Gout and sepsis may coexist, so when septic arthritis is
suspected, Gram’s stain and culture of synovial fluid still
should be performed, even if MSU crystals are identified.
6. Identification of MSU crystals from asymptomatic joints
may allow definite diagnosis in intercritical periods.
7. Although they are the most important risk factor for gout,
serum uric acid levels do not confirm or exclude gout, be-
cause many people who have hyperuricemia do not develop
gout, and serum levels may be normal during acute attacks.
8. Renal uric acid excretion should be determined in selected pa-
tients who have gout, especially those who have a family history
of young-onset gout, onset of gout under age 25, or renal calculi.
9. Although radiographs may be useful for differential diagno-
sis and may show typical features in chronic gout, they are
not useful in confirming the diagnosis of early or acute gout.
10. Risk factors for gout and associated comorbidity should be
assessed, including features of the metabolic syndrome
(obesity, hyperglycemia, hyperlipidemia, and hypertension).
From Zhang WDM, Pascual E, et al. EULAR evidence based rec-

ommendations for gout. Part I diagnosis. Report of a task force
of the standing committee for ESCISIT. Ann Rheum Dis 2006;
in press; with permission.
for crystal dissolution, although cells usually are lysed. Microcrystals are identified
better when looking in the clot formed by fibrins and cell debris, eventually after
centrifuging the SF. Detection of MSU crystals has excellent value in the diagnosis
of symptomatic gout or even of asymptomatic gout (knee or first MTP joint),
allowing a definite diagnosis in intercritical periods [50,51].
304 liotÉ & ea
Unusual clinical involvement
Common clinical aspects
Acute gout attacks occur mainly in the lower extremities, starting at the foot
joint, as has been known for centuries. Podagra is located by definition in the first
MTP joint. As the disease progresses, other joints may be involved, including the
knee and hip joint or upper limb. Podagra is more common in men, and women
show a higher frequency of upper limb joint involvement [63]. The most common
diagnoses of arthritis in the first MTP joint are crystal-induced synovitis, septic
arthritis, traumatic conditions, psoriatic arthritis, and reactive arthritis. When
causes other than gout involve the first MTP joint, this frequently is referred to as
pseudopodagra. Therefore, radiographs can be suitable in some unusual settings,
such as those involving young patients, to rule out apatite calcification, calcium
pyrophosphate deposit, or necrosis of the sesamoid bone.
Skin involvement
Unusual sites for tophi are reported, but rheumatologists should be aware of
isolated skin involvement. Cutaneous tophi with inflammatory aspects, or at the
opposite indolent, are observed commonly in elderly women receiving diuretics
for hypertension [63] and more rarely in men. MSU deposits might be respon-
sible for unusual panniculitis [64]. Long-standing tophus could represent a risk
factor for angiosarcoma [65].
Spinal involvement
Tophus of various sizes can develop in any anatomic structure of the spine,
leading to nerve root, cord compression [2,66–68], or even lumbar spinal steno-
sis. Gout can represent a significant etiologic factor in the development of symp-
tomatic spinal stenosis associated with cyst formation from a facet joint. Cervical
cord compression by tophus [68] is rare compared with those associated with
calcium pyrophosphate dihydrate deposition (CPPD) deposits. When fever is
present, clinical features and even imaging can mimic epidural abcess or spondy-
lodiscitis [69]. Radiographs can show erosive and destructive changes in cervical
disks. Gout tophi by MRI studies yield homogeneous and hypointense masses
on T1- and T2-weighted images, with multiple hypointense speckles. Preopera-
tive diagnosis is uncommon but should be suggested when addressing patients
who have long-standing gout, chronic arthropathy, and tophi. In addition to stan-
dard histologic examination, material should be sent for examination under po-
larized light, which can reveal deposition of urate crystals in such cases. It is not
possible to diagnose gout of the spine by standard examination of a fixed speci-
men, because fixation in water dissolves MSU crystals; alcoholic conservative
should be used. In this setting, De Galantha staining allows direct visualization of
MSU crystals. Surgical decompression is mandatory and effective, because pre-
operative diagnosis of spinal gout rarely is evoked preoperatively; in rare cases,

regression of cord compression is achieved under urate-lowering agents [70].
Peripheral nerve root compression
Clinicians should be aware of the possibility of tophi causing nerve root com-
pression, such as carpal tunnel syndrome (CTS) and cubital compression. Preva-
lence of CTS was estimated at 0.6% in a large series of 2649 CTS releases,
occurring, as expected, mainly in men [71]. Imaging, including CT scan, MRI,
and ultrasound, provides confirmation [72]. Tophi can be found in the floor of
the carpal tunnel, carpal bones, radiocarpal joint, and extensor tendons or tendon
sheaths of the wrist. Surgical liberation usually is mandatory to avoid sequellae.
Gout and septic arthritis
Fever is a common feature of acute gout attack, mainly in polyarthritis. It is

necessary to rule out septic arthritis, and Gram’s stain and culture of SF are
mandatory, even if MSU crystals are identified readily, when diagnosis is
suspected. Several dozen such cases are published, including Yu and colleagues’
[73,74]. Organisms grew from SF taken from 73% of their 30 patients.
Infectious necrotizing fasciitis recently has been reported in gouty patients,
with a prevalence of 4.8% of fasciitis observed at a Taiwanese hospital [73].
The portal of entry clearly was related to skin changes or complications asso-
ciated with tophi in 60% of the patients. Therefore, fasciitis should be discussed
when facing tissue inflammation that resembles erysipelas or cellulitis, shortly
before bullae appears as a late manifestation of fasciitis. Again, the intensity
of pain is out of proportion to the physical findings. Septic shock, multiorgan
failure, and even death can occur. In these series, Staphylococcus aureus and
streptococcus and gram-negative bacterias are responsible for fasciitis in patients
who have gout. Outcome was poor in the Taiwan series and carried a 20% high
mortality rate in spite of surgical procedures, including amputation and antibio-
therapy. Aggressive treatment with antibiotics and surgical cleaning is mandatory.
Because the breakdown of the skin around tophi carries a high risk for infection,
it is of importance to get a local treatment to prevent extensive infection.
Imaging
Radiographs are not useful for the diagnosis of acute gout except for dif-
ferential diagnosis. A pseudopodagra can be observed in apatite or CPPD deposit.
Also, when young patients present with subacute or acute pain under the first
MTP after a walk, a sesamoid necrosis or fracture of the first MTP should be
discussed and a specific radiograph prescribed (Walter-Muller view).
306 liotÉ & ea
Fig. 2. Radiographs of chronic gout arthropathy of the hands. Note the well-defined, punched-out
erosions with overhanging edges, asymmetric involvement, soft tissue swelling, and extension around
phalangeal bones.
In chronic disease evolving to destructive arthropathy, the radiologic hallmark

of tophus is well known (Fig. 2). Characteristic of gout is well-defined, punched-
out erosion with overhanging edges, with preservation of the joint space, lack of
periarticular osteopenia, asymmetric involvement, soft tissue nodules, and
extension around bone diaphysis (see Fig. 2) [75]. At the midfoot joint, a lateral
view can exhibit osteophytes on the dorsal part of the joint (Fig. 3). Tophi can
contribute to soft tissue swelling, with secondary calcium deposits in long-
standing disease. Anatomic distribution recently had been reviewed [76].
Modern imaging is still being evaluated. Ultrasound could be promising, and
MRI studies are of major interest in evaluating spinal involvement. To date,
various skin nodules have been imaged by comparing rheumatoid nodules, gout
tophus, sarcoid nodules, lipomas, and cysts. Tophi appear different from rheu-
matoid nodules: they are more heterogeneous, are more hypoechoic, can present
postacoustic shadow, and are more prone to be adjacent to bone erosions or at
Fig. 3. Radiographs of chronic gout arthropathy of the ankle and midfoot joints. Note the spikes of
the dorsum side of the midfoot and severe joint destruction and ankylosis.
Fig. 4. MRI study of the knee (A) T1-weighted sequence; (B) gadolinium T1-weighted sequence;
(C) T2-weighted sequence with fat sat sequence: lateral and axial views; and (D) lateral views.
Large tophi around the knee: large ovalar tophus at the posterior lower thigh (*), erosive prepatellar
and pretibial tophi (arrow).
least cortical irregularity [77]. Bursitis can occur. Hypoechoic areas might
decrease after aspiration of chalky material. Nodules can be measured readily but
reproducibility is ongoing. Diagnostic values of color Doppler technique remains
to be evaluated [78].
On MRI, tophi present as masses that usually have low or intermediate signal
intensity on T1-weighted images, low to intermediate T2-weighted images, and a
variable but characteristic enhancement pattern, especially for intra-articular tophi
(Fig. 4) [75]. Gadolinium can disclose an enhanced homogeneous or hetero-
genous rim signal around the tophus.
CT scan has been obtained in some cases. As described by Gerster and co-
workers [78], CT disclosed osteolytic lesions containing round or oval opacities,
with a mean density of approximately 160 Hounsfield units. Soft tissue tophi,
with dippled calcium deposits, can result in bone erosion clearly depicted at
CT scan [72].
Outcome and evaluation of gout
As new treatments are developed, there are no well-established outcome

measures or data on follow-up and outcome of gout cohorts, including patients
treated long-term, regarding chronic joint clinical and radiologic symptoms or
308 liotÉ & ea
quality of life. The Outcome Measure in Rheumatoid Arthritis Clinical Trials

(OMERACT) has begun developing sets of outcome criteria that will be dis-
cussed at their meeting in Malta in May, 2006. Clinical issues remain as do imag-
ing aspects related to tophus detection by ultrasound examination or MRI
imaging, documented so far only in case reports.
References
[1] Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:499 – 516.
[2] Lioté F. Hyperuricemia and gout. Curr Rheumatol Rep 2003;5:227 – 34.
[3] Dalbeth N, Haskard DO. Mechanisms of inflammation in gout. Rheumatology (Oxford)
2005;44:1090 – 6.
[4] Schumacher HR, Phelps P, Agudelo CA. Urate crystal induced inflammation in dog joints:
sequence of synovial changes. J Rheumatol 1974;1:102 – 13.
[5] Schiltz C, Lioté F, Prudhommeaux F, et al. Monosodium urate monohydrate crystal-induced
inflammation in vivo: quantitative histomorphometric analysis of cellular events. Arthritis
Rheum 2002;46:1643 – 50.
[6] Liu-Bryan R, Terkeltaub R. Evil humors take their toll as innate immunity makes gouty joints
TREM-ble. Arthritis Rheum 2006;54:383 – 6.
[7] Guerne PA, Terkeltaub R, Zuraw B, et al. Inflammatory microcrystals stimulate interleukin-6
production and secretion by human monocytes and synoviocytes. Arthritis Rheum 1989;32:
1443 – 52.
[8] Liu R, Lioté F, Rose DM, et al. Proline-rich tyrosine kinase 2 and Src kinase signaling transduce
monosodium urate crystal-induced nitric oxide production and matrix metalloproteinase 3 ex-
pression in chondrocytes. Arthritis Rheum 2004;50:247 – 58.
[9] Liu-Bryan R, Pritzker K, Firestein GS, et al. TLR2 signaling in chondrocytes drives cal-
cium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation.
J Immunol 2005;174:5016 – 23.
[10] Liu-Bryan R, Scott P, Sydlaske A, et al. Innate immunity conferred by Toll-like receptors 2 and
4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate mono-
hydrate crystal-induced inflammation. Arthritis Rheum 2005;52:2936 – 46.
[11] Murakami Y, Akahoshi T, Hayashi I, et al. Induction of triggering receptor expressed on mye-
loid cells 1 in murine resident peritoneal macrophages by monosodium urate monohydrate
crystals. Arthritis Rheum 2006;54:455 – 62.
[12] Ryckman C, McColl SR, Vandal K, et al. Role of S100A8 and S100A9 in neutrophil recruit-
ment in response to monosodium urate monohydrate crystals in the air-pouch model of acute
gouty arthritis. Arthritis Rheum 2003;48:2310 – 20.
[13] Tramontini N, Huber C, Liu-Bryan R, et al. Central role of complement membrane attack
complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis. Arthritis
Rheum 2004;50:2633 – 9.
[14] Marshall JS, Jawdat DM. Mast cells in innate immunity. J Allergy Clin Immunol 2004;114:
21 – 7.
[15] Webster ME, Maling HM, Zweig MH, et al. Urate crystal induced inflammation in the rat:
evidence for the combined actions of kinins, histamine and components of complement.
Immunol Commun 1972;1:185 – 98.
[16] Getting SJ, Flower RJ, Parente L, et al. Molecular determinants of monosodium urate crystal-
induced murine peritonitis: a role for endogenous mast cells and a distinct requirement for
endothelial-derived selectins. J Pharmacol Exp Ther 1997;283:123 – 30.
[17] Roberge CJ, de Medicis R, Dayer JM, et al. Crystal-induced neutrophil activation. V. Differen-
tial production of biologically active IL-1 and IL-1 receptor antagonist. J Immunol 1994;152:
5485 – 94.
[18] Di Giovine FS, Malawista SE, Nuki G, et al. Interleukin 1 (IL 1) as a mediator of crystal arthritis.
Stimulation of T cell and synovial fibroblast mitogenesis by urate crystal-induced IL 1.
J Immunol 1987;138:3213 – 8.
[19] Liu R, Aupperle K, Terkeltaub R. Src family protein tyrosine kinase signaling mediates mono-
sodium urate crystal-induced IL-8 expression by monocytic THP-1 cells. J Leukoc Biol 2001;70:
961 – 8.
[20] Liu R, O’Connell M, Johnson K, et al. Extracellular signal-regulated kinase 1/extracellular
signal-regulated kinase 2 mitogen-activated protein kinase signaling and activation of activator
protein 1 and nuclear factor kappaB transcription factors play central roles in interleukin-8
expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals
in monocytic cells. Arthritis Rheum 2000;43:1145 – 55.
[21] Hachicha M, Naccache PH, McColl SR. Inflammatory microcrystals differentially regulate the
secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a
possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med
1995;182:2019 – 25.
[22] Matsukawa A, Miyazaki S, Maeda T, et al. Production and regulation of monocyte chemo-
attractant protein-1 in lipopolysaccharide- or monosodium urate crystal-induced arthritis in
rabbits: roles of tumor necrosis factor alpha, interleukin-1, and interleukin-8. Lab Invest 1998;
78:973 – 85.
[23] Matsukawa A, Yoshimura T, Maeda T, et al. Analysis of the cytokine network among tumor
necrosis factor alpha, interleukin-1beta, interleukin-8, and interleukin-1 receptor antagonist in
monosodium urate crystal-induced rabbit arthritis. Lab Invest 1998;78:559 – 69.
[24] Nishimura A, Akahoshi T, Takahashi M, et al. Attenuation of monosodium urate crystal-
induced arthritis in rabbits by a neutralizing antibody against interleukin-8. J Leukoc Biol
1997;62:444 – 9.
[25] Inokuchi T, Moriwaki Y, Tsutsui H, et al. Plasma interleukin (IL)-18 (interferon-gamma-inducing
factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate
monohydrate crystal-induced secretion of IL-18. Cytokine 2006;33:21 – 7.
[26] Schreiner O, Wandel E, Himmelsbach F, et al. Reduced secretion of proinflammatory cytokines
of monosodium urate crystal-stimulated monocytes in chronic renal failure: an explanation for
infrequent gout episodes in chronic renal failure patients? Nephrol Dial Transplant 2000;15:
644 – 9.
[27] Lioté F, Champy R, Moenner M, et al. Elevated angiogenin levels in synovial fluid from pa-
tients with inflammatory arthritis and secretion of angiogenin by cultured synovial fibroblasts.
Clin Exp Immunol 2003;132:163 – 8.
[28] Terkeltaub R, Zachariae C, Santoro D, et al. Monocyte-derived neutrophil chemotactic factor/
interleukin-8 is a potential mediator of crystal-induced inflammation. Arthritis Rheum 1991;34:
894 – 903.
[29] Terkeltaub R, Baird S, Sears P, et al. The murine homolog of the interleukin-8 receptor
CXCR-2 is essential for the occurrence of neutrophilic inflammation in the air pouch model
of acute urate crystal-induced gouty synovitis. Arthritis Rheum 1998;41:900 – 9.
[30] Terkeltaub R, Curtiss LK, Tenner AJ, et al. Lipoproteins containing apoprotein B are a
major regulator of neutrophil responses to monosodium urate crystals. J Clin Invest 1984;73:
1719 – 30.
[31] Terkeltaub R, Martin J, Curtiss LK, et al. Glycosaminoglycans alter the capacity of low density
lipoprotein to bind to monosodium urate crystals. J Rheumatol 1990;17:1211 – 6.
[32] Terkeltaub RA, Dyer CA, Martin J, et al. Apolipoprotein (apo) E inhibits the capacity of
monosodium urate crystals to stimulate neutrophils. Characterization of intraarticular apo E and
demonstration of apo E binding to urate crystals in vivo. J Clin Invest 1991;87:20 – 6.
[33] Landis RC, Haskard DO. Pathogenesis of crystal-induced inflammation. Curr Rheumatol Rep
2001;3:36 – 41.
[34] Yagnik DR, Hillyer P, Marshall D, et al. Noninflammatory phagocytosis of monosodium urate
monohydrate crystals by mouse macrophages. Implications for the control of joint inflammation
in gout. Arthritis Rheum 2000;43:1779 – 89.
310 liotÉ & ea
[35] Landis RC, Yagnik DR, Florey O, et al. Safe disposal of inflammatory monosodium urate
monohydrate crystals by differentiated macrophages. Arthritis Rheum 2002;46:3026 – 33.
[36] Yagnik DR, Evans BJ, Florey O, et al. Macrophage release of transforming growth factor beta1
during resolution of monosodium urate monohydrate crystal-induced inflammation. Arthritis
Rheum 2004;50:2273 – 80.
[37] Lioté F, Prudhommeaux F, Schiltz C, et al. Inhibition and prevention of monosodium urate
monohydrate crystal-induced acute inflammation in vivo by transforming growth factor beta1.
[38] Fadok VA, Bratton DL, Konowal A, et al. Macrophages that have ingested apoptotic cells in
vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms
involving TGF-beta, PGE2, and PAF. J Clin Invest 1998;101:890 – 8.
[39] Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic
cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest 2002;109:
41 – 50.
[40] Murakami Y, Akahoshi T, Kawai S, et al. Antiinflammatory effect of retrovirally transfected
interleukin-10 on monosodium urate monohydrate crystal-induced acute inflammation in murine
air pouches. Arthritis Rheum 2002;46:2504 – 13.
[41] Cicuttini FM, Byron KA, Maher D, et al. Serum IL-4, IL-10 and IL-6 levels in inflammatory
arthritis. Rheumatol Int 1995;14:201 – 6.
[42] Miyata M, Ohira H, Sasajima T, et al. Significance of low mRNA levels of interleukin-4 and -10
in mononuclear cells of the synovial fluid of patients with rheumatoid arthritis. Clin Rheumatol
2000;19:365 – 70.
[43] Geske FJ, Monks J, Lehman L, Fadok VA. The role of the macrophage in apoptosis: hunter,
gatherer, and regulator. Int J Hematol 2002;76:16 – 26.
[44] Fadok VA, Chimini G. The phagocytosis of apoptotic cells. Semin Immunol 2001;13:365 – 72.
[45] Fadok VA, Bratton DL, Guthrie L, et al. Differential effects of apoptotic versus lysed cells on
macrophage production of cytokines: role of proteases. J Immunol 2001;166:6847 – 54.
[46] Jones ST, Denton J, Holt PJ, et al. Possible clearance of effete polymorphonuclear leucocytes
from synovial fluid by cytophagocytic mononuclear cells: implications for pathogenesis and
chronicity in inflammatory arthritis. Ann Rheum Dis 1993;52:121 – 6.
[47] Chen L, Hsieh MS, Ho HC, et al. Stimulation of inducible nitric oxide synthase by mono-
sodium urate crystals in macrophages and expression of iNOS in gouty arthritis. Nitric Oxide
2004;11:228 – 36.
[48] Akahoshi T, Nagaoka T, Namai R, et al. Prevention of neutrophil apoptosis by monosodium
urate crystals. Rheumatol Int 1997;16:231 – 5.
[49] Tudan C, Fong D, Duronio V, et al. The inhibition of spontaneous and tumor necrosis factor-
alpha induced neutrophil apoptosis by crystals of calcium pyrophosphate dihydrate and mono-
sodium urate monohydrate. J Rheumatol 2000;27:2463 – 72.
[50] Pascual E. Persistence of monosodium urate crystals and low-grade inflammation in the synovial
fluid of patients with untreated gout. Arthritis Rheum 1991;34:141 – 5.
[51] Pascual E, Batlle-Gualda E, Martinez A, et al. Synovial fluid analysis for diagnosis of inter-
critical gout. Ann Intern Med 1999;131:756 – 9.
[52] Pascual E, Castellano JA. Treatment with colchicine decreases white cell counts in synovial
fluid of asymptomatic knees that contain monosodium urate crystals. J Rheumatol 1992;19:
600 – 3.
[53] Schweyer S, Hemmerlein B, Radzun HJ, et al. Continuous recruitment, co-expression of tu-
mour necrosis factor-alpha and matrix metalloproteinases, and apoptosis of macrophages in
gout tophi. Virchows Arch 2000;437:534 – 9.
[54] Rull M, Clayburne G, Sieck M. l. Intra-articular corticosteroid preparations: different charac-
teristics and their effect during inflammation induced by monosodium urate crystals in the rat
subcutaneous air pouch. Rheumatology (Oxford) 2003;42:1093 – 100.
[55] Castillo EC, Kouri JB. A new role for chondrocytes as non-professional phagocytes. An in vitro
study. Microsc Res Tech 2004;64:269 – 78.
[56] Cheung HSHP, McCarty DJ. Phagocytosis of hydroxyapatite or calcium pyrophosphate dihy-
drate crystals by rabbit articular chondrocytes stimulates release of collagenase, neutral protease,
and prostaglandins E2 and F2 alpha. Proc Soc Exp Biol Med 1983;173:181 – 9.
[57] Bouchard L, de Medicis R, Lussier A, et al. Inflammatory microcrystals alter the functional
phenotype of human osteoblast-like cells in vitro: synergism with IL-1 to overexpress
cyclooxygenase-2. J Immunol 2002;168:5310 – 7.
[58] Vandivier RW, Fadok VA, Ogden CA, et al. Impaired clearance of apoptotic cells from cystic
fibrosis airways. Chest 2002;121(3 Suppl):89S.
[59] Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the
acute arthritis of primary gout. Arthritis Rheum 1977;20:895 – 900.
[60] Zhang WDM, Pascual E, et al. EULAR evidence based recommendations for gout. Part I
diagnosis. Report of a task force of the standing committee for ESCISIT. Ann Rheum Dis,
in press.
[61] Pascual E, Jovani V. Synovial fluid analysis. Best Pract Res Clin Rheumatol 2005;19:371 – 86.
[62] Lumbreras B, Pascual E, Frasquet J, et al. Analysis for crystals in synovial fluid: training of
the analysts results in high consistency. Ann Rheum Dis 2005;64:612 – 5.
[63] De Souza AW, Fernandes V, Ferrari AJ. Female gout: clinical and laboratory features. J
Rheumatol 2005;32:2186 – 8.
[64] Snider AA, Barsky S. Gouty panniculitis: a case report and review of the literature. Cutis
2005;76:54 – 6.
[65] Folpe AL, Johnston CA, Weiss SW. Cutaneous angiosarcoma arising in a gouty tophus: report
of a unique case and a review of foreign material-associated angiosarcomas. Am J Dermato-
pathol 2000;22:418 – 21.
[66] Bret P, Ricci AC, Saint-Pierre G, et al. [Thoracic spinal cord compression by a gouty tophus.
Case report. Review of the literature.] Neurochirurgie 1999;45:402 – 6 [in French].
[67] Mahmud T, Basu D, Dyson PH. Crystal arthropathy of the lumbar spine: a series of six cases
and a review of the literature. J Bone Joint Surg [Br] 2005;87:513 – 7.
[68] Diaz A, Porhiel V, Sabatier P, et al. [Tophaceous gout of the cervical spine, causing cord
compression. Case report and review of the literature.] Neurochirurgie 2003;49:600 – 4
[in French].
[69] Barrett K, Miller ML, Wilson JT. Tophaceous gout of the spine mimicking epidural infection:
case report and review of the literature. Neurosurgery 2001;48:1170 – 2 [discussion: 1172–3].
[70] Dhote R, Roux FX, Bachmeyer C, et al. Extradural spinal tophaceous gout: evolution with
medical treatment. Clin Exp Rheumatol 1997;15:421 – 3.
[71] Rich JT, Bush DC, Lincoski CJ, et al. Carpal tunnel syndrome due to tophaceous gout.
Orthopedics 2004;27:862 – 3.
[72] Chen CK, Yeh LR, Pan HB, et al. Intra-articular gouty tophi of the knee: CT and MR imaging
in 12 patients. Skeletal Radiol 1999;28:75 – 80.
[73] Yu KH, Ho HH, Chen JY, Luo SF. Gout complicated with necrotizing fasciitis—report of
15 cases. Rheumatology (Oxford) 2004;43:518 – 21.
[74] Yu KH, Luo SF, Liou LB, et al. Concomitant septic and gouty arthritis—an analysis of 30 cases.
Rheumatology (Oxford) 2003;42:1062 – 6.
[75] Gentili A. Advanced imaging of gout. Semin Musculoskelet Radiol 2003;7:165 – 74.
[76] Monu JU, Pope Jr TL. Gout: a clinical and radiologic review. Radiol Clin North Am 2004;
42:169 – 84.
[77] Nalbant S, Corominas H, Hsu B, et al. Ultrasonography for assessment of subcutaneous nodules.
J Rheumatol 2003;30:1191 – 5.
[78] Gerster JC, Landry M, Dufresne L, et al. Imaging of tophaceous gout: computed tomography
provides specific images compared with magnetic resonance imaging and ultrasonography.
Ann Rheum Dis 2002;61:52 – 4.
Renal Urate Transport

David B. Mount, MDa,b,c,T, Charles Y. Kwon, MDa,b,d,
Kambiz Zandi-Nejad, MDa,b
a
Harvard Medical School, Boston, MA, USA
b
Renal Division, Brigham and Women’s Hospital, Boston, MA, USA
c
Division of General Internal Medicine, VA Boston Healthcare System, Boston, MA, USA
d
Renal Division, Children’s Hospital of Boston, MA, USA
Several recent developments have created a renaissance of sorts for uric

acid homeostasis. In particular, there have been major advances in the molecular
understanding of renal urate transport. These developments include the molecu-
lar characterization of urate transporter-1 (URAT1), the urate exchanger in
the proximal tubule that reabsorbs the bulk of filtered urate from the glomerular
ultrafiltrate [1]. More recently, two candidates have emerged for the sodium-
dependent anion transporters that collaborate with URAT1 in urate reabsorption
by the proximal tubule [2–5]. The physiologic relationships between these apical
transporters are relevant particularly for the pathogenesis of hyperuricemia and
gout. There also is an increasing interest in the role of uric acid in hypertension
[6] and progressive renal disease [7] (reviewed elsewhere) [6,8]. Novel, pro-
vocative roles for uric acid have also been proposed in inflammation [9,10],
cardiovascular disease [11], heart failure [12,13], and the metabolic syndrome
[14–16], such that urate homeostasis is of relevance to an increasing number of
disorders. This brief review focuses on recent developments in the molecular
physiology and genetics of urate homeostasis.
Work in the authors’ laboratory has been supported by RO1 DK-57708 from the National
Institutes of Health (DBM), an Advanced Research Career Development Award from the Veterans
Administration (DBM), a Pediatric Scientist Development Award from the National Institutes of
Health (CYK), and American Heart Association Postdoctoral Fellowship Award 0225706T (KZ).
T Corresponding author. Renal Division, BWH, Room 540, HIM Building, 4 Blackfan Circle,
Boston, MA 02115.
E-mail address: dmount@rics.bwh.harvard.edu (D.B. Mount).
314 mount et al
Phylogeny and uric acid
In most mammalian species, uric acid generated from purine metabolism un-
dergoes oxidative degradation via the uricase enzyme to produce allantoin,
a more soluble metabolite. In humans, the uricase gene is crippled by two
mutations that introduce premature stop codons [17]. The absence of uricase,
combined with extensive reabsorption of filtered urate, results in urate levels in
human plasma that are approximately 10 times those of most other mammals
[18]. Whereas primates, such as the chimpanzee, share the same truncating
mutations in uricase, the existence of independent loss-of-function mutations in
the genome of gibbon apes suggests that this gene was subject to significant
negative pressure during the evolution of hominoids [19]. Highly speculative ad-
vantages conferred by the relative hyperuricemia in these species include reduced
oxidant stress and a decreased incidence of cancer [20], complexation of cir-
culating iron and inhibition of iron-catalyzed oxidation [21], an enhanced ability
to survive under conditions of low dietary salt [22], and even increased intel-
ligence [23]. The purported benefits of an increase in uric acid are offset in
part by the risk of gout [24] and nephrolithiasis [25], in addition to the host of
other disorders in which hyperuricemia is postulated to play a role. The risk
of hyperuricemia in humans is mitigated genetically by comparative repression
of the human xanthine oxidoreductase gene [26,27], the enzyme that mediates
the last two steps of purine metabolism [28]; transcription of this gene is con-
siderably more widespread and robust in mice [26,27]. This is a recurrent theme;
several other genes involved in urate homeostasis are differentially conserved or
preserved in various mammalian species, underlining the divergent evolutionary
pressure on these pathways.
Approximately one third of urate elimination occurs in the gastrointestinal
tract, with the remainder excreted in the urine [29]. In plasma, uric acid circu-
lates primarily as urate and is filtered freely by renal glomeruli. Subsequent
bidirectional transport along the nephron results either in net reabsorption
(humans, primates, rats, and dogs) or secretion (pigs and rabbits); pigs and
rabbits [30,31] seem to lack the apical urate-anion exchanger that is found
in all the ‘‘reabsorptive’’ species, presumably because of inactivation of the
SLC22A12 gene (Solute Carrier gene family 22, member 12) encoding URAT1
(discussed later). The fractional excretion of urate differs considerably in mam-
mals: 10% in humans versus approximately 40% in rats [32] and 200% in pig
[33]. Cebus monkeys also exhibit fractional excretion of approximately 10%
[34]; however, unlike other New World monkeys, Cebus monkeys possess an
active uricase enzyme and have uric acid levels that are approximately half
those of humans [35]. In contrast, chimpanzees lack uricase activity, exhibit
fractional excretion for urate of approximately 10%, and have circulating uric
acid levels that approximately are equal to those of humans [36]. Therefore, the
evolutionary loss of uricase and the development of highly efficient reabsorptive
mechanisms for urate seem to be separate, additive events that result in relative
hyperuricemia in humans and related hominoids.
renal urate transport 315
The four-component model
The dominant model of renal urate excretion has for decades consisted of four
steps: glomerular filtration, reabsorption from the glomerular ultrafiltrate, sub-
sequent secretion, and then ‘‘postsecretory reabsorption’’ [37]. Elements of this
four-component model appear in the current editions of leading physiology and
nephrology textbooks; however, the serious flaws in this model [29,38] neces-
sitate a brief review.
Regardless of the species studied, the bulk of urate transport occurs within the
proximal tubule, with minimal or nonexistent contributions from the distal
nephron [35]. Reabsorption and secretion can each be detected in reabsorptive
species, such as the dog [35]. The relative dominance of reabsorption or secre-
tion, however, can be influenced by pharmacologic manipulation or by genetic
background. Thus, in Dalmatian dogs, the fractional excretion of urate can equal
100% or just above 100%, suggesting minimal reabsorption or modest secretion
[39]; Dalmatians exhibit significant hyperuricosuria and modest hyperuricemia
as a result of defective hepatic transport of urate that limits metabolism via uricase
[40]. In contrast, mongrel dogs exhibit a predominance of urate reabsorption,
with fractional reabsorption of approximately 50% [39]; however, bidirectional
transport can be detected in mongrels [41] and secretion can be induced by a
combination of urate loading and osmotic diuresis [42]. Renal urate secretion can
be unmasked in humans after treatment with mannitol and a uricosuric agent [43].
In addition, patients who have renal hypouricemia (discussed later) can have
fractional excretions of urate that are greater than unity, indicative of tubular
secretion [44,45].
The four-component model evolved in the 1960s and 1970s from an
interpretation of the competing effects of uricosuric and antiuricosuric agents.
The key assumption underlying this model is that the antiuricosuric agent
pyrazinamide inhibits proximal tubular urate secretion. In a typical pyrazinamide
suppression test [46], the oral administration of 2 to 3 g results in a marked de-
crease in the fractional excretion of urate; this effect is mediated by pyrazinoate
(PZA), the deamidated metabolite [47]. Dog experiments from the mid 1960s
revealed that pyrazinamide abolished the secretory peak of 14C-labeled urate
(14C-urate) injected into the renal artery; given that the initial urinary bolus of
radioactive urate preceded that of 14C-inulin, the primary source of this urinary
14
C-urate peak was believed to be tubular secretion rather than glomerular ultra-
filtration. By extension, the antiuricosuric effect of pyrazinamide was attributed
to an inhibition of urate secretion [48]. The pyrazinamide suppression test thus
was adopted as a pharmacologic method to quantify tubular urate secretion [46].
The three-component model of renal urate handling originally was proposed
by Gutman and Yu in 1961, encompassing glomerular filtration, probenecid-
sensitive tubular reabsorption, and pyrazinamide-sensitive tubular secretion [49].
The full four-component model subsequently evolved to explain the interactions
between pyrazinamide and uricosuric agents, including probenecid [37,50],
chlorothiazide [50], benzbromarone [51], and sulfinpyrazone [37]. When these
316 mount et al
drugs are administered after pyrazinamide, there is a striking attenuation of their

uricosuric effect [29]. To explain this phenomenom, uricosuric agents were pos-
tulated to have a dominant effect on ‘‘postsecretory reabsorption,’’ given that
their ability to increase urate excretion was blunted when putative ‘‘upstream’’
secretion was inhibited with pyrazinamide. It follows that these processes occur
serially in anatomically separate segments of the proximal tubule; such a
progression is incorporated in current textbook models of renal urate transport.
Physiologic studies of reabsorptive species, however, typically indicate a co-
existence of reabsorption and secretion along the entire length of the proximal
tubule [35].
The alternative possibility, that PZA does not inhibit secretion but instead
stimulates urate reabsorption, was considered ‘‘rather awkward’’ [43] and ‘‘ex-
tremely unlikely’’ [46] during the initial formulation of the four-component
model. A seminal observation in 1985 by Guggino and Aronson, however, sug-
gested that PZA does indeed stimulate tubular reabsorption [38]; the same
investigators previously reported analogous data for lactate [30]. Using brush-
border membrane vesicles (BBMV) from renal cortex, it was demonstrated that
sodium-dependent uptake of PZA or lactate results in a marked stimulation of
vesicular urate uptake via the brush-border urate-anion exchanger (these and
subsequent insights discussed later).
Urate transporter-1 is the reabsorptive urate-anion exchanger
An apical urate-anion exchange activity was described first in nonprimate,

urate-reabsorbing species (ie, rats and dogs) [30,52–54]. This anion exchanger
accepts various monovalent organic anions, including urate, p-aminohippurate
(PAH), and lactate, in addition to chloride (Cl ) and hydroxyl (OH ); divalent
anions are not substrates [30]. Apical urate-anion exchange activity evidently is
absent in species with net urate secretion [30,55], although it is present and
highly sensitive to uricosuric agents in urate-reabsorbing species [52,53]; these
observations suggest a significant role for urate exchange in proximal reabsorp-
tion. A similar urate exchanger has been demonstrated in BBMV from human
kidneys, albeit with some important distinctions; notably, PAH and OH are not
substrates for the human exchanger [56]. This is reflected in the modest effect
of PAH infusion on urate excretion in humans; PZA, furthermore, is without
effect on PAH homeostasis, suggesting that the absorptive mechanism for PAH
and urate are distinct in this species [57].
The recent molecular identification of URAT1 as the dominant apical urate
exchanger of human proximal tubule [1] was a landmark event in the physiology
of urate homeostasis. The URAT1 protein is encoded by the SLC22A12 gene, part
of the rapidly expanding SLC22 family of organic ion transporters. URAT1
primarily is homologous to members of the organic anion transporter (OAT)
branch of this gene family; other subgroups include organic cation transporters
and organic cation transporter novel type/carnitine transporters [58]. Although
not acknowledged initially [1], URAT1 is the human ortholog of renal-specific

transporter (RST), cloned from murine kidney several years ago [59]. URAT1/
RST is in point of fact not renal specific, with detectable transcript in lung and
brain (Zandi Nejad, unpublished data, 2004). Regardless, immunohistochemistry
reveals the URAT1 protein at the apical membrane of proximal tubules in human
[1] and mouse [60] kidney. Heterologous expression in Xenopus oocytes indi-
cates that human URAT1 is capable of urate transport (14C-urate uptake), with a
Michaelis constant (Km) of 371 F 28 mM. Uricosuric drugs, such as probenecid
and losartan [61], are potent inhibitors of URAT1; this indicates that their effect
on serum urate is mediated through inhibition of urate reabsorption rather than an
activation of renal secretion. URAT1 has the highest affinity for aromatic organic
anions, such as nicotinate and PZA, followed by lactate, b-hydroxybutyrate,
acetoacetate, and inorganic anions, such as Cl and nitrate. These relative affini-
ties are manifest by a marked activation (trans-stimulation) of 14C-urate uptake
in URAT1-expressing oocytes that have been microinjected individually with
PZA, nicotinate, and lactate (ie, in-trans to the 14C-urate); the relative response
fits with the trans-stimulation of urate exchange in human BBMV sodium-
dependent transport of these monovalent anions [62] (discussed later). The same
anions are capable of cis-inhibiting the uptake of 14C-urate when present in the
extracellular medium, another operative characteristic of the anion exchanger.
In their report describing the identification of URAT1, Enomoto and co-
workers provide unequivocal genetic proof that this anion exchanger is essential
for normal urate homeostasis: a handful of patients who had ‘‘renal hypo-
uricemia’’ (OMIM #220150) [63] were shown to carry loss-of-function mutations
in the human SLC22A12 gene encoding URAT1, indicating that this exchanger
is essential for the proximal tubular reabsorption of urate [1]. Patients who
have homozygous loss-of-function mutations in SLC22A12 do not respond to
pyrazinamide and benzbromarone loading with urate retention and uricosuria,
respectively (discussed later). A very modest response to probenecid suggests,
however, that anion transporters other than URAT1 may participate in the luminal
reabsorption of urate from the glomerular ultrafiltrate [45].
The secondary sodium dependency of urate reabsorption
As discussed previously, URAT1 reabsorbs urate from the glomerular

ultrafiltrate by exchanging luminal urate with monovalent intracellular anions,
such as PZA. The intracellular concentration of these anions is determined largely
by sodium-dependent absorption from the same glomerular ultrafiltrate; this
generates a secondary sodium dependency of urate reabsorption, because these
anions increase proximal urate reabsorption via subsequent anion exchange. The
nephron thus is primed for urate reabsorption by the sodium-dependent loading
of proximal tubule cells with antiuricosuric anions.
Independent, overlapping studies from several laboratories suggest that a sin-
gle cotransport activity in renal BBMV is responsible for the sodium-dependent
318 mount et al
uptake of PZA, nicotinate, lactate, pyruvate, b-hydroxybutyrate, and acetoacetate

[64–66]; urate is not a direct substrate (ie, there is no evidence for direct sodium-
dependent urate uptake). These anions all are substrates for URAT1 and share
a tendency to increase serum uric acid in vivo. By extension from the BBMV
data [38,62], increased plasma concentrations of antiuricosuric anions result in
increased glomerular filtration, increased delivery to the proximal tubule, and
increased intracellular concentration in tubular epithelial cells. Increases in intra-
cellular activity of these anions in turn induce urate reabsorption and hyper-
uricemia, via trans-stimulation of URAT1 from inside the cell.
There are clear clinical consequences for this physiology. Hyperuricemia is a
well-recognized concomitant of the increased concentration of b-hydroxybutyrate
and acetoacetate found in diabetic ketoacidosis [67,68]. Increases in lactic acid,
as seen in alcohol intoxication [69], result in hyperuricemia resulting from
increased urate reabsorption [70]; transient increases in lactate or keto acids may
contribute to the association between gout and alcohol [71]. The effects of keto-
acids and lactate do not appear to be secondary to the respective acidoses, given
that the experimental infusion or ingestion of these anions also can lead to urate
retention [66,72,73]. Hyperuricemia also is a long-appreciated complication of
high-fat diet [74] and of starvation ketosis [75]. Ketoacidosis is thought to be
necessary for the weight-reduction seen with low-carbohydrate diets, with the
recent report of a particularly severe case of diet-associated ketosis [76];
hyperuricemia is assumed to also occur in ketotic patients, on such a low-
carbohydrate, Atkins diet. Finally, the treatment of hypercholesterolemia with
nicotinic acid (niacin) can be complicated by hyperuricemia [77], as can the
treatment of tuberculosis with pyrazinamide [78,79].
Patients who have renal hypouricemia and loss-of-function mutations in
URAT1 are found to lack a response to pyrazinamide and uricosurics [45]. This
provides genetic confirmation of the linkage between PZA and urate reabsorp-
tion; as predicted by the model shown in Fig. 1, a functional urate exchanger
is necessary for the antiuricosuric effect of PZA. Furthermore, BBMV urate
exchange is not detectable in animal species that secrete urate in the absence of
significant reabsorption [30]; presumably, the SLC22A12 gene is inactivated in
these species, much as the uricase gene is inactivated in humans and other homi-
noids. Again, PZA has no effect on urate transport in species in which secre-
tion predominates [29]. These observations all tend to refute the four-component
model, showing that PZA requires a functioning reabsorptive transporter for its
antiuricosuric effect.
The molecular identity of the sodium-dependent anion cotransporter(s) is not
as yet clear. A leading candidate gene, however, is SLC5A8, which encodes a
sodium-dependent lactate and butyrate cotransporter [3] expressed in the proxi-
mal tubule; the murine Slc5a8 protein can transport both PZA and nicotinate [4],
and preliminary data indicate that this transport can potentiate urate uptake in
cells that coexpress URAT1 [2]. More recently, the related cotransporter Slc5a12
was reported to transport nicotinate and other monocarboxylates [5]; intrarenal
localization of the Slc5a8 and Slc5a12 proteins indicate expression at the apical
Fig. 1. Urate transport mechanisms in the proximal tubule. Sodium-dependent entry of monovalent
anions, such as lactate and PZA, through the SLC5A8 and SLC5A12 cotransporters stimulates the
absorption of luminal urate via the anion exchanger URAT1. Apical secretion of urate may occur
through an ATP-driven efflux pathway (MRP4) or through voltage-sensitive electrogenic pathways
(OATv1 or UAT1). Basolateral entry of urate during urate secretion by the proximal tubule is
stimulated by sodium-dependent uptake of the divalent anion a-ketoglutarate via SLC13A3, leading
to urate-a-ketoglutarate exchange via OAT1 or OAT3. The identity of the exit pathways for urate
during urate reabsorption is not as yet known.
membrane of S2/S3 and S1 segments of the proximal tubule (Zandi-Nejad and

colleagues, submitted for publication, 2006), respectively, such that the two
cotransporters may contribute serially to sodium-dependent anion transport
within the proximal nephron. Finally, there is a residual question of molecular
heterogeneity in proximal tubular sodium-anion cotransport; prior evidence sug-
gests electrogenic [80] and electroneutral [64,81] modalities for BBMV sodium-
dependent monocarboxylate and/or nicotinate/PZA transport, whereas SLC5A8
[3] and Slc5a12 [5] appear to be electrogenic cotransporters.
Pharmacologic implications
The monovalent anions that interact with URAT1 have the dual potential to
increase urate absorption and urate excretion, because they can trans-stimulate
and cis-inhibit apical urate exchange. Thus, although urate retention is caused
by the low concentrations of circulating PZA generated in the typical pyrazin-
amide suppression test (approximately 80 mM, 10 mg/ml), higher concentrations
320 mount et al
achievable in chimpanzees result in uricosuria [82]; dissenting opinions

notwithstanding [83], these observations remain consistent with the basic scheme
of apical urate transport in the proximal tubule (Fig. 1). Thus, although 0.1-mM
sodium-PZA stimulates urate uptake by dog BBMV preparations, because of
trans-stimulation of urate exchange, 5-mM PZA inhibits the exchanger via
extracellular cis-inhibition (see Fig. 2) [38]. In human BBMV, the stimulatory
effect of PZA persists at 5 mM [62], suggesting that there are species-specific
differences in the ability of PZA to induce uricosuria. Regardless, similar bi-
phasic effects on urate excretion (ie, antiuricosuria at low dose and uricosuria at
high dose) long have been appreciated for salicylate [84]. Salicylate inhibits
human BBMV urate exchange [85] and human URAT1 [1], providing an expla-
nation for the high-dose uricosuric effect; the antiuricosuric effect at low dose
conceivably is the result of a trans-stimulation by intracellular salicylate [85].
Finally, the historically important effect of PZA to inhibit pharmacologic
uricosuria in humans likely is the net result of partial inhibition of renal urate
reabsorption by uricosurics and the particularly high affinity of URAT1 for
intracellular PZA, such that the antiuricosuric effect of PZA is dominant [29].
Again, salicylate has a similar effect, markedly reducing the uricosuric effect of
probenecid at low dose but not at high dose [84].
Fig. 2. The antiuricosuric agent pyrazinoate (PZA), a metabolite of pyrazinamide, has dual effects on
urate transport by the proximal tubule. Urate uptake by brush border membrane vesicles isolated from
dog kidney cortex is shown, in the presence of 100 mM sodium (Na+) with either 0.1-mM PZA (E),
0 PZA (&), or 5-mM PZA (.). The low concentration results in sodium-dependent uptake of PZA
and a potentiation of urate uptake via URAT1; in contrast, the higher concentration cis-inhibits
URAT1, thus reducing urate uptake by the membrane vesicles. (From Guggino SE, Aronson PS.
Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus mem-
branes. J Clin Invest 1985;76:543–7; with permission.)
Regulation of renal urate transport
Classical clinical teaching asserts that the serum concentration of uric acid
parallels extracellular volume status and salt absorption by the kidney [83], such
that salt-avid states (eg, those induced by diuretics) are characterized by hyper-
uricemia and often complicated by gout [86]. Indeed, it has been reported that
patients who have essential hypertension have a decreased fractional excretion of
urate [84–89]. Indices of proximal salt absorption show a significant correla-
tion with serum urate, such that proximal hyperabsorption of sodium (decreased
lithium clearance) is associated with hyperuricemia [87]. In rats, volume deple-
tion stimulates a marked increase in proximal tubular reabsorption of urate [90];
however, the mechanisms involved in the regulation of urate reabsorption by
extracellular volume status are not yet known. Angiotensin II (AT-II) infusion
does, however, decrease fractional excretion of urate; conceivably this is the
result of either hemodynamic effects or direct stimulation of tubular reabsorption
[89,91]. This effect of AT-II is relevant particularly to the hyperuricemia of the
metabolic syndrome [14,15], in that crosstalk between AT-II and insulin may play
a significant role in insulin resistance [92,93]. Acute insulin infusion also is
reported to reduce urate excretion [94,95], such that hyperinsulinemia may have
a direct impact on renal urate transport. Other mediators with potential effects
on renal urate transport include adenosine [96,97] and parathyroid hormone [98].
The URAT1, SLC5A8, and SLC5A12 proteins end with C-terminal sequence
motifs capable of interacting with scaffolding proteins that contain PDZ do-
mains [99]. Biochemical [100,101] and functional [102] interactions already have
been reported between URAT1 and PDZK1, one of a family of four PDZ proteins
(PDZK1/2 and NHERF1/2) that play increasingly appreciated roles in the regu-
lation of proximal tubular ion transport [102,103]. The proposed tethering of
URAT1 to the sodium-anion cotransporters may have additional roles in the
coordinated regulation of renal urate reabsorption. Even in the absence of such a
direct interaction, however, it is intuitively obvious from the antiuricosuric effect
of PZA and other anions that hyperuricemia and gout could result from increases
in the activity of either sodium-anion cotransport (SLC5A8/12) or of urate-anion
exchange (URAT1).
Other urate transporters in the proximal tubule
Considerably less is known regarding the molecular physiology of renal urate

secretion. There is evidence, however, for a voltage-sensitive urate transport
pathway in apical BBMV preparations from humans, weakly sensitive to urico-
suric drugs and PZA [56,85]. The lumen-positive voltage of the apical membrane
of the proximal tubule is hypothesized to favor urate secretion by this mechanism
[56]. Molecular candidates for this electrogenic pathway include urate transporter/
channel-1 (UAT1) [104] and voltage-driven organic anion transporter-1 (OATV1)
[105]. The apical ATP-driven efflux pump multidrug resistance protein 4 (MRP4)
322 mount et al
also is shown to mediate substantial urate efflux, suggesting a role in urate se-
cretion by the proximal tubule (see Fig. 1) [106].
At the basolateral membrane of proximal tubular cells, the entry of urate
from the surrounding interstitium appears to be driven by sodium-dependent
uptake of divalent anions, such as a-ketoglutarate, rather than monovalent car-
boxylates, such as PZA and lactate [107,108] (see Fig. 1). Candidate proteins for
this basolateral urate exchanger include OAT1 (SLC22A6) [109] and OAT3
(SLC22A8) [110,111], each of which functions as anion1 -dicarboxylate2 ex-
changers [111–113]. What currently is unknown is whether or not there are separate
pathways for urate exit at the basolateral membrane during urate reabsorption across
the proximal tubule or whether or not OAT1 or OAT3 functions in this capacity via
the exchange of intracellular urate with extracellular a-ketoglutarate. In this regard,
OAT1-deficient knockout mice exhibit a secretory defect for organic anions [114],
suggesting perhaps that basolateral transporters other than OAT1 or OAT3 function
in the reabsorption of urate.
Genetic influences on urate homeostasis
Although twin and family studies suggest a genetic influence on serum uric
acid levels, studies in most populations suggest a polygenic mode of inheritance
without a major gene effect [115]. A recent report from the Framingham Heart
Study reveals several potential loci that affect serum uric acid [116]. Perhaps the
strongest evidence for a genetic basis for gout and hyperuricemia is provided by
indigenous Pacific islanders [117–121]. Of particular interest, a recent study
implicates a major gene on chromosome 4q25 in the gout susceptibility of
Taiwanese aborigines, who share genetic ancestry with other Pacific islanders
[121]. Prior to molecular characterization of the predisposing gene, it is difficult
to speculate on the underlying pathophysiology of this association.
Two specific enzyme defects are shown to lead to overproduction of uric
acid. In addition to Lesch-Nyhan syndrome resulting from complete deficiency of
hypoxanthine hypoxanthine-guanine phosphoribosyltransferase (HPRT) (OMIM
#300322) [63], partial deficiency of this enzyme is a well-described cause of
hyperuricemia and gout (Kelley-Seegmiller syndrome) [122,123], (OMIM
#300323) [63]. Another X-linked cause is overactivity of the phosphoribosyl-
pyrophosphate synthetase (PRPS1) enzyme (OMIM #311850) [63] resulting from
a variety of point mutations or to increased PRPS1 transcription, the latter re-
ported in kindreds with structurally normal enzyme [124].
Several genetic causes of renal disease are associated with hyperuricemia
and gout. Most prominently, medullary cystic kidney disease type 2 (MCKD2)
(OMIM #603860) [63] and the allelic disorder, familial juvenile hyperuricemic
nephropathy (FJHN) (OMIM #603860 and #162,000) [63], are characterized by
a reduced fractional excretion of uric acid, progressive renal dysfunction,
frequent but variable hyperuricemia (92% hyperuricemia in one kindred [125]
and 0% in another [126,127]), and a high incidence of early-onset gout. This
disorder is caused primarily by mutations in uromodulin or Tamm-Horsfall gly-

coprotein [128], a glycosyl-phosphatidylinositol-anchored membrane protein
with restricted expression at the luminal membrane of the thick ascending limb
and distal convoluted tubule. Altered biosynthesis results in markedly reduced
uromodulin excretion and intracellular aggregation within the distal nephron
[129]. Although experimental [130] and genetic [123] forms of hyperuricemia
may lead to renal injury, the absence of hyperuricemia in some affected patients
suggests that the renal impairment in MCDK2 and FJHN is not a consequence of
hyperuricemia. Presumably, hyperuricemia in these patients is secondary to renal
tubular dysfunction, hypovolemia, and secondary neurohumoral activation of the
renin-angiotensin-aldosterone axis or other mediators. Indeed, hyperuricemia is
well described in other cellular and functional defects of the distal nephron,
including MCKD1 (chromosome 1q21), Bartter’s syndrome [131], and familial
hypomagnesemia [132]. Hyperuricemic renal disease also has been reported in a
kindred with mutations in the hepatocyte nuclear factor-1b (HNF-1b) transcrip-
tion factor [133]. Mutations in HNF-1b are associated with a spectrum of cystic,
dysplastic, and developmental abnormalities of the kidney [134]. Although the
related transcription factor HNF-1a is likely to regulate the expression of URAT1
[135,136], it is not yet known how dysregulated transcription of this or related
transporters contributes to the renal phenotype or hyperuricemia in patients who
have HNF-1b mutations.
Finally, as discussed previously, loss-of-function mutations in URAT1 are
associated with renal hypouricemia (OMIM #220150). These patients typically
have serum uric acid levels of approximately 1 mg per day, with marked in-
creases in their fractional urate clearance [45]. Clinical manifestations include a
characteristic syndrome of exercise-associated acute renal failure, which can be
recurrent. The mechanism of this renal injury is not known. The majority of renal
biopsies in a recent series, however, demonstrated evidence of acute tubular ne-
crosis, without intratubular deposition of uric acid [137]. An attractive hypothesis
is that the reduction in circulating uric acid, a known antioxidant [20,138], re-
duces the ability to cope with the increase in free radicals associated with stren-
uous exercise [139].
The hyperuricosuria associated with URAT1 dysfunction, typically greater
than 900 mg per day, is associated with renal stones in approximately 10% of
affected patients [45,140–142]. When analyzed biochemically, these episodes of
nephrolithias have included calcium oxalate [142] and uric acid [140,140] stones.
Hyperuricosuria is a well-described risk factor for calcium-oxalate stones [143];
affected patients generally have a urine pH greater than 5.0, with urinary super-
saturation of sodium urate and calcium oxalate resulting from concomitant in-
creases in urinary calcium and sodium [143,144]. In contrast, the uric acid stones
in patients who have ‘‘gouty diathesis’’ typically occur in the context of hyper-
uricemia and reduced fractional excretion of urate, with urine pH approximately 5
[145,146]. Recent data indicate a role for systemic insulin resistance in reducing
urinary ammonium excretion, generating an acid urine, and subsequent uric acid
crystallization [147]. The lesser role of hyperuricosuria per se in uric acid stones
324 mount et al
is underlined in renal hypouricemia; uric acid stones are not a universal problem
in this syndrome, despite the marked increase in urinary uric acid [45].
Although reduced urinary ammonium and a low urine pH is the most con-
sistent finding in idiopathic uric acid nephrolithiasis (UAN), the pathophysiology
underlying this defect is not completely clear. A novel gene, however, recently
was implicated in the high incidence of UAN observed in Talana, a genetically
isolated village in Sardinia [148,149]. Approximately 85% of the affected pa-
tients in this population have low urine pH, with hyperuricosuria (N700 mg/d)
in 35% [148]. The gene involved, denoted Talanin, is contained within a
67-kilobase ‘‘critical region’’ of 10q21-22 that is associated with severe UAN by
linkage-disequilibrium mapping. Talanin is encoded by one of at least four
alternative transcripts generated from within the larger ZNF36 gene; the Talanin
transcript shares coding exons with one of the other three major transcripts, with
transcriptional initiation at a unique TATA-box promoter just 5V of the criti-
cal region [149]. Although the function of Talanin is completely unknown, se-
quence analysis suggests that it might by an O-glycosylated transmembrane
protein. The open reading frame of the Talanin transcript is specific to humans;
there is no conservation of exon structure in this segment of the mouse and rat
ZNF36 gene, with inactivating mutations in the coding sequence of the Talanin
transcripts of Old World and New World monkeys [150]. Therefore, as in
other genes that have a role in uric acid homeostasis (uricase, xanthine oxidase,
and URAT1/SLC22A12), there seems to be differential evolutionary pressure
on ZNF36/Talanin.
Perspectives
Reduced renal excretion of urate [151] is the underlying pathophysiology in

the majority of gouty patients who have an underexcretor phenotype [152],
although more recent evidence suggests that patients who have higher levels of
uric acid excretion also have a diminished fractional excretion [88]. What is the
projected impact of the recent advances in molecular physiology on the under-
standing and management of gout? The immediate effect is conceptual, in that a
reconsideration of the relationship between sodium-anion cotransport (SLC5A8/
A12) and urate-anion exchange (URAT1) provides a framework to understand the
effect of uricosuric and antiuricosuric physiology. In particular, the loss of a PZA
response in patients lacking URAT1 [45], the major reabsorptive pathway for
urate, should lay to rest the concept that this drug has a dominant effect on urate
secretion rather than reabsorption; the durable four-component model should,
perhaps, have a similar fate. Moreover, if one extrapolates from the effect of
changes in circulating PZA/lactate/keto acids on serum urate, the possibility is
apparent that hyperuricemia might result from changes in the activity of URAT1,
SLC5A8/A12, or the scaffolding proteins that potentially bind them together
[101]. On a more practical level, the molecular characterization of proteins in this
‘‘metabolic pathway’’ of renal urate transport provides the requisite tools to begin
to study its regulation by AT-II, insulin, and other hormones. With respect to drug
targeting, development can be foreseen of compounds that modulate GPR109A
(G-protein receptor 109A, also known as PUMA-G or HM74A), the lipid-
lowering receptor for nicotinate/b-hydroxybutyrate [153,154], without interact-
ing with SLC5A8/A12 and URAT1 to cause hyperuricemia.
References
[1] Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion
exchanger that regulates blood urate levels. Nature 2002;417:447 – 52.
[2] Zandi-Nejad K, Plata C, Enck AH, et al. Slc5a8 functions as a sodium-dependent pyrazinoate
and nicotinate cotransporter; implications for renal urate transport. J Am Soc Nephrol 2004;
15:89A.
[3] Coady MJ, Chang MH, Charron FM, et al. The human tumour suppressor gene SLC5A8
expresses a Na + -monocarboxylate cotransporter. J Physiol 2004;557(Pt 3):719 – 31.
[4] Gopal E, Fei YJ, Miyauchi S, et al. Sodium-coupled and electrogenic transport of B-complex
vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family.
Biochem J 2005;388(Pt 1):309 – 16.
[5] Srinivas SR, Gopal E, Zhuang L, et al. Cloning and functional identification of slc5a12 as
a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2). Biochem J 2005;
392(Pt 3):655 – 64.
[6] Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension
and cardiovascular and renal disease? Hypertension 2003;41:1183 – 90.
[7] Nakagawa T, Mazzali M, Kang DH, et al. Hyperuricemia causes glomerular hypertrophy in
the rat. Am J Nephrol 2003;23:2 – 7.
[8] Sanchez-Lozada LG, Nakagawa T, Kang DH, et al. Hormonal and cytokine effects of uric
acid. Curr Opin Nephrol Hypertens 2006;15:30 – 3.
[9] Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune
system to dying cells. Nature 2003;425:516 – 21.
[10] Martinon F, Petrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3
inflammasome. Nature 2006;440:237 – 41.
[11] Waring WS, Webb DJ, Maxwell SR. Uric acid as a risk factor for cardiovascular disease.
Q J Med 2000;93:707 – 13.
[12] Hare JM, Johnson RJ. Uric acid predicts clinical outcomes in heart failure: insights regarding
the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 2003;107:
1951 – 3.
[13] Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure:
validation and application in metabolic, functional, and hemodynamic staging. Circulation
2003;107:1991 – 7.
[14] Fam AG. Gout, diet, and the insulin resistance syndrome. J Rheumatol 2002;29:1350 – 5.
[15] Bonora E, Kiechl S, Willeit J, et al. Prevalence of insulin resistance in metabolic disorders:
the Bruneck Study. Diabetes 1998;47:1643 – 9.
[16] Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic
syndrome. Am J Physiol Renal Physiol 2006;290:F625–31.
[17] Wu XW, Lee CC, Muzny DM, et al. Urate oxidase: primary structure and evolutionary im-
plications. Proc Natl Acad Sci U S A 1989;86:9412 – 6.
[18] Hediger MA. Kidney function: gateway to a long life? Nature 2002;417:393 – 5.
[19] Wu XW, Muzny DM, Lee CC, et al. Two independent mutational events in the loss of urate
oxidase during hominoid evolution. J Mol Evol 1992;34:78 – 84.
326 mount et al
[20] Ames BN, Cathcart R, Schwiers E, et al. Uric acid provides an antioxidant defense in humans
against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A
1981;78:6858 – 62.
[21] Davies KJ, Sevanian A, Muakkassah-Kelly SF, et al. Uric acid-iron ion complexes. A new
aspect of the antioxidant functions of uric acid. Biochem J 1986;235:747 – 54.
[22] Watanabe S, Kang DH, Feng L, et al. Uric acid, hominoid evolution, and the pathogenesis
of salt-sensitivity. Hypertension 2002;40:355 – 60.
[23] Oda M, Satta Y, Takenaka O, et al. Loss of urate oxidase activity in hominoids and its evo-
lutionary implications. Mol Biol Evol 2002;19:640 – 53.
[24] Choi HK, Mount DB, Reginato AM. Pathogenesis of gout. Ann Intern Med 2005;143:
499 – 516.
[25] Kramer HJ, Choi HK, Atkinson K, et al. The association between gout and nephrolithiasis in
men: the Health Professionals’ Follow-Up Study. Kidney Int 2003;64:1022 – 6.
[26] Xu P, LaVallee PA, Lin JJ, et al. Characterization of proteins binding to E-box/Ku86 sites
and function of Ku86 in transcriptional regulation of the human xanthine oxidoreductase gene.
J Biol Chem 2004;279:16057 – 63.
[27] Xu P, LaVallee P, Hoidal JR. Repressed expression of the human xanthine oxidoreductase
gene. E-box and TATA-like elements restrict ground state transcriptional activity. J Biol Chem
2000;275:5918 – 26.
[28] Berry CE, Hare JM. Xanthine oxidoreductase and cardiovascular disease: molecular mecha-
nisms and pathophysiological implications. J Physiol 2004;555(Pt 3):589 – 606.
[29] Roch-Ramel F, Guisan B. Renal transport of urate in humans. News Physiol Sci 1999;14:80 – 4.
[30] Guggino SE, Martin GJ, Aronson PS. Specificity and modes of the anion exchanger in dog
renal microvillus membranes. Am J Physiol 1983;244:F612–21.
[31] Martinez F, Manganel M, Montrose-Rafizadeh C, et al. Transport of urate and p-amino-
hippurate in rabbit renal brush-border membranes. Am J Physiol 1990;258(5 Pt 2):F1145–53.
[32] Roch-Ramel F, Diezi-Chomety F, De Rougemont D, et al. Renal excretion of uric acid in
the rat: a micropuncture and microperfusion study. Am J Physiol 1976;230:768 – 76.
[33] Simmonds HA, Hatfield PJ, Cameron JS, et al. Uric acid excretion by the pig kidney. Am J
Physiol 1976;230:1654 – 61.
[34] Roch-Ramel F, Weiner IM. Excretion of urate by the kidneys of Cebus monkeys: a micro-
puncture study. Am J Physiol 1973;224:1369 – 74.
[35] Weiner IM. Urate transport in the nephron. Am J Physiol 1979;237:F85–92.
[36] Fanelli Jr GM, Bohn DL, Reilly SS. Renal urate transport in the chimpanzee. Am J Physiol
1971;220:613 – 20.
[37] Diamond HS, Paolino JS. Evidence for a postsecretory reabsorptive site for uric acid in man.
J Clin Invest 1973;52:1491 – 9.
[38] Guggino SE, Aronson PS. Paradoxical effects of pyrazinoate and nicotinate on urate transport
in dog renal microvillus membranes. J Clin Invest 1985;76:543 – 7.
[39] Roch-Ramel F, Wong NL, Dirks JH. Renal excretion of urate in mongrel and Dalmatian dogs:
a micropuncture study. Am J Physiol 1976;231:326 – 31.
[40] Bannasch DL, Ryun JR, Bannasch MJ, et al. Exclusion of galectin 9 as a candidate gene for
hyperuricosuria in the Dalmatian dog. Anim Genet 2004;35:326 – 8.
[41] Zins GR, Weiner IM. Bidirectional urate transport limited to the proximal tubule in dogs.
Am J Physiol 1968;215:411 – 22.
[42] Yu TF, Berger L, Kupfer S, et al. Tubular secretion of urate in the dog. Am J Physiol 1960;
199:1199 – 204.
[43] Gutman AB, Yu TF, Berger L. Tubular secretion of urate in man. J Clin Invest 1959;38:
1778 – 81.
[44] Praetorius E, Kirk JE. Hypouricemia: with evidence for tubular elimination of uric acid. J Lab
Clin Med 1950;35:865 – 8.
[45] Ichida K, Hosoyamada M, Hisatome I, et al. Clinical and molecular analysis of patients with
renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc
Nephrol 2004;15:164 – 73.
[46] Steele TH. Urate secretion in man: the pyrazinamide suppression test. Ann Intern Med 1973;
79:734 – 7.
[47] Weiner IM, Tinker JP. Pharmacology of pyrazinamide: metabolic and renal function studies
related to the mechanism of drug-induced urate retention. J Pharmacol Exp Ther 1972;180:
411 – 34.
[48] Davis BB, Field JB, Rodnan GP, et al. Localization and pyrazinamide inhibition of distal
transtubular movement of uric acid-2–C14 with a modified stop-flow technique. J Clin Invest
1965;44:716 – 21.
[49] Gutman AB, Yu TF. A three-component system for regulation of renal excretion of uric acid
in man. Trans Assoc Am Physicians 1961;74:353 – 65.
[50] Steele TH, Boner G. Origins of the uricosuric response. J Clin Invest 1973;52:1368 – 75.
[51] Lemieux G, Vinay P, Gougoux A, et al. Nature of the uricosuric action of benziodarone.
Am J Physiol 1973;224:1440 – 9.
[52] Blomstedt JW, Aronson PS. pH gradient-stimulated transport of urate and p-aminohippurate
in dog renal microvillus membrane vesicles. J Clin Invest 1980;65:931 – 4.
[53] Kahn AM, Aronson PS. Urate transport via anion exchange in dog renal microvillus mem-
brane vesicles. Am J Physiol 1983;244:F56–63.
[54] Kahn AM, Branham S, Weinman EJ. Mechanism of urate and p-aminohippurate transport in
rat renal microvillus membrane vesicles. Am J Physiol 1983;245:F151–8.
[55] Werner D, Martinez F, Roch-Ramel F. Urate and p-aminohippurate transport in the brush
border membrane of the pig kidney. J Pharmacol Exp Ther 1990;252:792 – 9.
[56] Roch-Ramel F, Werner D, Guisan B. Urate transport in brush-border membrane of human
kidney. Am J Physiol 1994;266(5 Pt 2):F797–805.
[57] Boner G, Steele TH. Relationship of urate and p-aminohippurate secretion in man. Am J
Physiol 1973;225:100 – 4.
[58] Koepsell H, Endou H. The SLC22 drug transporter family. Pflugers Arch 2004;447:666 – 76.
[59] Mori K, Ogawa Y, Ebihara K, et al. Kidney-specific expression of a novel mouse organic cation
transporter-like protein. FEBS Lett 1997;417:371 – 4.
[60] Hosoyamada M, Ichida K, Enomoto A, et al. Function and localization of urate transporter 1
in mouse kidney. J Am Soc Nephrol 2004;15:261 – 8.
[61] Nakashima M, Uematsu T, Kosuge K, et al. Pilot study of the uricosuric effect of DuP-753,
a new angiotensin II receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 1992;42:
333 – 5.
[62] Roch-Ramel F, Guisan B, Schild L. Indirect coupling of urate and p-aminohippurate transport
to sodium in human brush-border membrane vesicles. Am J Physiol 1996;270(1 Pt 2):F61–8.
[63] Online mendelian inheritance in man. Available at http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM. Accessed March 20, 2006.
[64] Garcia ML, Benavides J, Valdivieso F. Ketone body transport in renal brush border membrane
vesicles. Biochim Biophys Acta 1980;600:922 – 30.
[65] Manganel M, Roch-Ramel F, Murer H. Sodium-pyrazinoate cotransport in rabbit renal brush
border membrane vesicles. Am J Physiol 1985;249(3 Pt 2):F400–8.
[66] Boumendil-Podevin EF, Podevin RA. Nicotinic acid transport by brush border membrane
vesicles from rabbit kidney. Am J Physiol 1981;240:F185–91.
[67] Goldfinger S, Klinenberg Jr E, Seegmiller JE. Renal retention of uric acid induced by infusion
of beta-hydroxybutyrate and acetoacetate. N Engl J Med 1965;272:351 – 5.
[68] Padova J, Bendersky G. Hyperuricemia in diabetic ketoacidosis. N Engl J Med 1962;267:530 – 4.
[69] Lieber CS, Jones DP, Losowsky MS, et al. Interrelation of uric acid and ethanol metabolism
in man. J Clin Invest 1962;41:1863 – 70.
[70] Fanelli Jr GM, Bohn D, Stafford S. Functional characteristics of renal urate transport in
the Cebus monkey. Am J Physiol 1970;218:627 – 36.
[71] Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake and risk of incident gout in men:
a prospective study. Lancet 2004;363:1277 – 81.
[72] Gibson HV, Doisy EA. A note on the effect of some organic acids upon the uric acid excretion
of man. J Biol Chem 1923;55:605 – 10.
328 mount et al
[73] Michael ST. The relation of uric acid excretion to blood lactic acid in man. Am J Physiol
1944;141:71 – 4.
[74] Harding VJ, Allin KD, Eagles BA. The influence of fat and carbohydrate diets upon the level
of blood uric acid. J Biol Chem 1927;74:631 – 43.
[75] Drenick EJ. Hyperuricemia, acute gout, renal insufficiency and urate nephrolithiasis due to
starvation. Arthritis Rheum 1965;8:988 – 97.
[76] Shah P, Isley WL. Ketoacidosis during a low-carbohydrate diet. N Engl J Med 2006;354:97 – 8.
[77] Gershon SL, Fox IH. Pharmacologic effects of nicotinic acid on human purine metabolism.
J Lab Clin Med 1974;84:179 – 86.
[78] Shapiro M, Hyde L. Hyperuricemia due to pyrazinamide. Am J Med 1957;23:596 – 9.
[79] Akalin E, Chandrakantan A, Keane J, et al. Normouricemia in the syndrome of inappropriate
antidiuretic hormone secretion. Am J Kidney Dis 2001;37:E8.
[80] Barac-Nieto M, Murer H, Kinne R. Lactate-sodium cotransport in rat renal brush border
membranes. Am J Physiol 1980;239:F496–506.
[81] Barbarat B, Podevin RA. Stoichiometry of the renal sodium-L-lactate cotransporter. J Biol
Chem 1988;263:12190 – 3.
[82] Fanelli Jr GM, Weiner IM. Pyrazinoate excretion in the chimpanzee. Relation to urate dis-
position and the actions of uricosuric drugs. J Clin Invest 1973;52:1946 – 57.
[83] Steele TH. Hyperuricemic nephropathies. Nephron 1999;81(Suppl 1):45 – 9.
[84] Yu TF, Gutman AB. Study of the paradoxical effects of salicylate in low, intermediate and
high dosage on the renal mechanisms for excretion of urate in man. J Clin Invest 1959;38:
1298 – 315.
[85] Roch-Ramel F, Guisan B, Diezi J. Effects of uricosuric and antiuricosuric agents on urate
transport in human brush-border membrane vesicles. J Pharmacol Exp Ther 1997;280:839 – 45.
[86] Aronoff A. Acute gouty arthritis precipitated by chlorothiazide. N Engl J Med 1960;262:
767 – 9.
[87] Cappuccio FP, Strazzullo P, Farinaro E, et al. Uric acid metabolism and tubular sodium han-
dling. Results from a population-based study. JAMA 1993;270:354 – 9.
[88] Perez-Ruiz F, Calabozo M, Erauskin GG, et al. Renal underexcretion of uric acid is present
in patients with apparent high urinary uric acid output. Arthritis Rheum 2002;47:610 – 3.
[89] Moriwaki Y, Yamamoto T, Tsutsumi Z, et al. Effects of angiotensin II infusion on renal
excretion of purine bases and oxypurinol. Metabolism 2002;51:893 – 5.
[90] Weinman EJ, Eknoyan G, Suki WN. The influence of the extracellular fluid volume on the
tubular reabsorption of uric acid. J Clin Invest 1975;55:283 – 91.
[91] Ferris TF, Gorden P. Effect of angiotensin and norepinephrine upon urate clearance in man.
Am J Med 1968;44:359 – 65.
[92] Ogihara T, Asano T, Ando K, et al. Angiotensin II-induced insulin resistance is associated
with enhanced insulin signaling. Hypertension 2002;40:872 – 9.
[93] Masuzaki H, Yamamoto H, Kenyon CJ, et al. Transgenic amplification of glucocorticoid ac-
tion in adipose tissue causes high blood pressure in mice. J Clin Invest 2003;112:83 – 90.
[94] Quinones Galvan A, Natali A, Baldi S, et al. Effect of insulin on uric acid excretion in humans.
Am J Physiol 1995;268(1 Pt 1):E1–5.
[95] Muscelli E, Natali A, Bianchi S, et al. Effect of insulin on renal sodium and uric acid handling
in essential hypertension. Am J Hypertens 1996;9:746 – 52.
[96] Balakrishnan VS, Coles GA, Williams JD. A potential role for endogenous adenosine in con-
trol of human glomerular and tubular function. Am J Physiol 1993;265(4 Pt 2):F504–10.
[97] Balakrishnan VS, Coles GA, Williams JD. Effects of intravenous adenosine on renal function
in healthy human subjects. Am J Physiol 1996;271(2 Pt 2):F374–81.
[98] Mintz DH, Canary JJ, Carreon G, et al. Hyperuricemia in hyperparathyroidism. N Engl J Med
1961;265:112 – 5.
[99] Songyang Z, Fanning AS, Fu C, et al. Recognition of unique carboxyl-terminal motifs by
distinct PDZ domains. Science 1997;275:73 – 7.
[100] Gisler SM, Pribanic S, Bacic D, et al. PDZK1: I. a major scaffolder in brush borders of proxi-
mal tubular cells. Kidney Int 2003;64:1733 – 45.
[101] Anzai N, Miyazaki H, Noshiro R, et al. The multivalent PDZ domain-containing protein
PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C-terminal.
J Biol Chem 2004;279:45942 – 50.
[102] Biber J, Gisler SM, Hernando N, et al. PDZ interactions and proximal tubular phosphate
reabsorption. Am J Physiol Renal Physiol 2004;287:F871–5.
[103] Hernando N, Wagner CA, Gisler SM, et al. PDZ proteins and proximal ion transport. Curr Opin
Nephrol Hypertens 2004;13:569 – 74.
[104] Lipkowitz MS, Leal-Pinto E, Rappoport JZ, et al. Functional reconstitution, membrane tar-
geting, genomic structure, and chromosomal localization of a human urate transporter. J Clin
Invest 2001;107:1103 – 15.
[105] Jutabha P, Kanai Y, Hosoyamada M, et al. Identification of a novel voltage-driven organic
anion transporter present at apical membrane of renal proximal tubule. J Biol Chem 2003;278:
27930 – 8.
[106] Van Aubel RA, Smeets PH, Van Den Heuvel JJ, et al. Human organic anion transporter MRP4
(ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric
substrate binding sites. Am J Physiol Renal Physiol 2004;288:5072 – 83.
[107] Kahn AM, Shelat H, Weinman EJ. Urate and p-aminohippurate transport in rat renal basolateral
vesicles. Am J Physiol 1985;249(5 Pt 2):F654–61.
[108] Werner D, Roch-Ramel F. Indirect Na+ dependency of urate and p-aminohippurate transport in
pig basolateral membrane vesicles. Am J Physiol 1991;261(2 Pt 2):F265–72.
[109] Ichida K, Hosoyamada M, Kimura H, et al. Urate transport via human PAH transporter hOAT1
and its gene structure. Kidney Int 2003;63:143 – 55.
[110] Cha SH, Sekine T, Fukushima JI, et al. Identification and characterization of human organic
anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol 2001;59:1277 – 86.
[111] Bakhiya A, Bahn A, Burckhardt G, et al. Human organic anion transporter 3 (hOAT3) can
operate as an exchanger and mediate secretory urate flux. Cell Physiol Biochem 2003;13:
249 – 56.
[112] Sweet DH, Chan LM, Walden R, et al. Organic anion transporter 3 (Slc22a8) is a dicarboxylate
exchanger indirectly coupled to the Na + gradient. Am J Physiol Renal Physiol 2003;284:
F763–9.
[113] Aslamkhan A, Han YH, Walden R, et al. Stoichiometry of organic anion/dicarboxylate ex-
change in membrane vesicles from rat renal cortex and hOAT1-expressing cells. Am J Physiol
Renal Physiol 2003;285:F775–83.
[114] Eraly SA, Vallon V, Vaughn DA, et al. Decreased renal organic anion secretion and plasma
accumulation of endogenous organic anions in OAT1 knockout mice. J Biol Chem 2006;281:
5072 – 83.
[115] Reed DR, Price RA. X-linkage does not account for the absence of father-son similarity
in plasma uric acid concentrations. Am J Med Genet 2000;92:142 – 6.
[116] Yang Q, Guo CY, Cupples LA, et al. Genome-wide search for genes affecting serum uric
acid levels: the Framingham Heart Study. Metabolism 2005;54:1435 – 41.
[117] Healey LA, Bayani-Sioson PS. A defect in the renal excretion of uric acid in Filipinos. Arthritis
Rheum 1971;14:721 – 6.
[118] Gibson T, Waterworth R, Hatfield P, et al. Hyperuricaemia, gout and kidney function in
New Zealand Maori men. Br J Rheumatol 1984;23:276 – 82.
[119] Chang HY, Pan WH, Yeh WT, et al. Hyperuricemia and gout in Taiwan: results from the
Nutritional and Health Survey in Taiwan (1993–96). J Rheumatol 2001;28:1640 – 6.
[120] Simmonds HA, McBride MB, Hatfield PJ, et al. Polynesian women are also at risk for hyper-
uricaemia and gout because of a genetic defect in renal urate handling. Br J Rheumatol 1994;
33:932 – 7.
[121] Shu-Chuan Cheng L, Chiang SL, Tu HP, et al. Genomewide scan for gout in taiwanese
aborigines reveals linkage to chromosome 4q25. Am J Hum Genet 2004;75:498 – 503.
[122] Kelley WN, Rosenbloom FM, Henderson JF, et al. A specific enzyme defect in gout asso-
ciated with overproduction of uric acid. Proc Natl Acad Sci U S A 1967;57:1735 – 9.
[123] Augoustides-Savvopoulou P, Papachristou F, Fairbanks LD, et al. Partial hypoxanthine-
330 mount et al
Guanine phosphoribosyltransferase deficiency as the unsuspected cause of renal disease span-

ning three generations: a cautionary tale. Pediatrics 2002;109:E17.
[124] Ahmed M, Taylor W, Smith PR, et al. Accelerated transcription of PRPS1 in X-linked over-
activity of normal human phosphoribosylpyrophosphate synthetase. J Biol Chem 1999;274:
7482 – 8.
[125] Bleyer AJ, Woodard AS, Shihabi Z, et al. Clinical characterization of a family with a muta-
tion in the uromodulin (Tamm-Horsfall glycoprotein) gene. Kidney Int 2003;64:36 – 42.
[126] Hateboer N, Gumbs C, Teare MD, et al. Confirmation of a gene locus for medullary cystic
kidney disease (MCKD2) on chromosome 16p12. Kidney Int 2001;60:1233 – 9.
[127] Wolf MT, Mucha BE, Attanasio M, et al. Mutations of the Uromodulin gene in MCKD
type 2 patients cluster in exon 4, which encodes three EGF-like domains. Kidney Int 2003;64:
1580 – 7.
[128] Hart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are responsible for medul-
lary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet
2002;39:882 – 92.
[129] Rampoldi L, Caridi G, Santon D, et al. Allelism of MCKD, FJHN and GCKD caused by
impairment of uromodulin export dynamics. Hum Mol Genet 2003;12:3369 – 84.
[130] Kang DH, Nakagawa T, Feng L, et al. A role for uric acid in the progression of renal disease.
J Am Soc Nephrol 2002;13:2888 – 97.
[131] Meyer 3rd WJ, Gill Jr JR, Bartter FC. Gout as a complication of Bartter’s syndrome. A possible
role for alkalosis in the decreased clearance of uric acid. Ann Intern Med 1975;83:56 – 9.
[132] Wolf MT, Dotsch J, Konrad M, et al. Follow-up of five patients with FHHNC due to muta-
tions in the Paracellin-1 gene. Pediatr Nephrol 2002;17:602 – 8.
[133] Bingham C, Ellard S, van’t Hoff WG, et al. Atypical familial juvenile hyperuricemic ne-
phropathy associated with a hepatocyte nuclear factor-1beta gene mutation. Kidney Int 2003;
63:1645 – 51.
[134] Igarashi P, Shao X, McNally BT, et al. Roles of HNF-1beta in kidney development and
congenital cystic diseases. Kidney Int 2005;68:1944 – 7.
[135] Li T, Walsh JR, Ghishan FK, Bai L. Molecular cloning and characterization of a human urate
transporter (hURAT1) gene promoter. Biochim Biophys Acta 2004;1681:53 – 8.
[136] Pontoglio M, Barra J, Hadchouel M, et al. Hepatocyte nuclear factor 1 inactivation results
in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell 1996;84:575 – 85.
[137] Ohta T, Sakano T, Igarashi T, et al. Exercise-induced acute renal failure associated with renal
hypouricaemia: results of a questionnaire-based survey in Japan. Nephrol Dial Transplant 2004;
19:1447 – 53.
[138] Peden DB, Hohman R, Brown ME, et al. Uric acid is a major antioxidant in human nasal
airway secretions. Proc Natl Acad Sci U S A 1990;87:7638 – 42.
[139] Vollaard NB, Shearman JP, Cooper CE. Exercise-induced oxidative stress: myths, realities
and physiological relevance. Sports Med 2005;35:1045 – 62.
[140] Kawabe K, Murayama T, Akaoka I. A case of uric acid renal stone with hypouricemia caused
by tubular reabsorptive defect of uric acid. J Urol 1976;116:690 – 2.
[141] Cheong HI, Kang JH, Lee JH, et al. Mutational analysis of idiopathic renal hypouricemia in
Korea. Pediatr Nephrol 2005;20:886 – 90.
[142] Kaneko K, Yamanobe T, Onoda M, et al. Analysis of urinary calculi obtained from a patient
with idiopathic hypouricemia using micro area x-ray diffractometry and LC-MS. Urol Res
2005;33:415 – 21.
[143] Sorensen CM, Chandhoke PS. Hyperuricosuric calcium nephrolithiasis. Endocrinol Metab Clin
North Am 2002;31:915 – 25.
[144] Pak CY, Poindexter JR, Peterson RD, et al. Biochemical distinction between hyperuricosuric
calcium urolithiasis and gouty diathesis. Urology 2002;60:789 – 94.
[145] Maalouf NM, Cameron MA, Moe OW, et al. Novel insights into the pathogenesis of uric
acid nephrolithiasis. Curr Opin Nephrol Hypertens 2004;13:181 – 9.
[146] Sakhaee K, Adams-Huet B, Moe OW, et al. Pathophysiologic basis for normouricosuric uric
acid nephrolithiasis. Kidney Int 2002;62:971 – 9.
[147] Abate N, Chandalia M, Cabo-Chan Jr AV, et al. The metabolic syndrome and uric acid
nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int 2004;
65:386 – 92.
[148] Ombra MN, Forabosco P, Casula S, et al. Identification of a new candidate locus for uric
acid nephrolithiasis. Am J Hum Genet 2001;68:1119 – 29.
[149] Gianfrancesco F, Esposito T, Ombra MN, et al. Identification of a novel gene and a common
variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate. Am J Hum Genet
2003;72:1479 – 91.
[150] Gianfrancesco F, Esposito T, Casu G, et al. Emergence of Talanin protein associated with
human uric acid nephrolithiasis in the Hominidae lineage. Gene 2004;339:131 – 8.
[151] Rieselbach RE, Sorensen LB, Shelp WD, et al. Diminished renal urate secretion per nephron
as a basis for primary gout. Ann Intern Med 1970;73:359 – 66.
[152] Boss GR, Seegmiller JE. Hyperuricemia and gout. Classification, complications and manage-
ment. N Engl J Med 1979;300:1459 – 68.
[153] Taggart AK, Kero J, Gan X, et al. (D)-beta-hydroxybutyrate inhibits adipocyte lipolysis via
the nicotinic acid receptor PUMA-G. J Biol Chem 2005;280:26649 – 52.
[154] Tunaru S, Kero J, Schaub A, et al. PUMA-G and HM74 are receptors for nicotinic acid
and mediate its anti-lipolytic effect. Nat Med 2003;9:352 – 5.
Treatment of Crystal Arthropathy—History

and Advances
George Nuki, MB, FRCP, FRCPET
Queen’s Medical Research Institute, University of Edinburgh, Scotland, UK
The history of gout and the many distinguished historical figures who have
suffered the agonies of this crystal deposition disorder have claimed the attention
of medical historians like no other disease. Flavors of this rich and colorful story
are captured in a charming and scholarly set of historical essays by Copeman [1],
Rodnan’s beautiful collection of prints and illustrations [2], and an excellent
introductory chapter to their comprehensive monograph on gout by Wyngaarden
and Kelley [3].
Emerging recognition of crystal-associated arthropathy
The earliest recorded drawings of crystals taken from a tophus from a patient
who had gout (Fig. 1) are those of Antoni Van Leeuwenhoek, the pioneer Dutch
microscopist, in 1769 [4]. At the time he did not recognize that they were crystals
and was unaware of their chemical composition. A century later, the English
chemist, Wollaston, a nephew of William Heberden, was able to show that ma-
terial obtained from a tophus in his own ear was composed of sodium urate [5],
after the first chemical identification of uric acid (‘‘lithic acid’’), in urinary cal-
culi, by the Swedish apothecary, Scheele, who worked after hours in the kitchen
of his apotheke in Koping in 1776 [6].
T University of Edinburgh, Osteoarticular Research Group, The Queen’s Medical Research

Institute (C2.23), 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK.
E-mail address: g.nuki@ed.ac.uk
334 nuki
Fig. 1. (A–D) Crystals of sodium urate from a gouty tophus drawn by Antoni van Leeuwenhoek,
the Dutch pioneer microscopist, in 1679.
Elevated levels of uric acid in the serum of patients who had gout were
demonstrated by Sir Alfred Baring Garrod. He first reported his findings in the
Transactions of the Medical Chirurgical Society of Edinburgh in 1848 [7]. In
what is now widely believed to be a milestone in the development of the disci-
pline of clinical chemistry, he subsequently described his semiquantitative thread
test for the measurement of urate [8]. Crystals of uric acid, that subsequently
could be weighed, were seen to form along a linen fiber suspended for 18 to
48 hours in the acidified serum of patients who had gout (Fig. 2). It was in his
Fig. 2. Demonstration of Garrod’s thread test by the late Professor H. L. F. Currey at the London
Hospital. Crystals of sodium urate have formed along a linen thread suspended for 48 hours in
acidified serum from a patient who had gout and hyperuricaemia.
treatment of crystal arthropathy 335
book, however, The Nature and Treatment of Gout and Rheumatic Gout, first
published in 1859 [9], that Garrod first described clearly the roles of hyper-
uricemia and urate crystals in the pathogenesis of gout. Wyngaarden and Kelley
[3] have drawn attention to the remarkable prescience of Garrod’s propositions
(Box 1) [9,10]. Support for the fourth of these, ‘‘that the deposited urate of soda
may be looked upon as the cause, and not the effect, of the gouty inflammation,’’
and his subsequent proposal [11], that acute attacks of gout were triggered by the
precipitation of sodium urate crystals in the joint or neighboring tissues, were
provided by the experiments of Freudweiler, who was able to mimic acute attacks
of gout by the intra-articular injection of microcrystals of sodium urate [12], and
by the experimental work of His, who showed that subcutaneous injection of
urate crystals in rabbits was followed by the formation of nodules with the his-
tologic characteristics of tophi [13]. The historical importance of these obser-
vations came to light only after Faires and McCarty [14] and Seegmiller and
colleagues [15,16] rediscovered the capacity of microcystals of sodium urate
to induce inflammatory responses in joints, skin, and subcutaneous tissues in
the early 1960s. The renewed interest in the role of microcrystals at that time
followed key clinical observations by McCarty and Hollander. In a landmark
paper published in 1961 [17], they demonstrated the diagnostic value of detecting
negatively birefringent crystals of monosodium urate within synovial fluid
leucocytes by polarizing light microscopy during acute attacks of gouty arthritis.
The application of this diagnostic technique soon led to the identification
of positively birefringent crystals, confirmed by x-ray diffraction to be calcium
pyrophosphate dehydrate (CPPD) in some patients with acute synovitis and pseu-
dogout [18,19]. Although the demonstration that acute synovitis could be induced
by the experimental injection of microcrystals of CPPD into normal canine and
human joints seemed to confirm the pathogenic role of CPPD crystals in pa-
tients who have pseudogout [20,21], the extent to which they are pathogenic, or
an epiphenomenon, in the wide range of clinical settings subsequently described
and classified by McCarty as manifestations of CPPD deposition disease [22] re-
mains much less certain. Cadaver studies undertaken approximately 80 years ago
showed that meniscus calcification is a common age-related finding, even in indi-
viduals who are asymptomatic [23]. This is confirmed by radiographic surveys.
The prevalence of meniscal chondrocalcinosis was approximately 27% in people
more than 85 years of age in an elderly cohort [24] and in the population at large
in the Framingham community study [25].
Basic calcium phosphate (BCP) crystals, including partially carbonate-
substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate,
also have been associated with several age-related joint pathologies. These in-
clude calcific periarthritis [26], first demonstrated radiographically approximately
100 years ago [27]; a destructive form of apatite-associated arthritis [28], best
known as the Milwaukee shoulder syndrome [29] but probably the same condi-
tion previously described as l’epaule senile haemorrhagique [30]; and, most com-
monly, osteoarthritis (OA). BCP crystals are found in up to 70% of OA synovial
fluids, often in the absence of overt inflammation, although there is some evi-
336 nuki
Box 1. Garrod’s propositions relating to uric acid, urate of soda, and gout
First, in true gout, uric acid, in the form of urate of soda, invariably
is present in the blood in abnormal quantities, before and at the
period of the seizure, and is essential to its production, but this
acid occasionally may exist largely in the circulating fluid without
the development of inflammatory symptoms, as, for example, in
some cases of lead poisoning and in a few other instances. Its
mere presence, therefore, does not explain the occurrence of the
gouty paroxysm.
Second, the investigations recently made in the morbid anatomy of
gout prove incontestably that true gouty inflammation is always
accompanied with a deposition of urate of soda in the inflamed part.a
Third, the deposit is crystalline and interstitial, and when once the
cartilage and ligamentous structures become infiltrated, such depo-
sition remains for a lengthened time.
Fourth, the deposited urate of soda may be looked on as the cause,
and not the effect, of the gouty inflammation.
Fifth, the inflammation that occurs in the gouty paroxysm tends to
the destruction of the urate of soda in the blood of the inflamed part
and, consequently, of the system generally.
Sixth, the kidneys are implicated in gout, probably in its early, and
certainly in its chronic, stages, and renal affection, perhaps only
functional at first, subsequently becomes structural; the urinary
secretion also is altered in composition.
Seventh, the impure state of the blood, arising principally from the
presence of urate of soda, is the probable cause of the disturbance
that precedes the seizure and many of the anomalous symptoms to
which gouty subjects are liable.
Eighth, the causes that predispose to gout, independent of those
connected with individual peculiarity are either those that produce an
increased formation of uric acid in the system or that lead to its
retention in the blood.
Ninth, the causes exciting a gouty fit are those that induce a less
alkaline condition of the blood or that greatly augment, for the time,
the formation of uric acid, or such as temporarily check the elimi-
nation power of the kidneys.
Tenth, in no disease but true gout is there a deposition of urate of
soda in the inflamed tissues
a
This fact I wish to impress forcibly on the minds of my readers,
because in the constancy of such deposition lies the clue that has long
been wanting: the occurrence of the deposit is perfectly pathognomonic
and at once separates gout from other diseases that at first sight may
appear allied to it.
From Garrod AB. The nature and treatment of gout and rheumatic gout.
London: Walton and Maberly; 1859.
dence to suggest that the presence of crystals in synovial fluid in OA may be

associated weakly with radiographic evidence of cartilage destruction [31].
Approaches to management
A bladder calculus recovered by Elliot Smith from an Egyptian mummy at

El Amrah in 1901 probably is the earliest physical evidence of a human disease
associated with crystal deposition. This dates back to 4800 bc, and lithotomy for
bladder stones may have been among the earliest treatments for a crystal
deposition disorder. Shushruta was removing vesical calculi in India, possibly as
early as the sixth century bc [32], and it is clear that lithotomists were active in
Ancient Greece at the time of Hippocrates. In the Hippocratic oath, lithotomy is
singled out as a practice not to be undertaken by his fellow physicians [33],
although Hippocrates often was bold in recommending other surgical procedures,
such as thoracotomy or trephining the skull [1]. ‘‘I will not cut persons labour-
ing under the stone, but leave this to be done by men who are practitioners of
this work’’ [33].
Hippocrates’ remarkable clinical observations on gout and its natural history
contained in his aphorisms [34] include some of the earliest references to the
management of this disease. Although he advocated the use of all empirically
proven remedies if used ‘‘in such a way as to do good, or at least do no harm’’
[1], his approach predominantly was dietary and conservative. Hippocrates
believed that gout developed after accumulation of bodily humors, such as
‘‘phlegm,’’ which resulted in the painful distension of joints after dietary and
sexual excess and a sedentary life. His dictums on diet include advice on the
preparation and the content of foods, and he recommended moderation, but not
abstinence, from wine, ‘‘whereby the humours may be kept in healthy balance
and disease obviated’’ [1]. Ptisan, a type of barley water, also was recommended.
Local approaches to treating painful joints
Hippocrates’ advice concerning local therapy is best known from his aphorism
X-25: ‘‘swellings and pains in the joints, without sores, whether from gout or
from sprains, in most cases are relieved by a copious affusion of cold water,
which reduces the swelling and removes the pain’’ [34]. But he also recom-
mended heat and counter irritation: ‘‘This is a long, painful, but not a mortal
illness; if the pain still continue, burn the veins above the joint with raw flax.’’
Uncertainty about the best approach to the local treatment of acute gout
persisted for the next 2500 years. In his De re Medicina [35], written in the first
century ad, the Roman writer, Celsus, advocated warm applications according to
the intensity of the inflammation but advised great caution with regard to cold,
believing that this could frustrate nature’s efforts to dispel the disease through the
medium of an acute attack [1]. Avicenna, the great Arabic Persian physician of
338 nuki
the eleventh century, subscribed to this belief and recommended that intractable
joints could be cauterized lightly with a hot iron through a layer of salt and oil
[36]. Yet earlier, in the second century ad, Aretaeus, the Cappadochian from
Asia Minor, who worked in Rome and was the first to suggest that a specific toxic
product, or ‘‘peccant humor,’’ was the cause of gout, observed that local re-
frigeration was more helpful than warmth in patients who have ‘‘hot species’’ of
arthritis [37]. He advocated cold sea water baths followed by an inunction of the
joint with oil or a cold poultice of cucumber, lemon peel, plantain leaves, and
rose petals wrapped in the unscoured wool of a sheep to which a little rose oil or
wine was added periodically. Nevertheless, extreme heat and counter irritation
became fashionable for the treatment of acute gout in the seventeenth century
with the introduction of the new treatment with moxa, from the East Indies, by
the Dutch (Fig. 3). Moxa was a fluffy, cotton-like plant that was placed on the
inflamed joint and ignited. Sir William Temple, an English diplomat who wrote
the celebrated Essay on the Cure of the Gout, in 1681, based on his personal
experience, believed that he had succeeded in curing himself with ‘‘the moxa’’
[38]. Thomas Sydenham, in his Treatise on the Gout, published in 1683 [39],
however, which contains his most famous classical clinical description of an
acute attack of gout, based on his own and his patients’ experiences, was
skeptical about the value of all local applications: ‘‘to ease the pain in the joint I
know of none (though I have tried abundance in myself and others) beside
coolers and repellents which I have already shown to be unsafe...let them be used
(by the patient) in the beginning of a fit and he will soon be convinced of their
insignificancy’’ [39].
Spa therapy with natural mineral waters, which had been used by the Greeks,
the Romans, and throughout Europe in the Middle Ages (Fig. 4), enjoyed a
fashionable vogue in Britain in the eighteenth century. Hydrotherapy was rein-
troduced at spas, such as Bath and Buxton, predominantly for the treatment of
Fig. 3. ‘‘The new treatment’’ of burning with moxa (1629).

Fig. 4. Spa treatment for gout and arthritis at Plomieres (1553).
gout. Although the lifestyle modification that accompanied the waters no doubt
was of some, probably temporary, therapeutic value, spa therapy was not without
its contemporary critics. In his celebrated Commentaries [40], Heberden wrote:
I have not been able to observe any good in arthritic cases from the external use
of these waters, either when the distemper was present or in its absence; on the
contrary it is rather appeared to increase the weakness of the limbs; and sea
bathing has contributed for more to recover the strength of gouty persons.
More recently, local therapy with ice has been shown effective (Effect size
[ES] 1.15; confidence interval [CI], 0.15–2.12) in relieving pain in acute attacks
of gout in a small randomized controlled trial (RCT) in which it was used as an
adjunct to colchicine and prednisolone [41].
Intra-articular approaches to therapy
The treatment of acute attacks of gouty arthritis with intra-articular injections

of corticosteroids is a relatively recent recommended approach, although it
has been the treatment of choice for pseudogout associated with CPPD crystal
340 nuki
deposition since McCarty first drew attention to pseudogout in 1961 [17]. The
use of intra-articular steroid injections for acute attacks of gout is not mentioned
in Wyngaarden and Kelley’s comprehensive monograph published in 1976 [3]. In
one uncontrolled trial, published in 1999 [42], of intra-articular triamcinolone
acetonide (10 mg) in 19 patients who had acute gouty arthritis, all patients had
complete pain relief within 48 hours.
Colchicine
The history of more targeted, more specific, pharmacologic therapy for crystal
arthropathies began with the use of colchicum for the treatment of ‘‘arthritis’’
approximately 4000 years ago. The use of a plant extract believed to be similar
to colchicine is recorded in the Ebers papyrus (1550 bc) [43]. In Ancient Greece,
colchicum or white Hellebore (Veratrum album) was used predominantly as a
purgative. Hippocrates advocated powerful purgation with white Hellebore for
intractable cases of chronic gout, as he believed ‘‘that the best natural relief for
this disease is an attack of dysentery’’ [1], but there is nothing to suggest that
he was aware that it might have more specific value in patients who had acute
attacks of gout. It was approximately 1000 years later, in the sixth century AD,
that the Byzantine Christian physician, Alexander of Tralles, used Hermodactyl
extracted from the corm of Colchicum variegate, a species similar to Colchicum
autumnale (autumn crocus or meadow saffron), as a more selective and specific
remedy [44]. Aetius of Amida, another Christian physician from Byzantium in
the sixth century AD, probably was the first to understand clearly that the thera-
peutic effects of Hermodactyl were distinct from its gastrointestinal (GI) side
effects [44].
Because of its narrow therapeutic margin and its powerful purgative effects,
the use of colchicine was diminished greatly for long periods in the twelfth and
thirteenth centuries, the seventeenth and early eighteenth centuries, and again in
more recent times. Colchicine use virtually was discontinued in continental
Europe in the Middle Ages after its use was forbidden by the influential Abbess
Hildegard of Bingen (1098–1179 ad): ‘‘It is a deadly poison and not a health
giving drug’’ [44].
Five hundred years later, Thomas Sydenham, often known as the English
Hippocrates, also rejected all medicines that were purgatives as too toxic to use.
Because of his considerable influence, colchicine was not used for the treatment
of gout for approximately 150 years until it was rediscovered by Baron Von
Stoerk in Vienna in the middle of the eighteenth century [45].
In more recent times physicians also have been deterred from using colchicine
because of reports of bone marrow suppression [46], myopathy, and neuropathy
[47], particularly in patients who have impaired renal function. Intravenous
administration no longer is recommended because of reports of several sudden
deaths [48]. Although colchicine has been shown to be symptomatically effective
in approximately 75% of patients who have acute gouty arthritis in one small,
short-term, placebo-controlled RCT [49] (SE for pain relief 0.87; CI, 0.25–1.50),
all patients who received colchicine (1 mg immediately followed by 0.5 mg every
2 hours) developed GI side effects (nausea, vomiting, or diarrhea), confirming
the age-old adage ‘‘that patients treated with colchicine often run before they
can walk.’’
Suggestions that use of colchicine in reduced doses (eg, 0.5 mg 3 times daily)
may have a more acceptable harm-to-benefit ratio [50] await substantiation with
controlled clinical trials. The effectiveness of prophylactic colchicine (0.5 mg
once a day for 6 months [51] or 0.6 mg twice a day for 3 months [52]) is dem-
onstrated in two placebo-controlled RCTs in patients commencing urate-lowering
drug therapy with probenecid (SE 0.74; CI, 0.08–1.40) [51] or allopurinol
(number needed to treat, 2; CI, 1–6) [52]. Diarrhea occurred in 38% of patients
receiving the higher dose of colchicine, but GI side effects were not increased in
those receiving only colchicine (0.5 mg daily).
A single study of colchicine prophylaxis in 10 patients who had recurrent
attacks of pseudogout, followed for a year before and after receiving colchicine
(0.6 mg twice a day), demonstrates a reduction from 3.2 to 1 attack per patient
per year [53]. Colchicine is used to treat patients who have refractory CPPD-
associated arthropathies [54] but good controlled trial data are lacking. Clinical
experience also suggests that BCP-associated arthropathies are managed best with
nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular therapies.
Nonsteroidal anti-inflammatory drugs
Fast-acting NSAIDs, used at maximum recommended doses, for short periods

have become the oral drugs of choice for the symptomatic treatment of acute
gouty arthritis [55] and pseudogout [56], provided there are no contraindications.
The evidence base for the use of NSAIDs is much stronger for acute gout [55,57]
than for pseudogout.
Indomethacin became the yardstick for comparing the efficacy of newer anti-
inflammatory drugs in patients who have acute gout after its efficacy was first
demonstrated in 1963 [58,59]. Initially, the high-dosage Emmerson regime
(indomethacin 100 mg every 4 hours until symptoms begin to resolve, followed
by a tapering protocol), was shown to be followed by pain relief in 82% of
patients within 4 hours of taking the first dose and seemed to be associated with
remarkably few adverse effects [60]. Others, however, soon reported a high
incidence of headaches, central nervous system symptoms, and GI side effects
[61,62], when such high doses were used, and subsequent recommendations were
for doses of 50 mg every 6 to 8 hours in the first 24 hours [63,64]. Over the years,
there have been many short-term comparative trials of newer NSAIDs using a
variety of trial designs and outcome measures in patients who have acute gout,
without any good evidence emerging to suggest that any particular NSAID has
superior efficacy or safety for treating acute gouty arthritis [55,57]. Even for
short-term treatment, NSAIDs are contraindicated in patients who have heart
failure, renal insufficiency, or a history of previous peptic ulceration, perforation,
342 nuki
or hemorrhage, and great caution needs to be exercised when considering their

use in patients who are frail and elderly and who have multiple pathologies.
Current guidelines for gastroprotection are advised when their use is considered
in patients at increased risk for peptic ulcers, perforations, or bleeds [55,57]. In
one well-designed, double-blind RCT, the selective cyclooxygenase (COX)-2
inhibitor, etoricoxib (120 mg), and indomethacin (50 mg 3 times a day) gave
comparable rapid pain relief in patients who had acute gout [65]. Nevertheless, in
view of recent studies highlighting the potential cardiovascular toxicity of coxibs
[66,67] and the weak evidence of increased risk of cardiovascular thrombogenic
events (odds ratio 1.49; CI, 0.42–5.31) in a systematic review and meta-analysis
of placebo-controlled trials of etoricoxib [68], it probably is wise to avoid the use
of a selective COX-2 inhibitor for treating acute gout in patients who have
established cardiovascular or cerebrovascular (CVS) disease, pending the acqui-
sition of better data on the relative CVS/GI risks and benefits of these agents in
the treatment of patients who have gout. Cardiovascular risk assessment is an
important part of the management of patients who have gout and hyperuricemia
who frequently have, or develop, cardiovascular comorbidity [55,57].
Approaches to lowering blood and tissue urate
Four therapeutic approaches to lowering plasma urate and the tissue pool of
urate have been undertaken over the years:
Dietary modification
Uricosuric drugs
Uricostatic drugs
Uricolytic drugs
Dietary modification
Dietary restriction was advocated as a treatment for gout long before the
importance of hyperuricemia and tissue accumulation of urate of soda first were
demonstrated in the middle of the nineteenth century by Garrod [7]. It already has
been emphasized that dietary advice was central to the recommendations for
treating gout made by Hippocrates [34]. Galen, Hippocrates’ most illustrious
follower, believed that tophi result from the local accumulation of ‘‘humours’’
and that they could be treated by a combination of dietary restriction and pro-
phylactic bleeding [69]. The basis for his dietary recommendations is not easy
to understand: ‘‘Barley bread is a very excellent thing, and a sausage in due
season; and a little cabbage half boiled, with a soup of mixed vegetables.’’ It is,
perhaps, particularly disappointing that he recommended ‘‘sea foods,’’ such as
oyster, limpet, and sea urchin soup; ‘‘such fishes as inhabit rocky places’’; and
meats, such as ‘‘mutton, goat, hares and wild boar,’’ in view of recent studies that
confirm the association of gout with diets rich in shellfish and red meat [70].
In the sixteenth century, the French surgeon, Ambroise Pare, himself a suf-
ferer of gout, seems to have been more in tune with current medical teaching
when he wrote [71], ‘‘Such gouty persons as remain intemperate and given to
gluttony...may hope for no health by the use of medicines’’ and ‘‘There have
been, as I know, not a few rich and riotous persons, who having spent their
estaites, have therewith changed their health together with their fortune and their
diet, and so have been freed from the goutte.’’ Although he advocated chicken,
he suggested that, ‘‘capon and suchlike birds are not good, being themselves
subject to goute in their feet’’ [1]. Physiologic studies undertaken in the 1970s on
chickens with an inherited susceptibility to dietary induction of gout and tophi
show this to be the result of impaired renal clearance of uric acid [72,73].
The relationship between gout, and diets rich in meat and alcohol were well
recognized in eighteenth-century England. ‘‘The people of distinction and
opulence indulge themselves...eating the most rich and luscious fleshes in great
quantity, and drink large amounts of generous wines. By this means Nature is
rendered incapable of managing the large quantity of blood, and carrying off the
secretions which ought to be made from it,’’ wrote Bernadino Rammazzini of
Padua in his De Morbus Artificiam (English translation, 1746) [1]. Sydenham
recommended a light but adequate diet but also was aware that ‘‘fasting and
actual abstinence is not good’’ [1].
Gout reached almost epidemic proportions in early nineteenth-century
England when ‘‘tophi like crocuses were bursting every where’’ [74]. There is
some reason to suppose that this was at least in part attributable to the prodigious
consumption of wine and port at this time. Analysis of fortified wines from
1770 to 1820, however, reveal significant contamination with lead [75], suggest-
ing that lead poisoning (saturnine gout), as well as alcohol, may have contributed.
Alcohol raises the serum urate by enhancing urate production and by reducing
renal clearance. Acetate conversion to acetyl coenzyme A in the metabolism
of alcohol [76] leads to degradation of adenine nucleotides and accelerated
urate production [77]. More importantly, the metabolism of alcohol to lactic acid
results in inhibition of uric acid secretion and a reduction in the fractional
clearance of uric acid by the kidney [78]. The purine content of beer also may
contribute [79]. Recent studies of a large cohort of male health professionals fol-
lowed for 12 years confirmed, for the first time, the long-held perception that
alcohol consumption is an important risk factor for the development of gout
[80]. Modest beer intake was associated with greater risk than spirits, despite
lower alcohol content, and regular consumption of two glasses of wine was
not associated with increased risk [80], contradicting, to some extent, the popu-
lar nineteenth-century stereotype of the gout sufferer as a portly wine drinker
(Fig. 5).
It has been known for decades that high protein diets may increase urinary uric
acid excretion [81] and milk proteins, in particular, may be protective. In a
subgroup of a male professionals cohort, whose diet contained a high intake of
dairy products, the relative risk (RR) of developing gout was reduced sig-
nificantly (RR 0.56; CI, 0.42–0.74) [82]. Consumption of milk proteins is shown
344 nuki
Fig. 5. Origin of the gout. Eighteenth-century print by Henry William Bunbury (1750–1811).
to result in a fall in serum urate levels [83], and serum urate levels rose sig-
nificantly in a RCT 4 weeks after starting a dairy-free diet [84].
Admiral Nelson, who began to have frequent attacks of gout when stationed in
Malta, ceased to be troubled with gout some months after abstaining from all
animal food and adopting a diet of milk, vegetables, and water [1].
The Rev. Sydney Smith, known as the witty canon of St Paul’s, and a notable
nineteenth-century sufferer of gout, wrote of the need for ‘‘stomatic monasti-
cism’’: ‘‘The sufferer must also enter into a solemn compact with his stomach to
relinquish all serious flirting with the sirens of the kitchen and the houris of the
wine cellar’’ [85].
Observational studies in small numbers of obese patients who had gout have
shown that gradual weight reduction by restriction of carbohydrate intake can be
associated with decreases in serum urate [86,87], although restricting the intake
of purine-rich foods has a greater effect.
At the turn of the twentieth century, after Miescher’s demonstration that
nucleoproteins were the main constituents of cell nuclei [88] and Nobel laureate
Emil Fischer’s landmark discovery that uric acid could be derived from purine
bases, such as xanthine and hypoxanthine [89], interest began to stir into the role
of dietary purines and endogeous purine metabolism in the synthesis of uric acid.
In Britain, Alexander Haig (1853–1924), a physician at St Bartholomew’s Hos-
pital, became obsessed with the notion that uric acid plays a role in the causation
of many diseases, including his own headaches, hypertension, and depression.
Much of this is related in his book, Uric Acid as a Factor in the Causation of
Disease, first published in 1892. Haig was among the first people to undertake
detailed analyses of the purine content (uric acid and xanthine) of various dietary
constituents. He also spent much of his professional career promoting a low-

purine diet after undertaking a series of physiologic studies on himself in which
he demonstrated that serum urate levels and urinary uric acid excretion could be
reduced by a diet from which he excluded all fish and animal proteins, tea, coffee,
and cocoa (Fig. 6). In the course of his experiments, he also came to understand
that uric acid in the body was derived from both endogenous synthesis and the
intake of purine-containing food and beverages [90]:
I have had in my experimental work the most absolute proof that a sufficient
supply of nitrogen is the prime necessity of nutrition. For before I became aware
that the uric acid which poisoned me was being poured in ready formed in flesh
foods, tea, coffee, etc., I believed that the only way to reduce uric acid was to
reduce total nitrogen, and this I proceeded to do, with the unfortunate result of
reducing myself to a condition of extreme debility and asthenia.
But when I found out in 1893, that all uric acid and xanthin swallowed appeared
in the blood, and eventually in the urine, I saw that I could take as much nitrogen
as was necessary for nutrition as long as I avoided substances containing much
uric acid or xanthin.
The considerable magnitude of the contribution of dietary purines to serum
urate and urinary uric acid excretion were demonstrated clearly 70 years later in
physiologic studies in which healthy volunteers were fed isocaloric, purine-free
formula diets [91].
Current guidelines for the treatment of gout emphasize the importance of
advice about lifestyle modification. Recommendations include weight reduction
Fig. 6. Dr. Alexander Haig’s chart of his own urine uric acid, urea and acid excretion from 1893 to
1897. The sharp fall in uric acid excretion in 1895 illustrates the effect of his purine-free diet.
(From Haig A. Uric acid as a factor in the causation of disease. 7th edition. London: J&A Churchill;
1908. p. 799.)
346 nuki
to ideal body weight, restriction of alcohol (especially beer) intake, and limited
consumption of foods with high purine contents (especially offal, red meat, and
shellfish) [55,57].
Uricosuric drugs
Many analgesic and anti-inflammatory drugs also increase renal excretion of

uric acid. The uricosuric effects of the quinoline analgesic, cinchophen, were
recognized approximately 100 years ago [92] and the drug continued to be used
for the treatment of gout in Europe, but not in the United States, for decades
despite reports of agranulocytosis and liver toxicity [93,94]. It also had been
known for 50 years that salicylates have sufficiently potent uricosuric properties
to control hyperuricemia in patients who have gout, when given in doses of 4 to
6 g daily [95]. Few patients can tolerate such a regime, and aspirin, paradoxi-
cally, is antiuricosuric when administered in lower doses [96]. It was with the
introduction of treatment with probenecid in 1951 [97], sulphinpyrazone in 1957
[98], and benzbromarone in 1965 [99] that physicians first were provided with
agents that could be used to control hyperuricemia and gout safely and effec-
tively in the majority of patients for long periods of time. The effectiveness of
probenecid is illustrated in one of Talbott’s case reports (Fig. 7) [100]. Mobili-
zation of tophi after long-term treatment with probenecid was demonstrated first
Fig. 7. Early case chart demonstrating the effect of probenecid on serum urate and time lost from work
because of recurrent episodes of acute gouty arthritis. (From Talbott JH. Gout. New York: Grune &
Stratton; 1967; with permission.)
by Yu and Gutman in 1951 [101]. Sulphinpyrazone (200–400 mg/day) is more

potent than probenecid (1–2 g/day), but neither is effective in patients who have
renal insufficiency (creatinine clearance less than 30 mL/min) [102], and in
approximately 25% of patients who have gout, adequate control of hyperuricemia
cannot be achieved [103,104]. Benzbromarone (100–200 mg/day) is a more
potent uricosuric, can be effective in patients who have moderate renal insuffi-
ciency, and can be useful particularly for patients who cannot tolerate allopurinol
and for managing transplant patients when allopurinol is contraindicated [105].
Because of a small number of reports of hepatic toxicity and failure, however, the
use of benzbromarone recently has been restricted in several European countries
[106], and it never has been licensed for use in the United States.
All uricosuric agents now are contraindicated in patients who have a history of
urolithiasis, and in patients who are receiving them, care needs to be taken to
ensure that a high fluid intake and urine output are maintained [63].
Azapropazone (1200–1800 mg/day) is a NSAID shown to have moderate
uricosuric potency [107] and efficacy in acute gouty arthritis [108] and in
reducing the frequency of attacks of gout during the intercritical period compared
with indomethacin plus allopurinol [109]. After examination of the United King-
dom General Practice database demonstrated that its use in general practice
was associated with a relatively high risk of upper GI bleeds and perforations
(RR 23.4; CI, 6.9–79.5 compared with RR 7.0; CI, 5.2–9.6 for high-dose ibu-
profen, diclofenac, naproxen, indomethacin, and ketoprofen) [110], however, use
of this uricosuric NSAID largely was discontinued in the United Kingdom, and
it never has been licensed for use in the United States.
Uricostatic drugs
The development of allopurinol in the late 1950s by scientists at the Burroughs

Wellcome research laboratories led to the most important advance in the treat-
ment of gout and the control of uric acid production. The work leading to this dis-
covery was a brilliant example of Gertrude Elion and George Hitchings’ targeted
approach to developing analogs of purine metabolites that selectively inhibited key
steps in cellular metabolic pathways and DNA synthesis. Elion and Hitchings
shared the 1988 Nobel Prize in Physiology or Medicine with Sir James Black
for ‘‘discoveries of important principles for drug treatment’’ [111]. Initially devel-
oped as a putative, but not promising, cancer chemotherapeutic agent, it was used
to inhibit the degradation of 6-mercaptopurine [112] and found to be an inhibitor
of xanthine oxidase [113]. Serum and urinary uric acid were reduced dramatically
when allopurinol was used first as an adjunct in a trial of 6-thiopurine in patients
who had leukemia and, subsequently, in patients who had gout [114]. Serum urate
levels begin to fall 1 to 2 days after starting allopurinol with maximal decrements
in 1 week [115]. Gradual resolution of tophi can be observed if the serum urate
level is maintained below 6 to 6.2 mg/dL (360–370 mmol/L) [116,117]. The
number of acute attacks of gout was diminished from 4.4 per year to 0.06 per year
in a cohort of 60 patients followed longitudinally [118]. A case chart from one of
348 nuki
Rundles’ early patients, illustrating many of these improvements, is shown in

Fig. 8. The reduction in urine uric acid excretion is not replaced stoichiometri-
cally by excretion of oxypurines (xanthine and hypoxanthine), as allopurinol has
an additional effect of inhibiting de novo purine synthesis, except in rare patients
who have primary purine overproduction associated with mutations of the purine
salvage enzyme, hypoxanthine guanine phosphoribosyltransferase [119].
Although it previously was suggested that doses of 300 mg of allopurinol
reduce serum urate to normal levels in 85% of patients and that in some patients
doses of 100 or 200 mg are adequate [120], more recent studies suggest that
frequently this is not the case. In one open comparison of allopurinol (300 mg
daily) and benzbromarone (100 mg daily), the plasma urate fell to 6 mg/dL
(360 mmol/L) in all patients treated with benzbromarone but only in 53% of those
receiving allopurinol in this dose [121]. Also, in a recent study of 762 patients
who had gout where the effects of allopurinol (300 mg daily) were compared
with a new xanthine oxidase inhibitor, febuxostat (80 mg and 120 mg daily),
the primary endpoint (serum urate measurements less than 6 mg/dL at the final
3 monthly measurements) was achieved in only 21% of the patients receiving
allopurinol compared with 53% of those receiving febuxostat (80 mg) and 62%
of those receiving 120 mg per day [122]. Although clearly this suggests that
Fig. 8. Serum urate and urine uric acid and oxypurine values in a 58-year-old man treated with
allopurinol in 1963. HPP, 4-hydroxypyrazolo(3,4-d)pyrimidine (allopurinol). (From Rundles RW,
Wyngaarden JB, Hitchings GH, et al. Effects of a xanthine oxidase inhibitor on thiopurine metabo-
lism, hyperuricaemia and gout. Trans Assoc Am Physicians 1963;76:126–40; with permission.)
allopurinol doses should be adjusted upwardly in many patients who have gout
and are being treated with this agent, studies are required to confirm that such a
strategy will result in optimal control of hyperuricemia in patients who have gout
without adverse effects. Care should be taken to reduce the dose of allopurinol
according to renal function in all patients who have a reduction in estimated
glomerular filtration rate [55,63], as there is evidence that adverse events, espe-
cially rashes, are more frequent in patients who have impaired renal function
[123]. This may be associated with raised plasma concentrations of the allopu-
rinol metabolite, oxipurinol, which is eliminated by the kidney [124].
Febuxostat (80 mg and 120 mg per day) has been shown, in phase II studies,
to be safe and effective in lowering serum uric acid levels in patients who have
gout and hyperuricemia [125], safe and more effective than allopurinol (300 mg
per day) in maintaining serum urate levels less than 6 mg/dL [122], and more
effective in reducing the size of tophi during 12 months [126] in phase III com-
parisons. It is not yet approved for the treatment of gout in the United States
or Europe.
Combining uricosuric and uricostatic drugs
Combining allopurinol treatment with probenecid or sulphinpyrazone for pa-

tients who have extensive tophaceous deposits and adequate renal function was
shown to result in increased elimination of urinary uric acid shortly after the
introduction of allopurinol therapy [127,128]. More recently, this also has
been demonstrated when allopurinol is combined with benzbromarone [121,129].
These combinations are effective despite the fact that uricosuric drugs increase
the clearance of the active allopurinol metabolite, oxypurinol [130–132].
Uricolytic agents
Humans are susceptible to developing gout because they lack the enzyme,
urate oxidase (uricase), which metabolizes uric acid to allantoin in most mam-
malian species.
Transient reduction of serum urate after infusion of purified uricase was re-
ported first in a paper in Science in 1957 (Fig. 9) [133]. More recently, repeated
injection of urate oxidase purified from Aspergillus fumigatus (uricozyme) and
the recombinant enzyme expressed in Strep Mitis (rasburicase) have been used to
prevent the development of the tumor lysis syndrome in patients undergoing
chemotherapy for malignancies [134,135]. Although currently not approved for
the management of gout, rasburicase has been given by repeated intravenous
injection with good effect in isolated cases of tophaceous gout in transplant re-
cipients [136] and patients who have tophaceous gout resistant to combined
treatment with allopurinol and benzbromarone [137]. Although this approach
currently is limited by the need for repeated intravenous infusions, the cost, and
concerns about the development of antibodies, rasburicase has been administered
monthly for more than a year without significant immune reactions [138]. In the
350 nuki
Fig. 9. Serum uric acid and urine allantoin before and after IV administration of purified uricase in
1957. (From London M, Hudson PB. Uricolytic activity of purified uricase in two human beings.
Science 1957;125:937–8; with permission.)
United States, a polyethylene glycol (PEG)–modified mammalian urate oxidase

is undergoing orphan drug development. Single subcutaneous injections were
followed by prolonged reduction of serum urate in 13 patients who had severe
refractory gout in an open phase I trial, but there was some evidence of devel-
opment of antibodies to the PEG [139]. In a phase II open study where multiple
intravenous injections of PEG-uricase were given to a similar cohort of 41 severe
refractory gout patients, sustained and substantial reduction of serum urate was
confirmed [140]. Rapid resolution of tophi was observed within 3 months in two
patients [141], and no serious immunologic side effects were observed [140].
Calcium pyrophosphate dehydrate– and basic calcium phosphate–associated

arthropathies
The history of therapy for pseudogout, chronic CPPD- and BCP-associated

crystal arthropathies, and crystal-associated periarthritis has been less exciting
than the history of the treatment of gout. Symptomatic therapy with NSAIDs,
joint aspirations, intra-articular steroids, and nonpharmacologic support have been
the core approach to management, but there are few controlled clinical trials.
Historical approaches to inhibiting pathologic calcification have included admin-
istration of bisphosphonates to try and prevent heterotopic bone formation after
hip surgery [142] and the administration of warfarin in low dosage, based on the
premise that it depresses the synthesis of the vitamin K–dependent Gla protein,
which may be involved in the process of ectopic calcification [143]. After the
demonstration that probenecid could block the production or release of pyro-
phosphate by chondrocytes in vitro in response to transforming growth factor b

[144], probenecid was used to treat patients who had refractory CPPD-associated
arthritis with some success in an uncontrolled trial [145]. Cheung proposed the
use of phosphocitrate as a potential therapeutic strategy for calcium crystal de-
position disorders [146], as this naturally occurring pyrophosphate analog can
inhibit calcium crystal nucleation and several crystal-induced inflammatory me-
diators (reviewed in [147]) and has been shown to inhibit disease progression in
murine progressive ankylosis [148].
In 1967, the key discovery that primary purine overproduction and severe
premature gout in boys who had Lesch-Nyhan syndrome resulted from an inher-
ited deficiency of the purine salvage enzyme, hypoxanthine guanine phospho-
ribosyltransferase [149], led to an explosion of knowledge about the regulation of
purine metabolism in humans and the pathogenesis of gout that rapidly led to the
development of rational and effective treatment and prevention of this disease.
This was characterized as the ‘‘purine revolution’’ [150], and the treatment of
gout with uric acid–lowering drugs became a paradigm for the successful treat-
ment and prevention of a chronic rheumatic disease.
There now are indications that we may be on the brink of an analogous
breakthrough in understanding how extracellular pyrophosphate promotes CPPD
deposition and inhibits the formation of apatite crystals in crystal-associated
disorders [151]. This, hopefully, will lead to new therapeutic approaches for
controlling CPPD and BCP crystal deposition. As in gout, some of the clues are
emerging from examining the consequences of critical gene mutations. In mice,
mutations of the pyrophosphate-generating ectoenzyme, nucleoside triphospate
pyrophosphohydrolase isoenzyme PC-1 ( NTP-PPH PC1) [152], and the ANK
gene [153], which codes for a transmembrane channel protein involved in pyro-
phosphate extrusion from cells, are associated with phenotypes that include
progressive ankylosis and matrix calcification with BCP. Paradoxically, however,
in humans, familial [154] and sporadic [155] forms of CPPD disease are asso-
ciated with mutations in ANKH, the human homolog of the ANK gene.
References
[1] Copeman WSC. A short history of the gout and the rheumatic diseases. Berkeley7 University
of California Press; 1964.
[2] Rodnan GP. A gallery of gout. Being a miscellany of prints and caricatures from the
16th century to the present day. Arthritis Rheum 1961;4:27 – 46.
[3] Wyngaarden JB, Kelley WN. An abbreviated history of gout. In: Wyngaarden JB, Kelley WN,
editors. Gout and hyperuricaemia. New York7 Grune and Stratton; 1976. p. 2 – 12.
[4] McCarty DJ. A historical note: Leeuwenhoek’s description of crystals from a gouty tophus.
[5] Wollaston WH. On gouty and urinary concretions. Philos Trans R Soc Lond 1797;87:386 – 415.
[6] Scheele KW. Examen chemicum calculi urinarii. Opuscula 1776;2:73.
[7] Garrod AB. Observations on certain pathological conditions of the blood and urine in gout,
rheumatism and Bright’s disease. Trans Med Chir Soc Edinburgh 1848;31:83 – 97.
352 nuki
[8] Garrod AB. On the blood and effused fluids in gout, rheumatism and Bright’s disease. Trans
Med Chir Soc Edinburgh 1854;37:49 – 59.
[9] Garrod AB. The nature and treatment of gout and rheumatic gout. London7 Walton and
Maberly; 1859.
[10] Garrod AB. The nature and treatment of gout and rheumatic gout. 2nd edition. London7 Walton
and Maberly; 1863. p. 251.
[11] Garrod AB. The nature and treatment of gout and rheumatic gout. 3rd edition. London7
Longmans; 1876.
[12] Freudweiler M. Experimentelle Untersuchungen uber das Wesen der Gichtknoten. Dtsch Arch
Klin Med 1899;63:266 – 335.
[13] His WJ. Schicksal und Wirkungen des sauren harnsauren Natrons in Bauch und Gelenk-
hohledes Kanninschens. Dtsch Arch Klin Med 1900;67:81 – 108.
[14] Faires JS, McCarty Jr DJ. Acute synovitis in normal joints of man and dog produced by
injections of microcrystalline sodium urate, calcium oxalate and corticosteroid esters. Arthritis
Rheum 1962;5:295 – 6.
[15] Seegmiller JE, Howell RR, Malawista SE. Inflammatory reactions to sodium urate. Its possible
relationship to genesis of acute gouty arthritis. JAMA 1962;180:469 – 75.
[16] Seegmiller JE, Howell RR. The old and the new concepts of acute gouty arthritis. Arthritis
Rheum 1962;5:616 – 23.
[17] McCarty Jr DJ, Hollander JL. Identification of urate crystals in gouty synovial fluid. Ann Intern
Med 1961;54:452 – 60.
[18] McCarty Jr DJ, Kohn NN, Faires JS. The significance of calcium phosphate crystals in the
synovial fluid of arthritis patients: the dpseudogout syndromeT. I. Clinical aspects. Ann Intern
Med 1962;56:711 – 37.
[19] Kohn NN, Hughes RE, McCarty Jr DJ, et al. The significance of calcium phosphate crystals
in the synovial fluid of arthritic patients. II. Identification of crystals. Ann Intern Med 1962;
56:738 – 45.
[20] McCarty Jr DJ, Phelps P, Pyerson J. Crystal-induced inflammation in canine joints. I. An
experimental model with quantification of the host response. J Exp Med 1966;124:99 – 114.
[21] McCarty Jr DJ, Gatter RA, Hughes RE. Pseudogout syndrome. IV. Early (perilacunar) and
dmatureT cartilaginous deposits of monoclinic and triclinic crystals of calcium pyrophosphate
dehydrate; Koch’s postulates and possible pathogenesis. Arthritis Rheum 1963;6:287.
[22] McCarty Jr DJ. Calcium pyrophosphate deposition disease: pseudogout: articular chondro-
calcinosis. In: McCarty Jr DJ, editor. Arthritis and allied diseases. 9th edition. Philadelphia7
Lea and Febiger; 1979. p. 1276 – 99.
[23] Mandl F. Zur Pathologie und Therapie der Zwischenknorpelekrankungen des Kniegelenkes.
Arch Klin Chir 1927;146:149 – 214.
[24] Ellman MH, Levin B. Chondrocalcinosis in elderly persons. Arthritis Rheum 1975;18:43 – 7.
[25] Felson DT, Anderson JJ, Naimark A, et al. The prevalence of chondrocalcinosis in the elderly
and its association with knee osteoarthritis: the Framingham Study. J Rheumatol 1989;16:
1241 – 5.
[26] Swannell AJ, Underwood FA, Dixon A. Periarticular calcific deposits mimicking acute ar-
thritis. Ann Rheum Dis 1970;29:380 – 5.
[27] Painter CF. Subdeltoid bursitis. Boston Med Surg J 1907;56:345 – 9.
[28] Dieppe PE, Doherty M, McFarlane DG, et al. Apatite associated destructive arthropathy. Br J
Rheumatol 1984;23:84 – 91.
[29] McCarty Jr DJ, Halverson PB, Carera GF, et al. ‘‘Milwaukee shoulder’’: association of micro-
spheroids containing hydroxyapatite crystals, active collagenase and neutral protease with
rotator cuff defects. Arthritis Rheum 1981;24:464 – 91.
[30] de Seze S, Babault A, Ramdon S. L’epaule senile haemorrhagique. L’Actualite Rheumatol
1968;1:107 – 15.
[31] Carroll GJ, Stuart RA, Armstrong JA, et al. Hydroxyapatite crystals are a frequent finding in
osteoarthritic synovial fluid, but are not related to increased concentration of keratin sulphate
or interleukin-1 beta. J Rheumatol 1991;18:861 – 6.
[32] Das S. Shusruta of India: pioneer of vesico lithotomy. Urology 1984;23:317 – 9.

[33] Adams F. The genuine works of Hippocrates. Translated from the Greek with a preliminary
discourse and annotations. London7 The Sydenham Society; 1849. p. 780.
[34] Hippocrates. The genuine works, vols. 1–2. London7 The Sydenham Society; 1849 [Adams
F, Trans.].
[35] Celsus. On medicine. London; 1755 [Grieve J, Trans.].
[36] Afnan SM. Avicenna: his life and works. London7 Allen and Unwin; 1958.
[37] Aretaeus the Cappadocian. The extant works. In: Adams F, editor. London7 The Sydenham
Society; 1856.
[38] Temple W. An essay on the cure of the gout. London: Edward Gellibrand; 1681.
[39] Sydenham T. Tractatus de podagra et hydrope. London7 Kettilby; 1683.
[40] Heberden W. Commentaries on the history and cure of diseases. London7 T Payne; 1802.
[41] Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty
arthritis. J Rheumatol 2002;29:331 – 4.
[42] Fernandez C, Noguera R, Gonzalez JA, et al. Treatment of acute attacks of gout with a small
dose of itraarticular triamcinolone acetonide. J Rheumatol 1999;26:2285 – 6.
[43] Bryan PW. The papyrus Ebers. London7 Geoffrey Bles; 1930.
[44] Copeman WSC. The story of colchicum. In: A short history of the gout and other rheumatic
diseases. Los Angeles7 University of California Press; 1964. p. 38 – 47.
[45] Von Stoerk A. An essay on the use and effects of the root of the Colchicum autumnale
or meadow saffron. London7 T Becket and PA de Honet; 1764 [in Latin].
[46] Yu T. The efficacy of colchicine prophylaxis in articular gout. A reappraisal after 20 years.
Semin Arthritis Rheum 1982;12:256 – 64.
[47] Kunci RW, Duncan GJ, Watson D, et al. Colchicine myopathy and neuropathy. N Engl J Med
1987;316:1562 – 8.
[48] Bonnel RA, Villalba ML, Kawoski CB, et al. Deaths associated with inappropriate intravenous
colchicine administration. J Emerg Med 2002;22:385 – 7.
[49] Ahern MJ, Reid C, Gordon TP, et al. Does colchicine work? The results of the first controlled
study in acute gout. Aust N Z J Med 1987;17:301 – 4.
[50] Morris I, Varughese G, Mattingly P. Cochicine in acute gout. BMJ 2003;327:1275 – 6.
[51] Paulus HE, Schlosstein LH, Godfrey RG, et al. Prophylactic colchicine therapy in intercritical
gout. A placebo-controlled study of probenecid–treated patients. Arthritis Rheum 1974;17:
609 – 14.
[52] Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when
initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;31:2429 – 32.
[53] Alvarellos A, Spilberg I. Colchine prophylaxis in pseudogout. J Rheumatol 1986;13:804 – 5.
[54] Rosenthal AK, Ryan LM. Treatment of refractory crystal-associated arthritis. Rheum Dis Clin
North Am 1995;21:151 – 61.
[55] Jordan KL, Cameron S, Snaith M, et al. British Society for Rheumatology and British Health
Professionals in Rheumatology Guidelines for the Management of Gout. Rheumatology,
in press.
[56] Abramson SB. Treatment of gout and crystal arthropathies and uses and mechanisms of action
of nonsteroidal anti-inflammatory drugs. Curr Opin Rheumatol 1992;4:295 – 300.
[57] Zhang W, Doherty M, Bardin T, et al. EULAR evidence-based recommendations for gout: part
II. Management. Ann Rheum Dis, in press.
[58] Smyth CJ, Velayos EE, Amoroso C. A method for measuring swelling of hands and feet. II.
Influence of new anti-inflammatory drug, indomethacinin acute gout. Acta Rheumatol Scand
1963;9:306 – 22.
[59] Hart FD, Boardman PL. Indomethacin: a new non-steroid anti-inflammatory agent. BMJ 1963;
2:965 – 70.
[60] Emmerson BT. Regimen of indomethacin therapy in acute gouty arthritis. BMJ 1967;2:272 – 4.
[61] Boardman PL, Hart FD. Side effects of indomethacin. Ann Rheum Dis 1967;26:127 – 32.
[62] Wallace SL. The treatment of gout. Arthritis Rheum 1972;15:317 – 23.
[63] Emmerson BT. The management of gout. N Engl J Med 1996;334:445 – 51.
354 nuki
[64] Terkeltaub RA. Gout (clinical practice). N Engl J Med 2003;349:1647 – 55.
[65] Schumacher Jr HR, Boice JA, Daikh DI, et al. Randomised double-blind trial of etoricoxib
and indometacin in treatment of acute gouty arthritis. BMJ 2002;324:1488 – 92.
[66] Solomon SD, McMurray JJF, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib
in a clinical trial for colorectal adenoma protection. N Engl J Med 2005;352:1071 – 80.
[67] Bresalier RS, Sandler RS, Quan H, et al. Cardivascular events associated with rofecoxib in
a colorectal adenoma prevention trial. N Engl J Med 2005;352:1092 – 102.
[68] Aldington S, Shirtcliffe P, Weatherall M, et al. Systematic review and meta-analysis of the
risk of major cardiovascular events with etoricoxib therapy. N Z Med J 2005;118:1684.
[69] Cox JR. Galen. The writings of Galen and Hippocrates epitomised. Philadephia; 1846.
[70] Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake, and
the risk of gout in men. N Engl J Med 2004;359:1093 – 103.
[71] Johnson T. The works of that famous chirurgeon Ambrose Parey. London7 Mary Clark for
John Clark; 1634.
[72] Peterson DW, Hamilton WH, Lilyblade AL. Hereditary susceptibility of dietary induction of
gout in selected lines of chickens. J Nutr 1971;101:347 – 54.
[73] Austic RE, Cole RK. Specificity of the renal transport impairment in chickens having
hyperuricaemia and articular gout. Proc Soc Exp Biol Med 1974;146:931 – 5.
[74] Bywaters EGL. Gout in the time and person of George IV. Ann Rheum Dis 1962;21:325 – 38.
[75] Ball CV. Two epidemics of gout. Bull Hist Med 1971;45:401 – 8.
[76] Puig JG, Fox IH. Ethanol-induced activation of adenine nucleotide turnover. Evidence for a
role of acetate. J Clin Invest 1984;74:936 – 41.
[77] Faller J, Fox IH. Ethanol-induced hyperuricaemia: evidence for increased urate production
by activation of adenine nucleotide turnover. N Engl J Med 1983;307:1598 – 602.
[78] Lieber CS, Jones DP, Losowski MS, et al. Interelation of uric acid and ethanol metabolism
in man. J Clin Invest 1962;41:1963 – 70.
[79] Gibson T, Rodgers AV, Simmonds HA. Beer drinking and its effect on uric acid. Br J
Rheumatol 1984;23:203 – 9.
[80] Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake and the risk of incident gout in men.
Lancet 2004;363:1277 – 81.
[81] Lewis DB, Doisy EA. 1. The influence of high protein diets on the endogenous uric acid
elimination. J Biol Chem 1918;36:1 – 7.
[82] Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake, and the
risk of gout in men. N Engl J Med 2004;350:1093 – 103.
[83] Garrel DR, Verdy M, Petitclerc C, et al. Milk- and soy-protein ingestion: acute effect on serum
uric acid concentration. Am J Clin Nutr 1991;53:665 – 9.
[84] Ghadirian P, Shatenstein B, Verdy M, et al. The influence of dairy products on plasma uric
acid in women. Eur J Epidemiol 1995;11:275 – 81.
[85] Smith S. The works of the Rev. Sydney Smith, vols. 1–3. London7 Longmans; 1840.
[86] Nicholls A, Scott JT. Effect of weight loss on plasma and urinary levels of uric acid. Lancet
1972;2:1223 – 4.
[87] Dessein PH, Shipton EA, Stanwix AE, et al. Beneficial effects of weight loss associated
with moderate calorie/carbohydrate restriction, and increased proportional intake of protein
and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum
Dis 2000;59:539 – 43.
[88] Miescher F. Physiologish-chemische Untersuchungen uber die Lachsmilch. Arch Exp Pathol
Pharmakol 1896;37:100 – 55.
[89] Fischer E. Untersuchungen in der Puringruppe. Berlin7 Springer- Verlag; 1907.
[90] Haig A. Uric acid as a factor in the causation of disease. 7th edition. London7 J&A Churchill;
1908. p. 797 – 9.
[91] Griebsch A, Zollner N. Effect of ribomononucleotides given orally on uric acid production
in man. Adv Exp Med Biol 1974;41:443 – 9.
[92] Nicolaaier O, Dohrn M. The action of cholin carbonic acid and its derivatives. Dtsch Arch
Klin Med 1908;43:331 – 5.
[93] Cutrin Prieto C, Nieto Pol E, Batalla Eiras A, et al. Toxic hepatitis from cinchophen: report
of 3 cases (In Spanish). Med Clin (Barc) 1991;97:104 – 6.
[94] Palmer WL, Woodall PS. Cinchophen. Is there a safe method of administration? JAMA 1936;
107:760 – 4.
[95] Marson FGW. Studies in gout, with particular reference to the value of sodium salicylate
in treatment. Q J Med 1953;22:331 – 46.
[96] Yu T-F, Gutman AB. Study of the paradoxical effects of salicylate in low, intermediate and
high dosage on the renal mechanisms for excretion of urate in man. J Clin Invest 1959;38:
1298 – 315.
[97] Talbott JH, Bishop C, Norcross BM, et al. The clinical and metabolic effects of Benemid
in patients with gout. Trans Assoc Am Physicians 1951;64:372 – 7.
[98] Burns JJ, Yu T-F, Ritterband A, et al. A potent new uricosuric agent, the sulfoxide metabolite
of the phenylbutazone analogue G-26571. J Pharmacol Exp Ther 1957;119:418 – 26.
[99] Delbarre F, Auscher C, Amor B. Action uricosurique de certains derives du benzofuranne. Soc
Med Hop Paris 1965;116:1193 – 6.
[100] Talbott JH. Gout. New York7 Grune & Stratton; 1967.
[101] Yu T-F, Gutman AB. Mobilization of gouty tophi by protracted use of uricosuric agents. Am J
Med 1951;11:765 – 9.
[102] Yu T-F. Milestones in the treatment of gout. Am J Med 1974;56:676 – 85.
[103] Gutman AB, Yu T-F. Protracted uricosuric therapy in tophaceous gout. Lancet 1957;2:
1258 – 60.
[104] Kuzell W, Glover R, Gibbs J, et al. Effect of Anturane on serum uric acid and cholesterol
in gout. A long-term study. Acta Rheumatol Scand Suppl 1964;8:31 – 40.
[105] Perez-Ruiz F, Calabozo M, Jose Fernandez Lopez M, et al. Treatment of chronic gout in pa-
tients with renal function impairment: an open, randomized, actively controlled study. J Clin
Rheumatol 1999;5:49 – 55.
[106] Jansen TLT, Reinders MK, Van Roon EN, et al. Benzbromarone withdrawn from the European
market: another case of dabsence of evidence is evidence of absenceT? Clin Exp Rheumatol
2004;22:651.
[107] Thomas AJ, Majoos FL, Nuki G. Preliminary studies with azapropazone in gout and hyper-
uricaemia. Eur J Rheumatol Inflamm 1983;6:149 – 54.
[108] Dieppe PA, Doherty M, Whicher JT, et al. The treatment of gout with azapropazone: clinical
and experimental studies. Eur J Rheumatol Inflamm 1981;4:392 – 400.
[109] Fraser RC, Davis RH, Walker FS. Comparative trial of azapropazone and indomethacin
plus allopurinol in acute gout and hyperuricaemia. J R Coll Gen Pract 1987;37:409 – 11.
[110] Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation asso-
ciated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343:769 – 72.
[111] Karolinska Institute. Nobel Assembly press release. October 17, 1988.
[112] Elion GB, Callahan S, Nathan H, et al. Potentiation by inhibition of drug degradation:
S-substituted purines and xanthine oxidase. Bichem Pharmacol 1963;12:85 – 93.
[113] Feigelson P, Davidson JK, Robins PK. Pyrazolopyrimidines as inhibitors and substrates
of xanthine oxidase. J Biol Chem 1957;226:993 – 1000.
[114] Rundles RW, Wyngaarden JB, Hitchings GH, et al. Effects of a xanthine oxidase inhibitor on
thiopurine metabolism, hyperuricaemia and gout. Trans Assoc Am Physicians 1963;76:126 – 40.
[115] Wyngaarden JB, Rundles RW, Metz EN. Allopurinol in the treatment of gout. Ann Intern
Med 1965;62:842 – 7.
[116] McCarthy GM, Barthelemy CR, Veum JA, et al. Influence of antihyperuricaemic therapy on
the clinical and radiographic progression of Gout. Arthritis Rheum 1991;34:1489 – 94.
[117] Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of a urate lowering therapy on the velocity
of size reduction of tophi in chronic gout. Arthritis Rheum 2002;47:355 – 60.
[118] Klein G, Rainer F, Schmid P, et al. (Clinical and socio-medical aspects of long-term uricostatic
treatment of primary gout (a 5–10 year study) (German). Z Rheumatol 1978;37:165 – 73.
[119] Kelley WN, Rosenbloom FM, Miller J, et al. An enzymatic basis for variation in response
to allopurinol. N Engl J Med 1968;278:287 – 93.
356 nuki
[120] Day RO, Miners JO, Birkett DJ, et al. Allopurinol dosage selection: relationships between
dose and plasma oxypurinol and urate concentrations and urinary urate excretion. Br J Clin
Pharmacol 1988;26:423 – 8.
[121] Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benzbromarone
for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic
gout. Ann Rheum Dis 1998;57:545 – 9.
[122] Becker MA, Schumacher Jr HR, Wortmann RL, et al. Febuxostat compared with allopurinol
in patients with hyperuricaemia and gout. N Engl J Med 2005;353:2450 – 61.
[123] Vazquez-Mellado J, Morales EM, Pacheco-Tena C, et al. Relation between adverse events
associated with allopurinol and renal function in patients with gout. Ann Rheum Dis 2001;60:
981 – 3.
[124] Emmerson BT, Gordon RB, Cross M, et al. Plasma oxypurinol concentrations during allo-
purinol therapy. Br J Rheumatol 1987;26:445 – 9.
[125] Becker MA, Schumacher Jr HR, Wortmann RL, et al. Febuxostat, a novel non- purine selec-
tive inhibitor of xanthine oxidase: a 28-day, multicenter, phase II, randomized, double-blind,
placebo-controlled dose-response clinical trial examining safety and efficacy in patients with
gout. Arthritis Rheum 2005;52:916 – 23.
[126] Wortmann RL, Schumacher Jr HR, Becker MA, et al. Reduction in topus size in subjects
with chronic gout treated with febuxostat or allopurinol for 52weeks—FACT trial [abstract].
Arthritis Rheum 2005;52(Suppl):S108.
[127] Rundles RW, Metz EN, Silberman HR. Allopurinol in the treatment of gout. Ann Intern Med
1966;64:229 – 58.
[128] Goldfarb E, Smyth CJ. Effects of allopurinol, a xanthine oxidase inhibitor, and sulphinpyrazone
upon the urinary and serum urate concentrations in eight patients with tophaceous gout.
[129] Matkies F. [Long-lasting normalization of uric acid after combination therapy with 300mg
allopurinol and 60mg benzbromarone in patients with gout and hyperuricaemia]. Med Klin
1992;87:460 – 2 [in German].
[130] Elion GB. Enzymatic and metabolic studies with allopurinol. Ann Rheum Dis 1966;25:
608 – 14.
[131] Elion GB, Yu T-F, Gutman AB. Renal clearance of oxypurinol, the chief metabolite of allo-
purinol. Am J Med 1968;45:69 – 77.
[132] Muller FO, Schall R, Groenewoud G, et al. The effect of benzbromarone on allopurinol/
oxypurinol kinetics in patients with gout. Eur J Clin Pharmacol 1993;44:69 – 72.
[133] London M, Hudson PB. Uricolytic activity of purified uricase in two human beings. Science
1957;125:937 – 8.
[134] Potaux L, Aparicio M, Maurel C, et al. Uricolytic therapy. Value of urate oxidase in the
treatment of hyperuricaemias. Nouv Press Med 1975;4:1109 – 12.
[135] Bessmertney O, Robitaille LM, Cairo MS. Rasburicase: a new approach for preventing and /or
treating tumor lysis syndrome. Curr Pharm Des 2005;11(32):4177 – 85.
[136] Rozenberg S, Roche B, Dorent R, et al. Urate oxidase for the treatment of tophaceous gout
in heart transplant recipients. A report of three cases. Rev Rhum Engl Ed 1995;62:392 – 4.
[137] Moolenburgh JD, Reinders MK, Jansen TL. Rasburicase treatment in severe tophaceous gout:
a novel therapeutic option. Clin Rheumatol 2005.
[138] Vogt B. Urate oxidase (rasburicase) for treatment of severe tophaceous gout. Nephrol Dial
Transplant 2005;20:431 – 3.
[139] Ganson NJ, Kelly SJ, Scarlett E, et al. Control of hyperuricaemia in subjects with refractory
gout, and induction of antibody against poly(ethylene) glycol (PEG), in a phase I trial of sub-
cutaneous PEGylated urate oxidase. Arthritis Res Ther 2005;8(1):R12 [Epub ahead of print].
[140] Sundy S, Becker MA, Baraf HSB, et al. A phase-2 study of multiple doses of intrave-
nous polyethylene glycol (PEG)–uricase in patients with hyperuricaemia and refractory gout
[abstract]. Arthritis Rheum 2005;52:S679.
[141] Baraf HSB, Kim S, Matsumoto AK, et al. Resolution of tophi with intravenous PEG-Uricase
in refractory gout [abstract]. Arthritis Rheum 2005;52:S105.
[142] Fleisch H. Bisphosphonates in bone disease. From the laboratory to the patient. New York7
Parthenon; 1997.
[143] Lian JB, Skinner M, Glimcher MJ, et al. The presence of g-carboxyglutamic acid in the
proteins associated with ectopic calcification. Biochim Biophys Res Com 1976;73:349 – 55.
[144] Rosenthal A, Ryan L. Probenecid inhibits transforming growth factor b1 induced pyrophos-
phate elaboration by chondrocytes. J Rheumatol 1993;21:896 – 900.
[145] Trostle D, Schumacher H. Probenecid therapy of refractory CPPD deposition disease. Arthritis
Rheum 1999;42(Suppl):S160.
[146] Cheung HS. Phosphocitrate as a potential therapeutic strategy for crystal deposition disease.
Curr Rheumatol Rep 2001;3:24 – 8.
[147] Whelan LC, Morgan MP, McCarthy GM. Basic calcium phosphate crystals as a unique thera-
peutic target in osteoarthritis. Front Biosci 2005;10:530 – 41.
[148] Krug HE, Mahowald ML, Halverson PB, et al. Phosphocitrate prevents disease progression
in murine progressive ankylosis. Arthritis Rheum 1993;36:1603 – 11.
[149] Seegmiller JE, Rosenbloom RM, Kelley WN. An enzyme defect associated with a sex-
linked human neurological disorder and excessive purine synthesis. Science 1967;155:1682 – 4.
[150] Lesch M. The purine revolution. N Engl J Med 1970;283:1221 – 2.
[151] Terkeltaub R. Inorganic phosphate generation and disposition in pathophysiology. Am J Physiol
Cell Physiol 2001;281:C1 – 11.
[152] Okawa A, Nakamura I, Goto S. Mutation in Npps in a mouse model of ossification of the
posterior longitudinal ligament of the spine. Nat Genet 1998;19:271 – 8.
[153] Sweet HO, Green MC. Progressive ankylosis, a new skeletal mutation in the mouse. J Hered
1981;72:87 – 93.
[154] Netter P, Loeuille D, Jouzeau JY, et al. Les chondrocacinoses articulaires familiales: etude
d’une famille alsacienne. Bull Acad Nat Med 2001;185:417 – 26.
[155] Zhang Y, Johnson K, Russell RGG, et al. Association of sporadic chondrocalcinosis with
a -4-basepair G-to-A transition in the 5V-untranslated region of ANKH that promotes enhanced
expression of ANKH protein and excess generation of extracellular pyrophosphate. Arthritis
Rheum 2005;52:1110 – 7.
Clinical Trials in Crystal Arthropathy

Nancy Joseph-Ridge, MDa,T,
Susan Cazzetta, BS Pharm, PharmD Candidatea,b,
Patricia MacDonald, BSN, NPa
a
TAP Pharmaceutical Products, Inc., Lake Forest, IL, USA
b
University of Florida College of Pharmacy, Gainesville, FL, USA
A literature search was conducted in the MEDLINE, EMBASE, Derwent

Drug File, Current Contents, BIOSIS, and International Pharmaceutical Abstracts
databases using various combinations of search terms, including apatite,
hydroxyapatite, basic calcium phosphate, crystal arthropathy, crystal arthritis,
crystal deposition, calcium pyrophosphate dihydrate, gout, hyperuricemia, mono-
sodium urate, pseudogout, and clinical trial. In addition, a manual search of
review articles was conducted to identify other studies. The abstracts of the
identified articles were reviewed, and if relevant, the full text was evaluated.
Clinical trials in the management of acute crystal arthropathy
The initial management of acute arthritis resulting from crystal arthropathy, re-
gardless of the type of crystal, is symptomatic therapy, including selective
and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and colchi-
cine [1–7].
The manuscript preparation was supported by a grant from TAP Pharmaceutical Products, Inc.
(Lake Forest, Illinois).
T Corresponding author. TAP Pharmaceutical Products, 675 Field Drive, Lake Forest, IL 60045.
E-mail address: Nancy.joseph-ridge@TAP.com (N. Joseph-Ridge).
360
Table 1
Selected clinical studies of nonsteroidal anti-inflammatory drugs in the treatment of gout
No. of
Reference NSAIDs studied patients Regimen Diagnosis Outcomes
Garcia de la Torre, Tenoxicam (T) versus 30 T: 40 mg once daily Acute gout of Pain: improved by 50% (10/15, 67%) with
1987 [23] placebo (P) knee, ankle, T versus P (4/15, 26%); Pb.05
wrist, big toe, Tenderness: improved by 50% (6/15, 40%)
or elbow with T versus P (1/15, 7%); Pb.05
joseph-ridge et al
Schumacher, Indomethacin (I) versus 150 men I: 50 mg 3 times daily Acute gout for Pain: no difference after 2 to 5 days using
2002 [27] etoricoxib (E) E: 120 mg once daily b24 hours 5-point Likert scale (difference +0.11, 95%
confidence interval 0.14 to +0.35)
Fraser, Indomethacin (I) versus 93 I: 200 mg/d in divided Acute gout No statistically significant difference in the
1987 [19] azapropazone (A) doses followed by a proportion of patients who reported that the
reducing regimen for treatment ‘‘suited them’’ after 4 days (I, 35/47
28 days [74%] versus A, 40/46 [87%]).
A: 600 mg 3 times daily
for 4 days followed by
600 mg twice daily for
28 days
Maccagno, Etodolac (E) versus 61 E: 300 mg twice daily Acute gout Pain score: no significant difference in 0 to
1991 [31] naproxen (N) 5 pain score (higher score indicating worse
pain) after 2, 4, or 7 days (mean pain score
at 2 days: 2.6 with E versus 2.8 with N;
mean pain score at 4 days: 1.8 with E
versus 2.0 with N)
N: 500 mg twice daily Pain score mean improvement: no significant
difference between E (1.4 at day 8) versus
N (1.4)
Lederman, Etodolac (E) versus 60 E: 300 mg twice daily Acute gout Pain: no signfiicant difference after 1, 2, 4,
1990 [30] naproxen (N) N: 500 mg twice daily and 7 days
Altman, Indomethacin (I) versus 59 I: up to 225 mg for 1 day Acute gout for Pain scores: no significant difference after 2,
1988 [18] ketoprofen (K) in divided doses followed b 48 hours 5, or 8 days using 0- to 3-point scale (higher
by 50 mg 3 times daily score indicating greater pain). Mean scores at
K: 450 mg in divided days 2, 5, and 8 were 0.9, 0.8, and 0.3 for
doses for 1 day followed I versus 1.1, 1.3, and 0.4 for K, respectively
by 100 mg 3 times daily
Lomen, Indomethacin (I) versus 29 I: 50 mg 4 times daily for Acute gout Improved pain: no signfiicant difference
1986 [17] flurbiprofen (F) 4 days followed by 25 mg between I and F in the proportion of patients
4 times daily for 5 days who had improved pain at rest after 2 days
F: 100 mg 4 times daily for (I, 11/12 [92%] versus F, 11/12 [92%])
1 day followed by 50 mg
4 times daily for 5 days
clinical trials in crystal arthropathy
361
362 joseph-ridge et al
Clinical studies comparing the various NSAIDs find similar pain relief effi-
cacy and tolerability profiles, with these agents generally considered first-line
therapy for those who have gout or pseudogout (Table 1) [8–10]. Until 1990,
NSAID studies involved acemethacin [11], ibuprofen [12,13], indomethacin
[11,14–20], oxamethacin [15], phenylbutazone [14,21], azapropazone [19], pro-
quazone [16], fenoprofen [21,22], flurbiprofen [17], tenoxicam [23], meclophe-
namate [20], ketoprofen [18], and sulindac [24]. No significant differences in
pain relief were found between the various NSAIDs.
In more recent studies, diclofenac, eterocoxib, rofecoxib, and ketorolac have
been investigated. Cheng and colleagues studied [25] the effect of rofecoxib,
diclofenac, and meloxicam on 62 patients experiencing an acute attack of gout.
Subjects (n = 62) received rofecoxib (50 mg), diclofenac sodium (150 mg sus-
tained release), or meloxicam (15 mg), each administered once daily for 7 days in
a single-blind, randomized controlled trial. There was no statistically significant
difference between patient-rated responses for rofecoxib and diclofenac. Inves-
tigator ratings were similar and by day 8, there were no statistical differences
among the three treatment groups.
Two studies investigated the effect of eterocoxib versus indomethacin in acute
gout [26,27]. In both double-blind studies, a total of 349 subjects were ran-
domized to eterocoxib (120 mg daily) or indomethacin (50 mg 3 times daily) for
8 days. Both trials showed similar efficacy between treatment arms at all points
of the trials.
Shrestha and colleagues [28] studied the effects of intramuscular ketorolac
(60 mg) in nine patients presenting to an emergency department with attacks of
acute gout. All patients were satisfied with ketorolac treatment. This study was
followed by a randomized, double-blind study examining the efficacy of intra-
muscular ketorolac (60 mg) versus oral indomethacin (50 mg) in 20 patients
presenting to an emergency department with acute gout [29]. Pain scores de-
creased similarly in both groups during the first 120 minutes of the study, with
some rebound of pain in ketorolac patients after 6 hours.
Two small, randomized double-blind trials [30,31] evaluated the use of
etodolac (300 mg) twice daily (n = 29, 31) versus naproxen (500 mg) two or three
times daily (n = 31, 29) for between 3 and 7 days for the treatment of acute gout
attacks. Improvement by the end of treatment occurred in 87% to 97% of subjects
in each treatment arm. There were no significant differences between the treat-
ment groups at any visit or at the final evaluation.
Colchicine is considered the classic treatment for acute crystal arthropathy
management; however, it is less effective in those who have pseudogout than
those who have gout [8,32]. One small (n = 43), randomized, placebo-controlled
trial finds colchicine associated with pain improvement after 48 hours. Colchicine
also is associated with diarrhea or vomiting within the first 24 hours [33].
Therefore, colchicine for an acute attack of arthropathy often is reserved for those
who cannot take or tolerate NSAIDs [34].
Corticosteroids, via oral, intravenous, intra-articular, or intramuscular routes,
are used in patients who have acute attacks of gout, pseudogout, and basic cal-
clinical trials in crystal arthropathy 363
cium phosphate (BCP) deposition, although studies are limited, with an absence
of systematic reviews or randomized controlled trials to confirm their efficacy
[5,34–39]. There is general agreement that corticosteroids should be reserved
for those who cannot be treated with NSAIDs or colchicine [8,10]. One pro-
spective trial [40] investigated the use of oral prednisone and intravenous
methylprednisolone for acute gout attacks in 13 patients during a 12-month
period. Oral prednisone dosages varied from an initial dose of 20 mg to 50 mg
per day (range 30 mg to 160 mg), with dosages tapered during a mean of 11 days.
Two patients received parenteral methylprednisolone at doses ranging from
30 mg to 160 mg, with conversion to oral prednisone as soon as possible. Com-
plete resolution of symptoms occurred within 7 to 10 days. A more recent
prospective, open-label study [41] evaluated the use of one dose of intra-articular
betamethasone (7 mg; n = 10) or intravenous methylprednisolone (125 mg; n = 7)
in patients who had contraindications to NSAIDs versus diclofenac (150 mg daily
for 3 days titrated to 75 mg daily for 3 additional days; n = 10). Patient-reported
improvement and severity of joint swelling improved promptly in all three
groups. Roane and coworkers [42] prospectively investigated the use of triam-
cinolone acetonide (60 mg intramuscularly) in 14 patients who had pseudogout
and conclude that it was safe, well tolerated, and effective. Alloway and col-
leagues [43] conducted a prospective, open-label study in which patients
experiencing acute gout attacks were assigned randomly to indomethacin
(50 mg 3 times daily; n = 10) or triamcinolone acetonide (60 mg intramuscularly;
n = 10) plus acetaminophen plus codeine as needed. There was no statistically
significant difference in the number of days to resolution of all symptoms at
each evaluation period.
Adrenocorticotropic hormone or corticotropin has been studied in patients
who have acute gout or pseudogout [44–50]. Although it was effective in re-
lieving pain, in one study quicker than indomethacin [44], its clinical usefulness
is limited by the need to administer multiple injections [8,10,51]. Like that of
corticosteroids, the use of corticotropin generally is reserved for those who
cannot tolerate NSAIDs or colchicine treatment [8].
Recently, there have been case reports regarding the use of the tumor necrosis
factor (TNF) inhibitors, etanercept and infliximab, in the treatment of patients
who have acute pain and inflammation who are unable to use NSAIDs or
colchicine [52,53]. Etanercept was injected subcutaneously twice weekly in a
53-year-old man who had frequent recurrent attacks of gout and who was taking
probenecid and urine alkalizers [52]. The intensity and frequency of the attacks
decreased after four injections, and inflammation decreased although serum
urate values remained similar. Fiehn and colleagues [53] describe a 44-year-old
man who had chronic gouty tophi, painful flares, and significant joint inflam-
mation who was given infliximab (400 mg intravenously [5 mg/kg] at weeks 0,
2, and 6). The patient experienced fast relief from pain and inflammation.
After experiencing a flare 6 weeks after the third injection, infliximab was
administered (400 mg intravenously every 6 weeks) with good response. These
case reports are difficult to assess because of the multiple medications that the
patients were taking. Randomized controlled clinical trials are needed to confirm
the safety and efficacy in gout patients. The overall expense of these agents may
preclude their use in gout.
Clinical trials in the prophylaxis of recurrent crystal arthropathy
Preventative measures or prophylaxis may be required to reduce the fre-

quency and severity of acute crystal arthropathy episodes or gout flares. Mul-
tiple retrospective studies postulate that colchicine prophylaxis is an effective
means of preventing acute gout [54–56]. Few randomized controlled trials for
preventing acute gout attacks have been conducted. In a 6-month, randomized,
double-blind study [57], 51 subjects were treated with probenecid (1.5-gm
daily) and either colchicine (1.5-mg daily) or placebo. The investigators analyzed
only 38 subjects who were assessed as compliant with probenecid, based on a
reduction in serum urate, and found that colchicine reduced the frequency of
acute attacks significantly. Borstad [58] conducted a randomized, double-blind,
prospective, 6-month clinical trial using colchicine as prophylaxis when initiat-
ing therapy with allopurinol. Forty-three subjects initiating allopurinol therapy
received colchicine (0.6 mg; n = 21) or placebo (n = 22) twice daily. Allopurinol
was initiated (100 mg per day) with the dose titrated to serum urate less than
6.5 mg/dL in 100-mg increments (mean dose 265 mg per day). When targeted
serum urate was reached and maintained, subjects reported fewer gout flares
after 6 months. Acute gout flares occurred in 14% of the colchicine group and
63% in the placebo group (P = 0.008). Subjects treated with colchicine had
fewer gout flares in the first 3 months of treatment and fewer flares in the 3- to
6-month treatment period. Because inflammation in osteoarthritis often is
secondary to the presence of calcium-containing crystals, Das and coworkers
[59] investigated whether or not colchicine would prevent crystal-induced acute
inflammatory flares in patients who have osteoarthritis. A randomized, double-
blind, placebo-controlled study was conducted in which colchicine (0.5 mg
twice daily) or placebo was added to NSAID treatment in 36 patients who had
osteoarthritis. Improvement was higher by 30% after 20 weeks in the col-
chicine group compared with the placebo-treated group. The investigators con-
clude that further evaluation of colchicine’s role in osteoarthritis is needed to
determine if the effect seen is the result of crystal-induced inflammation or to
other mechanisms.
Clinical studies of a new nonpurine selective inhibitor of xanthine oxidase
(XO), febuxostat, also include prophylaxis with either colchicine (0.6 mg once
or twice daily) or naproxen (250 mg twice daily) [60–62]. In phase II studies,
gout flares during colchicine prophylaxis occurred in approximately 10% of
subjects and increased to 40% to 53% of subjects when prophylaxis was with-
drawn after the mandated 2- to 4-week period [60]. In phase III studies, an
increase in acute gout flares also was noted after discontinuation of prophylaxis
after 8 weeks [62].
Clinical trials in management of chronic crystal arthropathy
Pseudogout and basic calcium phosphate
Strategies for the chronic management of those who have crystal arthropathy
depend on causative crystal identification and underlying or associated disease
states. In those who have pseudogout, underlying conditions that are associated
with this disorder, such as hyperparathyroidism, haemochromatosis, hypophos-
phatasia, hypomagnesaemia, and Wilson’s disease, should be ruled out and, if
identified, treated. The cause of BCP arthropathy is less clear but is known to
occur with degenerative joint disease. A prospective, self-controlled trial shows
that chronic long-term treatment with colchicine (0.6 mg twice daily) reduces the
number of recurrences of pseudogout [32]. Given the low frequency of recurrent
attacks of pseudogout or BCP arthropathy, however, the benefits of long-term
colchicine need to be weighed against the risks for side effects [2]. To date, no
effective chronic, long-term treatment exists for those who have calcium pyro-
phosphate dihydrate deposition (CPPD) or BCP crystal deposition disease [4].
Gout
Chronic management of gout is defined based on correction of hyperuricemia,

the underlying cause of this disease. In contrast to other crystal arthropathies,
gout recurrence is high. An observational study notes that after the initial
presentation of acute gout, there is a 62% recurrence rate within 1 year, 78% by
year 2, and 89% by year 5 [54]. Another study notes that the frequency of
recurrence of acute gouty arthritis also increases after withdrawal of long-term
urate-lowering treatment [63–65]. Long-term symptomatic treatment with an
NSAID or colchicine may provide some benefit; however, neither addresses the
hyperuricemic etiology of gout. A reasonable pharmacologic therapeutic target is
to reduce serum urate to subsaturation levels of 6.0 mg/dL or less [3,56,66–68].
This may be attained with a uricosuric that increases uric acid excretion or phar-
macologic agents that inhibit the enzyme XO, which reduces uric acid pro-
duction. Currently, the most commonly used agents are probenecid, a uricosuric,
and allopurinol, a purine analog and the only XO inhibitor available. Each of
these agents has clinical advantages and limitations, with the latter generally
resulting from dosing or tolerability and safety profiles (Table 2).
Clinical trials of agents in the treatment of gout
There have been few advances in the management of chronic gout in the past
40 years. Although probenecid and allopurinol remain the antihyperuricemic
agents prescribed most frequently, recent studies find promising results with new
Table 2
Summary of advantages and disadvantages of current and investigational agents used in the treatment
of hyperuricemia and gout
Mechanism of action
Drug and advantages Disadvantages
Allopurinol Widely used XO inhibitor May be associated with acute gout
Once-daily administration flare on initiation
Effective in underexcretors Adverse events are common and may be
and overproducers severe and serious (ie, hypersensitivity
Can be used (with dosage syndrome, liver and renal toxicity) and
modification) in those who occur with greater frequency in those
have renal impairment receiving concomitant diuretic agents
or ampicillin
Must modify dose in those who have
renal impairment
Associated with drug-drug interactions
(ie, oral anticoagulants, theophylline,
azathioprine)
Probenecid Uricosuric agent that May be associated with acute gout flare
reduces uric acid in on initiation
underexcretors and those Ineffective in those who have
who have normal renal diminished renal function
function without renal (creatinine clearance b50 mL/min)
stones or massive tophi Diminished efficacy in those treated
with acetylsalicylates
Adverse events include rash,
gastrointestinal symptoms, headache,
and serious events, such as nephrotic
syndrome and blood dyscrasias
Drug-drug interactions (ie, increased
plasma levels of concurrent agent)
may occur resulting from interference
with urinary excretion of other agents
(eg, NSAIDs or captopril)
Benzbromarone Uricosuric agent that Available in Europe, limited availability
effectively lowers serum in United States
uric acid in underexcretors May precipitate acute gout flare on
and overproducers initiation
Concerns regarding hepatotoxicity
Oxypurinol Like its parent compound, Patients who are intolerant of
a good inhibitor of allopurinol may exhibit toxicity to
xanthine oxidase oxypurinol
May be useful in patients May precipitate acute gout flare on
who are allopurinol initiation
intolerant
Febuxostat Nonpurine selective May precipitate acute gout flare on
inhibitor of XO initiation
Effectively lowers serum Most common side effects are liver func-
urate in underexcretors and tion abnormalities, diarrhea, headache,
overproducers and joint-related signs and symptoms
Administered orally and
once daily
(continued on next page)
Table 2 (continued )
Mechanism of action
Febuxostat May be used without
dosage adjustment in those
who have renal insufficiency
or hepatic impairment
Found safe and effective in
large, long-term clinical trials
Rasburicase Potent recombinant uric acid Parenteral route of administration
oxidase compound that Rapid reduction of serum urate may pre-
catalyzes enzymatic oxidation cipitate acute gout flare on initiation
of uric acid May administer only one course of rasbu-
Useful in patients who have ricase during patient’s lifetime because of
tumor lysis syndrome potential for antibody formation
Potential for anaphylactoid reactions
Carries black box warning for anaphylac-
toid reactions and for hemolysis and
methemoglobinemia, especially in those
who have glucose-6-phosphate dehydro-
genase deficiency
Long-term safety is unknown
PEG-uricase Effective recombinant porcine Administered intramuscularly
(Puricase)/ urate oxidase compound that May precipitate acute gout flare
uricase-PEG20 produces rapid and profound Potential for allergic reactions from
decrease in serum urate foreign protein
Potentially useful in patients Well-described safety and efficacy data
who have tumor lysis not yet published
syndrome and possibly those
who have refractory gout
PEG strands may reduce the
risk for immunogenicity
compared with rasburicase
Fenofibrate Hypolipidemic agent that Effects of fenofibrate on serum urate are
increases clearance of purine modest compared with allopurinol or
bases including uric acid febuxostat
Orally administered useful Hypouricemic efficacy not yet determined
adjunct to hyperuricemic in long-term studies
therapy in patients who have
concurrent hypertriglyceridemia
Losartan Orally administered angiotensin Effects of losartan are modest compared
II receptor antagonist that with other uricosurics, such as probenecid
interferes with urate reabsorption
Useful adjunct to hyperuricemic
therapy in patients who have
concurrent hypertension
E3040 Member of a new class of anti- Agent in early stages of investigation
inflammatory agents found to Efficacy and safety data still evolving
reduce plasma urate levels.
(continued on next page)
Table 2 (continued)
Mechanism of action
Y-700 XO inhibitor shown more potent Agent in early stages of investigation
than allopurinol Efficacy and safety data still evolving
May be safe in those who have
renal impairment
Scopoletin Agent with weak uricolytic and In early stages of investigation
potent uricosuric activity Efficacy and safety data still evolving
agents designed specifically for the treatment of hyperuricemia and those

designed for other indications but are found also to lower serum urate levels.
Probenecid
Probenecid is the uricosuric prescribed most commonly in the United States

[4]. It is effective in lowering serum urate in patients who have hyperuricemia
resulting from underexcretion and normal renal function without renal stones or
massive tophi [10]. Uricosurics in general, however, are ineffective in those who
have reduced renal function and efficacy may be diminished in those taking
salicylates [4,51].
There is insufficient evidence from systematic reviews or randomized trials
on the effects of probenecid to prevent gout attacks [69] and the clinical use-
fulness of probenecid is limited by its tolerability profile. One study of 37 male
patients assigned to treatment based on the last digit of their hospital number
[70] finds no significant difference between treatment with allopurinol (300 to
600 mg per day) and probenecid (1 to 2 g per day) in reducing acute gout
recurrence. After a mean follow-up period of 18.6 months, 45% (9/20) of those
treated with allopurinol and 47% (8/17) of those treated with uricosurics were
recurrence free. The results of this trial are difficult to interpret because of the
randomization treatment allocation and because of the five patients who
were allocated to probenecid but were switched to sulphinpyrazone because of
adverse events.
Probenecid is associated with rash, gastrointestinal symptoms, headache,
drug-drug interactions, and rare but serious reactions, such as nephrotic syndrome
and blood dyscrasias [71]. Caution is advised in patients who have a history of
peptic ulcer disease and those taking NSAIDs or captopril, as plasma levels of
these agents may be increased with concurrent probenecid use [72].
Benzbromarone
Benzbromarone, a uricosuric agent, is available for the treatment of gout in

select European countries but is not available in the United States. Clinical trials
show it to be an effective uricosuric and more effective than allopurinol
[66,67,73–75]. Benzbromarone is effective in those who have reduced renal
function [67]. Although effective, there is concern that benzbromarone is

hepatotoxic [76–78].
Allopurinol
Allopurinol is a purine analog that inhibits XO along with other enzymes in

the purine and pyrimidine pathway. At doses ranging from 100 to 900 mg per
day, with the most commonly prescribed dose 300 mg per day, it produces a dose-
dependent reduction in serum urate. This agent has been available for more than
40 years and historically is the urate-lowering agent prescribed most commonly
[10,79].
Although allopurinol has been available for a long time, there is insufficient
evidence from randomized controlled clinical trials on the ability of this agent to
prevent gout attacks. Some nonrandomized studies report that allopurinol reduces
acute gout attacks over time [80–82] and is comparable to probenecid [70] in
reducing the frequency of gout attacks. A prospective study by Perez-Ruiz and
colleagues [67] evaluates the efficacy of allopurinol in reducing serum urate.
Allopurinol is compared with benzbromarone in 86 male patients who have
primary chronic gout. Allopurinol-treated patients (300 mg per day) exhibited a
mean reduction of plasma urate of 2.75 mg/dL (from 8.6 to 5.85 mg/dL) in
normal excretors and of 3.34 mg/dL (from 9.10 to 5.76 mg/dL) in underexcretors.
Only 53% of patients, however, achieved the targeted serum urate concentration
of less than 6.0 mg/dL. This result was similar to that of other studies that
found the majority of patients who have gout who were treated with allopurinol
(300 mg per day) fail to attain serum urate targets of less than or equal to 6 mg/dL
[83–85].
Allopurinol is excreted mainly through the kidneys; therefore, dosage adjust-
ments are necessary in patients who have renal impairment. Although a dose of
300 mg per day is standard in those who have normal renal function, it is recom-
mended that the dose be reduced in those who have impaired renal function. In
addition, there are several clinically relevant drug-drug interactions that may
occur when allopurinol is given to patients receiving oral anticoagulants, theo-
phylline, and azathioprine, with these agents often requiring dose adjustment [72].
Up to 5% of patients are unable to tolerate allopurinol because of adverse
events, including headache and gastrointestinal irritation [10]. Less common but
more severe adverse events, such as bone marrow suppression and hyper-
sensitivity syndrome, are described. Allopurinol hypersensitivity syndrome can
range from a severe skin rash to a life-threatening illness, in which patients
develop toxic epidermal necrolysis, fever, hepatitis, eosinophilia, and worsening
renal function [86,87]. This syndrome occurs more frequently in those who have
renal insufficiency or those taking concomitant diuretic agents or ampicillin
[88–91]. It is postulated that clinicians often undertreat gout patients on a long-
term basis with allopurinol in an attempt to lessen the small risk of major
allopurinol sensitivity [92]. Desensitization to allopurinol is attempted in patients
who have minor hypersensitivity reactions with some success [93].
Oxypurinol
Oxypurinol is the primary metabolite of allopurinol and, like its parent com-
pound, is a good inhibitor of XO. Oxypurinol’s half-life is 9 to 15 times longer
than that of allopurinol and is shown to be effective in at least 50% of patients
who are allergic to allopurinol. Evidence of toxicity identical to that observed
with allopurinol, however, is seen in 30% to 50% of treated patients [94–96].
Oxypurinol compassionate-use protocols, in subjects intolerant or allergic to
allopurinol, have been conducted since 1966. One safety study conducted in
99 allopurinol-naive subjects, receiving 384 mg per day of oxypurinol for
14 days, reports 3% of subjects having related adverse events and concludes that
only approximately one half of patients who are allopurinol hypersensitive
can tolerate oxypurinol [95]. In a phase II, randomized, double-blind trial of
oxypurinol, the primary endpoint is the reduction in serum urate of 2.0 mg/dL
between baseline and week 14. The 77 enrolled subjects achieved a mean serum
urate decrease of 1.90 mg/dL (baseline mean 10.11 mg/dL; post-baseline mean
7.96 mg/dL). In another phase II trial, serum urate was lowered by 2.87 mg/dL
in 190 (of 533) compassionate-use patients in a 1-year treatment period [95].
Therefore, its usefulness in the treatment of gout may be limited given the ad-
vent of newer antihyperuricemic agents.
Febuxostat
Febuxostat, a new orally administered, potent nonurine selective inhibitor of

the oxidized and reduced forms of XO, currently is in late-stage development for
the treatment of hyperuricemia and gout [97–101]. Febuxostat is specific for
inhibition of XO and, unlike allopurinol, does not inhibit other enzymes involved
in purine or pyrimidine metabolism [98,102–104]. Pharmacokinetic clinical
studies indicate that febuxostat does not require dosage adjustment in those who
have renal insufficiency or those who have mild to moderate hepatic dysfunction
[105–107].
Several placebo- and comparator-controlled clinical trials performed in North
America and Japan have been conducted and confirm the efficacy and safety of
febuxostat in patients who have hyperuricemia and gout. A phase II, placebo-
controlled, 4-week, randomized, multicenter, double-blind study performed in the
United States evaluated the dose-response efficacy of febuxostat (40 mg, 80 mg,
and 120 mg once daily) in 153 patients who had hyperuricemia (baseline serum
urate 8.0 mg/dL) and gout [60]. Significantly greater proportions of subjects
who were febuxostat treated than those who were placebo treated (febuxostat,
40 mg [56%], 80 mg [76%], 120 mg [94%], placebo [0%]) achieved a serum
urate less than or equal to 6.0 mg/dL at the end of the study (day 28). A similar
response was seen at each weekly visit.
The phase II study has an ongoing open-label extension study, which, in a
2-year interim analysis, demonstrates that febuxostat has sustained urate-
lowering effects [108]. One hundred and sixteen subjects who had gout were
given febuxostat (80 mg once daily, titrated to 40 mg or 120 mg per day based
on serum urate and adverse events). The effects of febuxostat were sustainable,
with between 74% and 81% of subjects obtaining serum urate values less than
6.0 mg/dL at each visit during the 2-year analysis period [108].
In a phase III North American trial (United States and Canada), the serum
urate lowering efficacy and safety of febuxostat was compared with those of
allopurinol [62]. A total of 760 patients (96% men) was randomized to 52 weeks
of treatment with febuxostat (80 mg; n = 256), febuxostat (120 mg; n = 251), or
allopurinol (300 mg once daily; n = 253). The primary efficacy endpoint was the
percentage of patients reaching a serum urate level of less than 6.0 mg/dL at
the last 3 monthly visits. Significantly greater percentages of patients treated
with febuxostat (80 mg or 120 mg once daily) attained this primary endpoint
and maintained their last three serum urate levels of less than 6.0 mg/dL (53%
and 62%, respectively) compared with patients treated with allopurinol (21%)
(P b.001 for each febuxostat group versus allopurinol). A post hoc analysis of
the effect of serum urate levels on gout flare incidence shows that subjects who
achieved an average post-baseline serum urate level of less than 6.0 mg/dL had
fewer gout flares requiring treatment (6% versus 14%) and a greater median
reduction in tophus area (75% versus 50%) at week 52 compared with those who
did not, regardless of therapy. The most frequent treatment-related adverse
events with febuxostat were liver function abnormalities, diarrhea, headaches,
and joint-related or musculoskeletal and connective tissue signs and symptoms.
In another phase III study of febuxostat, 1067 subjects who had gout and
serum urate levels greater than or equal to 8.0 mg/dL were randomized in a
1:2:2:1:2 ratio to once-daily fixed dose of placebo, febuxostat (80 mg, 120 mg, or
240 mg), or allopurinol (100 mg per day for subjects who had renal impairment
or 300 mg per day for subjects who had normal renal function) for 28 weeks
[109]. At the end of the 28-week study, the percentages of subjects who met the
primary endpoint of last three serum urate values less than 6.0 mg/dL were 0%
among those treated with placebo, 48% in those treated with febuxostat (80 mg),
65% in those treated with febuxostat (120 mg), 69% in those treated with febu-
xostat (240 mg), and 22% in those treated with allopurinol. These percentages
were significantly higher in all febuxostat dose groups compared with placebo
or allopurinol ( Pb.05). There were 40 subjects in this study who had moderate
to mild renal impairment. Between 44% and 60% of these subjects treated with
febuxostat achieved serum urate less than 6.0 mg/dL at each of the last three
visits compared with 0% treated with placebo or allopurinol. The rate of adverse
events was low and similar between those who had normal renal function and
those who had moderate impairment. The most frequent treatment-related adverse
events were similar to those in the previously reviewed phase III study [62].
There are three double-blind, multicenter, placebo- or allopurinol-controlled
trials conducted in Japan evaluating the efficacy and safety of febuxostat in
subjects who had gout or hyperuricemia (baseline serum urate 8.0 mg/dL)
[110–112]. These clinical trials used lower doses of febuxostat (10 mg, 20 mg,
and 40 mg) and were of shorter duration than the North American trials. The
dose of allopurinol also was lower, as the treatment regimen used 100 mg once or
twice daily. These studies show similar results to the North American trials,
with febuxostat having significantly greater reduction in serum urate compared
with placebo or allopurinol.
Rasburicase
Uric acid oxidase, or uricase, is an enzyme found in most mammals, but not
humans, that catalyzes the enzymatic oxidation of uric acid into the more
(10 times) water-soluble allantoin, which then is excreted easily. Rasburicase is a
recombinant uric acid oxidase made from Aspergillus flavus with a terminal
half-life of approximately 17 hours [113]. An intravenous formulation of rasbu-
ricase recently was approved by the United States Food and Drug Administration
for the initial management of plasma urate levels in pediatric patients who have
leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer
therapy expected to result in tumor lysis and subsequent elevation of plasma
urate [114].
The profound effects of rasburicase on serum urate suggest that it may be a
useful agent in the management of patients who have gout [92] and, as such, the
agent currently is under evaluation in gout clinical trials in the United States.
A recently published case [115] involving a 33-year-old allopurinol-intolerant
female patient who had an 8-year history of hyperuricemia, 8 to 12 acute attacks
of gout per year, and severe tophi reports that rasburicase (0.15 mg/kg), ad-
ministered intravenously every 2 weeks for 2 months and monthly thereafter,
decreased serum urate levels, eliminated gout recurrence, and decreased tophi
size substantially. Serum urate levels decreased from approximately 850 mmol
(1.43 mg/dL) at baseline to less than 50 mmol (0.08 mg/dL) during the first week
after therapy and increased steadily during the subsequent weeks to levels before
therapy during the first 6-month treatment period. Thereafter, and for the rest of
the 3 years of monthly rasburicase therapy, serum urate decreased from 850 mmol
(1.43 mg/dL) to 658 mmol (1.11 mg/dL). Rasburicase was well tolerated with the
patient having mild inflammation of multiple joints (symmetrically fingers,
knees, and feet) during the first 2 months and no side effects during the follow-
ing 3 years of treatment.
The viability of rasburicase as a therapeutic treatment option for those who
have gout likely is limited [10]. In addition to its limitation of only one course per
lifetime, its parenteral route of administration is an undesirable treatment mode,
especially given the options for oral agents. The profound and rapid effects that it
has on serum urate may be associated with an increased risk for acute gout flare.
Furthermore, because rasburicase is a foreign protein, there is a significant risk
for anaphylactoid reactions [113]. Despite the exclusion of patients who have a
history of significant atopic allergy or bronchial asthma in clinical studies,
antibodies to uricase still occurred in 7% to 14% of patients treated [116–118].
Cases of anaphylactoid reactions also are reported, resulting in the product
carrying a black box warning to that effect and for hemolysis and methemo-
globinemia, especially for patients who have glucose-6-phosphate dehydro-

genase deficiency.
Polyethylene glycol–uricase/uricase–polyethylene glycol 20
In an attempt to neutralize the immunogenicity issues associated with rasbu-

ricase, polyethylene glycol (PEG) has been added to the uricase compound [119].
PEG-uricase is described as a recombinant porcine urate oxidase to which mul-
tiple strands of PEG of average molecular weight of 10,000 are attached. In
addition to reducing the immunogenicity, the attachment of PEG greatly prolongs
the circulating half-life of the compound. This mammalian PEG-uricase is re-
ported to be nonimmunogenic and effective in preventing urate nephropathy in a
uricase-deficient strain of mice [120]; however, some subjects entered in a phase I
trial exhibited antibodies [121].
PEG-uricase is found effective in treating tumor lysis by maintaining a plasma
urate of 9.0 mg/dL in a patient who has non-Hodgkin’s lymphoma without
producing antibodies [122] and shows promise in the treatment of patients who
have hyperuricemia and gout [123]. As a result, PEG-uricase has received orphan
drug designation for the treatment of refractory gout by the FDA Office of
Orphan Products Development, and the developing company recently announced
completion of patient dosing in a phase II clinical trial [124]. In this phase II
study, subjects who have refractory gout are administered PEG-uricase (8 mg
by intravenous infusion) once every 3 weeks for a total of five infusions. The
primary measure of efficacy is a reduction in plasma urate to less than 6.0 mg/dL
and a reduction in the ratio of urate to creatinine in urine to less than 0.2. The
ability of PEG-uricase to lower the total urate pool size (measured using a method
involving an infusion of uric acid labeled with N15, a stable nonradioactive
isotope of nitrogen) will be evaluated in a subset of subjects [121].
Clinical trials of other agents with antihyperuricemic effect
Fenofibrate
Fenofibrate is a hypolipidemic fibric acid derivative used commonly that in-

creases the clearance of purine bases hypoxanthine, xanthine, and uric acid. The
results of several studies suggest that fenofibrate may be a useful adjuvant with
traditional antihyperuricemic therapy in selected patients who have gout (ie, those
who have hypertriglyceridemia), with its uricosuric effect independent of its
lipid-lowering efficacy. Case reports suggest that the reductions in serum urate
seen with fenofibrate range between 15% and 35% [10,125].
In a study of five healthy subjects, fenofibrate was administered (150 mg
three times daily for 3 days) with allopurinol (300 mg) given 4 hours after the
last dose [126]. A significant 46% ( P b.05) reduction in urate from baseline
was observed. Takahashi and coworkers [127] assessed the effect of fenofibrate
(300 mg once daily; n = 27) or losartan (50 mg once daily; n = 25) in patients who
had gout receiving treatment with benzbromarone or allopurinol. After 2 months,
the addition of fenofibrate resulted in a statistically significant drop in serum
urate, although the effects were modest (approximately 15%) and less than that
observed in other studies. Feher and colleagues report that fenofibrate has a rapid
and reversible urate-lowering effect in patients who have hyperuricemia and
gout currently receiving allopurinol therapy [128]. Ten men ranging in age from
38 to 74 who had chronic tophaceous or recurrent gout were treated with allo-
purinol (300 to 900 mg daily) for at least 3 months and were given open-label
fenofibrate (200 mg) once daily for 3 weeks. At the 3- week visit, a significant
(P = 0.004) 19% decrease in serum urate was observed (0.37 F 0.04 to 0.30 F
0.02). Fenofibrate also produced a 36% increase in urate clearance (7.2 F 0.9 to
11.4 F 1.6; P = 0.006) with no change in creatinine clearance. The effect on
serum urate was reversible, with levels returning to baseline within 3 weeks of
fenofibrate discontinuation.
Fenofibrate offers a modest decrease in serum urate compared with several
other agents; nonetheless, it may be considered a useful agent for patients who
have hyperlipidemia and gout. Its hypouricemic efficacy needs to be confirmed in
larger and longer-term studies [10,129].
Losartan
Losartan is an angiotensin II receptor antagonist that interferes with urate

reabsorption in the proximal tubule, thereby lowering serum urate. Like feno-
fibrate, the maximal serum urate-lowering effects of losartan (7% to 15%) seem
to be less than the effect achievable with standard dosing regimens of primary
uricosuric drugs, such as probenecid [92,130–132].
Two studies performed in patients post renal [132] or heart [133] transplan-
tation report significant reductions in serum urate. As discussed previously, the
use of losartan in combination with antihyperuricemic patients who have gout
may offer a modest additional decrease in serum urate in addition to its effects on
hypertension [127]. In the Losartan Intervention For Endpoint (LIFE) reduction
in hypertension study [134], the effect of losartan is compared with atenolol
(a b-blocker with no known effect on serum urate concentration) in patients who
were not hyperuricemic (mean serum urate of 5.5 mg/dL). The investigators note
that baseline serum urate is associated significantly with an increased rate of the
composite outcome of cardiovascular death, fatal or nonfatal myocardial in-
farction, fatal or nonfatal stroke in the entire study population (hazard ratio 1.024
[1.017–1.032] per 10 mmol/L [0.168 mg/dL]; P b.0001). The baseline-to-end-of-
study increase in serum urate was significantly greater in those treated with
atenolol versus those treated with losartan (44.4 mmol/L [0.075 mg/dL] versus
17.0 mmol/L [0.286 mg/dL]; P b.0001). Serum urate as a time-varying covariate
was associated strongly with cardiovascular events in the entire population
(P b.0001), and the contribution of serum urate to the treatment effect of losartan
on cardiovascular events was 29%. This finding suggests attenuating serum urate
not only may reduce gout recurrence but also, perhaps more importantly, may
reduce cardiovascular events in a population already at high risk [135–137].
Other early investigational antihyperuricemic agents
E3040, a new class of anti-inflammatory agents, was found to reduce the

plasma urate level in phase I clinical studies. Yamada and colleagues [138]
assessed the fractional excretion of urate in an animal model of hyperuricemia
and found E3040 to have uricosuric activity in the proximal tubules.
A series of 1-phenylpyrazoles demonstrate XO inhibitory activity in vitro
and in a rat model of hyperuricemia [139]. Of these, the compound 1-(3-cyano-
4-neopentyloxyphenyl)pyrazole-4-carboxylic acid (Y-700) has the most potent
enzyme inhibition. In a rat model of hyperuricemia, Y-700 shows a more potent
and longer-lasting hypouricemic action than allopurinol [140]. A single oral dose
of Y-700 (5 mg, 20 mg, or 80 mg) in healthy, male Japanese volunteers caused a
dose-dependent reduction of serum urate levels [140]. In a pharmacokinetic
analysis that also enrolled healthy, male Japanese volunteers [141], Y-700 was
absorbed orally rapidly and was eliminated with a half-life of between 23.5 and
40.2 hours. Urinary excretion was less than 1.5% at doses of 0.5 to 80 mg. This
suggests that Y-700 may be safe in patients who have renal failure. Higher
(120 mg) and repetitive doses (once daily for 10 days) also have been assessed
in male volunteers [142]. No serious adverse events are reported, although ab-
dominal cramps, abdominal pain, and flatulence occurred.
Intraperitoneal administration of scopoletin, an agent with uricolytic and
uricosuric effects, was found in a study of hyperuricemic mice to be a potent
uricosuric (at doses of 100 and 200 mg) and a weak uricolytic (at doses of 50,
100, and 200 mg) [143].
Summary
There are few clinical trials evaluating crystal arthropathy. These clinical trials
demonstrate, however, effective management of acute arthritis. Crystal arthrop-
athy requires identification of the crystal (monosodium urate monohydrate
[MSU], CPPD, or BCP) and the underlying cause for appropriate management.
For acute arthritis, therapies include NSAIDs, colchicine, or corticosteroids. Of
the three types of crystal arthropathies, only that of gout, or MSU deposition, has
effective therapies aimed at reversing the underlying cause of hyperuricemia.
Clinical trials in gout demonstrate effective urate-lowering therapies, including
the uricosuric, probenecid, and XO inhibitor, allopurinol. These clinical trials
indicate that XO inhibitors are the most effective in reducing serum urate in
chronic treatment of gout and work well in patients who are overproducers or
underexcretors of uric acid. Uricosuric agents are not as effective in patients who
have renal impairment. Newer agents, such as febuxostat, a nonpurine selective
inhibitor of XO, demonstrate effectiveness in reducing serum urate. In addition,

clinical trials indicate that other agents with antihyperuricemic effects, such as
fenofibrate and losartan, may be useful as adjuvant urate-lowering therapies in
those who have comorbid conditions of hypertriglyceridemia and hypertension,
respectively. Among the newer agents investigated, recombinant urate oxidase
and PEG-uricase work well for the management of hyperuricemia associated with
tumor lysis. Further studies are needed, however, to assess the risk of antigenicity
and their efficacy in the treatment of those who have hyperuricemia and gout.
Acknowledgments
The authors thank Susan Ruffalo, PharmD, of MedWrite (Newport Coast,

California), for her editorial support and consolidating and incorporating the
authors’ comments.
References
[1] McCarty DJ. Crystals and arthritis. Dis Mon 1994;40:255 – 99.
[2] McGill NW. Gout and other crystal-associated arthropathies. Baillieres Clin Rheumatol 2000;
14:445 – 60.
[3] Wortmann RL, Kelley WN. Gout and hyperuricemia. In: Reddy C, Harris D, Sledge M, et al,
editors. Kelley’s textbook of rheumatology. Philadelphia7 Elsevier Saunders; 2005. p. 1402 – 29.
[4] Rosenthal AK, Ryan LM. Treatment of refractory crystal-associated arthritis. Rheum Dis Clin
North Am 1995;21:151 – 61.
[5] Schumacher HR. Crystal-induced arthritis: an overview. Am J Med 1996;100(2A):46S – 52S.
[6] Abramson SB. Treatment of gout and crystal arthropathies and uses and mechanisms of action
of nonsteroidal anti-inflammatory drugs. Curr Opin Rheumatol 1992;4:295 – 300.
[7] Wortmann RL. Treatment of acute gouty arthritis: one physician’s approach and where this
management stands relative to developments in the field. Curr Rheumatol Rep 2004;6:235 – 9.
[8] Pawlotsky Y. What is the optimal treatment for acute crystal-induced arthritis? Rev Rheum
[English edition] 1996;63:231 – 3.
[9] Meyers OL, Cassim B, Mody GM. Hyperuricaemia and gout: clinical guidelines 2003. S Afr
Med J 2003;93:961 – 71.
[10] Schlesinger N. Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs
2004;64:2399 – 416.
[11] Dorfler H. Therapie des akuten gichtanfalls mit acemetacin. Therapiewock 1985;35:1161 – 6.
[12] Franck WA, Brown MM. Ibuprofen in acute polyarticular gout [letter]. Arthritis Rheum 1976;
19:269.
[13] Schweitz MC, Nashel DJ, Alepa P. Ibuprofen in the treatment of acute gouty arthritis. JAMA
1978;239:34 – 5.
[14] Smyth CJ, Percy JS. Comparison of indomethacin and phenylbutazone in acute gout. Ann
Rheum Dis 1973;29:82 – 7.
[15] Polderman J, Colon M. Oxamethacin: a pilot field survey. J Int Med Res 1979;7:83 – 9.
[16] Ruosti A, Vainio U. Treatment of acute gouty arthritis with proquazone and indomethacin: a
comparative double-blind trial. Scand J Rheumatol Suppl 1978;21:15 – 7.
[17] Lomen PL, Turner LF, Lamborn KR, et al. Flurbiprofen in the treatment of acute gout. A
comparison with indomethacin. Am J Med 1986;80:134 – 9.
[18] Altman RD, Honig S, Levin JM, et al. Ketoprofen versus indomethacin in patients with acute
gouty arthritis: a multicenter, double blind comparative study. J Rheumatol 1988;15:1422 – 6.
[19] Fraser RC, Davis RH, Walker FS. Comparative trial of azapropazone and indomethacin plus
allopurinol in acute gout and hyperuricemia. J R Coll Gen Pract 1987;37:409 – 11.
[20] Eberl R, Dunky A. Meclofenomate sodium in the treatment of acute gout. Arzneimittelfor-
schung 1983;33:641 – 3.
[21] Weiner GL, White SR, Weitzner RI, et al. Double blind study of phenoprofen versus phen-
ylbutazone in acute gouty arthritis. Arthritis Rheum 1979;22:425 – 6.
[22] Wanasukapent S, Lertratenakul Y, Rubinstein HM. Effect of fenoprofen calcium on acute gouty
arthritis. Arthritis Rheum 1976;19:933 – 5.
[23] Garcia de la Torre I. Estudio doble-ciego paralelo, comparativo con tenaxicam vs placebo en
artritis gotosa aguda [Double-blind parallel-study comparin tenoxicam and placebo in acute
gouty arthritis]. Invest Med Int 1987;14:92 – 7 [in Spanish].
[24] Karachalios GN, Donas G. Sulindac in the treatment of acute gouty arthritis. Int J Tiss Res
1982;4:297 – 9.
[25] Cheng TT, Lai HM, Chiu CK, et al. A single-blind, randomized, controlled trial to assess the
efficacy and tolerability of rofecoxib, diclofenac sodium, and meloxicam in patients with acute
gouty arthritis. Clin Ther 2004;26:399 – 406.
[26] Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib
120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a
randomized controlled trial. Arthritis Rheum 2004;50:598 – 606.
[27] Schumacher HR, Boice JA, Daikh DI, et al. Randomized double blind trial of etoricoxib and
indometacin in treatment of acute gouty arthritis. BMJ 2002;324:1488 – 92.
[28] Shrestha M, Chiu MJ, Martin RI, et al. Treatment of acute gouty arthritis with intramuscular
ketorolac tromethamine. Am J Emerg Med 1994;12:454 – 5.
[29] Strestha M, Morgan DL, Moreden JM, et al. Randomized double-blind comparison of the
analgesic efficacy of intramuscular ketorolac and oral indomethacin in the treatment of acute
gouty arthritis. Ann Emerg Med 1995;26:682 – 6.
[30] Lederman R. A double-blind comparison of etodolac (Lodine) and high doses of naproxen in
the treatment of acute gout. Adv Ther 1990;7:344 – 54.
[31] Maccagno A, Di Giorgio E, Romanowicz A. Effectiveness of etodolac (Lodine) compared with
naproxen in patients with acute gout. Curr Med Res Opin 1991;12:423 – 9.
[32] Alvarellos A, Spilberg I. Colchicine prophylaxis in pseudogout. J Rheumatol 1986;13:804 – 6.
[33] Ahern MJ, Reid C, Gordon TP, et al. Does colchicine work? The results of the first controlled
study in acute gout. Aust N Z J Med 1987;17:301 – 4.
[34] Harris CM, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician 1999;59:
925 – 34.
[35] Hollander JL. Intra-articular hydrocortisone in the treatment of arthritis. Ann Intern Med 1953;
39:735 – 46.
[36] Hollander JL, Jessar RA, Brown Jr EM. Intra-articular corticosteroid therapy. Am Pract
1961;12:190 – 3.
[37] Hollander JL. Current concepts of pathogenesis of rheumatoid arthritis. Del Med J 1969;
41:65 – 6.
[38] Gray RG, Tenebaum J, Gottlieb NL. Local corticosteroid injection treatment in rheumatic
disorders. Semin Arthritis Rheum 1981;10:231 – 54.
[39] Gray RG, Gottlieb NL. Intra-articular corticosteroids: an updated assessment. Clin Orthop
1983;177:235 – 63.
[40] Groff GD, Franck WA, Raddatz DA. Systemic steroid therapy for acute gout: a clinical trial and
review of the literature. Semin Arthritis Rheum 1990;19:329 – 36.
[41] Werlen D, Gabay C, Vischer TL. Corticosteroid therapy for the treatment of acute attacks of
crystal-induced arthritis: an effective alternative to nonsteroidal anti-inflammatory drugs. Rev
Rhum 1996;63:248 – 54.
[42] Roane DW, Harris MD, Carpenter MT, et al. Prospective use of intramuscular triamcinolone
acetonide in pseudogout. J Rheumatol 1997;150:677 – 83.
[43] Alloway JA, Moriaty MJ, Hoogland YT, et al. Comparison of triamcinolone acetonide with
indomethacin in the treatment of acute gouty arthritis. J Rheumatol 1993;20:111 – 3.
[44] Axelrod D, Preston S. Comparison of parenteral adrenocrticostropic hormone with oral
indomethacin in the treatment of acute gout. Arthritis Rheum 1988;31:803 – 5.
[45] Wolfson WQ, Cohn C, Levine R. Rapid treatment of acute gouty arthritis by concurrent
administration of pituitary adrenocorticotropic hormone (ACTH) and colchicine. J Lab Clin
Med 1949;34:1766.
[46] Muzzolini M, Rosetto G, Compagnoni A. Terapia dell’attacco gottoso con ACTH sinetico ad
azione ritardata [Therapy of gout attacks with synthetic delayed-action ACTH]. Policlinico
[Med] 1970;77:322 – 32 [in Italian].
[47] Ritter J, Kerr LD, Valeriano-Marcet J, et al. ACTH revisited: effective treatment of acute crystal
induced synovitis in patients with multiple medical problems. J Rheumatol 1994;21:696 – 9.
[48] Ritter JM, Kerr LD, Valeriano-Marcet J, et al. The use of parenteral ACTH for acute crystal-
induced synovitis in patients with multiple medical problems. Arthritis Rheum 1992;35:S225–8.
[49] Taylor CT, Brooks NC, Kelley KW. Corticotropin for acute management of gout. Ann
Pharmacother 2001;35:365 – 8.
[50] Siegel LB, Alloway JA, Nashel DJ. Comparison of adrenocorticotropic hormone and triam-
cinolone acetonide in the treatment of gouty arthritis. J Rheumatol 1994;21:1325 – 7.
[51] Kim KY, Schumacher HR, Hunsche E, et al. A literature review of the epidemiology and
treatment of acute gout. Clin Ther 2003;25:1593 – 617.
[52] Tausche AK, Richter K, Grassler A, et al. Severe gouty arthritis refractory to anti-inflammatory
drugs: treatment with anti-tumour necrosis factor alpha as a new therapeutic option. Ann
Rheum Dis 2004;63:1351 – 2.
[53] Fiehn C, Wunder A, Krienke S, et al. Lack of evidence for inhibition of angiogenesis as a
central mechanism of the antiarthritic effect of methotrexate. Rheumatol Int 2005;25:108 – 13.
[54] Yu TF, Gutman AB. Efficacy of colchicine prophylaxis in gout. Prevention of recurrent
gouty arthritis over a mean period of five years in 208 gouty subjects. Ann Intern Med 1961;
55:179 – 92.
[55] Yu TF. The efficacy of colchicine prophylaxis in articular gout—a reappraisal after 20 years.
Semin Arthritis Rheum 1982;12:256 – 64.
[56] Li-Yu J, Clayburne G, Sieck M, et al. Treatment of chronic gout. Can we determine when urate
stores are depleted enough to prevent attacks of gout? J Rheumatol 2001;28:577 – 80.
[57] Paulus HE, Schlosstein LH, Godfrey RG, et al. Prophylactic colchicine therapy of intercritical gout.
A placebo-controlled study of probenecid-treated patients. Arthritis Rheum 1974;17:609 – 14.
[58] Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when
initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;31:2429 – 32.
[59] Das SK, Ramakrishnan S, Mishra K, et al. A randomized controlled trial to evaluate the slow-
acting symptom modifying effects of colchicine in osteoarthritis of the knee. A preliminary
report. Arthritis Rheum 2002;47:280 – 4.
[60] Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat, a novel nonpurine selective
inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-
blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients
with gout. Arthritis Rheum 2005;52:916 – 23.
[61] Wortmann R, Becker MA, Schumacher HR, et al. Gout flare prophylaxis during management of
chronic gout with febuxostat, a non-purine selective inhibitor of xanthine oxidase. Arthritis
Rheum 2004;50:S335–6.
[62] Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in
patients with hyperuricemia and gout. N Engl J Med 2005;353:2450 – 61.
[63] Gast LF. Withdrawal of long-term antihyperuricemic therapy in tophaceous gout. Clin
Rheumatol 1987;6:70 – 3.
[64] Van Lieshout-Zuidema MF, Breedveld FC. Withdrawal of long-term antihyperuricemic therapy
in tophaceous gout. J Rheumatol 1993;20:1383 – 5.
[65] Bull PW, Scott JT. Intermittent control of hyperuricemia in the treatment of gout. J Rheumatol
1989;16:1246 – 8.
[66] Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on the velocity
of size reduction of tophi in chronic gout. Arthritis Rheum 2002;47:356 – 60.
[67] Perez-Ruiz FD, Also-Ruiz A, Calabozo M, et al. Efficacy of allopurinol and benzbromarone
for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic
gout. Ann Rheum Dis 1998;57:545 – 9.
[68] Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum
urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty
arthritis with antihyperuricemic therapy. Arthritis Rheum 2004;51:321 – 5.
[69] Bishop C, Rand R, Talbott JH. Effect of benemid (p-[di-n-propylsulfamyl]-benzoic acid) on
uric acid metabolism in one normal and one gouty subject. J Clin Invest 1951;30:889 – 95.
[70] Scott JT. Comparison of allopurinol to probenecid. Ann Rheum Dis 1966;25:623 – 6.
[71] Conaghan PG, Day RO. Risks and benefits of drugs used in the management and prevention
of gout. Drug Saf 1994;11:252 – 8.
[72] Spieker LE, Ruschitzka FT, Lqscher TF, et al. The management of hyperuricemia and gout
in patients with heart failure. Eur J Heart Fail 2002;4:403 – 10.
[73] Schepers GW. Benzbromarone therapy in hyperuricaemia: comparison with allopurinol and
probenecid. J Int Med Res 1981;9:511 – 5.
[74] Arntz HR, Dreykluft HR, Leonardt H. Effect of uric acid lowering drugs in low dosage in
patients with hyperuricemia and hypertriglyceridemia in a randomized group study. Fortschr
Med 1979;97:1212 – 4.
[75] Berg H. Effectiveness and tolerance of long-erm uricosuric treatment. Z Gesamte Inn Med
1990;45:719 – 20.
[76] van der Klauw MM, Houtman PM, Stricker BH, et al. Hepatic injury caused by benzbroma-
rone. J Hepatol 1994;20:376 – 9.
[77] Gehenot M, Horsmans Y, Rahier J, et al. Subfulminant hepatitis requiring liver transplantation
after benzarone administration. J Hepatol 1994;20:842.
[78] Hautekeete ML, Henrion J, Naegels S, et al. Severe hepatotoxicity related to benzarone:
a report of three cases with two fatalities. Liver 1995;15:25 – 9.
[79] Bellamy N, Brooks PM, Emmerson BT, et al. A survey of the current prescribing practices of
anti-inflammatory and urate lowering drugs in gouty arthritis in New South Wales and
Queensland. Med J Aust 1989;151:535 – 7.
[80] Weinberger A, Pinkhas J. The efficacy of treatment with allopurinol versus uricosuric drugs in
gout. Panminerva Med 1978;20:155 – 6.
[81] Rundles RW, Metz EN, Silberman HR. Allopurinol in the treatment of gout. Ann Intern Med
1966;64:229 – 58.
[82] Beutler AM, Rull M, Schlesinger N, et al. Treatment with allopurinol decreases the number of
acute gout attacks despite persistently elevated serum uric acid [letter]. Clin Exp Rheumatol
2001;19:595.
[83] Wolf F, Cathey MA. The misdiagnosis of gout and hyperuricemia. J Rheumatol 1991;18:
1232 – 4.
[84] Bellamy N, Gilbert JR, Brooks PM, et al. A survey of current prescribing practices of
antiinflammatory and urate lowering drugs in gouty arthritis in the province of Ontario.
J Rheumatol 1988;15:1841 – 7.
[85] Beutler AM, Rull M, Schleschinger N, et al. Allopurinol may have protective effect against
acute gouty arthritis independent from its hypouricemic action. Arthritis Rheum 1996;
39(Suppl):S86.
[86] Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome. A review. Ann Pharmacother
1993;27:337 – 43.
[87] Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome, unnecessary morbidity and
mortality. Arthritis Rheum 1986;29:82.
[88] Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity: description and guidelines for
prescription in patients with renal insufficiency. Am J Med 1984;76:47 – 56.
[89] Adriani J, Naraghi M. Allopurinol: actions, adverse reactions, and drug interaction. Intern Med
1985;6:114.
[90] Young JL, Boswell RB, Nies AS. Severe allopurinol hypersensitivity syndrome. Association
with thiazides and prior renal compromise. Arch Intern Med 1974;134:553 – 8.
[91] Lupton GP, Odom RB. The allopurinol hypersensitivity syndrome. J Am Acad Dermatol
1979;1:365 – 74.
[92] Bieber JD, Terkeltaub RA. Gout: on the brinkof novel therapeutic options for an ancient
disease. Arthritis Rheum 2004;50:2400 – 14.
[93] Fam AG, Dunne SM, Iazzetta J, Paton TW. Efficacy and safety of desenstization to allopurinol
following cutaneous reactions. Arthritis Rheum 2001;44:231 – 8.
[94] Lockard O, Harmon C, Nolph K, et al. Allergic reaction to allopurinol with cross-reactivity to
oxypurinol. Ann Intern Med 1976;85:333 – 5.
[95] Walter-Sack I, de Vries JX, Kutschker C, et al. Disposition and uric acid lowering effect of
oxipurinol: comparison of different oxipurinol formulations and allopurinol in healthy indi-
viduals. Eur J Clin Pharmacol 1995;49:215 – 20.
[96] FDA Advisory Committee 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/
2004-4044b1.htm. Accessed September 23, 2005.
[97] Okamoto K, Eger BT, Nishino T, et al. An extremely potent inhibitor of xanthine oxido-
reductase. J Biol Chem 2003;278:1848 – 55.
[98] Takano Y, Hase-Aoki K, Horiuchi H, et al. Selectivity of febuxostat, a novel non-purine
inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci 2005;76:1835 – 47.
[99] Horiuchi H, Ota M, Kobayashi M, et al. A comparative study on the hypouricemic activity and
potency in renal xanthine calculus formation of two xanthine oxidase/xanthine dehydrogenase
inhibitors: TEI-6720 and allopurinol in rats. Res Commun Mol Pathol Pharmacol 1999;104:
307 – 19.
[100] Osada Y, Tsuchimoto M, Fukushima H, et al. Hypouricemic effect of the novel xanthine
oxidase inhibitor, TEI-6720, in rodents. Eur J Pharmacol 1993;241:183 – 8.
[101] Becker MA, Kisicki J, Khosravan R, et al. Febuxostat (TMX-67), a novel, non-purine, selec-
tive inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers.
Nucleosides Nucleotides Nucleic Acids 2004;23:35 – 40.
[102] Horiuchi H, Ota M, Nishimura S-I, et al. Allopurinol induces renal toxicity by impairing
pyrimidine metabolism in mice. Life Sci 2000;66:2051 – 70.
[103] Nishida Y, Kamatani N, Tanimoto K, et al. Inhibition of purine nucleoside phosphorylase
activity and of T-cell function with allopurinol-riboside. Agents Actions 1979;9:549 – 52.
[104] Yamamoto T, Moriwaki Y, Fuimura Y, et al. Effect of TEI-6720, a xanthine oxidase inhibitor,
on the nucleoside transport in the lung cancer cell line A549. Pharmacology 2000;60:34 – 40.
[105] Mayer MD, Khosravan R, Vernillet L, et al. Pharmacokinetics and pharmacodynamics of
febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal
impairment. Am J Ther 2005;12:22 – 34.
[106] Hoshide S, Takahashi Y, Ishikawa T, et al. PK/PD and safety of a single dose of TMX-67
(febuxostat) in subjects with mild and moderate renal impairment. Nucleosides Nucleotides
Nucleic Acids 2004;23:1117 – 8.
[107] Khosravan R, Grabowski BA, Mayer MD, et al. The effect of mild and moderate hepatic
impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel non-
purine selective inhibitor of xanthine oxidase. J Clin Pharmacol 2006;46:88 – 102.
[108] Schumacher HR, Wortmann R, Becker MA, et al. A phase 2, long term open-label safety and
efficacy study of febuxostat, a novel non-purine selective inhibitor of xanthine oxidase
[abstract]. Arthritis Rheum 2004;50(9 Suppl):S335.
[109] Schumacher HR, Becker MA, Wortmann RL, et al. Febuxostat vs. Allopurinol and placebo in
subjects with hyperuricemia and gout: the 28-week APEX study. Arthritis Rheum 2005;52:S680.
[110] Kamantani N, Fujimori SH, Hada T, et al. Phase II dose-response clinical trial using febuxostat
(TMX-67), a novel-type xanthine oxidase/xanthine dehydrogenase inhibitor, for gout and
hyperuricemia [abstract]. Arthritis Rheum 2003;48(9 Suppl):S530.
[111] Kamatani N, Fujimori S, Hada T, et al. Febuxostat, a novel non-purine selective inhibitor of
xanthine oxidase, in a phase III placebo-controlled double-blind clinical trial in Japanese
subjects with gout or hyperuricemia [abstract]. Arthritis Rheum 2004;50(9 Suppl):S337.
[112] Kamatani N, Fujimori S, Hada T, et al. Febuxostat, a novel non-purine selective inhibitor of
xanthine-oxidase, in an allopurinol-controlled phase III clinical trial in Japanese subjects with
gout or hyperuricemia [abstract]. Arthritis Rheum 2004;50(9 Suppl):S336–7.
[113] Pui CH. Rasburicase: a potent uricolytic agent. Expert Opin Pharmacother 2002;3:433 – 42.
[114] Davidson MB, Thakkar S, Hix JK, et al. Pathophysiology, clinical consequences, and treatment
of tumor lysis syndrome. Am J Med 2004;116:546 – 54.
[115] Vogt B. Urate oxidase (rasburicase) for treatment of severe tophaceous gout. Nephrol Dial
Transplant 2005;20:431 – 3.
[116] Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between
rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor
lysis. Blood 2001;97:2998 – 3003.
[117] Pui CH, Mahmoud HH, Wiley JM, et al. Recombinant urate oxidase for the prophylaxis or treat-
ment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol 2001;19:697 – 704.
[118] Pui CH, Jeha S, Irwin D, et al. Recombinant urate oxidase (rasburicase) in the prevention and
treatment of malignancy-associated hyperuricemia in pediatric and adult patients: results of a
compassionate-use trial. Leukemia 2001;15:1505 – 9.
[119] Bomalaski JS, Holtsberg FW, Ensor CM, et al. Uricase formulated with polyethylene glycol
(uricase-PEG 20): biochemical rationale and preclinical studies. J Rheumatol 2002;29:1942 – 9.
[120] Kelly SJ, Delnomdedieu M, Oliverio MI, et al. Diabetes insipidus in uricase-deficient mice: a
model for evaluating therapy with poly(ethylene glycol)-modified uricase. J Am Soc Nephrol
2001;12:1001 – 9.
[121] FDA Office of Orphan Products Development. Pegylated recombinant mammalian uricase
(PEG-uricase) as treatment for refractory gout. Available at: www.clinicaltrials.gov/ct/show/
NCT00111657. Accessed May 31, 2005.
[122] Chua CC, Greenberg ML, Viau AT, et al. Use of polyethylene glycol-modified uricase (PED-
uricase) to treat hyperuricemia in a patient with non-Hodgkin lymphoma. Ann Intern Med
1988;109:114 – 7.
[123] Bomalaski JS, Clark MA. Serum uric acid-lowering therapies: where are we heading in management
of hyperuricemia and the potential role of uricase. Curr Rheumatol Rep 2004;6:240 – 7.
[124] Savient Pharmaceuticals Inc. Patient dosing in phase 2 clinical trial of puricase for severe gout
completed. 12 Jan 2005. Available at: www.pharma-lexicon.com/medicalnews.php?newsid=18815.
Accessed May 31, 2005.
[125] Hepburn AI, Kaye SA, Feher MD. Fenofibrate; a new treatment for hyperuricemia and gout?
Ann Rheum Dis 2001;60:984 – 5.
[126] Yamamoto T, Moriwaki Y, Takahashi S, et al. Effect of fenofibrate on plasma concentration
and urinary excretion of purine bases and oxypurinol. J Rheumatol 2001;28:2294 – 7.
[127] Takahashi S, Moriwaki Y, Yamamoto T, et al. Effects of combination treatment using anti-
hyperuricemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis
2003;62:572 – 5.
[128] Feher MD, Hepburn AL, Hogarth MB, et al. Fenofibrate enhances urate reduction in men
treated with allopurinol for hyperuricemia and gout. Rheumatol 2003;42:321 – 5.
[129] Wortmann RL. Recent advances in the management of gout and hyperuricemia. Curr Opin
Rheumatol 2005;17:319 – 24.
[130] Sica DA, Schoolwerth AC. Part 1. Uric acid and losartan. Curr Opin Nephrol Hypertens 2002;
11:475 – 82.
[131] Ohnishi K, Kohno M, Yukiiri K, et al. Influence of the angiotensin II receptor antagonist
losartan on diuretic-induced metabolic effects in elderly hypertensive patients: comparison with
a calcium channel blocker. Int J Clin Pharmacol Ther 2001;39:417 – 22.
[132] Kamper AL, Nielsen AH. Uricosuric effect of losartan in patients with renal transplants.
Transplantation 2001;72:671 – 4.
[133] Minghelli G, Seydoux C, Goy JJ, et al. Uricosuric effect of the angiotensin II receptor
antagonist losartan in heart transplant recipients. Transplantation 1998;66:268 – 71.
[134] Hbleggen A, Alderman MH, Kjedsen SE, et al. The impact of serum uric acid on cardio-
vascular outcomes in the LIFE study. Kidney Int 2004;65:1041 – 9.
[135] Niskanen LK, Laaksonen DE, Nyyssonen K, et al. Uric acid level as a risk factor for car-
diovascular and all-cause mortality in middle-aged men: a prospective cohort study. Arch Intern
Med 2004;164:1546 – 51.
[136] Bengtsson C, Lapidus L, Stendahl C, et al. Hyperuricemia and risk of cardiovascular disease
and overall death. A 12-year follow-up of participants in the population study of women in
Gothenburg, Sweden. Acta Med Scand 1988;224:549 – 55.
[137] Lehto S, Niskanen L, Ronnomaa T, et al. Serum uric acid is a strong predictor of stroke in
patients with non-insulin-dependent diabetes mellitus. Stroke 1998;29:635 – 9.
[138] Yamada H, Kotaki H, Furitsu H, et al. Mechanism of the uricosuric action of the anti-
inflammatory drug E3040 used to treat inflammatory bowel disease I: study using a rat model
of hyperuricemia. Biopharm Drug Dispos 1999;20:77 – 83.
[139] Isibuchi S, Morimoto H, Oe T, et al. Synthesis and structure-activity relationships of
1-phenylpyrazoles as xanthine oxidase inhibitors. Bioorg Med Chem Lett 2001;11:879 – 82.
[140] Yamada I, Fukunari A, Osajima T, et al. Pharmacokinetics/pharmacodynamics of Y-700, a
novel xanthine oxidase inhibitor, in rats and man. Nucleosides Nucleotides Nucleic Acids
2004;23:1123 – 5.
[141] Osajima T, Kamezawa M, Fukunari A, et al. Pharmacokinetics and pharmacodynamics of
Y-700, a potent and non-renal excretion type of xanthine oxidase inhibitor, in healthy male
volunteers. Arthritis Rheum 2003;48(Suppl):S530.
[142] Noma S, Verho M, Iwane I, et al. Safety, tolerability, pharmacokinetics and lowering uric acid
effect of repeated daily dosing with Y-700, a novel xanthine oxidase inhibitor, in healthy
male volunteers. Arthritis Rheum 2003;48(Suppl):S530.
[143] Ding Z, Dai Y, Wang Z. Hypouricemic action of scopoletin arising from xanthine oxidase
inhibition and uricosuric activity. Planta Med 2005;71:183 – 5.
Calcium Crystal Deposition Diseases:

Update on Pathogenesis and Manifestations
E.S. Molloy, MBa,T, G.M. McCarthy, MDb,c
a
Department of Rheumatic and Immunologic Diseases, Cleveland Clinic Foundation,
9500 Euclid Avenue, A50 Cleveland, OH 44195, USA
b
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland,
123 St Stephen’s Green, Dublin 2, Ireland
c
Department of Rheumatology, Mater Misericordiae University Hospital, Eccles Street,
Dublin 7, Ireland
Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate (CPPD)

crystals are associated with several human diseases, especially various forms of
acute and chronic joint inflammation and joint degeneration. This article reviews
recent work that has advanced knowledge of the clinical syndromes associated
with calcium crystal deposition and the underlying mechanisms that may
contribute to these pathologic manifestations.
Basic calcium phosphate crystals
BCP crystals are composed predominantly of partially carbonate-substituted

hydroxyapatite and include octacalcium phosphate (OCP), tricalcium phosphate,
and magnesium whitlockite. BCP crystals are associated with several rheu-
matic syndromes, including acute calcific periarthritis, soft tissue calcification,
osteoarthritis (OA), and other degenerative arthropathies, such as Milwaukee
shoulder syndrome (MSS). Recently, they also have been linked to breast cancer
and atherosclerosis.
The key mechanisms whereby BCP crystals may cause tissue damage are (1)
induction of mitogenesis; (2) upregulation of matrix metalloproteinase (MMP)
T Corresponding author. Cleveland Clinic Foundation, Department of Rheumatic and Immuno-

logic Diseases, 9500 Euclid Avenue, A50, Cleveland, OH 44195.
E-mail address: eamonn.molloy@ireland.com (E.S. Molloy).
384 molloy & mccarthy
production; (3) stimulation of cyclooxygenase (COX) 1 and 2 and prostaglandin

E2 (PGE2) production; (4) stimulation of cytokine production, in particular
interleukin (IL) 1b; and (5) induction of nitric oxide (NO) production.
Pathogenesis
The degree of damage that can occur in apatite-associated destructive ar-

thropathies is marked. The basis of cartilage damage by calcium-containing
crystals still is somewhat speculative. Theoretically, crystals in cartilage may
injure chondrocytes directly. BCP crystals are shown to stimulate production of
MMP-1 and -13 from porcine chondrocytes [1] and NO production from bovine
chondrocytes [2], making in vivo pathologic interaction between these crystals
and chondrocytes feasible. In pathologic specimens, however, crystals rarely are
seen in immediate contact with chondrocytes and found engulfed by chondro-
cytes even less frequently. A significant contribution to BCP crystal-associated
cartilage damage ultimately may be derived from effects of these crystals on
synoviocytes (discussed later).
Basic calcium phosphate crystal-cell interaction

One of the earliest cellular effects of BCP crystals is a bimodal increase in
intracellular calcium ([Ca2+]i). Using the photoactive dye, fura-2, in a human
fibroblast model, Halverson and colleagues demonstrated that BCP crystals in-
duce a rapid tenfold increase in [Ca2+]i within seconds, returning to baseline
within 8 minutes [3]. As this increase was not apparent when BCP crystals were
added in calcium-free media, this immediate rise in [Ca2+]i was the result of
an influx predominantly of calcium from the extracellular space, not a release
of calcium from intracellular stores. A second increment in [Ca2+]i started at
60 minutes and continued to increase up to at least 3 hours after stimulation.
In contrast, epidermal growth factor induced the early transient rise of [Ca2+]i
but not the later sustained release. Increasing phagolysosomal pH by pretreat-
ment with ammonium chloride prevented crystal dissolution and abolished
the second rise in [Ca2+]i but had no effect on the early transient peak [3].
More recent work has further elucidated the mechanisms by which BCP crystals
can interact with cells [4]. Sun and coworkers evaluated the hypothesis that BCP
crystals could stimulate the influx of other molecules, such as DNA fragments and
small peptides from the extracellular space, and thus modulate normal molecular
signaling. Luciferase activity was enhanced greatly (500–1000-fold) in a dose-
dependent manner in cancer cell lines treated with a BCP crystal-cytomegalovirus
promoter (pCMV) luciferase plasmid mixture. The time course of luciferase
activity followed a pattern similar to the first, rapid, transient rise in [Ca2+]i that
occurs in response to BCP crystals. These effects of BCP crystals were inhibited by
several anticalcification agents, including etidronate and, in particular, phos-
phocitrate [4]. These results suggest that BCP crystals may stimulate the endo-
cytosis of various extracellular molecules, such as DNA fragments, nucleotides, or
calcium crystal deposition diseases 385
small peptides, that might exert important but as yet uncharacterized effects,
potentially contributing to the pathogenesis of BCP crystal-associated diseases.
Induction of mitogenesis
BCP crystals demonstrate a mitogenic effect in vitro in fibroblast cell lines and
osteoarthritic synovial fibroblasts [1,5], which may explain the synovial pro-
liferation seen in BCP crystal-associated degenerative arthropathies. Increased
cellularity in the synovial lining enhances the capacity for secretion of MMPs
and cytokines, which may promote chondrolysis. BCP crystals also enhance
survival of and induce DNA synthesis in murine macrophages in vitro [6].
Enhanced local macrophage survival or proliferation in the synovium also could
contribute to the synovial hypertrophy seen in association with BCP crystals.
It has been established that the mitogenic response to BCP crystals requires
endocytosis and intracellular crystal dissolution [7]. BCP crystals increase phos-
pholipase C (PLC) activity in synovial fibroblasts [8], which should result in
accumulation of diacylglycerol and enhanced protein kinase C (PKC) activity.
Mitchell and colleagues show that downregulation of PKC is associated with
inhibition of crystal-induced mitogenesis in Balb/c-3T3 fibroblasts [9]. Further
investigation of the molecular mechanisms behind the mitogenic response to BCP
crystals indicates a role for nuclear factor kB (NF-kB), PKC, and activator
protein 1 (AP-1) induction [10]. The PKC inhibitor, staurosporine, prevents BCP
crystal-induced NF-kB and c-fos messenger RNA (mRNA) expression and
mitogenesis but not c-jun mRNA upregulation. Although high-affinity receptor
protein tyrosine kinases with resultant recruitment and activation of phosphati-
dylinositol 3-kinase (PI3K) mediate the mitogenic response to other stimuli,
neither is required for BCP crystal-induced cell proliferation [10]. BCP crystals
activate extracellular signal-regulated kinase 1 and 2 (ERK1/2) but not the p38
mitogen-activated protein kinase (MAPK) pathway in human foreskin fibroblasts
(HFF) [11]. BCP crystals also cause phosphorylation of cyclic adenosine
monophosphate response element-binding protein (CREB) on serine 133, a step
critical to CREB’s activity as a nuclear transcription factor. C-fos activation is
believed to occur by a mechanism involving CREB phosphorylation. PD98059,
an inhibitor of MEK1, an upstream activator of the MAPK pathway, and U0126,
an inhibitor of MEK1/2, significantly inhibited crystal activation of p42/44
MAPK, CREB serine 133 phosphorylation, c-fos, and cell proliferation in a dose-
dependent fashion [11]. Zeng and colleagues describe the induction of early
growth response gene (Egr) 2 by BCP crystals, which could stimulate the
activities of several transcription factors that are associated with cell proliferation,
such as c-fos, serum response factor (SRF), and c-myc [12]. This upregulation of
Egr-2 is abrogated by U0126, a specific p44/p42 MAPK inhibitor, and TMB8, a
calcium chelator, but not by p38 MAPK or PKC inhibitors. BCP crystals also
may induce fibroblast mitogenesis via induction of Egr-1. Zeng and colleagues
demonstrate by reverse transcription polymerase chain reaction (RT-PCR) and
Egr-1 promoter analysis that BCP crystals induce Egr-1 transcription via a PKC-
a–dependent ERK1/2 MAPK pathway. Overexpression of Egr-1 stimulates

mitogenesis in a human fibroblast cell line [13].
Induction of matrix metalloproteinases production

MMPs are proteases that accelerate the degradation of cartilage matrix com-
ponents, such as type II collagen, fibronectin, laminin, and proteoglycan. BCP
crystals are shown to upregulate MMP-1, -3, -8, and -9 production from human
fibroblasts [14–17] and MMP-1 and -13 from porcine chondrocytes [1]. These
observations correlate with the detection of collagenase and neutral protease
activities in synovial fluid from patients who have MSS [18]. BCP crystals also
can downregulate the synthesis of tissue inhibitor of metalloproteinases (TIMP)
1 and 2 [19], which are capable of inhibiting the activities of all known MMPs.
This shifts the balance of MMP/TIMP activity further in favor of excess pro-
tease activity. It previously has been postulated that loss of coordinated regula-
tion of MMP/TIMP underlies the cartilage degradation in OA [20,21].
Although crystal endocytosis is necessary for BCP crystals to induce MMP-1
and MMP-3 synthesis, intralysosomal crystal dissolution is not, in contrast to the
requirement for both events to occur to obtain the maximal mitogenic response to
BCP crystals [22]. The collagenase subfamily of the MMPs includes MMP-1
(collagenase 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3). The col-
lagenase promoter contains a 12-O-tetradecanoyl-phorbol-13-acetate (TPA) re-
sponse element, the transcriptional activity of which depends on AP-1. AP-1 is a
heterodimer of the c-fos and c-jun proteins, which are known to be induced by
BCP crystals [16]. It also previously has been demonstrated that the ERK1/2
MAPK pathway is a key signal transduction pathway involved in crystal-induced
MMP-1 and -3 expression [23].
Recent studies have further characterized the molecular mechanisms involved in
BCP crystal induction of MMP production. Sun and coworkers [24] report that
human MMP-1 induction by BCP crystals is Ras dependent and involves multiple
elements, including AP-1 and polyomavirus enhancer activator 3 (PEA-3). AP-1
and PEA-3 are implicated in MMP-1 induction by phorbol ester, and their coop-
eration also is reported for other promoters. By transfecting canine synovial fibro-
blasts with human MMP-1 luciferase reporter plasmids, it is demonstrated that
the induction of MMP-1 promoter by BCP crystals is mediated largely through
the 72AP-1 element. Elimination of either the 72AP-1 or the 88PEA-3
elements abolishes the hMMP-1 promoter activity in response to BCP crystals. It
also is shown that cotransfection of plasmids encoding dominant negative Ras,
Raf, and MEK1/2 can block BCP crystal induction of MMP-1 and that U0126, a
MEK1/2-specific inhibitor, abrogates BCP crystal MMP-1 and c-fos induction.
Plasmids encoding dominant negative Rac or Rho have no effect on MMP-1 up-
regulation. The investigators conclude that multiple elements, including AP-1 and
PEA-3, are involved in BCP crystal-induced MMP-1 gene expression and that the
induction follows the Ras/Raf/MAPK/c-fos/AP-1/MMP-1 signaling pathway [24].
Reuben and colleagues [25] demonstrate that BCP crystal stimulation of
MMP-1 and MMP-3 mRNA and protein expression in human fibroblasts is de-
pendent on the calcium-dependent PKC signal transduction pathway and also

show the specific involvement of the PKC-a isoenzyme. They also identified that
the calcium-dependent PKC pathway cooperates with the distinct calcium-
independent p44/p42 MAPK pathway, which is also activated by BCP crystals in
human fibroblasts. More recently, it has been demonstrated that activation of
ERK1/2 lies downstream of the calcium-independent PKC isoform, PKC-m, in
BCP crystal-induced MMP-1 and -3 upregulation [26]. The investigators con-
clude that there are two independent but parallel pathways through which BCP
crystals activate fibroblasts, a calcium-dependent PKC-a–mediated pathway and
a calcium-independent pathway that involves sequential activation of PKC-m and
ERK1/2 MAPK.
Cytokine upregulation
Evidence is accumulating regarding the role of cytokines, such as trans-
forming growth factor-b1 (TGF-b1), IL-1b, and tumor necrosis factor a (TNF-a),
in the pathogenesis of OA [27]. IL-1b is believed the key cytokine involved in
progression of OA, whereas TNF is involved at disease onset. TGF-b1 and IL-1b
in particular are implicated in the regulation of crystal formation [28]. In turn,
BCP crystals can upregulate expression of various cytokines. BCP crystals are
shown to increase IL-1b expression in HFF [29] and in chondrocytes [2]. BCP
crystals also are shown to induce TNF-a mRNA expression and protein synthesis
in a murine monocyte cell line known to produce high levels of TNF-a, although
the capacity of BCP crystals to directly induce TNF-a and IL-1b in human
monocytes is weaker and less consistent than monosodium urate [30]. Aug-
mented proinflammatory cytokine (TNF-a, IL-1b and IL-8) mRNA expression
and protein secretion are detected in BCP crystal-stimulated monocyte-derived
macrophages in vitro [31]. PKC-a, ERK1/2, and c-jun N-terminal kinase (JNK)
activity are required for BCP crystal-induced TNF-a synthesis. PKC-a is an
upstream activator of ERK1/2 but not JNK. The precise contribution of cyto-
kine production in mediating the pathologic effects of BCP crystals requires
further clarification.
Increased prostaglandin production

Although the contribution of PGs to inflammation and nociception presum-
ably is the basis of the symptomatic benefit derived by OA patients taking
NSAIDs, the role of PGs in the pathophysiology of OA is not defined clearly.
Nevertheless, it is demonstrated that PGE2 mediates the IL-1b–induced cartilage
degradation in a synovial membrane-cartilage coculture model [32]. COX-2 ex-
pression is increased in the synovial blood vessels, lining cells, and fibroblast-like
cells in OA synovium [33]. COX-2 also is expressed in OA cartilage [33–35],
which releases PGE2 spontaneously in quantities 50-fold higher than normal
cartilage and 18-fold higher than normal cartilage in the presence of proinflam-
matory stimuli [35]. Knorth and colleagues, however, demonstrate that COX-1
may contribute to the pool of PGs in OA synovium [36].
It has been known for some time that BCP crystals can increase PGE2 pro-
duction in mammalian cells [14,37,38]. Only recently, however, has it been
demonstrated that this induction of PGE2 is associated with induction of both
COX isoforms in HFF [29]. Real-time PCR demonstrates a 23-fold upregula-
tion of COX-2 mRNA by BCP crystals, maximal at 4 hours. BCP crystals also
upregulate IL-1b mRNA expression peaking at 8 hours. Thus, although IL-1b
may contribute to the observed COX-2 upregulation, the different time courses of
induction suggest that BCP crystals induce COX-2 directly. Maximal (1.75-fold)
COX-1 mRNA induction is seen at 24 hours. Inhibition of PKC and PI3K
diminishes BCP crystal-induced COX-2 mRNA expression. BCP crystal-induced
COX-2 mRNA expression also is abrogated by phosphocitrate, which seems
to inhibit all biologic activities of BCP crystals. PGE2 production at 4 hours
is abolished by pretreatment with NS398, a selective COX-2 inhibitor. NS398,
however, only partially inhibits PGE2 production at 30 hours, suggesting that
COX-1 also contributes to BCP crystal-induced PGE2 production in human fi-
broblasts [29].
Increased nitric oxide production

NO is a pleiotropic mediator that is implicated in structural damage to OA
cartilage [39]. NO is generated by oxidation of arginine, catalyzed by the NO
synthases (NOS). One inducible NOS (iNOS) and two constitutive NOS are
identified. iNOS expression is upregulated in human OA cartilage [40]. Selective
inhibition of iNOS in a canine OA model results in reductions in MMP synthesis,
IL-1b expression, PGE2 production, chondrocyte apoptosis, and amelioration
of structural damage [41–44]. NO also is implicated in chondrocyte apoptosis,
which can in turn promote the formation of calcium-containing crystals [45].
Ea and coworkers find that OCP induces NO production and upregulated
iNOS expression in bovine chondrocytes [2]. This is mediated by activation of
p38 MAPK and JNK pathway by OCP, most likely under the control of AP-1.
Although OCP crystals also upregulate IL-1b expression, the induction of iNOS
expression and NO production is independent of IL-1b. Their study identified
another potential mechanism whereby BCP crystals can damage cartilage. Other
work suggests that BCP crystals induce iNOS and increase NO production
in OA synovial fibroblasts [46]. The involvement of NO production in BCP
crystal-induced MMP synthesis, IL-1b expression, and PGE2 production is
not elucidated but is of considerable interest as it would confirm the potential
of iNOS as an attractive therapeutic target in BCP crystal-associated arthritis.
Clinical manifestations of basic calcium phosphate crystal deposition
Intra-articular basic calcium phosphate deposition

The understanding of the exact relationship between intra-articular BCP
crystals and joint pathology is incomplete, especially because specialized tech-
niques are required to identify the crystals. Nonetheless, existing data support the
pathogenic role of BCP crystals in articular tissue degeneration. Intra-articular
BCP crystal deposition is associated with OA and MSS and with acute synovi-
tis and chronic arthritis, including erosive OA. The prevalence of intra-articular
BCP crystal deposition is not established. Apatite crystals are found in up to
67% of synovial fluid samples from patients who have knee joint OA [47–50].
BCP and CPPD crystals may coexist in 16% of OA synovial fluids [49]. BCP
crystals are found in 23% at first aspiration, but in 58% at the final aspiration
(at a mean interval of 3.6 F 1.6 years), suggesting that BCP crystals are gen-
erated as part of the pathologic process in OA [49]. The prevalence in normal
joints at different ages is not known. MSS and related BCP crystal-associated
destructive arthropathies also are of unknown prevalence.
OA is the most common form of arthritis and its prevalence is expected to
rise considerably as the population ages. It is the foremost cause of disability in
the elderly population, disabling approximately 10% of those over age 60 [51].
Estimates of the annual cost of OA to the United States economy exceed
$60 billion [51]. Concurrence of BCP crystals and OA is well established.
Crystals of BCP frequently are found in OA cartilage, synovium, and synovial
fluid. It is suggested that many OA joint fluids contain clusters of BCP crystals
that are too small or too few in number to be identified by conventional tech-
niques [50]. Ample data support the role of BCP crystals in cartilage degen-
eration, as their presence correlates strongly with severity of radiographic OA
[49,52], and larger joint effusions are seen in affected knee joints when com-
pared with joint fluid from OA knees without crystals [53].
MSS, a distinctive type of destructive arthropathy found in elderly patients, is
prototypic of BCP crystal-associated joint degeneration [54–56]. It is associated
with rotator cuff defects and numerous aggregates of BCP crystals in the fluids of
affected joints [55]. Although the shoulder predominates, knees, hips, elbows,
and other joints may be involved [54]. Joint effusion typically is present and may
be massive, extending into the subdeltoid region. Aspiration of affected shoul-
der joints routinely yields 3 to 160 mL of synovial fluid that frequently is blood
tinged and has a low, predominantly mononuclear, cell count. Rupture of the
effusion can lead to a massive extravasation of blood and synovial fluid into
the surrounding tissues [57]. The natural history of the condition is unclear, but
many cases seem to stabilize after a year or 2, with reduction of symptoms, joint
effusions, and no further radiographic changes. A kindred of five generations
affected with familial OA and MSS recently was described [58]. Twenty-eight
patients had varying degrees of upward subluxation of the humeral head. Of these
28 patients, seven had MSS. The mild to moderate upward subluxation of the
glenohumeral head observed in 22 remaining affected family members is be-
lieved possibly a precursor to the development of MSS.
Extra-articular basic calcium phosphate deposition

BCP crystals may form periarticular deposits that frequently are asymptom-
atic or give rise to acute calcific periarthritis or chronic calcific tendonitis. BCP
crystals also may be deposited in the soft tissues secondary to other diseases,
such as chronic renal failure, connective tissue diseases (in particular derma-
tomyositis and scleroderma), and chronic neurologic conditions. Idiopathic BCP

crystal deposition (or CPPD crystal deposition) also can occur, giving rise to
’’tumoral calcinosis,’’ or ligamentous calcification. When the latter surrounds the
odontoid process, it is termed the ‘‘dcrowded dens’’ syndrome.
There are few systematic studies of the incidence or prevalence of juxta-
articular deposits of BCP crystals. These deposits often are asymptomatic and
noted most commonly by chance on radiographs taken for other reasons. In a
large study of office workers published in 1941, a 2.7% prevalence of shoulder
deposits was noted in a North American, predominantly white, population, 34%
to 45% of which were associated with clinical problems [59]. Women were
affected more commonly than men and the prevalence was highest in those
between ages 31 and 40 (19.5%).
Pathologic assessments show that the calcific deposits are located in tendons,
peritendinous tissues, bursae, or ligaments. It is suggested that ‘‘dystrophic’’ ten-
don calcification occurs as a consequence of local trauma, ischemia, and ne-
crosis of tendons. Calcific periarthritis frequently localizes to the supraspinatus
tendon in a poorly vascularized area of the tendon sheath known as the critical
zone, a few millimeters from the bone insertion. Similarly, calcification in other
tendons seems to occur preferentially in hypovascular segments, suggesting local
necrosis followed by ectopic calcification.
Other evidence indicates that calcifying tendinitis is an active, cell-mediated
process in which local vascular and mechanical changes result in focal trans-
formation of tendinous tissues into fibrocartilaginous material containing chon-
drocytes. This is followed by local deposition of hydroxyapatite crystals within
extracellular matrix vesicle-like structures derived from these chondrocytes [60].
The most striking clinical presentation of juxta-articular BCP crystal deposits
is acute calcific periarthritis [61,62]. It most commonly involves the shoulder
but can occur at any joint. Calcific periarthritis is reported in children as young
as 3 but seems uncommon in the elderly. This suggests that many of the deposits
seen in young adults disappear spontaneously. Acute calcific periarthritis seems
to be induced by rupture of the deposit, possibly exposing the crystals to phago-
cytes. BCP crystals are shown to be intrinsically phlogistic. They are phago-
cytosed in vitro resulting in the release of inflammatory mediators [63]. Similarly,
in vivo models of inflammation show a brisk inflammatory reaction to apatite,
and injection into the tissues of human volunteers results in an inflammatory
response [64]. Phagocytosis may be one of the main ways in which the crystals
are removed.
Calcific deposits in the periarticular tissues also are associated with chronic
pain syndromes. In the shoulder, however, because chronic shoulder pain and
calcification are common and because prior damage to tendons may predispose to
the calcification, it is difficult to define what contribution, if any, the deposits
themselves make to the clinical findings. In some patients, recurrent acute attacks
around the shoulder, separated by pain-free periods of months or years, are fol-
lowed by the development of chronic pain. Damage to the tendons and muscles
of the rotator cuff may result and may lead to total disruption of the cuff apparatus.
Basic calcium phosphate crystal deposition in other diseases

Although BCP crystals long have been implicated in the pathogenesis of
several rheumatic syndromes, recent work has elucidated their potential in-
volvement in other diseases, including atherosclerosis and breast cancer. Arte-
rial intimal calcification is a common clinical and pathologic finding in patients
who have atherosclerosis [65] and the degree of intimal calcification has prog-
nostic significance [66,67]. Hydroxyapatite is the major constituent of the cal-
cific deposits seen in atherosclerotic vessels. Bostrom and colleagues describe a
microvascular pericyte-like cell that could undergo osteoblastic differentiation
under certain in vitro conditions in normal and diseased arteries [68]. These
calcifying vascular cells, as they were termed, localized to areas with increased
expression of bone morphogenetic protein 2, a potent osteogenic factor. Vascu-
lar smooth muscle cells (VSMCs) also may undergo osteoblastic differentiation.
Chondrocytes and osteoclasts also are identified in arterial tissue [69]. As these
osteoblasts and chondrocytes have the potential to generate matrix vesicles and
promote tissue calcification, the process of arterial calcification may be an active
cell-mediated process analogous to the deposition of hydroxyapatite in bone and
in articular tissues in BCP crystal-associated joint disease.
Macrophages play a key role in plaque development and rupture [70]. It has
been demonstrated that macrophages colocalize with hydroxyapatite particles in
the atheromatous plaque [65]. Recent work by Nadra and colleagues implicates
BCP crystals in the pathophysiology of atherosclerosis [31]. Engulfment of BCP
crystals by monocyte-derived macrophages results in secretion of TNF-a, IL-1b,
and IL-8. Involvement of PKC, ERK1/2, and JNK pathways in BCP crystal-
induced TNF-a production is demonstrated. The supernatants from BCP crystal-
stimulated macrophages activate endothelial cells in vitro as assessed by flow
cytometry measuring adhesion molecule expression and promotion of leukocyte
rolling and adhesion as visualized in a flow chamber. These data suggest that
BCP crystals within the atherosclerotic lesion, through their interaction with in-
timal macrophages, likely act as an inflammatory nidus by activating endothe-
lial cells and promoting inflammation. Other potential, but unproved, effects
of BCP crystals within atherosclerotic plaque include increase in plaque insta-
bility via induction of MMPs or, possibly, by TNF-a–mediated VSMC apoptosis.
The consequent production of TNF-a could promote smooth muscle cell
osteoblastic differentiation, thus increasing hydroxyapatite deposition and es-
tablishing a vicious circle of events within the vessel wall, which could explain
the observed positive correlation between coronary arterial calcification and car-
diovascular events.
Radiographic mammary microcalcifications are one of the most pertinent
diagnostic markers of breast cancer. Breast tissue calcification in the form of
hydroxyapatite is associated strongly with malignancy [71] and with poorer out-
comes compared with patients who do not have mammographic calcification
[72,73]. Morgan and coworkers demonstrate that BCP crystals augment mito-
genesis in breast cancer cell lines MCF7 and Hs578T and in normal human
mammary epithelial cells [74]. Treatment with bafilomycin A1, a proton pump
ATPase inhibitor, diminishes BCP-induced mitogenesis to control levels [75],

suggesting endocytosis and intracellular crystal dissolution are required for
BCP-induced mitogenesis. BCP crystals also stimulated production of MMP-1
in Hs578T cells; MMP-2, -9, and -13 in MCF7 cells; and MMP-9 in human
mammary epithelial cell lines [75]. MMPs can facilitate invasion and metasta-
sis of tumor cells by degrading connective tissue matrix components, including
basement membranes. Furthermore, BCP crystals enhanced PGE2 levels in
Hs578T cells considerably, which was attributable at least in part to upregulation
of COX-2 and can be prevented by pretreatment with aspirin [75]. Moreover,
high levels of PGE2 often are associated with estrogen-receptor negative tumors
that exhibit a high metastatic potential [76]. IL-1b, which can upregulate MMP-1
gene expression and PGE2 production in human cells, is induced potently by
BCP crystals at 2 and 4 hours. Treatment with phosphocitrate block BCP crystal-
induced mitogenesis and COX-2, MMP-1, and IL-1b induction at the tran-
scriptional level [75]. These results suggest that BCP crystals contained in
mammary microcalcifications are not an innocent bystander and may aggravate
the pathologic process of breast cancer.
Calcium pyrophosphate dihydrate crystals
Pathogenesis
CPPD crystals have several in vitro properties in common with BCP crystals,
such as induction of proto-oncogenes, mitogenesis, and MMP production, that
may contribute to joint degeneration. In addition, the ability of CPPD crystals to
upregulate production of IL-8, a potent neutrophil chemoattractant, and to ac-
tivate neutrophils, with a resultant release of reactive oxygen species and de-
granulation, underlies the acute inflammation of pseudogout. CPPD crystals
increase synovial neutrophil numbers not only by cellular recruitment but also by
inhibiting neutrophil apoptosis.
Calcium pyrophosphate dihydrate crystals crystals bind Toll-like receptors

Toll-like receptors (TLRs) are the human homologs of a family of receptors
with roles in host defense and inflammation that are widespread throughout
nature. Eleven TLRs are identified, which share a cytosolic Toll/IL-1 receptor
(TIR) domain that also is found in members of the IL-1 receptor family and an
extracellular leucine-rich repeat region that mediates ligand recognition [77].
TLR1, -2, -4, -5, and -6 are localized to the plasma membrane, whereas the others
are expressed preferentially in intracellular compartments, such as endosomes.
TLRs are not restricted to the site of preferential expression; for example, TLR2
is found to localize to phagosomes after exposure to certain microbial products.
Recognition of microbial components, for example lipopolysaccharide (mainly
TLR4) and peptidoglycan (TLR2), triggers the initial innate immune response
that leads ultimately to inflammatory gene expression and clearance of the
infectious agent [78]. Several nonbacterial ligands, however, are identified for
certain TLRs, such as fatty acids, fibronectin, and hyaluronic acid [79,80]. The
TIR domain transduces upregulation of proinflammatory genes through acti-
vation of NFkB. Cytosolic proteins, known as adaptor molecules (eg, MyD88,
Mal), couple TLRs through the TIR domain to downstream signaling pathways
and activation of transcription factors [77].
Certain TLRs are expressed in normal and rheumatoid arthritis synovial fi-
broblasts [81–83], indicating the potential for innate immune responses to be
driven by mesenchyme-derived cells in arthritis. A novel study by Liu-Bryan and
coworkers investigates the potential role of TLR2 in CPPD crystal-induced NO
production in chondrocytes [84]. TLR2 is expressed constitutively in chondro-
cytes and upregulated in articular cartilage in OA. This study demonstrates that
CPPD crystals use TLR2-mediated signaling to initiate NO production in chon-
drocytes. These results indicate that innate immunity may contribute to inflam-
mation and cartilage degradation in pseudogout.
Neutrophil chemotaxis
In addition to a direct chemotactic effect, IL-8 also can enhance neutrophil
chemotaxis by stimulating production of other chemotactic factors (eg, leu-
kotriene B4 and platelet activating factor) by activated neutrophils [85]. IL-8 also
can promote neutrophil recruitment by enhancing neutrophil-endothelial cell
adhesion by upregulation of neutrophil integrins [86]. Furthermore, IL-8 can
augment neutrophil activation and protease release [85]. Thus, IL-8 can play a
key role in the generation of the acute inflammation typical of pseudogout and
also may contribute to matrix degradation in CPPD crystal-associated arthritis.
Liu and colleagues [87] have explored the signal transduction pathways involved
in CPPD crystal-induced IL-8 expression in human monocytic cells. CPPD
crystals induce activation of JNK, ERK1/2, and p38 MAPK pathways. CPPD
crystal induction of the IL-8 promoter is mediated through ERK1/2 signaling and
requires NF-kB complex c-Rel/RelA and AP-1 transcriptional activity. NF–IL-6
is involved to a lesser degree. Activation of the p38 MAPK pathway modulates
AP-1 binding to the IL-8 promoter in response to CPPD crystals, although the
downstream effectors of this response remain to be elucidated. Upregulation
of expression of certain genes that can promote IL-8 expression, such as IL-1,
TNF-a, and COX-2, may play a role given that p38 MAPK inhibitors can sup-
press these responses in CPPD crystal-stimulated cells. The significance of
activation of the JNK pathway by CPPD crystals in this study is not certain at this
time, but this cascade may participate in regulation of activation of AP-1, NF-kB,
and NF–IL-6.
Neutrophil activation
Tudan and colleagues demonstrate that CPPD crystal-induced neutrophil
oxidative and degranulation responses are mediated via PKC, PLC (probably
the PLC g2 isoform), and PI3K/Akt pathways [73,88–90]. They also note an
association between ERK1/2 and neutrophil activation that is PI3K independent.
Full inhibition of any of these pathways, however, results in only a partial

suppression of CPPD crystal-induced neutrophil activation not exceeding 50%
inhibition. Most recently, they examined the role of p38 MAPK in CPPD crystal-
induced neutrophil responses [91]. CPPD crystal-induction of p38 MAPK also is
only partly responsible for the neutrophil oxidative and degranulation response,
as evidenced by the reduction by approximately 50% of CPPD crystal-induced
superoxide anion generation and myeloperoxidase and lysozyme release after
pretreatment with SB203580, a specific p38 MAPK inhibitor.
Inhibition of neutrophil apoptosis

Neutrophils generally have short lifetimes of less than 24 hours, after which
they undergo apoptosis facilitating their clearance by other phagocytic cells,
typically macrophages. A significant delay in apoptosis and clearance may lead to
excessive accumulation and tissue damage by prolonging neutrophil responses to
the inflammatory stimulus. In the study by Tudan and colleagues [91], CPPD
crystals induces a twofold transient increase in p38 phosphotransferase kinase
activity above basal levels but suppressed the TNF-a–associated sixfold in-
duction of p38 activity to levels seen with CPPD stimulation alone. This modu-
latory effect of CPPD crystals seems to reduce p38 MAPK activity below a
threshold level required to induce apoptosis in neutrophils. This probably occurs
via the inhibition of caspase 3, previously noted to be involved in CPPD crystal-
induced repression of TNF-a–induced neutrophil apoptosis [92]. Furthermore,
CPPD crystal-related suppression of TNF-a–induced caspase 3 activation and
neutrophil apoptosis is abrogated by inhibition of the MEK1/2-ERK1/2 or
PI3K/Akt pathways.
Effects on chondrocytes and osteoblasts

The deposition of monosodium urate (MSU) crystals in the joint can promote
not only acute inflammation but also chronic inflammation that may result in
cartilage damage and bony erosions. Bouchard and coworkers examined the
interaction between CPPD crystals and human osteoblastic cells in vitro [93].
CPPD crystals adhered to and were phagocytosed partly by the cells and stim-
ulated COX-2, PGE2, IL-6, and IL-8 production. They also diminished the 1,25
dihydroxycholecalciferol-induced activity of alkaline phosphatase and osteocal-
cin. Thus, CPPD crystals can alter the phenotype of these cells, potentially reduc-
ing the anabolic effect of osteoblasts on bone, which may contribute to damage
to juxtaarticular bone in crystal-associated arthritis.
Clinical manifestations of CPPD crystal deposition
Although there is some overlap, CPPD crystals differ from BCP crystals in
spectrum of their clinical manifestations, despite their frequent coexistence within
articular tissues. The most frequent manifestation of CPPD deposition is chon-
drocalcinosis, the asymptomatic radiographic finding of calcification of articular
or fibrocartilage. CPPD deposition is associated with attacks of acute pseudo-
gout, characterized by joint effusions with marked neutrophilia and a form of

secondary OA (pyrophosphate arthropathy) with a pattern of joint involve-
ment that differs from primary OA. The latter most commonly involves the knee
followed by the wrists, metacarpophalangeal joints, hips, shoulders, elbows, and
ankles. CPPD crystals, however, also may be found in the synovial fluids of
patients who have primary OA, either alone or in association with BCP crys-
tals [49,50]. CPPD also, more rarely, may present with a pseudorheumatoid or
pseudoankylosing spondylitis pattern or may mimic neuropathic arthropathy.
Tenosynovitis also is reported and is associated with tendon rupture [94]. Soft-
tissue CPPD deposits may present as tumor-like masses, analogous to the tumoral
calcinosis of BCP crystals, including presentation as the crowded dens syn-
drome [95]. These lesions may present with severe neurologic symptoms [96,97].
Yamakawa and colleagues describe five cases of tumoral CPPD deposition and
review the 54 case reports in the literature [98]. They propose that these patients
can be divided into two broad categories based on the location of the deposit:
central (head and neck) and distal (extremity). The most notable difference
between these groups was the differing modes of presentation. The central de-
posits presented most frequently with a painful mass (46%) or neurologic dis-
turbance (33%), whereas the distal type generally presented with a painless mass
or swelling (57%) or an acute attack with a picture resembling tophaceous gout
(38%). There was a histologic finding of chondroid metaplasia within and around
these lesions, as CPPD crystals can be generated within this metaplastic cartilage
analogous to the postulated mechanism in articular cartilage.
Summary
BCP and CPPD crystals are associated with distinct clinical syndromes. Al-
though there are some similarities in the cellular responses to these crystals,
specific effects of each crystal type are reported that may explain their differing
clinical presentations. Advances have been made in the understanding of the
pathophysiology of crystal-associated diseases, which may in the future be trans-
lated into effective treatments for these disorders.
References
[1] McCarthy GM, Westfall PR, Masuda I, et al. Basic calcium phosphate crystals activate human
osteoarthritic synovial fibroblasts and induce matrix metalloproteinase-13 (collagenase-3) in
adult porcine articular chondrocytes. Ann Rheum Dis 2001;60:399 – 406.
[2] Ea H-K, Uzan B, Rey C, et al. Octacalcium phosphate crystals directly stimulate expression of
inducible nitric oxide synthase through p38 and JNK mitogen-activated protein kinases in
articular chondrocytes. Arthritis Res Ther 2005;7:R915 – 26.
[3] Halverson PB, Greene A, Cheung HS. Intracellular calcium responses to basic calcium
phosphate crystals in fibroblasts. Osteoarthritis Cartilage 1998;6:324 – 9.
[4] Sun Y, Zeng XR, Wenger L, et al. Basic calcium phosphate crystals stimulate the endocytotic
activity of cells-inhibition by anti-calcification agents. Biochem Biophys Res Commun 2003;

312:1053 – 9.
[5] Cheung HS, Story MT, McCarty DJ. Mitogenic effects of hydroxyapatite and calcium pyro-
phosphate dihydrate crystals on cultured mammalian cells. Arthritis Rheum 1984;27:668 – 74.
[6] Hamilton JA, McCarthy G, Whitty G. Inflammatory microcrystals induce murine macrophage
survival and DNA synthesis. Arthritis Res 2001;3:242 – 6.
[7] Cheung HS, McCarty DJ. Mitogenesis induced by calcium-containing crystals. Role of intra-
cellular dissolution. Exp Cell Res 1985;157:63 – 70.
[8] Rothenberg RJ, Cheung H. Rabbit synoviocyte inositol phospholipid metabolism is stimulated
by hydroxyapatite crystals. Am J Physiol 1988;254:C554 – 9.
[9] Mitchell PG, Pledger WJ, Cheung HS. Molecular mechanism of basic calcium phosphate crystal-
induced mitogenesis. Role of protein kinase C. J Biol Chem 1989;264:14071 – 7.
[10] McCarthy GM, Augustine JA, Baldwin AS, et al. Molecular mechanism of basic calcium
phosphate crystal-induced activation of human fibroblasts. Role of nuclear factor kappab, acti-
vator protein 1, and protein kinase c. J Biol Chem 1998;273:35161 – 9.
[11] Nair D, Misra RP, Sallis JD, et al. Phosphocitrate inhibits a basic calcium phosphate and calcium
pyrophosphate dihydrate crystal-induced mitogen-activated protein kinase cascade signal trans-
duction pathway. J Biol Chem 1997;272:18920 – 5.
[12] Zeng XR, Sun Y, Wenger L, et al. Induction of early growth response gene Egr2 by basic calcium
phosphate crystals through a calcium-dependent protein kinase C-independent p44/42 mitogen-
activated protein kinase pathway. Cells Tissues Organs 2003;174:63 – 72.
[13] Zeng XR, Sun Y, Wenger L, et al. Basic calcium phosphate crystal-induced Egr-1 expression
stimulates mitogenesis in human fibroblasts. Biochem Biophys Res Commun 2005;330:658 – 64.
[14] Cheung HS, Halverson PB, McCarty DJ. Release of collagenase, neutral protease, and pros-
taglandins from cultured mammalian synovial cells by hydroxyapatite and calcium pyrophos-
phate dihydrate crystals. Arthritis Rheum 1981;24:1338 – 44.
[15] McCarthy GM, Mitchell PG, Cheung HS. The mitogenic response to stimulation with basic
calcium phosphate crystals is accompanied by induction and secretion of collagenase in human
fibroblasts. Arthritis Rheum 1991;34:1021 – 30.
[16] McCarthy GM, Mitchell PG, Struve JA, et al. Basic calcium phosphate crystals cause coordinate
induction and secretion of collagenase and stromelysin. J Cell Physiol 1992;153:140 – 6.
[17] Reuben PM, Wenger L, Cruz M, et al. Induction of matrix metalloproteinase-8 in human
fibroblasts by basic calcium phosphate and calcium pyrophosphate dihydrate crystals: effect of
phosphocitrate. Connect Tissue Res 2001;42:1 – 12.
[18] Halverson PB, Cheung HS, McCarty DJ, et al. ‘‘Milwaukee shoulder’’–association of micro-
spheroids containing hydroxyapatite crystals, active collagenase, and neutral protease with
rotator cuff defects. II. Synovial fluid studies. Arthritis Rheum 1981;24:474 – 83.
[19] Bai G, Howell DS, Howard GA, et al. Basic calcium phosphate crystals up-regulate metallo-
proteinases but down-regulate tissue inhibitor of metalloproteinase-1 and -2 in human fibro-
blasts. Osteoarthritis Cartilage 2001;9:416 – 22.
[20] Martel-Pelletier J, McCollum R, Fujimoto N, et al. Excess of metalloproteases over tissue
inhibitor of metalloprotease may contribute to cartilage degradation in osteoarthritis and
rheumatoid arthritis. Lab Invest 1994;70:807 – 15.
[21] Dean DD, Martel-Pelletier J, Pelletier JP, et al. Evidence for metalloproteinase and metallo-
proteinase inhibitor imbalance in human osteoarthritic cartilage. J Clin Invest 1989;84:678 – 85.
[22] McCarthy GM, Cheung HS, Abel SM, et al. Basic calcium phosphate crystal-induced col-
lagenase production: role of intracellular crystal dissolution. Osteoarthritis Cartilage 1998;6:
205 – 13.
[23] Brogley MA, Cruz M, Cheung HS. Basic calcium phosphate crystal induction of collagenase 1
and stromelysin expression is dependent on a p42/44 mitogen-activated protein kinase signal
transduction pathway. J Cell Physiol 1999;180:215 – 24.
[24] Sun Y, Wenger L, Brinckerhoff CE, et al. Basic calcium phosphate crystals induce matrix
metalloproteinase-1 through the Ras/mitogen-activated protein kinase/c-Fos/AP-1/metallopro-
teinase 1 pathway. Involvement of transcription factor binding sites AP-1 and PEA-3. J Biol
Chem 2002;277:1544 – 52.
[25] Reuben PM, Brogley MA, Sun Y, et al. Molecular mechanism of the induction of
metalloproteinases 1 and 3 in human fibroblasts by basic calcium phosphate crystals. Role
of calcium-dependent protein kinase C alpha. J Biol Chem 2002;277:15190 – 8.
[26] Reuben PM, Sun Y, Cheung HS. Basic calcium phosphate crystals activate p44/42 MAPK
signal transduction pathway via protein kinase Cmicro in human fibroblasts. J Biol Chem
2004;279:35719 – 25.
[27] Goldring SR, Goldring MB, Buckwalter J. The role of cytokines in cartilage matrix degeneration
in osteoarthritis. Clin Orthop Relat Res 2004;427:S27 – 36.
[28] Picher M, Graff RD, Lee GM. Extracellular nucleotide metabolism and signaling in the
pathophysiology of articular cartilage. Arthritis Rheum 2003;48:2722 – 36.
[29] Morgan MP, Whelan LC, Sallis JD, et al. Basic calcium phosphate crystal-induced prostaglan-
din E2 production in human fibroblasts: role of cyclooxygenase 1, cyclooxygenase 2, and
interleukin-1beta. Arthritis Rheum 2004;50:1642 – 9.
[30] Meng ZH, Hudson AP, Schumacher Jr HR, et al. Monosodium urate, hydroxyapatite, and
calcium pyrophosphate crystals induce tumor necrosis factor-alpha expression in a mononuclear
cell line. J Rheumatol 1997;24:2385 – 8.
[31] Nadra I, Mason JC, Philippidis P, et al. Proinflammatory activation of macrophages by basic
calcium phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of
inflammation and arterial calcification? Circ Res 2005;96:1248 – 56.
[32] Hardy MM, Seibert K, Manning PT, et al. Cyclooxygenase 2-dependent prostaglandin E2
modulates cartilage proteoglycan degradation in human osteoarthritis explants. Arthritis Rheum
2002;46:1789 – 803.
[33] Siegle I, Klein T, Backman JT, et al. Expression of cyclooxygenase 1 and cyclooxygenase 2 in
human synovial tissue: differential elevation of cyclooxygenase 2 in inflammatory joint diseases.
[34] Pelletier JP, Mineau F, Fernandes JC, et al. Diacerhein and rhein reduce the interleukin 1beta
stimulated inducible nitric oxide synthesis level and activity while stimulating cyclooxygenase-2
synthesis in human osteoarthritic chondrocytes. J Rheumatol 1998;25:2417 – 24.
[35] Amin AR, Attur M, Patel RN, et al. Superinduction of cyclooxygenase-2 activity in human
osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin Invest 1997;99:1231 – 7.
[36] Knorth H, Dorfmuller P, Lebert R, et al. Participation of cyclooxygenase-1 in prostaglandin
E2 release from synovitis tissue in primary osteoarthritis in vitro. Osteoarthritis Cartilage 2004;
12:658 – 66.
[37] Cheung HS, Halverson PB, McCarty DJ. Phagocytosis of hydroxyapatite or calcium pyro-
phosphate dihydrate crystals by rabbit articular chondrocytes stimulates release of collagenase,
neutral protease, and prostaglandins E2 and F2 alpha. Proc Soc Exp Biol Med 1983;173:181 – 9.
[38] Rothenberg RJ. Modulation of prostaglandin E2 synthesis in rabbit synoviocytes. Arthritis
Rheum 1987;30:266 – 74.
[39] Lotz M. The role of nitric oxide in articular cartilage damage. Rheum Dis Clin North Am 1999;
25:269 – 82.
[40] Amin AR, Di Cesare PE, Vyas P, et al. The expression and regulation of nitric oxide synthase in
human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide
synthase. J Exp Med 1995;182:2097 – 102.
[41] Pelletier JP, Jovanovic D, Fernandes JC, et al. Reduced progression of experimental osteoarthritis
in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum 1998;41:
1275 – 86.
[42] Pelletier J, Jovanovic D, Fernandes JC, et al. Reduction in the structural changes of experi-
mental osteoarthritis by a nitric oxide inhibitor. Osteoarthritis Cartilage 1999;7:416 – 8.
[43] Pelletier JP, Lascau-Coman V, Jovanovic D, et al. Selective inhibition of inducible nitric oxide
synthase in experimental osteoarthritis is associated with reduction in tissue levels of catabolic
factors. J Rheumatol 1999;26:2002 – 14.
[44] Pelletier JP, Jovanovic DV, Lascau-Coman V, et al. Selective inhibition of inducible nitric oxide
synthase reduces progression of experimental osteoarthritis in vivo: possible link with the
reduction in chondrocyte apoptosis and caspase 3 level. Arthritis Rheum 2000;43:1290 – 9.
[45] Hashimoto S, Ochs RL, Rosen F, et al. Chondrocyte-derived apoptotic bodies and calcification
of articular cartilage. Proc Natl Acad Sci USA 1998;95:3094 – 9.
[46] Whelan L, O’Byrne JM, Sallis JD, et al. Basic calcium phosphate crystals stimulate nitric oxide
synthase and modulate bcl-2/bax expression in human synovial fibroblasts. Arthritis Rheum
2002;46:S140.
[47] Dieppe PA, Crocker PR, Corke CF, et al. Synovial fluid crystals. Q J Med 1979;48:533 – 53.
[48] Gibilisco PA, Schumacher Jr HR, Hollander JL, et al. Synovial fluid crystals in osteoarthritis.
[49] Nalbant S, Martinez JA, Kitumnuaypong T, et al. Synovial fluid features and their relations to
osteoarthritis severity: new findings from sequential studies. Osteoarthritis Cartilage 2003;11:
50 – 4.
[50] Swan A, Chapman B, Heap P, et al. Submicroscopic crystals in osteoarthritic synovial fluids.
Ann Rheum Dis 1994;53:467 – 70.
[51] Buckwalter JA, Saltzman C, Brown T, et al. The impact of osteoarthritis: implications for
research. Clin Orthop Relat Res 2004;427:S6 – 15.
[52] Halverson PB, McCarty DJ. Patterns of radiographic abnormalities associated with basic cal-
cium phosphate and calcium pyrophosphate dihydrate crystal deposition in the knee. Ann
Rheum Dis 1986;45:603 – 5.
[53] Carroll GJ, Stuart RA, Armstrong JA, et al. Hydroxyapatite crystals are a frequent finding in
osteoarthritic synovial fluid, but are not related to increased concentrations of keratan sulfate or
interleukin 1 beta. J Rheumatol 1991;18:861 – 6.
[54] Dieppe PA, Doherty M, Macfarlane DG, et al. Apatite associated destructive arthritis. Br J
Rheumatol 1984;23:84 – 91.
[55] McCarty DJ, Halverson PB, Carrera GF, et al. ‘‘Milwaukee shoulder’’–association of micro-
rotator cuff defects. I. Clinical aspects. Arthritis Rheum 1981;24:464 – 73.
[56] Neer 2nd CS, Craig EV, Fukuda H. Cuff-tear arthropathy. J Bone Joint Surg [Am] 1983;65-A:
1232 – 44.
[57] McCarty DJ, Swanson AB, Ehrhart RH. Hemorrhagic rupture of the shoulder. J Rheumatol
1994;21:1134 – 7.
[58] Pons-Estel BA, Gimenez C, Sacnun M, et al. Familial osteoarthritis and Milwaukee shoulder
associated with calcium pyrophosphate and apatite crystal deposition. J Rheumatol 2000;27:
471 – 80.
[59] Bosworth BM. Calcium deposits in the shoulder and subacromial bursitis. A survey of 12,222
shoulders. JAMA 1941;116:2477 – 82.
[60] Sarkar K, Uhthoff HK. Ultrastructural localization of calcium in calcifying tendinitis. Arch
Pathol Lab Med 1978;102:266 – 9.
[61] Fam AG, Rubenstein J. Hydroxyapatite pseudopodagra. A syndrome of young women. Arthritis
Rheum 1989;32:741 – 7.
[62] McCarthy GM, Carrera GF, Ryan LM. Acute calcific periarthritis of the finger joints: a syndrome
of women. J Rheumatol 1993;20:1077 – 80.
[63] Dayer JM, Evequoz V, Zavadil-Grob C, et al. Effect of synthetic calcium pyrophosphate and
hydroxyapatite crystals on the interaction of human blood mononuclear cells with chondrocytes,
synovial cells, and fibroblasts. Arthritis Rheum 1987;30:1372 – 81.
[64] Dieppe PA, Doherty M, Papadimitriou GM. Inflammatory responses to intradermal crystals in
healthy volunteers and patients with rheumatic diseases. Rheumatol Int 1982;2:55 – 8.
[65] Stary HC. Natural history of calcium deposits in atherosclerosis progression and regression.
Z Kardiol 2000;89(Suppl 2):28 – 35.
[66] Arad Y, Spadaro LA, Goodman K, et al. Prediction of coronary events with electron beam
computed tomography. J Am Coll Cardiol 2000;36:1253 – 60.
[67] Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after
angioplasty. An observational study using intravascular ultrasound. Circulation 1992;86:64 – 70.
[68] Bostrom K, Watson KE, Horn S, et al. Bone morphogenetic protein expression in human
atherosclerotic lesions. J Clin Invest 1993;91:1800 – 9.
[69] Doherty TM, Asotra K, Fitzpatrick LA, et al. Calcification in atherosclerosis: bone biology and
chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A 2003;100:11201 – 6.
[70] Uzui H, Harpf A, Liu M, et al. Increased expression of membrane type 3-matrix metal-
loproteinase in human atherosclerotic plaque: role of activated macrophages and inflammatory
cytokines. Circulation 2002;106:3024 – 30.
[71] Frappart L, Boudeulle M, Boumendil J, et al. Structure and composition of microcalcifications in
benign and malignant lesions of the breast: study by light microscopy, transmission and scanning
electron microscopy, microprobe analysis, and X-ray diffraction. Hum Pathol 1984;15:880 – 9.
[72] Holme TC, Reis MM, Thompson A, et al. Is mammographic microcalcification of biological
significance? Eur J Surg Oncol 1993;19:250 – 3.
[73] Tabar L, Chen HH, Duffy SW, et al. A novel method for prediction of long-term outcome of
women with T1a, T1b, and 10–14 mm invasive breast cancers: a prospective study. Lancet
2000;355:429 – 33.
[74] Morgan MP, Cooke MM, Christopherson PA, et al. Calcium hydroxyapatite promotes mito-
genesis and matrix metalloproteinase expression in human breast cancer cell lines. Mol Carcinog
2001;32:111 – 7.
[75] Cooke MM, McCarthy GM, Sallis JD, et al. Phosphocitrate inhibits calcium hydroxyapatite
induced mitogenesis and upregulation of matrix metalloproteinase-1, interleukin-1beta and
cyclooxygenase-2 mRNA in human breast cancer cell lines. Breast Cancer Res Treat 2003;79:
253 – 63.
[76] Rolland PH, Martin PM, Jacquemier J, et al. Prostaglandin in human breast cancer: Evidence
suggesting that an elevated prostaglandin production is a marker of high metastatic potential for
neoplastic cells. J Natl Cancer Inst 1980;64:1061 – 70.
[77] Dunne A, O’Neill LA. Adaptor usage and Toll-like receptor signaling specificity. FEBS Lett
2005;579:3330 – 5.
[78] Rhee SH, Hwang D. Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as
determined by activation of NF kappa B and expression of the inducible cyclooxygenase. J Biol
Chem 2000;275:34035 – 40.
[79] Lee JY, Zhao L, Youn HS, et al. Saturated fatty acid activates but polyunsaturated fatty acid
inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem 2004;279:
16971 – 9.
[80] Lee JY, Sohn KH, Rhee SH, et al. Saturated fatty acids, but not unsaturated fatty acids, induce
the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 2001;
276:16683 – 9.
[81] Seibl R, Birchler T, Loeliger S, et al. Expression and regulation of Toll-like receptor 2 in
rheumatoid arthritis synovium. Am J Pathol 2003;162:1221 – 7.
[82] Seibl R, Kyburz D, Lauener RP, et al. Pattern recognition receptors and their involvement in the
pathogenesis of arthritis. Curr Opin Rheumatol 2004;16:411 – 8.
[83] Pierer M, Rethage J, Seibl R, et al. Chemokine secretion of rheumatoid arthritis synovial
fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol 2004;172:1256 – 65.
[84] Liu-Bryan R, Pritzker K, Firestein GS, et al. TLR2 signaling in chondrocytes drives cal-
cium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation.
J Immunol 2005;174:5016 – 23.
[85] Hoch RC, Schraufstatter IU, Cochrane CG. In vivo, in vitro, and molecular aspects of
interleukin-8 and the interleukin-8 receptors. J Lab Clin Med 1996;128:134 – 45.
[86] Detmers PA, Lo SK, Olsen-Egbert E, et al. Neutrophil-activating protein 1/interleukin 8
stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human
neutrophils. J Exp Med 1990;171:1155 – 62.
[87] Liu R, O’Connell M, Johnson K, Pritzker K, et al. Extracellular signal-regulated kinase 1/
extracellular signal-regulated kinase 2 mitogen-activated protein kinase signaling and acti-

vation of activator protein 1 and nuclear factor kappaB transcription factors play central roles
in interleukin-8 expression stimulated by monosodium urate monohydrate and calcium pyro-
phosphate crystals in monocytic cells. Arthritis Rheum 2000;43:1145 – 55.
[88] Tudan C, Jackson JK, Charlton L, et al. Activation of S6 kinase in human neutrophils by calcium
pyrophosphate dihydrate crystals: protein kinase C-dependent and phosphatidylinositol-3-kinase-
independent pathways. Biochem J 1998;331(Pt 2):531 – 7.
[89] Tudan C, Jackson JK, Pelech SL, et al. Selective inhibition of protein kinase C, mitogen-
activated protein kinase, and neutrophil activation in response to calcium pyrophosphate
dihydrate crystals, formyl-methionyl-leucyl-phenylalanine, and phorbol ester by O-(chloroacetyl-
carbamoyl) fumagillol (AGM-1470; TNP-470). Biochem Pharmacol 1999;58:1869 – 80.
[90] Jackon JK, Tudan C, Burt HM. The involvement of phospholipase C in crystal induced human
neutrophil activation. J Rheumatol 2000;27:2877 – 85.
[91] Tudan C, Jackson JK, Higo TT, et al. Calcium pyrophosphate dihydrate crystal associated
induction of neutrophil activation and repression of TNF-alpha-induced apoptosis is mediated by
the p38 MAP kinase. Cell Signal 2004;16:211 – 21.
[92] Tudan C, Jackson JK, Blanis L, et al. Inhibition of TNF-alpha-induced neutrophil apoptosis by
crystals of calcium pyrophosphate dihydrate is mediated by the extracellular signal-regulated
kinase and phosphatidylinositol 3-kinase/Akt pathways up-stream of caspase 3. J Immunol
2000;165:5798 – 806.
[93] Bouchard L, de Medicis R, Lussier A, et al. Inflammatory microcrystals alter the func-
tional phenotype of human osteoblast-like cells in vitro: synergism with IL-1 to overexpress
cyclooxygenase-2. J Immunol 2002;168:5310 – 7.
[94] Waguri-Nagaya Y, Kubota Y, Sekiya I, et al. Extensor tendon rupture related to calcium
pyrophosphate crystal deposition disease. Rheumatol Int 2002;21:243 – 6.
[95] Sato Y, Yasuda T, Konno S, et al. Pseudogout showing meningoencephalitic symptoms: crowned
dens syndrome. Intern Med 2004;43:865 – 8.
[96] Muthukumar N, Karuppaswamy U, Sankarasubbu B. Calcium pyrophosphate dihydrate depo-
sition disease causing thoracic cord compression: case report. Neurosurgery 2000;46:222 – 5.
[97] Muthukumar N, Karuppaswamy U. Tumoral calcium pyrophosphate dihydrate deposition
disease of the ligamentum flavum. Neurosurgery 2003;53:103 – 8 [discussion: 108–9].
[98] Yamakawa K, Iwasaki H, Ohjimi Y, et al. Tumoral calcium pyrophosphate dihydrate crys-
tal deposition disease. A clinicopathologic analysis of five cases. Pathol Res Pract 2001;197:
499 – 506.
Calcium Crystal Deposition and Osteoarthritis

Ann K. Rosenthal, MDa,b,T
a
Division of Rheumatology, Department of Medicine, Medical College of Wisconsin,
Milwaukee, WI, USA
b
Zablocki VA Medical Center, Milwaukee, WI, USA
Articular calcium crystal deposition diseases and osteoarthritis are highly

prevalent conditions in elderly populations. Calcium pyrophosphate dihydrate
(CPPD) and basic calcium phosphate (BCP) crystals are the two most common
forms of pathologically relevant calcium crystals in articular tissues. Although
the relationship between calcium crystal deposition diseases and osteoarthritis
remains somewhat controversial, it is unlikely that chance explains the coexis-
tence of these two processes. Good evidence from the clinic and laboratory
suggests that the presence of one of these pathologic processes influences the
development of the other. This article reviews some background about calcium
crystals and summarizes the evidence that they are biologically active particles
that develop in the setting of cartilage damage and contribute to osteoarthritis.
Hopefully, further study of the complex factors involved in the pathogenesis of
calcium crystal deposition disease and osteoarthritis will lead to better treatments
for the many causes of cartilage degeneration.
Calcium pyrophosphate dihydrate crystals
CPPD crystals occur commonly in articular hyaline and fibrocartilage in

persons over age 60 [1]. They are visible under polarizing light microscopy in
This work was supported by a Merit Review grant from the Department of Veterans Affairs and
Grants AG015337 and AR052615 from the National Institutes of Health.
T Rheumatology Section, CC-111W, Zablocki VA Medical Center, 5000 West National Avenue,
Milwaukee, WI 53295-1000.
E-mail address: ann.rosenthal@med.va.gov
402 rosenthal
synovial fluids of affected joints as positively birefringent rhomboid particles.

They can be identified radiographically as dense linear cartilage calcifications,
known as chondrocalcinosis. CPPD crystals initially were recognized as patho-
gens in patients who had gout-like arthritis and who had uricase-resistant intra-
articular crystals [2]. Almost simultaneously, CPPD crystal deposits were
described in a family that had early onset of osteoarthritis-like joint pathology [3].
This dual description accurately predicts the heterogeneity of the clinical
settings in which CPPD crystals are found. The most common clinical presen-
tation of CPPD crystal deposition is as a chronic degenerative arthritis [4]. The
presence of significant cartilage degeneration in unusual locations, such as the
metacarpal-phalangeal joints or wrist, and certain radiographic features [5]
suggest the presence of articular CPPD crystals. Less commonly, CPPD crystals
cause an acute monoarticular arthritis, known as pseudogout, or a more diffuse
inflammatory syndrome similar to rheumatoid arthritis. In addition, some patients
who have chronic degenerative arthritis associated with CPPD crystals describe
acute attacks of inflammation. CPPD crystals also can be found in asymptomatic
joints and in association with neuropathic arthritis [6].
The prevalence of CPPD crystal deposition in the population remains uncer-
tain. Many studies exploring the epidemiology of CPPD crystal disease use
radiographic chondrocalcinosis as a diagnostic criterion. This finding may either
underestimate or overestimate clinically relevant CPPD crystal deposition [7].
Chondrocalcinosis often is not visible in severely damaged or small joints or with
certain radiographic techniques, such as standing knee films. Recent evidence
confirms these findings, showing that ultrasonography can identify CPPD de-
posits too small to be visible on plain radiographs [8]. Nonetheless, the best
estimates rely on these studies. Data from the Framingham study demonstrate an
8% prevalence of knee chondrocalcinosis in people ages 63 to 93. Rates increase
to 27% when only people over 85 are included [9], and higher rates are seen in
hospitalized patients [10]. In the few studies in which articular tissues were
examined directly for CPPD crystals, or when only osteoarthritic joints are in-
cluded, much higher rates are described. For example, Sokoloff and Varma show
that 52% of osteoarthritis patients over age 75 had CPPD crystals in articular
tissue specimens [11]. Twenty-five to 33% of synovial fluids from patients who
had osteoarthritis contained CPPD crystals at the time of joint replacement for
osteoarthritis (Fig. 1) [12,13].
CPPD deposition can be categorized as sporadic (idiopathic), familial, or
metabolic. The vast majority of cases are sporadic. For sporadic CPPD deposition
disease, age is the best characterized and strongest risk factor. Clinically evident
sporadic CPPD deposition is rare under age 60. Prior injury, in particular menis-
cal damage in the knee, also predisposes to CPPD deposition [14]. As discussed
previously, osteoarthritis significantly increases the risk for CPPD crystal deposi-
tion [11]. Premature CPPD crystal deposition may be familial or metabolic. There
are a handful of metabolic syndromes that clearly promote CPPD crystal depo-
sition. The strongest associations are with gout, hyperparathyroidism, hemo-
chromatosis, hypophosphatasia, and hypomagnesemia [15,16].
calcium crystal deposition and osteoarthritis 403
Fig. 1. Frequency of BCP and CPPD crystals in synovial fluids from patients who have osteoarthritis.
(Black bars represent data from Nalbant S, Martinez J, Kitumnuaypong T, et al. Synovial fluid
features and their relations to osteoarthritis severity: new findings from sequential studies.
Osteoarthritis Cartilage 2003;11:50–4. Hatched bars represent data from Derfus B, Kurian J,
Butler J, et al. The high prevalence of pathologic calcium crystals in pre-operative knees. J Rheumatol
2002;29:570–4.)
Although the cause of CPPD deposition disease is not known, the current
paradigm of crystal formation in cartilage involves multiple participants. Chon-
drocytes near CPPD crystal deposits are abnormally large and share some
characteristics with the hypertrophic chondrocytes responsible for matrix
mineralization in growth plate cartilage [17,18]. Overproduction of inorganic
pyrophosphate, the anionic component of CPPD crystals [19,20], is a key feature
of these chondrocytes. Excess pyrophosphate production may be related to
abnormalities of the recently described ANK protein, a putative pyrophosphate
transporter [21]. Mutations in the ANK protein are linked to some cases of
familial CPPD crystal deposition disease [22]. Excess extracellular inorganic
pyrophosphate produced by chondrocytes complexes with ambient calcium
to form crystals. There also is increasing evidence that alterations in cartilage
extracellular matrix facilitate CPPD crystal formation. These include loss of
pericellular proteoglycans, collagen fibril disruption, and increased concentra-
tions of some matricellular proteins [23]. In addition, extracellular matrix changes
likely promote the activity of extracellular organelles, known as matrix vesicles
[24]. These small membrane-bound, chondrocyte-derived vesicles act as sites for
nucleation and growth of crystals in cartilage matrix [25].
Basic calcium phosphate crystals
BCP crystals include partially carbonate-substituted hydroxyapatite, octacal-

cium phosphate, and tricalcium phosphate. These crystals comprise calcium and
inorganic phosphate and often are referred to as hydroxyapatite because of their
chemical similarity to the normal calcium phosphate mineral found in bones and
404 rosenthal
teeth. They are not visible under light or polarizing light microscopy, and, cur-
rently, there are no readily available tests for bedside identification. BCP crystals
are visible under light microscopy with alizarin red staining, but unfortunately,
this dye also binds to other calcium-containing particulates [26]. von Kossa’s
stain can be used to identify BCP crystals in tissues. For research purposes, a
semiquantitative radioactive binding assay based on the ability of BCP crystals to
bind to bisphosphonates is used [27]. Unfortunately, highly accurate techniques,
such as x-ray diffraction and Fourier transform infrared spectrophotometry, are
expensive, require large volume samples, and have limited practical use [26].
Like CPPD crystals, articular BCP crystals occur in a wide range of clinical
settings. The clinical syndromes associated with BCP crystals frequently are
misdiagnosed [28] and, lacking good diagnostic techniques, are significantly
under-recognized. When BCP crystals are found in joints, they are associated
with a severe destructive degenerative arthritis, often affecting large joints [29].
In its full-blown form, this is known as Milwaukee shoulder syndrome [30,31].
Milwaukee shoulder syndrome typically affects elderly women. They have pain,
stiffness, and loss of motion of the shoulder. Knees may be affected similarly. On
physical examination, large cool effusions often are noted. Radiographs confirm
the diagnosis by demonstrating severe rotator cuff thinning, loose bodies, and
extensive bone destruction. Synovial fluids show little evidence of inflammation,
with low white blood cell counts and high levels of active proteases [32,33]. In its
less extreme form, BCP crystals occur in the synovial fluids of 40% to 70% of
patients who have clinical osteoarthritis, where they are markers for severe joint
degeneration (see Fig. 1) [12,13]. BCP crystal deposits also are clinically signifi-
cant when they occur periarticularly. Around the shoulder, they cause the com-
mon clinical syndrome known as calcifying tendonitis. When deposits occur near
the small joints of the hands and feet, they can cause an acute inflammatory
periarthritis [34]. These young, often female, patients present with acute pain,
swelling, and redness around a finger or toe associated with flecks of soft tissue
calcium on radiographs [34].
The lack of a good clinical test for BCP crystals limits knowledge of the
prevalence of BCP-associated syndromes. Intra-articular BCP crystals almost
invariably are associated with advanced age and worsening radiographic grade of
degenerative arthritis [13,35]. Clinical syndromes associated with BCP crystals
seem slightly more common in women. Other possible risk factors for intrarticu-
lar BCP crystals include CPPD deposition disease, trauma, chronic renal failure,
and neurologic abnormalities involving the affected joint [31]. In contrast, syn-
dromes associated with periarticular BCP crystals have a different population
distribution. The incidence of calcifying tendonitis, for example, peaks at 30 to
60 years of age [36].
Less is known about the genesis of BCP than CPPD crystals. They are cer-
tainly less stringently associated with cartilage than CPPD crystals and are found
commonly in skin, soft tissues, and blood vessels. There is some support for the
hypothesis that they develop at sites of cartilage metaplasia, even in noncartilage
containing tissues [37]. Matrix vesicles, similar to those responsible for CPPD
crystal formation, likely participate in BCP crystal formation [38]. Histologic

studies demonstrate the presence of matrix vesicles near BCP crystals deposits in
tendon [38] and cartilage [39]. Isolated matrix vesicles from osteoarthritic car-
tilage can generate BCP crystals in vitro [24]. Ample evidence also supports a
role for disruption of the normal extracellular matrix at sites of BCP crystal
formation [38,40].
Mixed calcium crystal deposition
Although there are some conditions that clearly are associated with one or the
other of the pathogenic calcium crystals, these crystals often coexist in a single
patient [12,13]. Indeed, the presence of both CPPD and BCP crystals in a single
joint is not uncommon [41]. A familial form of calcium crystal deposition in
which CPPD and BCP crystals coexist also recently has been reported [42].
Relationship between crystals and osteoarthritis
There are clear and important differences between CPPD and BCP crystals in
terms of their associated clinical patterns and etiologies. There is a paucity of
studies, however, examining their role in osteoarthritis. For purposes of effi-
ciently discussing the relationship between calcium crystals and osteoarthritis,
CPPD and BCP crystals considered together. Two potential hypotheses are ex-
plored. First, the evidence is considered that calcium crystals cause or worsen os-
teoarthritis. Second, the opposite hypothesis, that osteoarthritis causes or worsens
calcium crystal deposition, is considered. These two hypotheses are not mutually
exclusive and it is likely that elements from both are true.
Evidence that calcium crystals cause or worsen osteoarthritis
Clinical evidence
Most evidence supporting the hypothesis that calcium crystals cause or worsen
osteoarthritis is based on epidemiologic studies. There is significant clinical
support for the hypothesis that intra-articular calcium crystals are risk factors for
incident or progressive osteoarthritis. For example, Sokolov and Varma show that
CPPD crystals are six times more likely to be found in osteoarthritic than in
normal joints [11]. Others confirm these findings [43,44]. Although the presence
of CPPD crystals in knee fluids from patients who have osteoarthritis is asso-
ciated with increased disability [45], whether or not this relationship can be ex-
trapolated to small joints is unclear. For example, Caspi and coworkers were
unable to demonstrate a similar relationship in hand joints [46]. Multiple studies
correlate the presence of intra-articular BCP crystals with severe radiographic
destruction [13,41]. A recent study by Nalbant and colleagues find that syno-
vial fluid CPPD and BCP crystals are predictors of rapidly worsening knee
406 rosenthal
osteoarthritis [12]. Articular CPPD crystals also correlate with higher rates of
proteoglycan turnover in cartilage of affected joints [47]. The development of
severe and premature osteoarthritis in patients who have familial forms of CPPD
crystal deposition supports a causal association [3]. Similarly, the presence of
CPPD crystals in relatively normal cartilage in patients who have familial CPPD
disease precludes the theory that these particles simply are epiphenomena of
severe cartilage degeneration [48]. This hypothesis is refuted further by the rarity
of calcium crystals in joints damaged by inflammatory arthritis, such as rheu-
matoid arthritis.
Laboratory evidence
Animal studies. There are only a handful of studies that directly examine the
effects of calcium crystals in animal models of osteoarthritis. Perhaps the
strongest work is from Fam and colleagues [49]. They injected CPPD crystals
into rabbit knees rendered osteoarthritic by partial meniscectomy and resection of
the collateral and sesamoid ligaments. Histologic osteoarthritis worsened
significantly with exposure to repeated injections of either high- or low-dose
CPPD crystals compared with controls. In some animals with spontaneous
osteoarthritis, calcific deposits precede significant articular damage. For example,
in the guinea pig model of spontaneous osteoarthritis, calcifications in the me-
niscus occur before the development of visible hyaline articular cartilage degen-
eration. The investigators propose that mechanical changes in the calcified
meniscus alter the biomechanics of the joint and contribute to hyaline cartilage
damage [50].
In vitro studies. Many laboratory studies support the hypothesis that calcium
crystals contribute to osteoarthritis. Most do so by demonstrating potential
mechanisms through which calcium crystals cause damage to articular tissues.
There is support for theories involving the induction of an inflammatory response
by calcium crystals and those postulating direct deleterious effects of crystals on
articular tissues.
Calcium crystals are phlogistic and can initiate a strong inflammatory response
under certain conditions [51,52]. CPPD and BCP crystals elicit the production of
prostaglandins, interleukins, and cytokines from phagocytes and activate neu-
trophils and the complement cascade [52]. Despite these clear effects in vitro, the
role of inflammation in clinical calcium crystal deposition diseases and
osteoarthritis is debated. Calcium crystals often are found in uninflamed joints.
Even highly phlogistic crystals, such as monosodium urate crystals, can be
present in joints in the absence of clinical signs or symptoms of inflammation
[53]. Calcium crystals are less inflammatory than urate crystals [54]. Like gout
crystals, however, their inflammatory potential likely is modulated by their size
and shape and the nature and extent of adherent proteins [52,55]. Conversely,
although inflammation of the synovium in osteoarthritis also is variable, in-
creasing evidence exists to suggest it may be an excellent predictor of rapid
progression of joint damage in osteoarthritis [56].
There also is ample and elegant support for the hypothesis that CPPD and
BCP crystals affect cartilage and synovium directly and adversely, even in the
absence of inflammatory mediators. Calcium crystals elicit mitogenesis in fibro-
blast cultures [57,58], potentially mimicking synovial overgrowth and attendant
articular damage. Calcium crystals also can induce secretion of prostaglandin E2,
collagenases, and neutral proteases from canine synovial cells [57]. BCP crystals
elicit a similar response from osteoarthritic human synovial fibroblasts and adult
porcine articular chondrocytes [59]. Nitric oxide production also is stimulated in
articular chondrocytes by BCP crystals [60], as is increased production of key
proteases, such as stromelysin and gelatinase, and decreased production of
protease inhibitors, such as tissue inhibitor of metalloproteases [61].
There is little experimental evidence to suggest that calcium crystals act as
mechanical irritants in the joint, but it remains an intriguing possibility. Hayes
and colleagues find an increase in proteoglycan turnover and cartilage wear after
exposure of equine cartilage plugs to CPPD or BCP crystals [62].
Evidence that osteoarthritis causes or worsens calcium crystal formation
Clinical evidence
There is less direct evidence to support the hypothesis that osteoarthritis
causes or worsens calcium crystal formation, yet this hypothesis remains equally
compelling. The epidemiologic studies (discussed previously) suggest that cal-
cium crystals occur commonly in osteoarthritic joints, although they are relatively
rare in normal joints or in inflammatory joint disease [11,43,44]. This observation
sheds little light on the causal nature of this association. A recent longitudinal
study of synovial fluids, however, suggests that osteoarthritis may facilitate the
development of calcium crystals. Nalbant and coworkers show that some osteo-
arthritic synovial fluids have no crystals when sampled early in the disease. When
fluids from these same joints, however, were examined years later, calcium
crystals were present, suggesting that crystals may develop as a result of pro-
gressive osteoarthritis [12].
Laboratory evidence
Animal studies. In some animal models of osteoarthritis, calcium crystals form
in cartilage after the disease is well established. For example, in a rabbit model of
osteoarthritis based on transection of the anterior cruciate ligament, calcification
of the meniscal fibrocartilage occurs late in the development of the disease. These
calcium deposits correlate with other stigmata of phenotypic changes in
chondrocytes, including the production of type X collagen and changes in cell
shape [63].
In vitro studies. Laboratory studies that support the hypothesis that osteo-
arthritis causes or worsens calcium crystal formation typically support one of two
hypotheses. The first is that the damaged extracellular matrix in osteoarthritic
cartilage facilitates matrix mineralization by reducing inhibitors or increasing
408 rosenthal
stimulants of pathologic mineralization in the normally unmineralized articular

cartilage matrix. The second is that osteoarthritis produces changes in the
chondrocyte that force it to assume a hypertrophic phenotype. These altered
chondrocytes then promote mineralization of their surrounding matrix.
There is ample evidence to support the hypothesis that extracellular matrix
changes in osteoarthritic cartilage facilitate crystal formation. Histologic studies
show a loss of proteoglycans and disruption of collagen fibril formation around
calcium crystals [18]. Identical changes also occur in osteoarthritis [64]. Simi-
larly, high levels of osteopontin [65], calcium and phosphate [66], and other
mineral-promoting factors are found in osteoarthritic cartilage. Few mechanistic
studies have explored the role of matrix changes in calcium crystal development.
The strongest support comes from work with model systems of calcium crystal
formation in solution and by matrix vesicles. Mandel and Mandel demonstrate a
marked reduction in concentrations of calcium and pyrophosphate necessary for
CPPD crystal formation in a solid matrix compared with those necessary to
generate crystals in solution [67]. Derfus and coworkers show that matrix vesicles
from osteoarthritic cartilage have identical mineralization capacities to those
isolated from normal cartilage [68]. They suggest this paradoxic finding strongly
supports an important role for the extracellular milieu in matrix vesicle miner-
alization. It is likely that normal articular cartilage matrix contains mineralization
inhibitors whereas osteoarthritic matrix contains less large proteoglycans,
disrupted collagen fibrils, and increased quantities of matricellular proteins that
promote mineralization.
There also is excellent evidence to support the hypothesis that phenotypic
changes in chondrocytes from osteoarthritic cartilage facilitate calcium crystal
formation. One theory explaining both osteoarthritis and calcium crystal
formation is that in these diseases, chondrocytes undergo terminal differentiation
and assume characteristics similar to those of hypertrophic chondrocytes respon-
sible for endochondral bone formation [69,70]. This is demonstrated elegantly by
the work of Kirsch and coworkers [71]. They show that chondrocytes in
osteoarthritic cartilage have many features of the hypertrophic phenotype. These
chondrocytes display increased alkaline phosphatase enzyme activity and higher
levels of annexins and type X collagen. Furthermore, they elaborate matrix
vesicles, which seem to be actively involved in mineral formation. These features
are not seen in chondrocytes from healthy articular cartilage but are well
described in cartilage containing CPPD or BCP crystal deposits [17]. Other
features of hypertrophic chondrocytes that might promote calcium crystal for-
mation also are documented in osteoarthritis. For example, pyrophosphate levels
are increased in osteoarthritic synovial fluid [72]. Upregulation of the putative
pyrophosphate transporter, ANK, also is demonstrated in osteoarthritic chon-
drocytes [73]. Recently, polymorphisms in the gene coding for an enzyme
responsible for pyrophosphate elaboration, ENPP1, are linked to hand osteo-
arthritis [74]. Levels of activity of transglutaminase enzymes, which also
are markers of chondrocyte hypertrophy in growth plate chondrocytes [75],
are increased in osteoarthritic cartilage [76]. These enzymes contribute to cal-
cium crystal formation [77,78]. Growth factors, such as the bone morphoge-
netic proteins and transforming growth factor-beta, may contribute to minerali-
zation [79] and cartilage degeneration [80] by promoting phenotypic changes
in chondrocytes.
References
[1] Mitrovic D, Stankovic A, Iriarte-Borda O, et al. The prevalence of chondrocalcinosis in the

human knee joint. An autopsy survey. J Rheumatol 1988;15:633 – 41.
[2] McCarty D, Kohn N, Faires J. The significance of calcium pyrophosphate crystals in the syno-
vial fluid of arthritic patients. 1. Clinical aspects. Ann Intern Med 1962;56:711 – 37.
[3] Zitnan D, Sitaj S. Chondrocalcinosis articularis: section I. Clinical and radiological study.
Ann Rheum Dis 1963;22:142 – 52.
[4] McCarty DJ. Pseudogout: articular chondrocalcinosis; calcium pyrophosphate crystal deposition
disease. In: Hollander J, McCarty Jr D, editors. Arthritis and allied conditions. 8th edition.
Philadelphia7 Lea & Febiger; 1972. p. 1140 – 60.
[5] Uri D, Martel W. Radiologic manifestations of the crystal-related arthropathies. Semin Roent-
genol 1996;31:229 – 38.
[6] McCarty DJ. Diagnostic mimicry in arthritis: patterns of joint involvement associated with
calcium pyrophosphate dihydrate crystal deposits. Ann Rheum Dis 1975;25:804 – 9.
[7] Ryan L, Cheung H. The role of crystals in osteoarthritis. Rheum Dis Clin North Am 1999;
25:257 – 67.
[8] Fredini B, Filippou G, Falsetti P, et al. Diagnosis of calcium pyrophosphate dihydrate crystal
deposition disease: ultrasonographic criteria proposed. Ann Rheum Dis 2005;64:638 – 40.
[9] Felson D, Anderson J, Naimark A, et al. The prevalence of chondrocalcinosis in the elderly and
its association with knee osteoarthritis: the Framingham study. J Rheumatol 1989;16:1241 – 5.
[10] Wilkins E, Dieppe P, Maddison P, et al. Osteoarthritis and articular chondrocalcinosis in the
elderly. Ann Rheum Dis 1983;42:280 – 4.
[11] Sokoloff L, Varma A. Chondrocalcinosis in surgically resected joints. Arthritis Rheum 1988;31:
750 – 6.
[12] Nalbant S, Martinez J, Kitumnuaypong T, et al. Synovial fluid features and their relations to
osteoarthritis severity: new findings from sequential studies. Osteoarthritis Cartilage 2003;11:
50 – 4.
[13] Derfus B, Kurian J, Butler J, et al. The high prevalence of pathologic calcium crystals in pre-
operative knees. J Rheumatol 2002;29:570 – 4.
[14] Doherty M, Watt I, Dieppe P. Localised chondrocalcinosis in post-meniscetomy knees. Lancet
1982;1:1207 – 10.
[15] Hamilton E. Diseases associated with CPPD deposition disease. Arthritis Rheum 1976;
19(Suppl):353 – 7.
[16] Jones AC, Chuck AJ, Arie EA, et al. Diseases associated with calcium pyrophosphate deposition
disease. Semin Arthritis Rheum 1992;22:188 – 202.
[17] Ishikawa K. Chondrocytes that accumulate proteoglycans and inorganic pyrophosphate in the
pathogenesis of chondrocalcinosis. Arthritis Rheum 1985;28:118 – 9.
[18] Ishikawa K, Masuda I, Ohira T, et al. A histologic study of calcium pyrophosphate dihydrate
crystal-deposition disease. J Bone Joint Surg [Am] 1989;71:875 – 86.
[19] Park W, Masuda I, Cardenal A, et al. Generation of inorganic pyrophosphate from extracellular
adenosine triphosphate. J Rheumatol 1996;23:1233 – 6.
[20] Costello J, Ryan L. Modulation of chondrocyte production of extracellular inorganic pyro-
phosphate. Curr Opin Rheum 2004;16:268 – 72.
[21] Ho A, Johnson M, Kingsley D. Role of the mouse ank gene in tissue calcification and arthritis.
Science 2000;289:265 – 70.
410 rosenthal
[22] Williams C. Familial calcium pyrophosphate dihydrate deposition disease and the ANKH gene.
Curr Opin Rheumatol 2003;15:326 – 31.
[23] Masuda I, Ishikawa K, Usuku G. A histologic and immunohistochemical study of calcium
pyrophosphate dihydrate crystal deposition disease. Clin Orthop 1991;263:272 – 87.
[24] Derfus B, Kranendonk S, Mandel N, et al. Human osteoarthritic matrix vesicles generate apa-
tite and calcium pyrophosphate dihydrate in vitro. J Bone Joint Surg [Am] 1994;18:502 – 3.
[25] Derfus B, Rachow J, Mandel N, et al. Articular cartilage vesicles generate calcium pyrophos-
phate dihydrate-like crystals in vitro. Arthritis Rheum 1992;35:231 – 40.
[26] Rosenthal A, Mandel N. Identification of crystals in synovial fluids and joint tissues. Curr
Rheumatol Rep 2001;3:11 – 6.
[27] Halverson P, McCarty D. Identification of hydroxyapatite crystals in synovial fluids. Arthritis
Rheum 1979;22:389 – 93.
[28] Claudepierre P, Rahmouni A, Bergamasco P, et al. Misleading clinical aspects of hydroxyapatite
deposits: a series of 15 cases. J Rheumatol 1996;24:531 – 5.
[29] Schumacher H, Miller J, Ludivico C, et al. Erosive arthritis associated with apatite crystal
deposition. Arthritis Rheum 1981;24:31 – 7.
[30] McCarty D, Halverson P, Carrera G, et al. Milwaukee shoulder syndrome: association of micro-
rotator cuff defects, I. clinical aspects. Arthritis Rheum 1981;24:464 – 73.
[31] Halverson P, Carrera G, McCarty D. Milwaukee Shoulder Syndrome: Fifteen additional cases
and a description of contributing factors. Arch Intern Med 1990;150:677 – 82.
[32] Halverson P, Cheung H, McCarty D, et al. Milwaukee Shoulder: association of microspheroids
containing hydroxyapatite crystals, active collagenase and neutral protease with rotator cuff
defects: II. Synovial fluid studies. Arthritis Rheum 1981;24:474 – 83.
[33] Garancis J, Cheung H, Halverson P. ‘‘Milwaukee Shoulder’’—association of microspheroids
containing hydroxyapatite crystals, active collagenase, and neutral protease with rotator cuff
defects.III. Morphologic and biochemical studies of an excised synovium showing chondroma-
tosis. Arthritis Rheum 1981;24:484 – 91.
[34] Fam A, Rubenstein J. Hydroxyapatite pseudopodagra. Arthritis Rheum 1989;32:741 – 7.
[35] Halverson P. Basic calcium phosphate (apatite, octacalcium phosphate, tricalcium phosphate)
crystal deposition diseases and calcinosis. In: Koopman W, Moreland L, editors. Arthritis and
allied conditions. Philadelphia7 Lippincott Williams & Wilkins; 2004. p. 2397 – 416.
[36] Duvauferrier R, Meadeb J, DeKorvin B, et al. Maladie des depots d’hydroxyapatite. Encycl Med
Chir 1992;31316B10:1 – 7.
[37] Uhthoff H. Calcifying tendonitis, an active cell-mediated calcification. Vichows Arch 1975;
366:51 – 8.
[38] Archer R, Bayley J, Archer C, et al. Cell and matrix changes associated with pathological
calcification of the human rotator cuff tendons. J Anat 1993;182:1 – 12.
[39] Ali S. Apatite-type crystal deposition in arthritic cartilage. Scan Electron Microsc 1985;4:1555 – 66.
[40] Boskey A, Bullough P. Cartilage calcification: normal and aberrant. Scan Electron Microsc
1984;11:943 – 52.
[41] Halverson P, McCarty D. Patterns of radiographic abnormalities associated with basic calcium
pyrophosphate and calcium pryophosphate dihydrate crystal deposition. Ann Rheum Dis 1986;
45:603 – 5.
[42] Pons-Estel B, Giminez C, Sacnun M, et al. Familial osteoarthritis and Milwaukee Shoulder
associated with calcium pyrophosphate and apatite crystal deposition. J Rheumatol 2000;27:
471 – 80.
[43] Dieppe P, Crocker P, Corke C, et al. Synovial fluid crystals. Q J Med 1979;48:533 – 55.
[44] Schumacher H, Gordon G, Paul H, et al. Osteoarthritis, crystal deposition, and inflammation.
Semin Arthritis Rheumat 1981;11:116 – 9.
[45] Ledingham J, Regan M, Jones A, et al. Radiographic patterns and associations of osteoarthritis
of the knee in patients referred to hospital. Ann Rheum Dis 1993;52:520 – 6.
[46] Caspi D, Flusser G, Farber I, et al. Clinical, radiologic, demographic, and occupational aspects
of hand osteoarthritis in the elderly. Semin Arthritis Rheum 2001;30:321 – 31.
[47] Carroll G, McCappin S, Bell M, et al. Comparison of keratan sulfate concentrations and the
size distribution of proteoglycans in the synovial fluid of patients with osteoarthritis and
pyrophosphate arthropathy. Rheumatol Int 1991;11:63 – 8.
[48] Bjelle A. Cartilage matrix in hereditary pyrophosphate arthropathy. J Rheumatol 1981;8:959 – 64.
[49] Fam A, Morava-Protzner I, Purcell C, et al. Acceleration of experimental lapine osteoarthritis by
calcium pyrophosphate microcrystalline synovitis. Arthritis Rheum 1995;38:201 – 10.
[50] Kapadia R, Badger A, Lein J, et al. Meniscal ossification in spontaneous osteoarthritis in guinea
pigs. Osteoarthritis Cartilage 2000;8:374 – 7.
[51] Landis R, Haskard D. Pathogenesis of crystal-induced inflammation. Curr Rheum Reports 2001;
3:36 – 41.
[52] Terkeltaub R. Pathogenesis and treatment of crystal-induced inflammation. In: Koopman W,
Moreland L, editors. Arthritis and allied conditions. Philadelphia7 Lippincott Williams &
Wilkins; 2005. p. 2357 – 72.
[53] Pascual E, Batlle-Gualda E, Martinez A, et al. Synovial fluid analysis for diagnosis of inter-
critical gout. Ann Intern Med 1999;131:756 – 9.
[54] DiGiovine F, Malawista S, Thornton E, et al. Urate crystals stimulate production of tumor
necrosis factor alpha from human blood monocytes and synovial cells. Cytokine mRNA and
protein kinetics and cellular distribution. J Clin Invest 1991;87:1375 – 81.
[55] Prudhommeaux F, Schlitz C, Liote F, et al. Variation in the inflammatory properties of basic
calcium phosphate crystals according to crystal type. Arthritis Rheum 1996;39:1319 – 26.
[56] Ayral X, Pickering E, Woodworth T, et al. Synovitis: a potential predictive factor of structural
progression of medial tibiofemoral knee osteoarthritis—results of a 1 year longitudinal
arthroscopic study in 422 patients. Osteoarthritis Cartilage 2005;13:361 – 7.
[57] Cheung H, McCarty D. Biologic effects of calcium-containing crystals on synoviocytes. In:
Rubin R, Weiss G, Putney Jr J, editors. Calcium in biological systems. New York7 Plenum
Publishing; 1985. p. 719 – 24.
[58] Cheung H. Calcium crystal effects on the cells of the joint: implications for the pathogenesis of
disease. Curr Opin Rheumatol 2001;12:223 – 7.
[59] McCarthy G, Westfall P, Masuda I, et al. Basic calcium phosphate crystals activate human
osteoarthritic synovial fibroblasts and induce matrix metalloproteinase-13 (collagenase-3) in
adult porcine articular chondrocytes. Ann Rheum Dis 2001;60:399 – 406.
[60] Ea H-K, Uzan B, Rey C, et al. Octacalcium phosphate crystals directly stimulate expression of
inducible nitric oxide synthase throgh p38 and JNK mitogen-activated protein kinases in articular
chondrocytes. Arthritis Res 2005;7:R915 – 26.
[61] O’Shea F, McCarthy G. Basic calcium phosphate deposition in the joint: potenial therapeutic
target in osteoarthritis. Curr Opin Rheumatol 2004;16:273 – 8.
[62] Hayes A, Harris B, Dieppe P, et al. Wear of articular cartilage: the effect of crystals. Proc Inst
Mech Eng [H] 1993;207:41 – 58.
[63] Hellio Le Graverand M, Sciore P, Eggerer J, et al. Formation and phenotype of cell clusters
in osteoarthritic meniscus. Arthritis Rheum 2001;44:1808 – 18.
[64] Pritzker K. Pathology of osteoarthritis. In: Brandt K, Doherty M, Lohmander S, editors.
Osteoarthritis. Oxford (England)7 Oxford University Press; 2003. p. 49 – 58.
[65] Attur M, Dave M, Stuchin S, et al. Osteopontin: an intrinsic inhibitor of inflammation in
cartilage. Arthritis Rheum 2001;44:578 – 84.
[66] Pritzker M, Chateauvert J, Gympas M. Osteoarthritic cartilage contains increased calcium,
magnesium, and phosphorus. J Rheumatol 1987;14:806 – 10.
[67] Mandel NS, Mandel GS. Nucleation and growth of CPPD crystals and related species in vitro.
In: Rubin RP, Weiss G, Putner JW, editors. Calcium in biological systems. New York7 Plenum
Press; 1985. p. 711 – 7.
[68] Derfus BA, Kurtin SM, Camacho NP, et al. Comparison of matrix vesicles derived from normal
and osteoarthritic human articular cartilage. Connect Tissue Res 1996;35:391 – 6.
[69] Poole A, Matsui Y, Hinek A, et al. Cartilage macromolecules and the calcification of cartilage
matrix. Anat Rec 1989;224:167 – 79.
412 rosenthal
[70] von der Mark K, Kirsch T, Nerlich A, et al. Type X collagen synthesis in human osteoarthritic
cartilage. Indication of chondrocyte hypertrophy. Arthritis Rheum 1992;35:806 – 11.
[71] Kirsch R, Swoboda B, Nah H-D. Activation of annexin II and V expression, terminal differ-
entiation, mineralization and apoptosis in human osteoarthritic cartilage. Osteoarthritis Cartilage
2000;8:294 – 302.
[72] Doherty M, Belcher C, Regan M, et al. Association between synovial fluid levels of inorganic
pyrophosphate and short term radiographic outcome of knee osteoarthritis. Ann Rheum Dis
1996;55:432 – 6.
[73] Johnson K, Terkeltaub R. Upregulated ank expression in osteoarthritis can promote both
chondrocyte MMP-13 expression and calcification via chondrocyte extracellular PPi excess.
Osteoarthritis Cartilage 2004;12:321 – 35.
[74] Suk E-K, Malkin I, Dahm S, et al. Association of ENPP1 gene polymorphisms with hand
osteoarthritis in a Chuvasha population. Arthritis Res 2005;7:R1082 – 90.
[75] Nurminskaya M, Linsenmayer T. Analysis of up-regulated genes during chondrocyte hyper-
trophy. Ann N Y Acad Sci 1996;785:309 – 10.
[76] Summey BJ, Graff R, Lai T, et al. Tissue transglutaminase localization and activity regulation in
the extracellular matrix of articular cartilage. J Orthop Res 2002;20:76 – 82.
[77] Johnson K, van Etten D, Nanda H, et al. Distinct transglutaminase 2-independent and trans-
glutaminase 2-dependent pathways mediate articular chondrocyte hypertrophy. J Biol Chem
2003;278:18824 – 32.
[78] Heinkel D, Gohr C, Uzuki M, et al. Transglutaminase contributes to CPPD crystal formation in
osteoarthritis. Front Biosci 2004;9:3257 – 61.
[79] Rosenthal A, Cheung H, Ryan L. Transforming growth factor beta 1 stimulates inorganic
pyrophosphate elaboration by porcine cartilage. Arthritis Rheum 1991;34:904 – 11.
[80] Fahlgren A, Andersson B, Messner K. TGF-b1 as a prognostic factor in the process of early
osteoarthrosis in the rabbit knee. Osteoarthritis Cartilage 2001;9:195 – 202.
Calcium Deposition and Associated Chronic

Diseases (Atherosclerosis, Diffuse Idiopathic
Skeletal Hyperostosis, and Others)
Fabiola Atzeni, MD, PhDa,T, Piercarlo Sarzi-Puttini, MDa,
Maorizio Bevilacqua, MDb
a
Rheumatology Unit, L Sacco University Hospital, Milan, Italy
b
Endocrine and Diabetes Unit, Department of Medicine, L Sacco University Hospital, Milan, Italy
Extracellular matrix mineralization or calcification is regulated strictly under

physiologic conditions and usually confined to bone tissue. Under pathogenic
situations, however, ectopic calcification may occur (1) when the concentrations
of calcium and phosphate in extracellular fluid exceed the saturation point
(metastatic calcification); (2) as a consequence of the replacement or transition of
injured, degenerated, and necrotic tissue by mineral depositions (dystrophic cal-
cification); or (3) by means of the transdifferentiation of mesenchymal cells into
bone tissue (ectopic calcification) [1,2].
Among the various forms of ectopic calcification, vascular wall calcification
is the most common and is known to involve two mechanisms: passive
calcification resulting from the breakdown of the protection system (a form of
dystrophic calcification) and active calcification resulting from the transdiffer-
entiation of mesenchymal cells in the vascular wall (ectopic ossification). Both
mechanisms contribute to the formation of vascular lesions and play a central role
in the development of atherosclerotic plaque calcification in the elderly [3].
Calcification in atherosclerotic lesions involves factors that are important for
bone mineralization, including matrix vesicles, bone morphogenetic protein
(BMP-2), osteopontin (OPN), osteocalcin, and collagen I [3,4].
T Corresponding author. Rheumatology Unit, L Sacco University Hospital, Via GB Grassi, 74,
20157 Milano, Italy.
E-mail address: sarzi@tiscali.it (F. Atzeni).
414 atzeni et al
Several matrix proteins, such as matrix Gla protein (MGP), OPN, and osteo-
calcin, are identified as protective factors against dystrophic calcification in
nonosseous tissues [5,6]. As the inactivation of MGP in knockout animals leads
to heavy and diffuse vascular calcification, MGP seems to play a central role in
protecting the vascular wall from dystrophic calcification, and MGP deficiency or
altered carboxylation also causes a high level of BMP-2 activity that leads to
hyperostosis in diffuse skeletal idiopathic hyperostosis (DISH) [7,8].
MGP is an important regulator of calcification in cartilage and blood vessels,
but a major difference between vascular calcification and bone mineralization is
the presence of oxidized lipids, the accumulation of which in the subendothelial
space of arteries promotes arterial calcification whereas, in skeletal bone, they
inhibit bone formation [9,10]. Calcium can be deposited throughout the vas-
culature in various forms of calcium phosphates, including calcium hydroxy-
lapatite (CHA) and basic calcium phosphate (BCP). Data suggest that calcium
deposition in arteries and calcium loss from bone resulting from osteoporosis
often coexist, and vascular calcification and bone modeling may have com-
mon mechanisms.
Vascular calcification
Vascular calcium deposition can be divided into four histoanatomic variants:

atherosclerotic calcification, medial arterial calcification, vascular calciphylaxis,
and cardiac valve calcification (Table 1) [3].
Atherosclerotic calcification
Atherosclerosis is characterized by inflammatory metabolic changes with

arterial lipid accumulation, and the lesions frequently become calcified [11,12].
Cardiovascular calcification is a common consequence of aging, diabetes, hyper-
cholesterolemia, mechanically abnormal valve function, and chronic renal insuf-
ficiency and is a type of dystrophic calcification characterized initially by cellular
necrosis, inflammation, and lipoprotein and phospholipid complexes [13,14]. The
Table 1
Histoanatomic variants of vascular calcification and examples of associated diseases
Histoanatomic variants Associated diseases
Atherosclerotic calcification Atherosclerosis
Hypercholesterolemia
Medial arterial calcification Type 2 diabetes
Type 1 diabetes
End-stage renal disease
Vascular calciphylaxis Acute renal insufficiency with muscle injury
Iatrogenic hyperphosphatemia
Cardiac valve calcification Senile calcific aortic sclerosis
calcium deposition & associated chronic diseases 415
process may begin early and accelerate as the disease progresses and more
complex lesions develop. Calcium deposits in coronary arteries indicate the
presence of plaque, but it is not necessarily true that the absence of coronary
calcium indicates an absence of atheromatous plaque [15].
Plaque structure and composition greatly affect the clinical expression of
atherosclerosis. A plaque may be diffuse or amorphous, but observations of bone-
like plaque regions and a series of remarkable studies published in the past
decade support the idea that calcium deposition in plaque is an active and regu-
lated process akin to bone formation.
Recent evidence indicates that many matrix elements play a significant role
in atherosclerotic calcification (Fig. 1) [6,7].
Matrix protein
MGP is a member of the family of extracellular mineral-binding Gla proteins
expressed in various tissues. It accumulates particularly in bone, cartilage, and
blood vessels and protects arterial walls and permanent cartilage from mineral
deposits [16,17].
In atherosclerotic arteries, Gla-containing proteins play an essential role in
clearing calcium phosphate (hydroxyapatite) for which Gla residues have a strong
affinity [18]. Gla is formed post-translationally from glutamic acid as a result of
g-carboxylation by vitamin K–dependent g-glutamate carboxylase. MGP is 10-kd
circulating protein containing five Gla residues shown to be present in association
with vascular smooth muscle cells (VSMCs), the elastic laminae of the tunica
Plaque
Lipid oxidation (LDL- Dysregulated calcium homeostasis

cholesterol)
Necrotic foam cells Dysregulated Collagen
debris Matrix protein (MGP,
Foam cells
OPN, ONS etc.)
Osteogenic signals CSF-1, TNF-a,

RANKL
Mononuclear phagocytic-cell Osteoclast-

like cells
Calcium Deposition
Fig. 1. Possible mechanisms involved in atherosclerotic calcification.
416 atzeni et al
media, and the extracellular matrix of the adventitia [19,20]. It is expressed in

chondrocytes and in normal and atherosclerotic arteries [18].
Mice lacking the gene encoding MGP show extensive calcification of cartilage
and the medial layer of arteries [21]. Furthermore, a single mutation in MGP
gene-coding regions is capable of causing Keutel syndrome, a rare human re-
cessive disorder characterized by diffuse cartilage calcifications, the presence of
which indicates the importance of MGP in preventing dystrophic calcification
[22]. Similarly, the inhibition of vitamin K–dependent carboxylation in mice
by vitamin K antagonism or poor vitamin K intake also promotes vascular
calcification [23–25]. Schurgers and colleagues [26] demonstrate that impaired
MGP carboxylation is associated with intimal (atherosclerosis) and medial
vascular calcification (Mfnckeberg’s sclerosis), suggesting that vitamin K–
induced modification is essential to the function of MGP as an inhibitor of ec-
topic calcification.
Human MGP promoter polymorphisms are identified and prove associated
with low MGP expression and low serum MGP levels and, as suggested by
animal models of impaired MGP expression, lead to an increased risk of myo-
cardial infarction [27,28]. Schurgers and colleagues [29] demonstrate that low
levels of circulating MGP and its impaired g-carboxylation at its tissue expres-
sion site are associated with the development and progression of cardiovascu-
lar disease.
The expression of the MGP gene depends on various growth factors and
hormones [30]. It is assumed that MGP precursors are processed into the general
circulation in an active or secretory form, so the physiologic functions of MGP
can be local and systemic; however, how differently these functions affect
osseous and extraosseous tissue remains to be clarified.
Etiopathogenesis
There are strong, well-documented, and well-recognized links between hyper-
cholesterolemia, lipid oxidation, and atherosclerosis, but only recently has a
connection has been made between elevated low-density lipoprotein (LDL)
cholesterol levels and dysregulated calcium homeostasis [10,31]. Parhami and
coworkers [9] and Parhami and Demer [10] examined the role of oxidized LDL
cholesterol on calcifying vascular cell (CVC) activity in vitro and found that it
upregulates CVC osteogenic mineralization and differentiation but only in con-
cert with physical cell-cell interactions between CVCs and macrophages. The
osteogenic differentiation of CVCs can be recapitulated by inducing oxidative
stress, which, intriguingly, concomitantly suppresses osteoblast differentiation,
indicating the existence of reciprocal cell type-specific responses [32]. Activated,
cholesterol-laden foam cells, therefore, participate in generating multiple osteo-
genic signals that potentially are mediated by tumor necrosis factor (TNF)-a and
oxidized lipids [33,34].
In addition to colony-stimulating factor 1 (CSF-1) and receptor activator of
nuclear factor kB ligand (RANKL), osteoclast formation and function are in-
fluenced by other cytokines, some of which (in particular proinflammatory cyto-
kines) also are implicated in atherogenesis [34,35]. The expression patterns of

RANKL, CSF-1, and TNF-a in atherosclerotic plaques are consistent with ar-
terial osteoclast-like cells developing from mononuclear phagocytic cell pre-
cursors (see Table 1) [34].
Recent studies suggest that vascular calcification not only is the result of
passive calcium-phosphate deposition on atherosclerotic arteries but also of
active mechanisms regulated by bone-associated genes [9,36]. Several studies
demonstrate the upregulation of bone-associated proteins, such as OPN, osteo-
calcin, BMP-2a, and osteonectin (OSN), at the sites of calcified atherosclerotic
plaques [18,37–40]. At the same time, and under normal circumstances, the
arterial wall is protected from mineral deposits by MGP [20,29]. In tissues as
functionally diverse as cartilage and arteries, MGP has the general function of
inhibiting mineral precipitation in extracellular fluid, in which the concentrations
of calcium and phosphate approach the salt solubility product. The micro-
environments in atherosclerotic plaques may foster conditions that favor the
precipitation of calcium: in particular, plaque sites containing necrotic foam cells
debris may act as a locus for mineral precipitation because they can release high
concentrations of mitochondrial phosphate and phosphatidylserine-containing
molecules, and this series of events could tip local ionic balance sufficiently to
instigate precipitation [12].
OPN is another bone-matrix protein expressed in arteries, and Speer and
coworkers [41] demonstrate that it inhibits the calcification of vascular structures
in vivo. Its ability to inhibit cell-mediated calcification is dependent on serine
phosphorylation. OPN is not found in normal arteries, but it is expressed in
plaque and colocalizes with calcified plaque regions [42]. It is possible, therefore,
that it may play a protective role where necessary and only be expressed in
plaque in response to local conditions that might tend to favor mineralization.
Rattazzi and coworkers [43] recently have shown that the deposition of
hydroxyapatite is preceded by the formation of fibro-fatty nodules populated by
cells that resemble chondrocytes morphologically and are surrounded by dense
connective tissue that stains positive for type II collagen; the few remaining
chondrocyte-like cells are located adjacent to, or inside, the large areas of calci-
fication. This finding suggests that the mechanism of calcification partially may
recapitulate the process of endochondral bone formation [43]. The molecular
mechanisms regulating vascular calcification remain obscure, but it is suggested
that locally disturbed calcium and phosphate metabolism in atherosclerotic
plaques may contribute to its development [44].
Medial artery calcification
Medial artery calcification is the nonendochondral ossification process of

the arterial tunica media that is highly characteristic of diabetes and end-stage
renal disease [45,46]. Vattikuti and Towler [47] hypothesize that a migratory
adventitial cell myofibroblast population responding to VSMC-OPN production
contributes to vascular remodeling, and others support that the these cells are
418 atzeni et al
implicated in the medial calcification of diabetes and (potentially) end-stage renal

disease [48–50]. It is known that hyperglycemia and hyperphosphatemia (Pi)
induce OPN expression [50–52]. High serum phosphate levels correlate closely
with the extent of vascular calcification and vascular disease, and one of the most
frequent causes of hyperphosphatemia is chronic renal failure and subsequent
kidney dialysis, which typically lead to serum inorganic phosphate levels of more
than 2 mmol [53,54]. Nishizawa and colleagues [55] hypothesize that elevated
extracellular Pi levels increase Pi transport, leading to increased intracellular Pi in
VSMCs. By means of a still unknown mechanism, high intracellular Pi levels
activate specific signaling pathways that increase the expression of osteogenic
genes (including Cbfa1 and osteocalcin) and stimulate the secretion of potential
mineral nucleating molecules, such as calcium-binding proteins. The net effect is
enhanced susceptibility to vascular calcification (Fig. 2) [55].
Vascular calciphylaxis
Vascular calciphylaxis is a component of widespread soft tissue calcification

that occurs when the physiologic calcium phosphate solubility threshold is
exceeded [56].
It seems that vascular calciphylaxis has led to the evolution of various miner-
alization inhibitors, tissue pyrophosphate generating systems, and OPN. Tissue
pyrophosphate is generated by a family of three ectonucleotide pyrophosphatase/
Hyperphosphatemia
increased
intracellular Pi
Elevated extracellular Pi levels
in VSMCs.
Increase Pi transport
Expression of osteogenic genes (including Cbfa-1
and osteocalcin), Secretion of potential mineral
nucleating molecules such as calcium-binding
proteins.
Vascular Calcification
Fig. 2. Mechanism of medial artery calcification. ( Adapted from Nishizawa Y, Jono S, Ishimura E,
et al. Hyperphosphatemia and vascular calcification in end-stage renal disease. J Ren Nutr 2005;15:178–82.)
phosphodiesterases and plays an important role in limiting the calcification of

‘‘soft tissues,’’ such as ligaments and tendons [56].
Consequences of vascular calcification
The deleterious clinical consequences of vascular calcification are clear: the

anatomy and extent of calcific vasculopathy lead to stroke, amputation, and
cardiovascular mortality [45,57–59]. The deposition of calcification in valves
and arteries diminishes their elasticity, which is a major cause of aneurysm and
stenosis. Arterial obstruction resulting from calcification and other processes
can lead to heart attack and stroke. Mineralization in the femoral arteries can
cause intermittent claudication, leading to decreased mobility. Patients who
have diabetes have an increased mortality rate and are at higher risk of lower-
extremity amputation in the setting of medial artery calcification [45]. The risk
of stroke, particularly high in postmenopausal women, is increased in the
presence of aortic arch calcification [57,58]. Given the aging and ‘‘dysmeta-
bolic’’ population, a better understanding of vascular calcification is sorely
needed to improve human health and health care [58–61].
Diffuse idiopathic skeletal hyperostosis
DISH, a skeletal disease characterized by the ligamentous ossification of the

anterolateral spine, was described first by Forestier and Rotes–Querol [62] more
than 50 years ago.
It involves the calcification and ossification of soft tissue, in particular
ligaments and entheses, and has a marked predilection for the axial skeleton
(especially the thoracic spine) but also may affect peripheral joints [8,63]. It leads
to the ossification of the spinal anterior longitudinal ligament and causes the
production of flowing osteophytes that involve particularly the right side of the
spine while preserving the intervertebral disc space [64]. Other entheseal regions
in the peripheral joints may be affected, including the peripatellar ligaments, the
Achilles tendon insertion, the plantar fascia, and the olecranon [65]. Diagnosis is
based solely on radiographic abnormalities defined using the criteria of Resnick
and Niwayama [66].
Etiopathogenesis
The cause of DISH remains unknown, but several risk factors are implicated
on the basis of its frequent association with various metabolic conditions, in-
cluding hyperinsulinemia with or without diabetes mellitus, obesity, hyperuri-
cemia, dyslipidemia, hypertension, and the prolonged use of isoretinol [67–70].
How is the process initiated, however, and what is the link between these
metabolic disorders and new bone formation in DISH (Fig. 3)? The ossification
420 atzeni et al
Metabolic disorders Environmental factors

Matrix Gla protein (MGP/Mgp)
(diabetes mellitus, glucose
intolerance, dyslipidemias, Anatomical factors
hypertension,hyperuricemi
ligament cell altered
a) Mechanical stress
NFkappaB carboxylation ?
atherosclerosis
damage to the endothelium PDGF-BB and deficit of Toxic factors

and aggregation of blood TGFbeta1 BMP-2 ?
platelets PGI2 production
immobility of the
thoracic spine prolonged use
hypervascularity of isoretinol
and rarefaction of
the adjacent bone
growth factor
(IGF-I ) Genetic
factors
osteoblast
proliferation Bone deposition
Fig. 3. Etiopathogenesis of DISH.
process starts in the innermost layer of the anterior longitudinal ligament, at the
site of its attachment to the vertebral body, and then extends to meet the other arm
of ossification coming from the vertebra above or below. It is believed that this
new formation is the result of abnormal osteoblast cell growth/activity in the
bony ligamentous region, which may be a clue to the pathogenesis of DISH [71].
The growth of osteoblasts is maintained by several growth factors that may not
be confined to bone. Insulin-like growth factor I stimulates alkaline phosphatase
activity and type II collagen in osteoblasts and growth hormone can induce the
local production of insulin-like growth factor I and insulin-like growth factor
binding proteins in chondrocytes and osteoblasts [72]. Denko and colleagues [73]
find that patients who have DISH have high insulin and growth hormone levels,
which may explain the osteoblast cell growth and proliferation. Because the
ossification starts in certain sites, El Miedany and coworkers [71] suggest that
hypervascularity could be the localizing factor in the process. Furthermore, in
predisposed patients who have hyperlipidemia, diabetes mellitus, or (possibly)
hyperinsulinemia, there is an increased likelihood of atherosclerosis, the earliest
stages of which leads to endothelial damage, the aggregation of blood platelet-
derived growth factor, and, finally, osteoblast proliferation. Kosaka and
coworkers [74] indicate the possibility that, after being stimulated by environ-
mental factors involving platelet-derived growth factor-BB and transforming
growth factor-1b in ligament cells, nuclear factor kB influences the osteoblastic
differentiation of undifferentiated mesenchymal cells.
Sarzi-Puttini and colleagues [75] find higher serum MGP concentrations in

male and female patients who have DISH than in healthy control subjects
(5.7 nmol/L versus 3.3 nmol/L, P b 0.001) and conclude that MGP may be a
marker of hyperostosis because it is produced in larger amounts by patients
who have hyperostosis-inducing osteometabolic syndromes, such as DISH.
Chondrocalcinosis
Calcium pyrophosphate dihydrate deposition (CPPD) disease is a metabolic

arthropathy caused by calcium pyrophosphate crystal deposits. It is frequent in
the second half of life (6% of the population ages 60 to 70; 30% of the elderly
ages N80) [76,77].
The characteristic radiographic features of CPDD disease include soft tissue
calcification, joint space narrowing, bone sclerosis, subchondral cyst formation
without osteophyte formation, and large intraosseous geodes. Triangular
fibrocartilage calcification frequently is found, and isolated scapho-trapezio-
trapezoid arthritis is specific to CPDD [77,78].
The molecular mechanisms regulating joint calcification remain obscure, but
three participants now are recognized: (1) the overproduction of pyrosphosphate
secreted by chondrocytes; (2) increased calcium concentration; and (3) changes
in cartilage extracellular matrix. Histologic evidence further supports the role of
extracellular matrix changes in the formation of CPPD crystals in areas of
abnormal pericellular matrix (they are not seen in normal matrix). Laboratory
findings also support the role of enzymes called transglutaminases, which modify
extracellular matrix protein in CPPD disease post-translationally: the activation of
extracellular tranglutaminases promotes CCPD crystal formation [79–82].
The levels of calcium-binding proteins, including S-100, OPN, and OSN
(secreted protein acid-rich and rich in cysteine), are increased in the extracellular
matrix of CPPD-diseased cartilage [83]. OPN may play an important role in
CCPD crystal formation because (1) it has a large calcium-binding capacity; (2) it
is seen in other conditions involving pathologic calcification, such as athero-
sclerosis; (3) it is increased in the areas in which the crystals are formed; and (4) it
is a transglutaminase substrate. The levels of S-100, another calcium-binding
protein, are increased around CCPD crystals [84–86]. It is believed [81] that
matrix vesicles are involved in CCPD crystal formation insofar as those isolated
from articular cartilage can produce CCPD in vitro. The mechanisms, however,
by means of which the extracellular matrix changes and matrix vesicles form
CPPD crystals are understood poorly.
Miscellaneous
BCP crystals frequently may form asymptomatic deposits that may give rise to
several clinical syndromes, including calcific periarthritis, Milwaukee shoulder
422 atzeni et al
syndrome, osteoarthritis, calcific tendinitis and bursitis, and mixed crystal depo-
sition in and around joints [87,88].
Milwaukee shoulder syndrome is one of the better-defined BCP crystal-
associated syndromes [88]. It is characterized by the gradual onset of mild to
moderate shoulder pain that often is bilateral and worse at night. Renal disease
may be a predisposing factor. The pathogenesis of Milwaukee shoulder syndrome
remains obscure but recent data show that low doses of warfarin are effective in
some cases of soft tissue calcification because it depresses the synthesis of the
vitamin K–dependent Gla protein, suggesting that this matrix protein may play a
pathogenetic role [89].
Calcific tendinitis of the shoulder is a dynamic process. It is reported that the
cells surrounding tendon calcifications contain OPN [90]. Resorption probably is
mediated by cathepsin K–containing multinucleated giant cells. Metalloprotein-
ases are found in the synovial fluids of patients who have rotator cuff tears
[90,91].
Recent advances in areas of medicine, such as oncology, have strengthened the
argument that BCP crystals, once believed inert structures, have many potential
pathophysiologic functions. Microcalcifications containing CHA often are
associated with malignant human breast lesions. OSN, OPN, and bone sialo-
protein (BSP), three bone matrix proteins involved in bone matrix mineralization,
are expressed in human breast cancers. Hirota and coworkers [92] find that the
OPN protein produced by macrophages seems to play a significant role in the
development of calcifying foci within the necrotic areas of breast cancers. Recent
studies show that BSP, an Arg-Gly-Asp (RDG)–containing phosphoprotein,
initiates CHA deposition and mediates the attachment of osteoclasts to the same
crystals before their resorption [93]. The level of BSP expression correlates with
the development of bone metastases and poor survival, suggesting that the
ectopic expression of bone matrix proteins may be involved in conferring osteo-
tropic properties to circulating metastatic breast cancer cells [93].
In conclusion, several matrix proteins are identified as protective factors in
nonosseous tissues, and alterations in them are found associated with several
calcium deposition diseases.
References
[1] Giachelli CM. Ectopic calcification: new concepts in cellular regulation. Z Kardiol 2001;90:
31 – 7.
[2] Karsenty G. Minireview: transcriptional control of osteoblast differentiation. Endocrinology
2001;142:2731 – 3.
[3] Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective.
Am J Physiol Endocrinol Metab 2004;286:E686 – 96.
[4] Tintut Y, Demer LL. Recent advances in multifactorial regulation of vascular calcification. Curr
Opin Lipidol 2001;12:555 – 60.
[5] Moe SM, Chen NX. Pathophysiology of vascular calcification in chronic kidney disease. Circ
Res 2004;95:560 – 7.
[6] Roy ME, Nishimoto SK. Matrix Gla protein binding to hydroxyapatite is dependent on the ionic
environment: calcium enhances binding affinity but phosphate and magnesium decrease affinity.
Bone 2002;31:296 – 302.
[7] Luo G, Ducy P, McKee MD, et al. Spontaneous calcification of arteries and cartilage in mice
lacking matrix GLA protein. Nature 1997;386:78 – 81.
[8] Sarzi-Puttini P, Atzeni F. New developments in our understanding of DISH (diffuse idiopathic
skeletal hyperostosis). Curr Opin Rheumatol 2004;16:287 – 92.
[9] Parhami F, Morrow AD, Balucan J, et al. Lipid oxidation products have opposite effects on
calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of
arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 1997;17:680 – 7.
[10] Parhami F, Demer LL. Arterial calcification in face of osteoporosis in ageing: can we blame
oxidized lipids? Curr Opin Lipidol 1997;8:312 – 4.
[11] Detrano RC, Doherty TM, Davies MJ, et al. Predicting coronary events with coronary calcium:
pathophysiologic and clinical problems. Curr Probl Cardiol 2000;25:374 – 402.
[12] Doherty TM, Asotra K, Fitzpatrick LA, et al. Calcification in atherosclerosis: bone biology and
chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A 2003;100:11201 – 6.
[13] Campell CY, Nasir K, Blumenthal RS. Metabolic syndrome, subclinical coronary atheroscle-
rosis, and cardiovascular risk. Am Heart Hosp J 2005;3:105 – 10.
[14] Ferramosca E, Burke S, Chasan-Taber S, et al. Etiopathogenesis, diagnosis and prevention of
vascular calcification in end stage renal disease. Curr Med Chem Cardiovasc Hematol Agents
2005;3:165 – 71.
[15] Qiao JH, Doherty TM, Fishbein MC, et al. Calcification of the coronary arteries in the absence of
atherosclerotic plaque. Mayo Clin Proc 2005;80:807 – 9.
[16] Rutsch F, Terkeltaub R. Parallels between arterial and cartilage calcification: what understand-
ing artery calcification can teach us about chondrocalcinosis. Curr Opin Rheumatol 2003;15:
302 – 10.
[17] Luo G, D’Souza R, Hogue D, et al. The matrix Gla protein gene is a marker of the chon-
drogenesis cell lineage during mouse development. J Bone Miner Res 1995;10:325 – 34.
[18] Bostrom K, Watson KE, Horn S, et al. Bone morphogenetic protein expression in human
atherosclerotic lesions. J Clin Invest 1993;91:1800 – 9.
[19] Cancela L, Hsieh CL, Francke U, et al. Molecular structure, chromosome assignment, and
promoter organization of the human matrix Gla protein gene. J Biol Chem 1990;265:15040 – 8.
[20] Dhore CR, Cleutjens JP, Lutgens E, et al. Differential expression of bone matrix regulatory
proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2001;21:1998 – 2003.
[21] El-Maadawy S, Kaartinen MT, Schinke T, et al. Cartilage formation and calcification in arteries
of mice lacking matrix Gla protein. Connect Tissue Res 2003;44:272 – 8.
[22] Munroe PB, Olgunturk RO, Fryns JP, et al. Mutations in the gene encoding the human matrix
Gla protein cause Keutel syndrome. Nat Genet 1999;21:142 – 4.
[23] Howe AM, Webster WS. Warfarin exposure and calcification of the arterial system in the rat. Int
J Exp Pathol 2000;81:51 – 6.
[24] Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in
rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998;18:1400 – 7.
[25] Villines TC, Hatzigeorgiou C, Feuerstein IM, et al. Vitamin K1 intake and coronary calcification.
Coron Artery Dis 2005;16:199 – 203.
[26] Schurgers LJ, Dissel PE, Spronk HM, et al. Role of vitamin K and vitamin K dependent proteins
in vascular calcification. Z Kardiol 2001;90:57 – 63.
[27] Farzaneh-Far A, Davies JD, Braam LA, et al. A polymorphism of the human matrix gamma-
carboxyglutamic acid protein promoter alters binding of an activating protein-1 complex and is
associated with altered transcription and serum levels. J Biol Chem 2001;276:32466 – 73.
[28] Herrmann SM, Whatling C, Brand E, et al. Polymorphisms of the human matrix gla protein
(MGP) gene, vascular calcification, and myocardial infarction. Arterioscler Thromb Vasc Biol
2000;20:2386 – 93.
[29] Schurgers LJ, Teunissen KJ, Knapen MH, et al. Novel conformation-specific antibodies against
424 atzeni et al
matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as

marker for vascular calcification. Arterioscler Thromb Vasc Biol 2005;25:1629 – 33.
[30] Stheneur C, Dumontier MF, Guedes C, et al. Basic fibroblast growth factor as a selective
inducer of matrix Gla protein gene expression in proliferative chondrocytes. Biochem J 2003;
369:63 – 70.
[31] Navab M, Van Lenten BJ, Reddy ST, et al. High-density lipoprotein and the dynamics of
atherosclerotic lesions. Circulation 2001;104:2386 – 7.
[32] Mody N, Parhami F, Sarafian TA, et al. Oxidative stress modulates osteoblastic differentiation
of vascular and bone cells. Free Radic Biol Med 2001;31:509 – 19.
[33] Tintut Y, Patel J, Territo M, et al. Monocyte/macrophage regulation of vascular calcification
in vitro. Circulation 2002;105:650 – 5.
[34] Fuller K, Murphy C, Kirstein B, et al. TNF-alpha potently activates osteoclasts, through a
direct action independent of and strongly synergistic with RANKL. Endocrinology 2002;143:
1108 – 18.
[35] Tintut Y, Patel J, Parhami F, et al. Tumor necrosis factor-alpha promotes in vitro calcification
of vascular cells via the cAMP pathway. Circulation 2000;102:2636 – 42.
[36] Jeriorska M, McCollum C, Wooley DE. Observations on bone formation and remodelling
in advanced atherosclerotic lesions of human carotid arteries. Virchows Arch 1998;433:559 – 65.
[37] Champagne CM, Takebe J, Offenbacher S, et al. Macrophage cell lines produce osteoinductive
signals that include bone morphogenetic protein-2. Bone 2002;30:26 – 31.
[38] Zebboudj AF, Imura M, Bostrom K. Matrix GLA protein, a regulatory protein for bone mor-
phogenetic protein-2. J Biol Chem 2002;277:4388 – 94.
[39] Fukui N, Zhu Y, Maloney WJ, et al. Stimulation of BMP-2 expression by pro-inflammatory
cytokines IL-1 and TNF-alpha in normal and osteoarthritic chondrocytes. J Bone Joint Surg
[Am] 2003;85-A:59 – 66.
[40] Denhardt DT, Giachelli CM, Rittiling SR. Role of osteopontin in cellular signaling and toxicant
injury. Annu Rev Pharmacol Toxicol 2001;41:723 – 49.
[41] Speer MY, McKee MD, Guldberg RE, et al. Inactivation of the osteopontin gene enhances
vascular calcification of matrix Gla protein-deficient mice: evidence for osteopontin as an
inducible inhibitor of vascular calcification in vivo. J Exp Med 2002;196:1047 – 55.
[42] Fitzpatrick LA, Severson A, Edwards WD, et al. Diffuse calcification in human coronary
arteries. Association of osteopontin with atherosclerosis. J Clin Invest 1994;94:1597 – 604.
[43] Rattazzi M, Bennett BJ, Bea F, et al. Calcification of advanced atherosclerotic lesions in the
innominate arteries of ApoE-deficient mice: potential role of chondrocyte-like cells. Arterioscler
Thromb Vasc Biol 2005;25:1420 – 5.
[44] Higgins CL, Marvel SA, Morrisett JD. Quantification of calcification in atherosclerotic lesions.
Arterioscler Thromb Vasc Biol 2005;25:1567 – 76.
[45] Chen NX, Moe SM. Arterial calcification in diabetes. Curr Diab Rep 2003;3:28 – 32.
[46] Quinibi WY, Nolan CA, Ayus JC. Cardiovascular calcification in patients with end-stage renal
disease: A century-old phenomenon. Kidney Int Suppl 2002;82:73 – 80.
[47] Vattikuti R, Towler DA. Osteogenic regulation of vascular calcification: an early perspective.
Am J Physiol Endocrinol Metab 2004;286:E686 – 96.
[48] Li G, Chen YF, Kelpke SS, et al. Estrogen attenuates integrin-beta(3)-dependent adventitial
fibroblast migration after inhibition of osteopontin production in vascular smooth muscle cells.
Circulation 2000;101:2949 – 55.
[49] Towler DA, Bidder M, Latifi T, et al. Diet-induced diabetes activates an osteogenic gene
regulatory program in the aortas of low density lipoprotein receptor-deficient mice. J Biol Chem
1998;273:30427 – 34.
[50] Bidder M, Shao JS, Charlton-Kachigian N, et al. Osteopontin transcription in aortic vascular
smooth muscle cells is controlled by glucose-regulated upstream stimulatory factor and activator
protein-1 activities. J Biol Chem 2002;277:44485 – 96.
[51] Chen NX, O’Neill KD, Duan D, et al. Phosphorus and uremic serum up-regulate osteopontin
expression in vascular smooth muscle cells. Kidney Int 2002;62:1724 – 31.
[52] Takemoto M, Yokote K, Yamazaki M, et al. Enhanced expression of osteopontin in human

diabetic artery and analysis of its functional role in accelerated atherogenesis. Arterioscler
Thromb Vasc Biol 2000;20:624 – 8.
[53] Block GA, Port FK. Re-evaluation of risks associated with hyperphosphatemia and hyper-
parathyroidism in dialysis patients: recommendations for a change in management. Am J Kidney
Dis 2000;35:1226 – 37.
[54] Winchester JF, Rotellar C, Goggins M, et al. Calcium and phosphate balance in dialysis patients.
Kidney Int Suppl 1993;41:S174 – 8.
[55] Nishizawa Y, Jono S, Ishimura E, et al. Hyperphosphatemia and vascular calcification in end-
stage renal disease. J Ren Nutr 2005;15:178 – 82.
[56] Johnson K, Goding J, Van Etten D, et al. Linked deficiencies in extracellular PP(i) and
osteopontin mediate pathologic calcification associated with defective PC-1 and ANK expres-
sion. J Bone Miner Res 2003;18:994 – 1004.
[57] Iribarren C, Sidney S, Sternfeld B, et al. Calcification of the aortic arch: risk factors and asso-
ciation with coronary heart disease, stroke, and peripheral vascular disease. JAMA 2000;283:
2810 – 5.
[58] Arad Y, Goodman KJ, Roth M, et al. Coronary calcification, coronary disease risk factors,
C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study.
J Am Coll Cardiol 2005;46:158 – 65.
[59] London GM, Guerin AP, Marchais SJ, et al. Arterial media calcification in end-stage renal
disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003;18:
1731 – 40.
[60] Lindroos M, Kupari M, Valvanne J, et al. Factors associated with calcific aortic valve
degeneration in the elderly. Eur Heart J 1994;15:865 – 70.
[61] Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature
2001;414:782 – 7.
[62] Forestier J, Rotes–Querol J. Senile ankylosing hyperostosis of the spine. Ann Rheum Dis 1950;
9:321 – 30.
[63] Belanger TA, Rowe DE. Diffuse idiopathic skeletal hyperostosis: musculoskeletal manifes-
tations. J Am Acad Orthop Surg 2001;9:258 – 67.
[64] Resnick D, Shapiro RF, Wiesner KB, et al. Diffuse idiopathic skeletal hyperostosis (DISH):
ankylosing hyperostosis of Forestier and Rotés Querol. Semin Arthritis Rheum 1978;7:153 – 87.
[65] Benjamin M, Kumai T, Milz S, et al. The skeletal attachment of tendons—tendon ‘‘entheses’’.
Comp Biochem Physiol A 2002;133:931 – 45.
[66] Resnick D, Niwayama G. Radiographic and pathologic features of spinal involvement in diffuse
idiopathic skeletal hyperostosis (DISH). Radiology 1976;119:559 – 68.
[67] Kiss C, Szilagyi M, Paksy A, et al. Risk factors for diffuse idiopathic skeletal hyperostosis: a
case–control study. Rheumatol 2002;41:27 – 30.
[68] Troillet N, Gerster JC. Forestier disease and metabolism disorders. A prospective controlled
study of 25 cases. Rev Rhum Ed Fr 1993;60:274 – 9.
[69] Vezyroglou G, Mitropoulos A, Antoniadis C. A metabolic syndrome in diffuse idiopathic skele-
tal hyperostosis. A controlled study. J Rheumatol 1996;23:672 – 6.
[70] Dougados M, Leporho MA, Esmilaire L, et al. Taux plasmatiques des vitamines A et E au cours
de la maladie hyperostosique, la spondyloarthrite ankylosante, et la polyarthrite rheumatoide.
Rev Rhum Mal Osteoartic 1988;55:251 – 4.
[71] El Miedany YM, Wassif G, El Baddini M. Diffuse idiopathic skeletal hyperostosis (DISH): is it
of vascular aetiology? Clin Exp Rheumatol 2000;18:193 – 200.
[72] Vetter U, Zapf J, Heit W, et al. Human fetal and adult chondrocytes. Effects of insulin-like
growth factors I and II, insulin and growth hormone on clonal growth. J Clin Invest 1986;77:
1903 – 8.
[73] Denko CW, Boja B, Moskowitz RW. Growth promoting peptides in osteoarthritis and diffuse
idiopathic skeletal hyperostosis – insulin, insulin-like growth factor-I, growth hormone.
J Rheumatol 1994;21:1725 – 30.
426 atzeni et al
[74] Kosaka T, Imakiire A, Mizuno F, et al. Activation of nuclear factor kappaB at the onset of
ossification of the spinal ligaments. J Orthop Sci 2000;5:572 – 8.
[75] Sarzi-Puttini P, Bevilacqua M, Atzeni F, et al. Matrix GLA protein: evidence of persistently
increased concentrations in DISH patients. Arthritis Rheum 2003;48:S534.
[76] Wise CM. Crystal-associated arthritis in the elderly. Clin Geriatr Med 2005;21:491 – 511.
[77] McCarthy GM. Crystal deposition diseases: out of sight, out of mind. Curr Opin Rheumatol
2005;17:312 – 3.
[78] Saffar P. Chondrocalcinosis of the wrist. J Hand Surg 2004;29:486 – 93.
[79] Hirose J, Ryan LM, Masuda I. Up-regulated expression of cartilage intermediate-layer protein
and ANK in articular hyaline cartilage from patients with calcium pyrophosphate dihydrate
crystal deposition disease. Arthritis Rheum 2002;46:3218 – 29.
[80] Rosenthal AK, McCarty BA, Cheung HS, et al. A comparison of the effect of transforming
growth factor beta 1 on pyrophosphate elaboration from various articular tissues. Arthritis
Rheum 1993;36:539 – 42.
[81] Kalva S, Rosenthal AK. Extracellular matrix changes regulate calcium crystal formation in
articular cartilage. Curr Opin Rheumatol 2005;17:325 – 9.
[82] Anderson HC. Matrix vesicles and calcification. Curr Rheumatol Rep 2003;5:222 – 6.
[83] Wada T, McKee MD, Steitz S, et al. Calcification of vascular smooth muscle cell cultures:
inhibition by osteopontin. Circ Res 1999;84:166 – 78.
[84] Kaartinen MT, Pirhonen A, Linnala-Kankkunen A, et al. Cross-linking of osteopontin by tissue
transglutaminase increases its collagen binding properties. J Biol Chem 1999;274:1729 – 35.
[85] Harmey D, Hessle L, Narisawa S, et al. Concerted regulation of inorganic pyrophosphate and
osteopontin by Akp2, Enpp1 and Ank. Am J Pathol 2004;164:1199 – 209.
[86] Aeschlimann D, Kaupp O, Paulsson M. Transglutaminase-catalyzed matrix cross-linking in
differentiating cartilage: identification of osteonectin as a major glutaminyl substrate. J Cell Biol
1995;120:1461 – 70.
[87] Malloy ES, McCarthy GM. Hydroxyapatite deposition disease of the joint. Curr Rheumatol Rep
2003;5:215 – 21.
[88] Halverson PB. Crystal deposition disease of the shoulder (including calcific tendonitis and
Milwaukee shoulder syndrome). Curr Rheumatol Rep 2003;5:244 – 7.
[89] Halverson PB, McCarty DJ. Clinical aspects of basic calcium phosphate crystal deposition.
Rheum Dis Clin North Am 1988;14:427 – 39.
[90] Hurt G, Baker Jr CL. Calcific tendinitis of the shoulder. Orthop Clin North Am 2003;34:567 – 75.
[91] Garcia GM, McCord GC, Kumar R. Hydroxyapatite crystal deposition disease. Semin
Musculoskelet Radiol 2003;7:187 – 93.
[92] Hirota S, Ito A, Nagoshi J, et al. Expression of bone matrix protein messenger ribonucleic acids
in human breast cancers. Possible involvement of osteopontin in development of calcifying foci.
Lab Invest 1995;72:64 – 9.
[93] Bellahcene A, Castronovo V. Expression of bone matrix proteins in human breast cancer:
potential roles in microcalcification formation and in the genesis of bone metastases. Bull Cancer
1997;84:17 – 24.
Imaging Features of
Crystal-Induced Arthropathy
Marc H. Choi, John D. MacKenzie, Murray K. DalinkaT
Department of Radiology, Hospital of the University of Pennsylvania,
3400 Spruce Street/1 Silverstein, Philadelphia, PA 19104, USA
Crystal-induced arthropathies constitute a spectrum of inflammatory arthriti-

des that is induced by cellular reaction to crystal deposition in and around joints.
A variety of microcrystals may be deposited and can induce an inflammatory
response. The three most common types of crystal-induced arthropathy are gout,
calcium pyrophosphate dihydrate (CPDD) deposition disease, and calcium
hydroxyapatite deposition disease (HADD). Each has a characteristic clinical pre-
sentation, crystal type that may be aspirated from affected tissues, and ra-
diographic appearance. Each of these entities may occur as a primary abnormality
or secondary to an underlying disorder. Sometimes these diseases may coexist
in the same joint or individual. Imaging frequently plays a crucial role in the
diagnosis of crystal-induced arthropathies and may help to monitor disease pro-
gression and treatment response.
Gout
Gout is a common peripheral arthritis that develops from the deposition of

sodium urate crystals in one or more joints. When left untreated, crystal depo-
sition leads to recurrent episodes of joint inflammation and joint destruction.
The clinical manifestations of gout may be subdivided into early and late
presentations and acute and chronic attacks of arthritis. Imaging aids in the
clinical evaluation of patients who have gout aids in monitoring patients with
this disorder.
T Corresponding author.
E-mail address: murray.dalinka@uphs.upenn.edu (M.K. Dalinka).
428 choi et al
Etiology
Gout may be caused by uric acid overproduction or underexcretion. Altered

metabolism of urate precipitates urate salt deposition and leads to gout [1].
Diseases that are associated with uric acid overproduction include primary enzy-
matic defects of purine synthesis or increased nucleic acid turnover, such as
myeloproliferative and lymphoproliferative disorders, hemoglobinopathies, mas-
sive cell lysis from chemo- or radiation therapy, and saturnine gout. Decreased
uric acid excretion and elevated serum uric acid levels may occur secondary to
chronic renal failure, thiazide or other diuretic therapy, or pharmacologic agents
that alter renal function.
The combination of elevated serum and soft tissue uric acid levels and acido-
sis likely accelerates urate crystal formation. Rapid changes in uric acid levels
are believed to be responsible for acute attacks of gout; however, the presence of
hyperuricemia is not diagnostic of gout because most patients who have hyper-
uricemia do not have gout. If untreated, hyperuricemia increases the risk for gout,
and approximately 90% of patients who have chronic hyperuricemia develop
gout within 30 years [2]. The key to the diagnosis is joint aspiration with synovial
fluid analysis depicting negatively birefringent urate crystals on polarized light
microscopy, or classic radiographic findings [3]. Imaging in conjunction with
tissue aspiration/biopsy helps to establish a firm diagnosis of gout before initi-
ating potentially toxic therapy.
Clinical features
Gout is the most common form of crystal arthropathy. Although gout affects
less than 0.5% of the population, the prevalence of the disease increases with age
[4]. Typically, patients present with acute signs and symptoms years before
radiographic abnormality is manifest; however, on rare occasions patients may
present with chronic arthritis.
Classically, the disease begins at night in men between the ages of 30 to
60 years with the sudden onset of acute and severe pain with a predilection for the
metatarsophalangeal (MTP) joint of the first digit (podagra). The first MTP joint
is involved in approximately 50% of patients at onset, and eventually in 90% of
patients who have untreated gout. The excruciating joint pain usually subsides
within 2 to 24 hours with less severe pain occasionally lasting for a few weeks.
The acute attacks of gout recur frequently and when they increase in number the
disease is more likely to become polyarticular. Approximately 25% of patients
have five or more acute attacks per year before treatment. Patients with early
onset of gout typically have more frequent attacks than do patients in the chronic
stage. After an initial series of acute attacks, patients may enter a symptom-free
period (‘‘intercritical gout’’) that may last from months to years [2].
With chronic gout, tophi are deposited in a periarticular location. Tophi are the
hallmark of chronic gout and they may be identified on radiographs; biopsy rarely
is necessary because the diagnosis of gout usually is well established by the time
imaging features of crystal-induced arthropathy 429
tophi appear. The rate of tophi formation is dependent upon the level of uric acid;
approximately half of the patients who have untreated gout develop tophi after
10 years and more than 70% have tophi after 20 years [5]. The early diagnosis
and treatment of gout has resulted in a decline in the incidence of chronic
tophaceous gout although it still occurs, in part secondary to misdiagnosis,
mismanagement, and poor patient compliance/adherence.
Imaging gout
Radiographic examination in patients who have gout is used mainly to evalu-

ate joint destruction and disease progression, to document the presence of tophi,
and to help exclude other diagnoses. Radiographic findings may be categorized
into the nonspecific changes that are seen in early gout, the subtle alterations of
intercritical gout, and the more specific changes of chronic tophaceous gout [3].
In the early stage of gout, the radiographs usually are normal or show nonspecific
soft tissue swelling in the affected joint secondary to synovitis, capsular disten-
tion, and periarticular soft tissue edema. As the attack subsides, the radiographic
abnormalities usually disappear [3]. Other causes of monoarticular soft tissue
swelling, including infectious arthritis, pseudogout, and trauma, must be ex-
cluded [6]. In the intercritical period, which occurs between the acute period and
the development of chronic tophaceous gout, subtle joint alterations (eg, small,
well-defined erosions) may be visualized at the periphery of affected joints.
The distribution of radiographic abnormalities in gouty arthritis is variable,
but the disease tends to affect the lower extremities more often than the upper
extremities and the small joints more often than the large joints. An asymmetric
and monoarticular distribution is characteristic of gout with the first MTP
joint (podagra) affected most often followed by the first interphalangeal and
tarsometatarsal joints. Approximately 85% to 90% of patients who have gout
experience podagra at some point in the disease. Most first presentations are
monoarticular. Bilateral and symmetric or asymmetric polyarticular involvement
may be present within any of the foot joints. All compartments of the hand and
wrist, knee, shoulder, hip, and sacroiliac joint (15% unilateral) are favored sites.
The ankle, tarsal, and knee are involved frequently early in the course of
the disease. There is preference for peripheral joints with the feet, elbow, and
wrist [7].
Characteristic findings occur in chronic gout. These include tophi, erosions
with overhanging edges, relative preservation of the joint space, and lack of
osteopenia. The hallmark of chronic gout is the presence of multiple macroscopic
tophi (Figs. 1 and 2)—a mixture of monosodium monohydrate crystals in a
matrix of amorphous debris containing urate, proteinaceous deposits, and lipids
with a surrounding foreign body reaction. Generally, they are ovoid and asym-
metric and usually are radiographically invisible until they reach 5 mm to 10 mm
in diameter [8,9]. Large tophi may be palpable. Faint calcification may occur in
up to 50% of tophi; however, cloudlike masses of densely calcified tophi are
atypical [9] and may reflect a coexisting abnormality of calcium metabolism,
430 choi et al
Fig. 1. Tophaceous gout. Large tophus at MTP joint of first toe and erosion with overhanging edge
at fifth metatarsal. Additional small erosions are present at the medial cuneiform–first metatar-
sal articulation.
such as renal insufficiency (Fig. 3) [10,11]. Erosions in chronic gout are common
and usually are associated closely with the tophaceous deposits because the
erosions may occur secondary to chronic pressure from the adjacent tophus.
When characteristic erosions are seen along with tophi the diagnosis of gout is
almost certain. Frequently, these erosions are round or oval in shape and well
circumscribed, and typically are eccentric and oriented along the long axis of
bone (see Figs. 1 and 2). Most often they are juxta-articular but may be intra-
articular or located at a distance form the joint. Intra-articular erosions tend to
involve the joint margins before extending to the middle of the joint [5].
Interosseous erosions may have sclerotic borders that produce a punched-out
appearance [12].
A characteristic feature of gouty erosions is the overhanging edge, an elevated
margin of bone that extends over the expected confines of the cortex at the site
Fig. 2. Gouty arthritis. Multiple changes of gouty arthritis are present in the hand. There is
asymmetric soft tissue swelling and small erosions at the second metacarpophalangeal articulation.
Large erosions are identified about the proximal interphalangeal joint of the second digit that are
more marked on the radial aspect of the joint where there is an overhanging edge. Smaller erosions are
present in the other digits.
Fig. 3. Calcified tophus. Classic tophus with increased density at the first MTP joint and additional
tophus at the medial aspect of the interphalangeal joint of the first digit in this patient who had gout
and renal failure.
of erosion (see Fig. 1) [13]. The overhanging edge is seen in approximately 40%
of patients who have tophaceous gout and may represent new bone formation
around a gradually enlarging tophus. Occasionally, extensive osseous erosions
produce a mutilating arthritis that mimics the opera-glass hand deformity that is
seen occasionally with rheumatoid or psoriatic arthritis [14].
The joint space is relatively well preserved, even in the presence of extensive
juxta-articular erosions. Large tophi are an important radiographic feature that
helps to differentiate gout from other causes of arthritis. If joint space narrowing
has occurred, the radiographic appearance may mimic the uniform narrowing of
rheumatoid arthritis or advanced osteoarthritis (OA) [2]; however, patients who
have joint space narrowing generally have had long-standing disease and the
clinical diagnosis of gout already is well established (Fig. 4). Ankylosis with
obliteration of the joint space is rare [11,15].
Osteopenia is an atypical feature of gout. When bone density is diminished in
long-standing gouty arthritis, disuse is believed to be the underlying cause of the
osteopenia [15]. Periarticular osteopenia may be seen during an acute gouty
attack, presumably from inflammation-induced hyperemia; however, this is tran-
sient and the bone density tends to be preserved, even in advanced chronic gout
with articular destruction. Infrequently, a zone of osteoporosis in the subchondral
bone may progress to a cystic abnormality [9]. Interosseous tophi and sub-
chondral cysts may mimic focal osteoporosis and should not be confused with
diffuse periarticular osteopenia.
Localized increased bone density may be seen in a minority of patients (~ 6%)
that has advanced tophaceous gout, predominantly in the hands and feet. The
increased bone density may represent calcification of interosseous monosodium
urate deposits [5]. The radiographic appearance may resemble an area of bone
infarction or enchondroma.
Occasionally, bone proliferation is present in gouty arthritis. Enlargement of
the ends and shafts of involved bones can produce club-shaped metatarsal and
432 choi et al
Fig. 4. Advanced gout with joint destruction. Radiograph of the foot shows marked joint destruction
and large tophus at the first MTP joint. Joint destruction and erosions are identified at the
tarsometatarsal joints and the second MTP joint with lateral subluxation.
phalangeal heads (see Fig. 1). This is termed ‘‘mushrooming.’’ Irregular bone
spicules at sites of muscle and tendon insertion, such as the calcaneus, olecranon,
and patella, may be observed [16]. A fine lacy periosteal new bone formation
may occur secondary to periosteal reaction that is caused by cortical destruction
by adjacent crystal deposition; often, this is seen best on the medial aspect of the
first MTP joint [17]. Bilateral olecranon bursitis (Fig. 5) is characteristic of gout
as is bilateral swelling at the dorsum of the foot and calcaneus.
Hyperuremic patients may present with urinary calculi before developing
gouty arthritis [18]. A non-contrast CT scan performed with thin slices (3–5 mm)
through the urinary-collecting system has replaced intravenous urography as the
gold standard for detecting urinary calculi [19]. Urate stones as small as 2 mm
may be detected readily [20]. CT rarely is useful in patients who have gout other
than for the detection of urinary calculi. Although several papers have de-
Fig. 5. Olecranon bursitis. Soft tissue swelling and calcification about the olecranon bursa, a
characteristic finding in gout that often is bilateral.
scribed MRI findings in patients who have gout, MRI is not used in diagnosis
or management.
Calcium pyrophosphate dihydrate deposition disease
CPPD deposition disease is characterized by the presence of CPPD crystals

within and around joints. CPPD crystals elicit an inflammatory response that
results in arthritis, synovitis, or tendonitis. The soft tissue calcification from
CPPD crystal deposition and the joint degeneration that result from CPPD
arthropathy tend to have characteristic imaging appearances. Before discussing
the clinical and imaging features, a review of nomenclature is helpful to under-
stand better the clinical and radiographic manifestations of CPPD deposition
disease [21].
Chondrocalcinosis signifies deposits of calcium salts in cartilaginous tissue.
Most often, articular chondrocalcinosis results from CPPD crystal deposition in
hyaline and fibrocartilage; however, chondrocalcinosis also may occur from the
deposition of calcium apatite, dicalcium phosphate dehydrate, or calcium oxalate.
Chondrocalcinosis may be seen without symptoms of arthropathy. Articular and
periarticular calcifications are general terms that are used for the radiologic
description of calcification in or around a joint but not necessarily in cartilage.
CPPD deposition disease describes a crystal arthropathy that is induced by
CPPD crystals. CPPD deposition disease is synonymous with CPPD arthropathy
and pyrophosphate arthropathy. It is characterized by joint inflammation and a
typical pattern of structural joint damage that may occur with or without radio-
graphically visible chondrocalcinosis [22,23]. Pseudogout syndrome is a subset
of CPPD deposition disease that mimics the clinical manifestations of gout, but is
caused by calcium pyrophosphate crystals rather than monosodium urate crystals.
Clinical features
The prevalence of CPPD deposition increases with age; it is common in the

geriatric population where it frequently is asymptomatic. There is a 5% incidence
of radiographic chondrocalcinosis by age 70 and a 50% incidence by age 90 [24].
An autosomal dominant form of CPPD has been described with an earlier age of
onset than the idiopathic form [25]; it often is associated with severe symptoms.
CPPD deposition disease may cause an idiopathic arthritis in middle-aged or
elderly patients; it affects both sexes equally. Additionally, CPPD deposition has
been reported in association with a host of disorders. The incidence of primary
hyperparathyroidism is as high as 15% in patients who have CPPD [26].
Chondrocalcinosis is found in up to 41% of patients who have hemochromatosis
and the articular manifestations share many similarities with CPPD arthropathy
[27–29]. CPPD deposition disease also has been described in patients with
secondary hemochromatosis related to hereditary spherocytosis [29].
434 choi et al
Although common, CPPD deposition disease was described first in the

1960s [30,31]. CPPD deposition disease is a great mimic, because the clinical
presentation may resemble gout, rheumatoid arthritis, OA, traumatic arthritis,
neuropathic joint, ankylosing spondylitis, rheumatic fever, or psychogenic
arthritis [32]. The clinical presentation of CPPD arthropathy generally falls
into five distinct clinical patterns: lanthanic, pseudogout syndrome, pseudo-
rheumatoid arthritis, pseudoneuropathic arthropathy, and pseudoostoeoarthritic
types [33].
The lanthanic or asymptomatic type is the most common clinical pattern of
CPPD deposition disease. CPPD deposits are visible on radiographs but the
particular joint is without the clinical signs and symptoms of an arthropathy,
although symptomatic CPPD arthropathy may be present in other joints. The
pseudoosteoarthritis type (pseudo-OA) of CPPD deposition disease simulates
OA clinically and radiographically, often with chondrocalcinosis superimposed
upon the typical radiographic findings of OA. Additionally, some patients pres-
ent with progressive joint degeneration that is typical of OA, with joint space
narrowing, osteophyte formation, and subchondral sclerosis and cysts, but with-
out radiographic chondrocalcinosis. There may be superimposed acute inflamma-
tory episodes in addition to the chronic arthritic symptoms. The pseudo-OA
pattern may be present in approximately 50% of patients who have CPPD arthropa-
thy. An atypical joint distribution may occur in joints that are not affected
readily by OA (ie, predominant involvement of the patellofemoral joint in the
knee and the radiocarpal and metacarpophalangeal (MCP) joints in the wrist
and hands).
The pseudogout syndrome manifests with self-limited acute or subacute epi-
sodes of mono- or pauci-articular arthritis similar to gout; however, the aspirated
crystals are weakly positive under polarizing light and are characteristic for
CPPD as is the radiographic appearance. The pseudorheumatoid type manifests
with symptoms and signs that are similar to rheumatoid arthritis: morning stiff-
ness that lasts for weeks to months, fatigue, synovial thickening, restricted joint
motion, and elevated erythrocyte sedimentation rate with a symmetric pattern;
however, the presence of classic chondrocalcinosis differentiates the two [34]. In
the pseudoneuropathic type patients present with radiographic findings that
simulate a neuropathic joint (joint destruction, subluxation, and heterotopic new
bone formation), but without neurologic abnormality [35,36].
The pathophysiology of CPPD deposition disease is not understood com-
pletely. In some cases, CPPD crystal deposition in cartilage seems to be related to
defects in calcium and inorganic phosphate metabolism [24]. This theory is sup-
ported by the association of CPPD with hypophosphatasia and hyperparathy-
roidism. Synovial fluid pyrophosphate has been found to be increased in patients
who have CPPD. Because not all individuals who have hypercalcemia or
hypophosphatasia develop calcium pyrophosphate crystals other factors must be
involved. The phenomenon of CPPD crystal shedding is believed to explain acute
bouts of arthritis [37]. Cartilaginous deposits of crystals are cast into the articular
cavity and subsequently precipitate acute arthritis.
The diagnostic criteria for definitive, probable, or possible CPPD deposition

disease were outlined by McCarty [26]. A definite diagnosis is established when
a characteristic x-ray diffraction pattern of crystals from aspiration/biopsy of the
joint is demonstrated or when the combination of polyarticular chondrocalcinosis
on radiographs and absent/weakly birefringent crystals from joint aspiration/
biopsy is found on polarizing microscopy. If only one of the latter two criteria is
present then the diagnosis is probable [38]. A possible diagnosis can be suggested
when acute or chronic arthritis occurs in a typical location and is accompanied by
the characteristic radiographic features, without chondrocalcinosis. Because the
diagnosis and the consequent therapeutic measures may be based, in part, upon
the radiographs, an understanding of the varied radiographic manifestations of
CPPD deposition disease is important.
Imaging features in calcium pyrophosphate dihydrate deposition disease
Radiography is the imaging modality of choice for the diagnosis and evaluation
of patients who are suspected of having CPPD deposition disease. Radiographs
can document the presence of chondrocalcinosis and periarticular calcifications,
characterize the distribution and severity of the arthritis, evaluate disease pro-
gression, and exclude other diagnoses. Characteristic radiographic findings
coupled with absent/weakly birefringent crystals on polarizing microscopy makes
a definitive diagnosis of CPPD deposition disease.
CPPD crystals may be deposited in and around joints and often have a char-
acteristic radiographic appearance and distribution. The crystal deposits occur in
fibrocartilage and hyaline cartilage, most frequently in the knee, symphysis pubis,
wrist, elbow, and hip [36]. From anatomic and radiologic studies of knee joints,
the prevalence of cartilage CPPD deposits in the elderly is between 2% and 28%
[39]. In one autopsy survey, the incidence of intra-articular calcifications in-
creased with age; between the 60- and 69-year age group and the older than
80-years age group the incidence increased from 11% to 38% for women and
from 20% to 29% for men [40].
Fig. 6. CPPD knee. The calcifications clearly outline the fibrocartilage in the menisci and the more
central hyaline articular cartilage.
436 choi et al
Fig. 7. CPPD wrist. The triangular fibrocartilage is calcified densely as is the articular cartilage over
the distal ulna (arrows).
Fibrocartilage calcification is most common in the menisci of the knee,

triangular fibrocartilage of the wrist, symphysis pubis, annulus fibrosis, and
glenoid and acetabular labrum (Figs. 6 and 7). Fibrocartilaginous calcifications
are shaggy and irregular radiodense areas that most often are located centrally in
the joint. Hyaline cartilage calcifications are identified as a thin line parallel to,
and a few millimeters subjacent to, the subchondral bone (Fig. 8). Hyaline car-
tilage calcification occurs most commonly in the wrist, knee, elbow, and hip
(Fig. 9).
Calcification within the synovial membrane is a common feature of
CPPD; it usually is seen with chondrocalcinosis, but at times it may be the
dominant radiographic feature. Synovial calcification is seen most often about
the knee, MCP and MTP joints, and the radiocarpal and distal radioulnar articu-
lations of the wrist (see Fig. 9). They tend to appear amorphous or cloudlike
and are located at the joint margins where they may simulate idiopathic syno-
vial osteochondromatosis.
Fig. 8. (A,B) CPPD elbow and shoulder. The articular cartilage calcification (arrows) parallels the
subchondral bone. Note the synovial calcification in the lateral elbow (arrowhead).
Fig. 9. CPPD knee. Extensive calcification in the meniscus (large arrow), articular cartilage (arrows),
and synovium (long arrows).
CPPD crystal deposition of the joint capsule is most common in the elbow and
MTP articulations, but it also may be found in the MCP and glenohumeral joints.
Capsular calcifications tend to be fine, irregular linear densities that span the
articulation. They may be associated with joint contractures, particularly in the
elbow [36].
Tendon calcifications occur commonly in the Achilles, triceps, quadriceps,
and supraspinatus tendons. Tendon calcifications are thin, linear, and extend a
considerable distance from the osseous insertion; they imitate findings of idio-
pathic calcific tendonitis. Unlike the thin and linear appearance of tendon and
ligament calcification, bursa calcifications typically are amorphous or cloudlike
[41]. Bursa calcification is associated commonly with olecranon bursitis. In the
shoulders, tendon and bursa calcifications frequently are asymptomatic; when
symptomatic, they present with acute pain and tenderness. Occasionally, CPPD
may be be mistaken for gout, particularly in the digits where CPPD soft tissue
tumorlike collections of calcifications can resemble gouty tophi [42].
Structural joint changes that are associated with CPPD crystal deposition are
common and often are characteristic of the disease. The changes are similar to
OA with joint space narrowing, subchondral sclerosis, and subchondral cyst for-
mation (Figs. 10 and 11). They are not always accompanied by radiologically
evident calcification [41], and in the absence of calcification it may be difficult to
differentiate OA from CPPD arthropathy. The intra-articular joint distribution and
the joints that are involved aid in this differentiation.
The location of the structural damage in particular joints helps to distinguish
CPPD arthropathy from OA. As with OA, CPPD arthropathy tends to be bilateral
and asymmetric and is most common in the knee (see Fig. 11); however, ad-
vanced, asymmetric, or isolated involvement of the patellofemoral compartment
should raise the possibility of CPPD, particularly when accompanied by erosions
of the adjacent supracondylar femoral cortex. CPPD favors the radiocarpal
438 choi et al
Fig. 10. CPPD arthropathy with scapholunate advanced collapse of the wrist. There is narrowing of
the radiocarpal joint with a large ‘‘cystic’’ lesion (geode) in the distal radius. There is widening of the
scapholunate ligament with proximal migration of the capitate. Calcification adjacent to the proximal
lunate is likely in articular cartilage.
compartment of the wrist and frequently involves the MCP joints, atypical loca-
tions for OA. Isolated involvement of the radiocarpal or trapezioscaphoid articu-
lations in the wrist is much more typical of CPPD crystal deposition disease.
Scapholunate advanced collapse of the wrist is seen in OA, rheumatoid arthritis,
and CPPD. CPPD crystal deposition in the scapholunate ligament predisposes to
disruption of the joint with subsequent scapholunate-associated collapse [43]. A
pattern of joint degeneration that is atypical of OA, but typical for CPPD,
involves the MCP joints.
Nonweight-bearing joints, which are affected infrequently by OA, are in-
volved commonly by CPPD arthropathy. The subchondral cysts that are asso-
ciated with CPPD arthropathy often are more numerous and larger. Cysts in
Fig. 11. CPPD arthropathy simulating neuropathic joint. AP (A) and lateral (B) view of knee reveal
extensive joint destruction, particularly in the medial compartment. The widening of the lateral
compartment may be from ligamentous laxity. There is extensive lateral meniscal and synovial
calcification (arrows).
CPPD arthropathy also tend to have sclerotic margins and vary more in shape
and size. Variable osteophyte formation is seen more commonly with CPPD
arthropathy. Large, irregular bony excrescences are sometimes present in
CPPD arthropathy.
Hydroxyapatite deposition disease
In 1966, calcium hydroxyapatite (HA) crystals were implicated as a cause of

calcifications of the periarticular soft tissues and tendons, particularly in the
shoulder [44]. It is now known that deposits of this crystal may be responsible for
an idiopathic disorder (HADD), in which HA crystals are deposited particularly
in the periarticular tissues, mainly tendons and bursa. This entity has been
described under several names, including ‘‘calcific periarthritis,’’ ‘‘periarticular
apatite deposition,’’ and ‘‘calcifying tendinitis’’ [45].
Clinical features
HADD usually is monoarticular and occurs most frequently about the

shoulder, although other or multiple joint involvement may occur. The crystal
deposits may be asymptomatic; symptoms occur in 34% to 45% of patients in
whom calcifications are present. The disease has no gender predilection and
typically occurs between the ages of 40 and 70 years. The disorder may be
familial; recently, certain histocompatibility antigens were identified as having a
frequent association with this disorder [46]. The crystal deposition also may
occur in an intra-articular location. It may be a primary phenomenon or occur in
association with other disorders, including trauma, renal osteodystrophy, and
collagen vascular disease, particularly scleroderma and mixed connective tissue
disease. Deposition of this crystal also may be seen in patients who have tumoral
calcinosis and as a complication of multiple intra-articular steroid injections [47].
Typically, the onset of symptoms is acute with severe pain, tenderness, and a
local inflammatory response that may be associated with restrictive motion. Less
commonly, the disorder may be chronic, with less severe symptoms leading to
various degrees of incapacitation [44]. HADD is a well-recognized cause of
periarticular inflammation that may cause bursitis or tendonitis. More recently,
intra-articular HA deposition has been implicated as a cause of acute arthritis
[48,49].
Etiology
The mechanism by which calcification occurs within a tendon is understood

poorly. A ‘‘degenerative theory’’ proposes that trauma or stress that is associated
with a local decrease in blood supply leads to tendinous tears with resulting
calcification [50]. Uhthoff and coworkers [51] suggested that hypoxia in the
region of the tendon that is induced by mechanical, metabolic, or other factors
440 choi et al
results in transformation of this region into fibrocartilage. The calcification is

mediated by the chondrocytes and is associated with vascular proliferation and
subsequent resorption of the calcific focus by macrophages. Calcification may
not be the inciting agent, and symptoms may occur with the dissolution of
calcium. When rupture of the calcific deposit occurs the HA crystals are spilled
into the surrounding soft tissue space or bursa, which sets off the acute inflam-
matory response.
The needlelike crystals on electron microscopy may be identified as purple
clumps by light microscopy with Wright’s stain. Complementary techniques for
identifying the crystals include electron microscopy and electron probe analy-
sis [45].
Imaging features in hydroxyapatite crystal deposition disease
The clinical features of periarticular HADD may mimic fracture, infection,

gout, or CPPD crystal deposition disease. Radiographic examination frequently
allows a definitive diagnosis of HA deposition. Often, imaging features vary,
depending on the chronicity and activity of disease. The general radiographic
features of periarticular HA crystal deposition are cloudlike and poorly defined
calcific deposits that initially blend into the surrounding soft tissues. With time
the HA crystal deposition may appear denser, homogenous, and more sharply
delineated, with a linear or circular configuration. Although osteoporosis, cystic
lesions, reactive sclerosis, and contour irregularities may be present, adjacent
osseous tissues usually are normal.
Capsular, tendinous, and bursal tissues about the shoulder are the most
common sites of articular and periarticular calcific deposits. In the shoulder, HA
Fig. 12. Classic HADD in supraspinatus tendon. (A) Calcification in supraspinatus tendon adjacent to
its insertion into the greater tuberosity of the humerus. (B) T2-weighted fat-suppressed coronal image
reveals low signal (calcification) in supraspinatus tendon with extensive edema and fluid in the
subacromial-subdeltoid bursa, mainly about the calcification.
Fig. 13. Calcific tendonitis with adjacent erosion. HADD deposition in distal supraspinatus tendon
with adjacent erosion in the humeral head (arrow).
crystal deposition is bilateral in nearly 50% of cases, and it is most common in

the supraspinatus tendon (Fig. 12). The other tendons of the rotator cuff and the
bicipital tendon may be involved. Calcification in the subacromial bursa appears
as a teardrop-shaped, ulcerated, or ‘‘skullcap’’ radiodensity that extends under the
greater tuberosity [52]. Osseous erosions may be located adjacent to tendon and
ligament insertion sites (Fig. 13). These may be associated with marrow edema
on MRI.
Besides the shoulder, HA crystal deposition may occur in the collateral
ligaments of the elbow—at the insertion of the triceps tendon into the olecranon
process (Fig. 14)—which is associated occasionally with triceps tendon rupture.
Fig. 14. HADD in a patient who had chronic renal failure and was on dialysis. Extensive calcification
in triceps tendon.
442 choi et al
Fig. 15. Calcific periarthritis HADD in the gluteus maximus tendon at its insertion into the greater
trochanter (arrow).
Deposition of HA crystal also may occur in the axial skeleton. The longus
colli muscle, the principal flexor of the cervical spine, is involved most com-
monly in the neck. Other locations with HA crystal deposition in the spine have
been reported, including the infraoccipital region and interspinous bursae in
association with neck pain. In the hip, pelvis, and thighs, calcifications that have
a varied appearance are frequent in the gluteal insertions into the greater tro-
chanter and surrounding bursae (Fig. 15) [53–57].
HA crystal deposition may remain static for a long time. In other instances,
calcified deposits may change in size over time and become larger, smaller, or
disappear entirely (Fig. 16); however, reappearance of calcification also has been
reported [45]. Frequently, these changes in size and appearance occur in the
Fig. 16. HADD with disappearance of calcification. (A) Calcification adjacent to lateral acetabu-
lar margin in patient who had acute hip pain. (B) Two years later the calcification has re-
sorbed completely.
absence of symptoms. In addition, there is no definite correlation between the

sizes of periarticular calcifications and symptoms.
Articular deposition
HA crystals may become deposited in the synovial membrane, in the joint

capsule, or occasionally in cartilage (chondrocalcinosis). Joints frequently in-
volved by HA crystal deposition include the shoulder, knee, hip, and small joints
of the hand and feet. Generally, the calcifications appear as homogeneous,
cloudlike, intra-articular radiodensities that do not follow anatomic structures. In
some patients, synovial fluid or cartilage may reveal calcium HA and CPDD
crystals, a condition that is termed ‘‘mixed calcium phosphate crystal deposition
disease.’’ This disorder should be suspected if radiographs reveal extensive car-
tilage calcification and diffuse intra-articular and capsular calcification or dense,
homogeneous calcific deposits within tendons.
Intra-articular accumulation of HA crystals may occur in the absence of ra-
diographically apparent calcification. Synovial membrane, capsule, or both can
be involved that contain amorphous or fluffy cloudlike areas of increased ra-
diodensity. Rarely, chondrocalcinosis also is present within the meniscus of the
knee. Because HA crystal deposition is associated with OA, the radiographic
feature of one may accompany the other. Typically, small joints are affected, but
involvement of other joints, such as the wrist, knee, hip, and shoulder, have
been reported.
Destructive arthropathy that is associated with HA crystal deposition in the
shoulder is referred to as a Milwaukee shoulder syndrome. This consists of joint
space loss, subchondral sclerosis, osseous debris, joint disorganization, and
deformity. A large effusion that contains calcified debris may be present. The
humeral head is displaced superiorly, and even may contact the acromion as a
result of associated disruption of the rotator cuff with remodeling and erosion of
the acromial undersurface.
Associated arthropathy of the knee in patients who had shoulder arthropathy
has been reported. Unicompartmental involvement is typical, particularly the
lateral fibisfemoral articulation, which leads to narrowing, collapse of the articu-
lar surface, sclerosis and fragmentation, and valgus angulation.
Summary
The radiographic appearance of MSU, CPPD, and HA crystal-induced ar-

thropathies have been reviewed. The recognition of the often distinctive radio-
graphic appearance of crystal-induced disease may allow a specific diagnosis.
Radiography has a small role in the diagnosis of initial attacks of acute gouty
arthritis. Radiographic findings are a late manifestation of the disease, and in-
clude lobulated eccentric soft tissue masses, intra-articular and extra-articular
osseous erosions, relative preservation of joint space, subperiosteal apposition
444 choi et al
of bone, intraosseous calcification, and secondary degenerative changes, with-

out osteoporosis.
In CPPD crystal disease, characteristic radiologic features include articular
and periarticular calcification and an arthropathy that consists of joint space
narrowing, bone sclerosis, prominent subchondral cyst formation, occasional se-
vere and progressive destructive bone changes, and variable osteophyte forma-
tion. Often, these findings are seen in a characteristic intra-articular distribution
with involvement of characteristic sites, such as the patellofemoral compartment
of the knee and the radiocarpal compartment of the wrist. The findings may occur
in the absence of radiographically demonstrable chondrocalcinosis.
HA crystal deposition leads to periarticular calcifications that are associated
with typical radiographic findings. These are observed most frequently in the
shoulder, with calcifications of varying size and shape in the tendons, bursae, and
capsule. The disease may be mono- or polyarticular in distribution. When intra-
articular, HA crystals can cause joint destruction.
References
[1] German DC, Holmes EW. Hyperuricemia and gout. Med Clin North Am 1986;70:419.
[2] Pennes DR, Martel W. Hyperuricemia and gout. Semin Roentgenol 1986;21:245.
[3] Monu JU, Pope Jr TL. Gout: a clinical and radiologic review. Radiol Clin North Am 2004;
42:169.
[4] Agudelo CA, Wise CM. Gout: diagnosis, pathogenesis, and clinical manifestations. Curr Opin
Rheumatol 2001;13:234.
[5] Hench PS. The diagnosis of gout and gouty arthritis. J Lab Clin Med 1936;220:48.
[6] Siva C, Velazquez C, Mody A, et al. Diagnosing acute monoarthritis in adults: a practical
approach for the family physician. Am Fam Physician 2003;68:83.
[7] Resnick D, Niwayama G. Diagnosis of bone and joint disorders with emphasis on articular
abnormalities. Philadelphia7 WB Saunders; 1981.
[8] Rosenburg EF, Arens RA. Gout: clinical, pathologic, and roentenographic observations. Radiology
1947;49:169 – 77.
[9] Tallbott JH. Gout. New York7 Grune & Stratton; 1967.
[10] Levin MH, Lichtenstein L, Scott HW. Pathologic changes in gout; survey of eleven necropsied
cases. Am J Pathol 1956;32:871.
[11] Watt I, Middlemiss H. The radiology of gout. Review article. Clin Radiol 1975;26:27.
[12] Vyhnanek L, Lavicka J, Blahos J. Roentgenological findings in gout. Radiol Clin (Basel)
1960;29:257.
[13] Martel W. The overhanging margin of bone: a roentgenologic manifestation of gout. Radiology
1968;91:755.
[14] Swezey RL, Bjarnason DM, Alexander SJ, et al. Resorptive arthropathy and the opera-glass
hand syndrome. Semin Arthritis Rheum 1972;2:191.
[15] Agudelo CA, Schumacher HR. The synovitis of acute gouty arthritis. A light and electron
microscopic study. Hum Pathol 1973;4:265.
[16] Wright JT. Unusual manifestations of gout. Australas Radiol 1966;10:365.
[17] Bloch C, Hermann G, Yu TF. A radiologic reevaluation of gout: a study of 2,000 patients. AJR
Am J Roentgenol 1980;134:781.
[18] Kelley WN, Fox IH. Gout and related disorders of purine metabolism. In: Kelley WN, Harris
ED, Ruddy S, editors. Textbook of rheumatology, vol. 1. Philadelphia7 Saunders; 1985. p. 1359.
[19] Colistro R, Torreggiani WC, Lyburn ID, et al. Unenhanced helical CT in the investigation of
acute flank pain. Clin Radiol 2002;57:435.
[20] Tublin ME, Murphy ME, Delong DM, et al. Conspicuity of renal calculi at unenhanced CT:
effects of calculus composition and size and CT technique. Radiology 2002;225:91.
[21] Steinbach LS, Resnick D. Calcium pyrophosphate dihydrate crystal deposition disease revisited.
Radiology 1996;200:1.
[22] Resnick D, Utsinger PD. The wrist arthropathy of ‘‘pseudogout’’ occurring with and without
chondrocalcinosis. Radiology 1974;113:633.
[23] Utsinger PD, Zvaifler NJ, Resnick D. Calcium pyrophosphate dihydrate deposition disease
without chondrocalcinosis. J Rheumatol 1975;2:258.
[24] McCarty DJ. Arthritis associated with crystals containing calcium. Med Clin North Am 1986;
70:437.
[25] Reginato A, Valenzuela F, Martinez V, et al. Polyarticular and familial chondrocalcinosis.
Arthritis Rheum 1970;13:197.
[26] McCarty DJ. Pseudogout, articular chondrocalcinosis. 8th edition. Philadelphia7 Lea &
Febiger; 1972.
[27] Adamson III TC, Resnik CS, Guerra Jr J, et al. Hand and wrist arthropathies of hemochroma-
tosis and calcium pyrophosphate deposition disease: distinct radiographic features. Radiology
1983;147:377.
[28] Atkins CJ, McIvor J, Smith PM, et al. Chondrocalcinosis and arthropathy: studies in
haemochromatosis and in idiopathic chondrocalcinosis. Q J Med 1970;39:71.
[29] Dymock IW, Hamilton EB, Laws JW, et al. Arthropathy of haemochromatosis. Clinical and
radiological analysis of 63 patients with iron overload. Ann Rheum Dis 1970;29:469.
[30] McCarty DJ, Kohn NN, Faires JS. The significance of calcium phosphate crystals in the syno-
vial fluid of arthritic patients: the ‘‘pseudogout syndrome’’. I. Clinical Aspects. Ann Intern Med
1962;56:711.
[31] Zitnan D, Sitaj S. [Chondrocalcinosis polyarticularis (familiaris): roentgenological and clinical
analysis]. Cesk Rentgenol 1960;14:27.
[32] McCarty DJ. Diagnostic mimicry in arthritis - patterns of joint involvement associated with
calcium pyrophosphate dihydrate crystal deposits. Bull Rheum Dis 1974;25:804.
[33] McCarty DJ. Pseudogout, articular chondrocalcinosis. 7th edition. Philadelphia7 Lea &
Febiger; 1966.
[34] Resnick D, Williams G, Weisman MH, et al. Rheumatoid arthritis and pseudo-rheumatoid
arthritis in calcium pyrophosphate dihydrate crystal deposition disease. Radiology 1981;
140:615.
[35] Helms CA, Chapman GS, Wild JH. Charcot-like joints in calcium pyrophosphate dihydrate
deposition disease. Skeletal Radiol 1981;7:55.
[36] Resnick D, Niwayama G, Goergen TG, et al. Clinical, radiographic and pathologic abnormali-
ties in calcium pyrophosphate dihydrate deposition disease (CPPD): pseudogout. Radiology
1977;122:1.
[37] Bjelle A. Pyrophosphate arthropathy. Scand J Rheumatol 1979;8:145.
[38] Dalinka M, Zlatkin M. Crystal deposition diseases: current concepts. Postgrad Radiol 1998;8:88.
[39] McCarty DJ. Pseudogout—the CPPD crystal deposition disease. Resid Staff Physician 1977;
12:71 – 85.
[40] Mitrovic DR, Stankovic A, Iriarte-Borda O, et al. The prevalence of chondrocalcinosis in the
human knee joint. An autopsy survey. J Rheumatol 1988;15:633.
[41] Resnik CS, Resnick D. Crystal deposition disease. Semin Arthritis Rheum 1983;12:390.
[42] Leisen JC, Austad ED, Bluhm GB, et al. The tophus in calcium pyrophosphate deposition
disease. JAMA 1980;244:1711.
[43] Chen C, Chandnani VP, Kang HS, et al. Scapholunate advanced collapse: a common wrist
abnormality in calcium pyrophosphate dihydrate crystal deposition disease. Radiology 1990;
177:459.
[44] McCarty Jr DJ, Gatter RA. Recurrent acute inflammation associated with focal apatite crystal
deposition. Arthritis Rheum 1966;9:804.
446 choi et al
[45] Faure G, Daculsi G. Calcified tendinitis: a review. Ann Rheum Dis 1983;42(Suppl 1):49.
[46] Amor B, Cherot A, Delbarre F, et al. Hydroxyapatite rheumatism and HLA markers. J
Rheumatol Suppl 1977;3:101.
[47] Dalinka MK, Stewart V, Bomalaski JS, et al. Periarticular calcifications in association with intra-
articular corticosteroid injections. Radiology 1984;153:615.
[48] Dieppe PA, Crocker P, Huskisson EC, et al. Apatite deposition disease. A new arthropathy.
Lancet 1976;1:266.
[49] Schumacher HR, Cherian PV, Reginato AJ, et al. Intra-articular apatite crystal deposition. Ann
Rheum Dis 1983;42(Suppl 1):54.
[50] Selby CL. Acute calcific tendinitis of the hand: an infrequently recognized and frequently
misdiagnosed form of periarthritis. Arthritis Rheum 1984;27:337.
[51] Uhthoff HK, Sarkar K, Maynard JA. Calcifying tendinitis: a new concept of its pathogenesis.
Clin Orthop Relat Res 1976;118:164 – 8.
[52] Winn RS, Melhorn JM, De Smet AA. Layering of calcifications in synovial effusions. J Can
Assoc Radiol 1981;32:66.
[53] Wepfer JF, Reed JG, Cullen GM, et al. Calcific tendinitis of the gluteus maximus tendon (glu-
teus maximus tendinitis). Skeletal Radiol 1983;9:198.
[54] Chen CK, Yeh LR, Pan HB, et al. Intra-articular gouty tophi of the knee: CT and MR imaging
in 12 patients. Skeletal Radiol 1999;28:75.
[55] Gerster JC, Landry M, Dufresne L, et al. Imaging of tophaceous gout: computed tomography
provides specific images compared with magnetic resonance imaging and ultrasonography.
Ann Rheum Dis 2002;61:52.
[56] Hsu CY, Shih TT, Huang KM, et al. Tophaceous gout of the spine: MR imaging features.
Clin Radiol 2002;57:919.
[57] Jbara M, Patnana M, Kazmi F, et al. MR imaging: arthropathies and infectious conditions of
the elbow, wrist, and hand. Magn Reson Imaging Clin N Am 2004;12:361.

2006 Gout

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

2006 Gout

Uploaded by

Copyright:

Available Formats

Rheum Dis Clin N Am 32 (2006) ix

Erratum to ‘‘New Therapeutics in

In the February 2006 issue of Rheumatic Disease Clinics of North America,

DOI of original article title 10.1016/j.rdc.2005.10.004.

Hyon Choi, MD, DrPH, FRCPC

Crystal deposition arthropathy continues to be one of the most common in-

Hyon Choi, MD, DrPH, FRCPC

Epidemiology of Crystal Arthropathy

Gout is an inflammatory arthritis mediated by the crystallization of uric acid

Definitive diagnosis of gout requires either the presence of monosodium urate

T Division of Rheumatology, Vancouver General Hospital, The University of British Co-

spective cohort of male health professionals (Health Professionals Follow-Up

Data on the incidence of gout are limited. The Rochester Epidemiology

Risk factors for gout

prevalence of gout in this population approaching that of rheumatoid arthritis

Modifiable risk factors

Serum uric acid and gout

Annual Incidence of Gout

4 P for trend = < 0.001

0 <21 21-22.9 23-24.9 25-29.9 30-35 >=35

Fig. 2. Relation between BMI and incidence of gout in men.

control studies that assessed dietary intake retrospectively in confirmed cases of

Total Meat Seafood Purine-rich Vegetables

Purine-rich Food Group Quintile (serving/d)

1.5 Low-Fat Dairy Intake High-Fat Dairy Intake

Dairy Intake Quintiles (serving/d)

Beer Liquor Wine

Alcohol Types (serving/time)

acknowledged to have a large purine content, which is predominantly guanosine,

Medications, supplements, and toxins

Many medications and substances affect serum urate levels, potentially

Associated medical conditions

renal insufficiency, kidney stone, type 2 diabetes, and cardiovascular disorders.

Calcium pyrophosphate dihydrate deposition and pseudogout

A definitive diagnosis of calcium pyrophosphate dihydrate (CPPD) deposition

Basic calcium phosphate deposition arthropathy

Basic calcium phosphate (BCP) crystal deposition is associated with several

Hyperuricemia and Associated Diseases

In the years after introduction of effective urate-lowering therapy, many

T Corresponding author. Rheumatology Section, MC 0930, University of Chicago Medical

Physicochemical and population definitions of hyperuricemia exist [3]. The

Hyperuricemia and hypertension

An association of hyperuricemia and hypertension [8–12] long has been rec-

1. Prevalences of hyperuricemia of approximately 20% to 40% in untreated

Despite these findings, conflicting results of epidemiologic studies and

ment of a cause-effect relationship in either direction. For example, the high

Hyperuricemia and chronic kidney disease

Despite the nearly invariable occurrence of hyperuricemia in chronic kidney

Hyperuricemia and cardiovascular disease

Coronary heart disease

The weight of recent evidence supports the view that hyperuricemia is an

cardiovascular event (hazard ratio 1.024 per 10 mmol/L increment in baseline

Stroke and peripheral artery disease

Uric acid administration is protective against experimental ischemic stroke in

Congestive heart failure

Hyperuricemia is a common finding in congestive heart failure [86], and

Hyperuricemia, metabolic syndrome, and its components

Complexity in defining the role of hyperuricemia in chronic diseases, such

Epidemiologic studies have established a strong positive correlation between

prescribed dietary restrictions

The issue of hypertriglyceridemia and hyperuricemia is addressed in many

In the prospective GREACE study, addition of atorvastatin to the standard

The relationship between hyperuricemia and insulin resistance may be indi-