ARTHRITIS & RHEUMATISM

Vol. 64, No. 8, August 2012, pp 25292536

DOI 10.1002/art.34488
2012, American College of Rheumatology

Starting Dose Is a Risk Factor for

Allopurinol Hypersensitivity Syndrome
A Proposed Safe Starting Dose of Allopurinol
Lisa K. Stamp,1 William J. Taylor,2 Peter B. Jones,3 Jo L. Dockerty,4 Jill Drake,1
Christopher Frampton,1 and Nicola Dalbeth5
were identified. There was an increase in the risk of
AHS as the starting dose of allopurinol corrected for the
estimated GFR increased. For the highest quintile of
starting dose per estimated GFR, the odds ratio was
23.2 (P < 0.01). Receiver operating characteristic analysis indicated that 91% of AHS cases and 36% of
controls received a starting dose of allopurinol of >1.5
mg per unit of estimated GFR (mg/ml/minute).
Conclusion. Our findings indicate that starting
allopurinol at a dose of 1.5 mg per unit of estimated
GFR may be associated with a reduced risk of AHS. In
patients who tolerate allopurinol, the dose can be gradually increased to achieve the target serum urate level.

Objective. Allopurinol is the most commonly used

urate-lowering therapy in gout. Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially fatal
adverse event. Dosing guidelines based on creatinine
clearance have been proposed based on the recognition
that dosages of >300 mg/day may be associated with
AHS, particularly in patients with renal impairment.
However, the relationship between the allopurinol starting dose and AHS is unknown. This study was undertaken to determine the relationship between allopurinol
dosing and AHS.
Methods. A retrospective casecontrol study of
patients with gout who developed AHS between January
1998 and September 2010 was undertaken. For each
case, 3 controls with gout who were receiving allopurinol
but did not develop AHS were identified. Controls were
matched with cases for sex, diuretic use at the time of
initiating allopurinol, age (10 years), and estimated
glomerular filtration rate (estimated GFR). Starting
dose and dose at the time of the reaction in cases were
compared between cases and controls.
Results. Fifty-four AHS cases and 157 controls

Sustained reduction of the serum urate level to

6 mg/dl is the mainstay of gout treatment (13).
Indications for urate-lowering therapy include 2 gout
attacks per year, chronic gouty arthropathy, tophi, radiographic changes in gout, and urate nephropathy (4,5),
as well as polyarticular gout. Allopurinol, the most
commonly used urate-lowering therapy, is generally well
tolerated; approximately 2% of patients develop a mild
rash (6) and up to 5% of patients stop allopurinol
because of any adverse event.
A rare but potentially fatal adverse event is
allopurinol hypersensitivity syndrome (AHS). AHS is
characterized by rash (e.g., Stevens-Johnson syndrome,
toxic epidermal necrolysis), eosinophilia, leukocytosis,
fever, hepatitis, and renal failure. The mortality associated with AHS is reported to be as high as 27% (7,8).
There is no cure; early diagnosis and allopurinol withdrawal are important. Supportive care is the mainstay of
treatment (7,9).
Risk factors for the development of AHS include
female sex, age, renal impairment, diuretic use, recent

Lisa K. Stamp, MBChB, PhD, FRACP, Jill Drake, BN,

Christopher Frampton, PhD: University of Otago, Christchurch, New
Zealand; 2William J. Taylor, MBChB, PhD, FRACP: University of
Otago, Wellington, New Zealand; 3Peter B. Jones, MBChB, PhD,
FRACP: University of Auckland, Hamilton, New Zealand; 4Jo L.
Dockerty, MBChB, FRACP: Dunedin Hospital, Dunedin, New Zealand; 5Nicola Dalbeth, MD, FRACP: University of Auckland, Auckland, New Zealand.
Dr. Dalbeth has received consulting fees, speaking fees,
and/or honoraria from Takeda, Ardea, and Novartis (less than $10,000
each) and holds a patent for Fonterra milk products for gout.
Address correspondence to Lisa K. Stamp, MBChB, PhD,
FRACP, University of Otago, Christchurch, PO Box 4345,
Christchurch 8140, New Zealand. E-mail: lisa.stamp@cdhb.govt.nz.
Submitted for publication November 29, 2011; accepted in
revised form March 27, 2012.
2529

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STAMP ET AL

initiation of allopurinol therapy, and, in some ethnic

groups, the HLAB*5801 genotype (1014). The relationship between allopurinol dose and AHS is a subject
of controversy (10,15). Dose reduction in renal impairment is based on a reported relationship between fulldose allopurinol (300 mg/day) in patients with renal
impairment and the development of AHS (16). This
observation, along with recognition that excretion of the
active metabolite oxypurinol is significantly reduced in
patients with impaired renal function, led to the suggestion that allopurinol dose should be determined according to creatinine clearance (16). However, there is no
clear evidence that creatinine clearancebased allopurinol dosing reduces the incidence of AHS. In a large
casecontrol study of AHS, there was a trend toward
lower allopurinol doses in the AHS group compared to
allopurinol-tolerant controls (10). In another study,
AHS did not occur more frequently in those taking
higher than creatinine clearancebased doses compared
with those receiving the creatinine clearancebased dose
(15). Furthermore, the current allopurinol dosing guidelines do not differentiate between starting dose and
maintenance dose.
The aim of this study was to determine the
relationship of the starting dose and the dose of allopurinol at the time of the reaction to the occurrence of
AHS in patients with gout.

PATIENTS AND METHODS

Study design. A retrospective casecontrol study design was used to determine the role of the allopurinol dose in
AHS. Ethics approval was obtained from the Multi-Region
Ethics Committee, New Zealand. Cases were identified in the
5 major regions of New Zealand (Auckland, Waikato, Wellington, Christchurch, and Dunedin), representing 3 million
people (three-fourths of the New Zealand population).
Cases. Patients with gout who developed AHS between
January 1, 1998 and September 30, 2010 were identified by
physician recall, International Classification of Diseases (ICD)
code searches, local area database searches, and via the Centre
for Adverse Reactions Monitoring (CARM). We searched for
the following ICD codes: from ICD-9, codes 693.0 dermatitis
due to drugs and medicines taken internally, 695.1 erythema
multiforme, and 974.7 poisoning by uric acid metabolism
drugs; and from ICD-10, codes L27.0 general skin eruptions
due to drugs, L27.1 local skin eruption due to drugs, L51.0
nonbullous erythema multiforme, L51.1 bullous erythema
multiforme, L51.2 toxic epidermal necrolysis, and T50.4 drugs
affecting uric acid metabolism.
Clinical notes were reviewed to identify patients in
whom a diagnosis of AHS could potentially be made. Patients
who were prescribed allopurinol for indications other than gout

were excluded. Standardized data were collected for each

potential case, including age, sex, ethnicity, height, weight,
date of gout diagnosis, starting date and dose of allopurinol,
diuretic use and dose at the time of starting allopurinol, time
from initiation of allopurinol treatment until reaction, dose
of allopurinol at the time of the reaction, clinical features,
treatment given, and patient outcome. Laboratory results, including serum urate, creatinine, alanine transaminase (ALT),
and aspartate aminotransferase (AST) levels, and eosinophil
count prior to starting allopurinol and at the time of the
reaction were collected. Estimated glomerular filtration rate
(estimated GFR) was determined using the Modification of
Diet in Renal Disease study equation (17).
Potential AHS cases were adjudicated by a single
investigator (LKS), who was blinded with regard to the allopurinol dose, using the Gutierrez-Macias criteria (18). These
criteria consist of a clear history of exposure to allopurinol;
lack of exposure to another drug potentially causing the
reaction; and 2 of the major criteria (worsening renal function,
acute hepatocellular injury, or rash) or 1 of the major criteria
and 1 of the minor criteria (fever, eosinophilia, or leukocytosis)
(18). While these criteria do not state exact values for deterioration in renal and liver function, we used an increase in
creatinine level of 2025% from baseline and an increase in
ALT and/or AST levels of 1.5 times the upper limit of
normal.
Controls. For each AHS case, 3 control subjects who
were receiving allopurinol for gout but did not develop AHS
were identified. Controls were matched with the cases for
age (10 years) and for the following reported risk associations for AHS: sex, diuretic use at the time of initiating
allopurinol treatment, and renal function. Renal function was
assessed by estimated GFR according to the following bands:
5, 515, 1530, 3050, 5070, 7090, 90110, 110130, and
130 ml/minute/1.73 m2.
Standardized data were collected for each control
subject, including ethnicity, date of diagnosis, starting dose of
allopurinol, diuretic use at the time allopurinol treatment was
started, dose of allopurinol at the matched time from initiation
of allopurinol treatment that the reaction occurred in the case,
and the maximum allopurinol dose reached.
Statistical analysis. Analysis of variance and chisquare tests were used to compare demographic and clinical
features in cases and controls. Conditional logistic regression
analysis was used to determine the association between ethnicity, tophi, and quintile of starting dose per estimated GFR
and the development of AHS, allowing for multiple matching
of controls to cases (3:1). These associations were summarized as odds ratios (ORs) and 95% confidence intervals (95%
CIs). Analysis of the dose as a function of the estimated GFR
showed that differences in renal function did not explain the
observed difference in dose between cases and controls. The
optimal allopurinol starting dose for predicting the development of AHS was determined using a receiver operating
characteristic (ROC) curve. Expert opinion of the authors was
used to determine an appropriate dose for starting allopurinol
based on the ROC curve and taking the standard tablet sizes
for allopurinol into consideration, to ensure that the proposed
doses were clinically practical.

ALLOPURINOL HYPERSENSITIVITY

2531

Table 1. Demographic characteristics of the AHS cases and matched controls*

Age, mean (range) years

Sex, no. (%) male
No. (%) receiving diuretic at the time allopurinol was started
Baseline creatinine, mean (range) mmoles/liter
Baseline estimated GFR, mean (range) ml/minute
% with baseline estimated GFR of 60 ml/minute
Ethnicity, no. (%)
New Zealand European
Maori and Pacific Islander
Chinese
Other
No. (%) with tophi
Serum urate level at diagnosis, mean (range) mg/dl
BMI, mean SD kg/m2
Weight, mean SD kg
* AHS
Data
Data
Data

Cases
(n 54)

Controls
(n 157)

64.8 (2487)
30 (55.6)
26 (48.1)
145 (68850)
50.2 (6112)
33.3

64.1 (2392)
87 (55.4)
77 (49.0)
134 (70510)
51.3 (11115)
30.3

26 (48.1)
16 (29.6)
10 (18.5)
2 (3.7)
15 (27.8)
9.9 (7.118.2)
31.3 6.1
88.6 29.5

63 (40.1)
75 (47.8)
1 (0.64)
18 (11.5)
78 (49.6)
10.1 (3.515.9)
34.6 6.5
99.9 24.9

P
0.79
1.0
0.91
0.37
0.73
0.68
0.001

0.021
0.62
0.064
0.04

allopurinol hypersensitivity syndrome; estimated GFR estimated glomerular filtration rate; BMI body mass index.
were available for 39 cases and 137 controls.
were available for 19 cases and 46 controls.
were available for 50 cases and 67 controls.

RESULTS
Identification of cases and controls. A total of
7,551 potential cases were identified for case note
review. All 7,551 notes were reviewed, and 70 possible
AHS cases were identified. The main reasons for exclusion were that the patient was not receiving allopurinol
or allopurinol was used for a nongout indication. All
cases identified by physician recall or by the CARM
search were also captured in the ICD code searches.
After adjudication, 54 cases of AHS were confirmed.
The remainder had a reaction to allopurinol but did not
fulfill the criteria for AHS. For 49 of the 54 cases, 3
well-matched controls were identified. In the remaining
5 cases, 2 well-matched controls were identified, resulting in a total of 157 controls.
Demographic characteristics of the cases and
controls. The demographic and clinical features are
outlined in Table 1, showing good matching between
cases and controls. Thirty-six of 54 cases (66.6%) and
108 of 157 controls (68.9%) had an estimated GFR of
60 ml/minute.
Cases and controls were not matched for the
presence of tophi or for ethnicity, and there was no
association between these 2 factors. Multivariate analysis allowing for matching between cases and controls
showed that the presence of tophi was associated with a
reduced risk of AHS (OR 0.29 [95% CI 0.010.83], P
0.021). Ethnicity was associated with risk of AHS (P
0.001). Compared with New Zealand Europeans, there

was a decreased risk of AHS in patients of Maori or

Pacific Island descent (OR 0.24, P 0.02) and an
increased risk of AHS in those of Chinese descent (OR
70.8, P 0.005).
Clinical features and outcomes of AHS cases.
The median time from starting allopurinol to the occurrence of AHS was 30 days (range 11,080 days), and
90% of AHS cases occurred within the first 180 days
(Figure 1). The clinical features of AHS and which
specific criteria were fulfilled by the cases are outlined in

Figure 1. Days from starting allopurinol treatment to the occurrence

of allopurinol hypersensitivity syndrome in patients with gout.

2532

STAMP ET AL

Table 2. Clinical features of the 54 AHS cases*

Major criteria
Worsening renal impairment
Acute hepatocellular injury
Rash
Toxic epidermal necrolysis
Erythema multiforme
Diffuse maculopapular
Exfoliative
All 3 major criteria present
Rash plus renal deterioration
Rash plus hepatocellular injury
Rash only
Renal deterioration only
Minor criteria
Fever
Eosinophilia
Leukocytosis
3 minor criteria present
2 minor criteria present
1 minor criterion present
0 minor criteria present
Criteria fulfillment
At least 2 major criteria
1 major and at least 1 minor criteria
Rash only
Plus 3 minor
Plus 2 minor
Plus 1 minor
Fever
Eosinophilia
Leukocytosis
Renal only
Plus 3 minor
Plus 1 minor (leukocytosis)

Table 3. Allopurinol starting doses in cases and controls, stratified

by dose recommendation based on creatinine clearance*
29 (53.7)
17 (31.5)
52 (96.3)
10 (18.5)
4 (7.4)
27 (50)
13 (24.1)
9 (16.7)
18 (33.3)
8 (14.8)
17 (31.5)
2 (3.7)
32 (59.3)
26 (48.2)
24 (44.4)
14 (25.9)
10 (18.5)
20 (37)
10 (18.5)
35 (64.8)
19 (35.2)
17
2
6
9
5
3
1
2
1
1

* Values are the number (%) of cases. AHS allopurinol hypersensitivity syndrome.
Some patients had more than one type of rash.

Table 2. Among the patients with renal deterioration,

the median increase in creatinine level was 55% from
baseline. Among the patients with acute hepatocellular
injury, the median increase in ALT level was 2.4 times
the upper limit of normal.
Of the 54 cases, 43 (79.6%) required hospitalization. Six of these 43 cases were admitted to the intensive
care unit. Twenty-five patients received corticosteroids,
2 received cyclosporin A, and 4 received antihistamines.
Three of the 54 patients (6%) died, 45 recovered, and
the outcome for 6 patients could not be determined.
Relationship between the allopurinol starting
dose and AHS. AHS cases started allopurinol at a
significantly higher dosage than controls (mean SEM
starting dosage 183.5 14.0 mg/day versus 112.2 6.3
mg/day) (P 0.001). Nineteen percent of the controls
and 19% of the cases began allopurinol at the creatinine
clearancebased dose, according to the Hande guidelines (16). Cases were more likely to start allopurinol at

Allopurinol starting dose higher

than the creatinine clearance
based dose
Allopurinol starting dose the
same as or lower than the
creatinine clearancebased dose

Cases
(n 53)

Controls
(n 152)

23 (43.4)

18 (11.8)

0.001

30 (56.6)

134 (88.2)

0.001

* Values are the number (%) of patients.

doses that were higher than the creatinine clearance

based dose than were controls (OR 16.7 [95% CI
5.747.6], P 0.001) (Table 3) and controls were more
likely to start allopurinol at doses that were lower than
the creatinine clearancebased dose than were cases
(OR 6.9 [95% CI 2.916.5], P 0.001).
There was a significant increase in the percentage
of patients developing AHS as the allopurinol dose
corrected for the estimated GFR increased. The proportion of cases for each quintile of starting allopurinol dose
corrected for the estimated GFR is shown in Figure 2.
Multivariate analysis, allowing for the effects of ethnicity and tophi with matching between cases and controls, revealed a strong dose-response relationship between the starting dose of allopurinol adjusted for
estimated GFR and the risk of AHS (overall dose effect
P 0.001). The risk of AHS in the 2 highest quintiles of
allopurinol dose corrected for the estimated GFR remained statistically significant in multivariate analysis.
There was no relationship between allopurinol
starting dose and serum urate level in the whole group

Figure 2. Percentage of patients who developed allopurinol hypersensitivity syndrome (AHS) in each quintile of the starting dose of
allopurinol corrected for the estimated glomerular filtration rate
(estimated GFR). Numbers above the bars are the odds ratio. P
0.05 versus the lowest quintile.

ALLOPURINOL HYPERSENSITIVITY

(cases and controls) or in the cases alone (P 0.05

for both), but there was a negative correlation for the
controls (r 0.06, P 0.04). This suggests that the
higher starting doses of allopurinol in the cases were not
a result of a higher serum urate level.
Repeating the analyses with exclusion of the 20%
of cases and controls of Chinese ethnicity resulted in no
change in the statistical significance levels in any of the
analyses.
Allopurinol dose can be increased in patients
who tolerate it. Cases were receiving a significantly
higher allopurinol dosage than controls at the time AHS
occurred (mean SEM 217.9 9.0 mg/day versus
150.3 5.5 mg/day) (P 0.001). At the time of the
reaction, 11.5% of the cases and 26% of the controls
were receiving the creatinine clearancebased allopurinol dose. Cases were more likely to be receiving doses
that were higher than the creatinine clearancebased
allopurinol dose (29 of 52 cases [55.8%] versus 27 of 150
controls [18%]) (OR 28.5 [95% CI 6.047.6], P 0.001).
Controls were more likely than cases to be receiving
doses that were lower than the creatinine clearance
based allopurinol dose (84 of 150 controls [56%] versus
17 of 52 cases [32.7%]) (OR 5.3 [95% CI 2.113.7], P
0.001). Only 10 of 53 cases (18.8%) had the dosage of
allopurinol increased between the time allopurinol was
started and the time the reaction occurred, as compared to 50 of 150 controls (33.3%). In the 10 cases in
whom the dosage was increased, the mean increase was
197.5 mg/day between the starting dosage and the dosage at the time of the reaction. In the 50 controls, the
mean increase in allopurinol was 110.5 mg/day. Allowing
for matching between cases and controls, the mean
increase in dosage was significantly larger in the cases
(P 0.002). All controls subsequently had increases in
the dosage of allopurinol after the matched time (time at
which AHS occurred in cases). The mean increase in
allopurinol dosage was 83 mg/day, and the mean SEM
maximum dosage was 229.3 8.8 mg/day.
Can a safe starting dose of allopurinol be determined? ROC analysis indicated that the starting dose of
allopurinol in 91% of AHS cases and 36% of controls
was 1.5 mg per unit of estimated GFR (mg/ml/
minute). In comparison, 79% of AHS cases and 53% of
controls started at a dose of 2.0 mg of allopurinol per
unit of estimated GFR (mg/ml/minute). A starting dose
based on an estimated GFR of 1.5 mg/ml/minute was
selected as a reasonable tradeoff between a clinically
practicable dose and the absolute risk of AHS (Table 4).

2533

Table 4. Proposed starting dosage of allopurinol based on 1.5 mg per

estimated GFR*
Estimated GFR,
ml/minute/1.73 m2

Allopurinol
starting dosage

5
515
1630
3145
4660
6190
91130
130

50 mg/week
50 mg twice weekly
50 mg every 2 days
50 mg/day
50 mg and 100 mg on alternate days
100 mg/day
150 mg/day
200 mg/day

* Consideration should be given to starting allopurinol at even lower

doses in patients at high risk of developing allopurinol hypersensitivity
syndrome, such as those with HLAB*5801. Estimated GFR
estimated glomerular filtration rate.

DISCUSSION
We have shown that the starting dose of allopurinol is a significant risk factor for AHS. However, in
those who tolerate allopurinol, the dose can be increased
safely, a finding confirmed in a recent dose-escalation
study (19).
The mechanisms leading to AHS remain unclear.
Three potential factors are genetic background, drug
accumulation, and immunologic responses. Recent studies have highlighted a significant association between
HLAB*5801 and AHS in the Han Chinese (10) and
Thai (12) populations and a weaker effect in Europeans
(13). There is some controversy regarding the effect of
HLAB*5801 in the Japanese population (11,20). In
addition, the incidence of severe cutaneous adverse
reactions to allopurinol have been reported to be higher
in Korean patients with stage IIIV chronic kidney
disease and HLAB*5801 (21). Ethnicity was a strong
risk factor for AHS in the present study, where those of
Chinese descent were overrepresented among cases,
while patients of Maori/Pacific Island ethnicity were less
likely to develop AHS compared to Europeans. Part of
this ethnic influence may relate to genetic background,
although environmental risk factors may also be involved.
Interestingly, patients with tophi were less likely
to develop AHS than those without, but the reason for
this is unclear, especially since no relationship between
the presence of tophi and ethnicity was observed. Of the
10 cases who were of Chinese ethnicity, 8 did not have
tophi, which may have contributed to some of the
observed negative association. However, our multivariate analysis, which simultaneously included ethnicity and
tophi, indicated that each of these was independently
associated with the risk of AHS.

2534

There is no clear relationship between plasma

oxypurinol level and AHS. There are case reports of
AHS occurring well within the reported therapeutic
range for plasma oxypurinol levels (30100 moles/liter)
(22). Conversely, many patients without AHS have
plasma oxypurinol levels of 100 moles/liter (22,23).
Immunologic mechanisms seem likely to play an important role. The onset of AHS within weeks after starting
allopurinol suggests a delayed-type hypersensitivity reaction. Deposition of IgM in the dermalepidermal
junction of the skin from a patient with severe AHS has
been reported (24). Liver biopsy specimens from patients with AHS have shown infiltration of T lymphocytes and neutrophils (25,26). Lymphocyte studies from
patients with AHS have shown that oxypurinol and
allopurinol can induce cellular proliferation (25,27).
How the starting dose of allopurinol could influence
these factors is unclear. One explanation is that lower
starting doses of allopurinol might lead to desensitization in those who are genetically susceptible or at risk of
drug accumulation, thereby preventing AHS.
The higher starting dose of allopurinol observed
in the cases compared to the controls in the present
study was not related to differences in weight, body mass
index, or use of furosemide, although it may be a
surrogate marker for other biologic factors. In addition,
because cases and controls were matched for renal
function and age, the relationship of these factors cannot
be directly evaluated in this study. A protocol for starting
a patient on allopurinol treatment has not been determined, leading to variations in clinical practice. Our
results indicate that allopurinol should be started at a
low dose in order to reduce the risk of AHS. We suggest
a starting dose of 1.5 mg per unit of estimated GFR. This
is based on 90% sensitivity for predicting AHS from the
ROC analysis. Despite such dosing, AHS may still occur,
and patients beginning allopurinol treatment should be
advised to discontinue allopurinol and seek medical
attention should they develop a rash or fever. Furthermore, in high-risk groups, such as the Han Chinese or
patients with the HLAB*5801 genotype, even the starting doses suggested may be considered too high; clinicians need to consider this when choosing a starting dose
of allopurinol.
Effective long-term management of gout requires
a treat-to-target serum urate level approach. The
British Society for Rheumatology guidelines suggest a
target serum urate level of 5 mg/dl (28), while the
European League Against Rheumatism recommendations suggest a serum urate level of 6 mg/dl, perhaps
lower in patients with severe or tophaceous gout (5). An

STAMP ET AL

important consequence of creatinine clearancebased

allopurinol dosing is failure to achieve the target serum
urate level in the majority of patients (29). In the present
study, we demonstrated that in patients who tolerate
allopurinol, the dose can be increased, supporting uptitration to achieve the target serum urate level rather
than a creatinine clearancebased maximum dose
approach. Although the mean maximal dose was relatively low in the present study, a recent study has shown
that in patients in whom the creatinine clearancebased
allopurinol dose fails to achieve the target serum urate
level, higher doses are well tolerated and are effective in
lowering the serum urate level to 6 mg/dl (19).
The median time to occurrence of AHS in our
cohort was 30 days, with 90% of cases occurring within
180 days after starting allopurinol. The rate of increase
of allopurinol has not been formally studied, but gout
flares commonly occur during the first 612 months of
therapy. The risk of gout flare is reduced by starting
allopurinol at a low dose with a gradual up-titration and
by administration of low-dose colchicine or a nonsteroidal antiinflammatory drug during the first 6 months of
urate-lowering therapy (30). Based on the first 30 days
being the period of highest risk for AHS and the results
of our previous dose-escalation study (19), we advocate
increasing the allopurinol dose at monthly intervals until
the target serum urate level is achieved. We did not
identify an upper limit of allopurinol dose where an
increased risk of AHS occurred.
A starting dose of allopurinol of 1.5 mg per unit
of estimated GFR with monthly up-titration of the dose
is very conservative compared with usual practice, and
may seem overly cautious given the low absolute risk of
AHS. When treating a chronic condition, it is more
important to achieve long-term adherence to therapy
than to achieve the target in the shortest time. A start
low, go slow approach probably results in fewer episodes of acute gout during treatment initiation and
improves compliance. For patients in whom allopurinol
treatment fails to achieve the target serum urate level
due to intolerance or treatment resistance, newer uratelowering therapies are available. These are more expensive and lack long-term safety and efficacy data. An
understanding of the relationship between the allopurinol starting dose and AHS as observed in this study may
improve the safe and cost-effective long-term management of gout with allopurinol.
This study has a number of limitations. Although
it represents a large study for a rare condition, the
number of cases included was small. There is no specific
ICD code for AHS; thus, we used the only published

ALLOPURINOL HYPERSENSITIVITY

definition of AHS and carefully selected cases to fit this

definition. Importantly, we excluded 28 potential cases
who had presumed adverse drug reactions to allopurinol
but did not meet these strict criteria for AHS. We
acknowledge the potential pitfalls of case definition,
particularly in such a heterogeneous syndrome, but
believe that this methodology is robust and that using
widely accepted criteria will allow comparison with other
studies of AHS.
The ethnicity of the study population, which was
not matched between cases and controls, may limit the
generalizability of the results. The higher number of
Chinese patients among the cases may relate to the
known association between AHS and HLAB*5801 in
those of Chinese ethnicity and the higher prevalence of
HLAB*5801 in those of Chinese descent (1520%)
compared to those of European descent (16%) (13).
The results, and therefore our conclusion that AHS is
related to the starting dose of allopurinol, did not
change, however, when the analysis was limited to those
of European, Maori, or Pacific Island descent. Due to
the retrospective study design, we were unable to determine HLAB*5801 genotype or plasma oxypurinol concentrations. The rate at which allopurinol was increased,
which may influence the risk of AHS, was not standardized. Therefore, the question remains as to whether the
rate of increase in combination with the starting dose is
important. In the present study, the estimated GFR was
used rather than the creatinine clearance, upon which
the Hande criteria are based. These methods are not
fully interchangeable for the assessment of renal function. Finally, despite careful matching of cases and
controls for recognized risk factors for AHS, with the
exception of HLA genotype, there may be other unidentified risk factors.
The choice of ROC cutoff for the starting dose
was based on clinician opinion and consideration of
practical dosing with the available allopurinol tablet
strengths. Validation in an independent cohort of patients will be required to confirm our observation of
the relationship between the allopurinol starting dose
and AHS. To determine whether the proposed dosing
strategy results in fewer cases of AHS would require a
very large randomized controlled trial to have adequate
power and would probably not be feasible.
In summary, we have shown that the starting dose
of allopurinol is an important risk factor for the development of AHS. Using ROC analysis, a starting dose of
allopurinol of 1.5 mg per unit of estimated GFR is
appropriate to minimize the risk of AHS. Progressive
up-titration of allopurinol is not associated with an

2535

increased risk of AHS, and once allopurinol treatment is

established, this strategy should be adopted to achieve
the target serum urate level.
ACKNOWLEDGMENTS
We acknowledge the assistance of Karen Lindsay,
Karen Pui, Angela Crowley, Karen Dentener, Sanjib Ghosh,
and Philip Robinson with data collection.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Stamp had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Stamp, Taylor, Jones, Dockerty, Drake,
Frampton, Dalbeth.
Acquisition of data. Stamp, Jones, Dockerty, Drake, Dalbeth.
Analysis and interpretation of data. Stamp, Taylor, Drake, Frampton,
Dalbeth.

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