56 Journal of The Association of Physicians of India ■ Vol.
63 ■ December 2015
Pathogenesis and Clinical Management of Gouty
Arthritis
Renu Saigal1, Abhishek Agrawal2
G out, the most common of the
crystal arthritides is a result
of disturbed uric acid metabolism
and precipitation of urate crystals
in extra cellular space of joints,
periarticular tissue, bones and
other organs.
In the West, gout affects around
1% of adult men over 45 years of
age. The estimated incidence being
0.6 to 2.1 per 1000 per year, with a
prevalence of 9.5 to 13.5 per 1000
persons of all ages. 1 The incidence
of gout has been on rise globally;
potentially attributable to recent
shifts in diet, lifestyle, medical
care, and increased longevity. 2
Ribose 5-P + ATP
(Purines-Endogenous and Dietary)
PRPP Synthetase
5-Phosphoribosyl -1-Pyrophosphate (PRPP)
Glutamine
Inosine
HPRT*
Hypoxanthine
Xanthine Oxidase
Xanthine
Xanthine Oxidase
Uric Acid
(*Hypoxanthine-guanosine phosphoribosyl transferase)
Fig. 1: Urate biosynthesis
update article
Gout is three to four times more
common in males than in pre-
menopausal females; incidence in
women increases after menopause
and after the age of 60, approaches
that in men. 3
This update aims to highlight
recent developments in
understanding pathogenesis of gout
along with current management
strategies.
Pathophysiology of Gout
Uric Acid Metabolism4,5
In humans, uric acid is the end
product of purine metabolism in
the liver (Figure 1).
Uric Acid Excretion
Humans lack the enzyme
uricase, which degrades uric acid
to highly soluble allantoin. Two
third of the urate load is excreted
by the kidneys. Here post-secretary
reabsorption in the S3 segment of
proximal renal tubule is the major
contributor for the reabsorption
of filtered urate load. The major
genes that encode ion transporters
involved in urate renal transport
have been identified.
The most important among these
is the anion exchanger URAT1
encoded by SLC22A12 (solute
carrier family 22 [organic anion/
urate transporter ] member 12)
gene on chromosome 11q13 which
drives urate anions reabsorption. 6
The hexose transporter SLC2A9
(also called the glucose transporter
1
Consultant Rheumatologist and Sr Physician Apex Hospital, Jaipur; Former Professor and Head; 2Professor,
Department of Medicine, SMS Medical College & Hospital, Jaipur, Rajasthan
Received: 26.05.2011; Revised: 22.09.2014; Re-revised: 20.08.2015; Accepted: 26.08.2015
9, GLUT9, or fructose transporter
encoded by gene on chromosome
4) is involved in voltage-dependent
urate anion reabsorption at
the proximal tubule.7 Genetic
polymorphisms of SLC2A9 may
point towards the mechanisms by
which high fructose intake and
hyperglycemia are linked with
hyperuricemia and gout. Single
nucleotide polymorphism (SNP)
of ABCG2 (ATP-binding cassette
subfamily G member 2), the key
transporter for tubular secretion
of urate; is strongly associated
with hyperuricemia in men, post
menopausal women and hormone
therapy users.
Hyperuricemia and Gout
The natural history of articular
gout is typically composed of
four periods: asymptomatic
hyperuricemia, episodes of acute
attacks of gout (acute gouty arthritis)
with asymptomatic intervals
(intercritical gout), and chronic
gouty arthritis. Hyperuricemia is a
major contributor to gout, in 85% to
90% of people it develops because
of underexcretion (excretion
<330 mg/d) of urate while its
overproduction (excretion >600
mg/d) accounts for only 10% to 15%
of hyperuricemia cases (Table 1).
The common precipitants of
an acute attack of gout such as
strenuous exercise, cold, alcoholism
and overeating, act by inducing
accelerated degradation of ATP
into AMP, (a precursor of uric acid)

Table 1: Causes of Hyperuricemia
Drugs causing hyperuricemia
Aspirin (low dose) Frusemide
Amiloride Levodopa
Alcohol Niacin
Chlorthalidone Pyrazinamide
Cisplatin Parathyroid hormone
Cyclosporine A Tacrolimus
Ethacrynic acid Thiazide
Ethambutol Theophylline
Overproduction of uric acid
Genetic : Inborn error of purine metabolism
↑ Nucleic acid turnover :
– Malignancies : Myelo or
lymphoproliferative
– Excessive alcohol, purine or fructose
intake
– Psoriasis, hemolytic disorders
– Obesity –BMI >30 kg/m2
– Heavy exercise
Underexcretion of uric acid
Chronic kidney disease
Drugs (vide supra)
HT
Metabolites (lactate and ketones)
Lead intoxication
furthermore, ethanol ingestion
contributes to hyperuricemia
by associated dehydration and
metabolic acidosis.
Crystal-Induced Inflammation
Hyperuricemia is necessary but
not sufficient for the development
of gout. The urate precipitation is
modulated by lower temperature
at the foot, intra-articular fluid
dehydration (onset at night time),
cation concentration and the
presence of various nucleating
agents, such as insoluble
collagens, chondroitin sulfate,
proteoglycans, cartilage fragments,
and other crystals. 4 Among these
the immunoglobulin G (IgG) is
prominent as monosodium urate
(MSU) crystals from tophi and
synovial fluid during acute gout
are found to be coated with IgG. 8
The nucleation and subsequent
growth rates of MSU crystals are
directly proportional to the degree
of MSU supersaturation.
MSU crystals are pro-
inflammatory and can initiate,
amplify and sustain an intense
inflammatory response. 5 Innate
Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015 57
MSU Crystals
Initiation Phase
MSU Crystal Phagocytosis
NALP 3 Inflammosome Acvaon
Caspase 1 Cleavage & Acvaon
Cleavage of Pro IL 1B
Monocyte or
Maturaon and Secreon of IL- 1B
Undifferenated Macrophage
Amplification Phase Interacon of IL- 1B with IL-1 R-MyD88 Complex
Endothelial Cells
Endothelial Acvaon and Release of Cytokines
Recruitment & Acvaon of Neutrophils and Other Cells
(MSU: Monosodium urate, IL: Interleukin, IL-1R: Interleukein-1 receptor:
MyD88: Myeloid differentiation factor 88)
Fig. 2: Pathogenesis of urate-induced inflammation
immune system responds by macrophage and synovial
t o a va r i e t y o f p a t h o g e n s a n d fibroblasts and resulting cytokine
endogenous molecules (including release caused vascular endothelial
urate crystals), through recognition cell activation and vasodilatation,
of pathogen-associated molecular increased plasma proteins
p a t t e r n s ( PA M P s ) o r d a n g e r - permeability and leukocyte
associated molecular patterns recruitment. This may require the
(DAMPs). 9 MSU crystals in the presence of cell surface receptors
j o i n t c a v i t y , a c t i va t e s y n o v i a l of the innate immune system like:
endothelial cells followed by the toll-like receptors-1 (TLR -1), TLR-2
recruitment and activation of mast or TLR-4, the TLR adapter protein,
cells and blood monocytes. 4 Later, myeloid differentiation factor 88
neutrophils get recruited, leading (MyD88), or an adapter protein
to further MSU crystal phagocytosis shared by TLR-2 and TLR-4: CD 14.
and cell activation. Normally MSU Triggering receptors expressed on
crystals are coated with serum myeloid cell 1 (TREM-1) present on
proteins (apolipoprotein E or monocytes and neutrophils, act as
apolipoprotein B) which inhibits amplifier of the immune response. 11
the binding of MSU crystals to cell Phagocytosis of MSU Crystals
receptors. causes generation of reactive
Initiation Phase (Figure 2) oxygen species through activation
In acute gout, Interleukin-1β of NADPH oxidases leading to
(IL-1β) is the core inflammatory activation of NLRP3 (NACHT,
mediator released as a result of LRR and pyrin domain containing
interaction of MSU to mononuclear p r o t e i n ) i n f l a m m a s o m e . 12
and synovial lining cells. 10 IL-1β Inflammasomes are molecular
can induce the expression of a wide platforms which function as
range of inflammatory mediators pathogen sensors similar to TLRs.
leading to neutrophil influx in the Additional triggers for
synovium. provoking inflammation include
Phagocytosis of MSU crystals dietary factors such as long-chain
58 Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015
Fig. 3: Needle shaped MSU
crystals (as seen under light
microscope)
free fatty acids or ethanol, which
act by activating TLRs, in particular
TLR4. These TLR ligands include
high-mobility group protein B1
(HMGB1), DNA and the calcium-
binding proteins S100A8 and
S100A9. A rapid change in ATP
concentration causes activation of
purinergic receptor P2X ligand-
gated ion channel 7 receptor
(P2X7R) which leads to rapid
exit of intracellular potassium
triggering NLRP3 inflammosome
activation. 13 NLRP3 inflammasome
mediates the activation of caspase-
1, causing cleavage of pro-IL-1β
to the active form of IL-1β and
IL-18. Besides IL-1β, both IL-6
and TNFα are also upregulated.
Colchicine is thought to block IL-1β
maturation by inhibition of NLRP3
inflammasome activation. 14
Novel agents targeting elements
of the NLRP3 inflammasome, IL-1β
or the IL-1R-MyD88 complex may
provide more directed therapies
for prevention and treatment of
acute gout.
In patients with chronic renal
failure, MSU induced release
of IL-1, IL-6, and TNF from the
monocytes is blunted causing
reduced gout attacks in spite of
high degree of hyperuricemia in
these patients. 15
Amplification Phase (Figure 2)
After being secreted in the
extracellular space, IL-1 ß interacts
with IL-1 receptor (IL-1R) complex
leading to recruitment of MyD88
(an intracellular adaptor protein
involved in IL-1R signaling),
activation of endothelium;
and chemokines (IL-8, S100 or
macrophage inflammatory protein
-2) and cytokines (IL-1, TNF-α)
production. 16
Spontaneous Resolution of Acute
Attack
Subsidence of an acute gout attack
occurs due to multiple feedback
mechanisms, most important being
the apoptotic clearance of damaged
neutrophils, induced by peroxisome
proliferator–activated receptor-γ
(PPAR-γ) expression in monocytes.
Formation of differentiated
macrophage with increased anti
inflammatory cytokines IL-10
and transforming growth factor
(TGF-β1) in the synovial fluid,
lowering endothelial activation,
monocyte and neutrophil adhesion
and recruitment, and reduced IL-1
and IL-1R expression. 17
Intercritical Gout
Following resolution of an acute
attack, the MSU crystals still persist
either free or as microtophi in the
synovium. These crystals promote
a state of low-grade persistent
inflammation in the synovium. 18
Formation of Tophi and Joint Damage
In patients with repeated attacks
of acute gout, tissue deposits
of MSU crystals surrounded by
granulomatous inflammation
known as tophi are found in
numerous tissues besides joint
and skin, including the kidney
and larynx. Tophi are associated
with destruction of surrounding
cartilage and bone brought about
by crystal–chondrocyte cell
membrane interactions. These
include chondrocyte activation,
and inducible nitric oxide synthase
(iNOS), leading to nitric oxide
release through TLR2 signalling
via MyD88, IRAK1 (IL-1 receptor-
associated kinase 1) and TRAF-6
(TNF receptor associated factor-6)
resulting in NFκB (nuclear factor
k a p p a B ) a c t i va t i o n a n d o ve r -
expression of MMPs (matrix
metalloproteinases).
Accurate Diagnosis of Gout
Typical Clinical Picture
The presence of Acute
monoarthitis involving first
metatarsophalangeal (Podagra),
where inflammation peaks in 24
hours, and may involve midtarsal,
ankle, knee, wrist or elbow joints.
There may be presence of tophi. A
rapid response to colchicine further
establishes a diagnosis of gout.
Atypical gout is seen in elderly,
as oligo/polyarticular subacute/
persistent arthritis of unusual
joints, also affecting bursae, tendon
sheaths making distinction from
chronic arthritides difficult.
Serum Uric Acid Estimation
Serum uric acid (SUA) is usually
elevated but may be normal in
about 30% patients during an
acute attack because of IL-6 and
endogenous cortisol secretion,
which are uricosuric so SUA should
be repeated after 2 weeks.
Synovial Fluid (SF) Examination
A fresh sample SF should be
aspirated to demonstrate the
presence of monosodium urate
(MSU) crystals for a definite
diagnosis of gout. SF if not examined
immediately may be refrigerated
for days to months. MSU crystal
identification is considered the
gold standard for diagnosis. 19
The MSU crystals are needle
shaped negatively birefringent
crystals, easily detected by an
ordinary polarizing microscope.
The MSU crystals are yellow
when parallel to slow axis of
red compensator and blue when
perpendicular to red compensator
shining on the dark microscope
field. Caution should be exercised
not to take SF in formalin as urate
crystals dissolve in formalin. Under
light microscopy also MSU crystals
may be seen as needle shaped
crystals (Figure 3).
Ultrasound (US)
A short 4-joint (including both
knees and both first MTP joints)
US screening may be done as a
useful complement to clinical

Fig. 4: Double Contour Sign in
Gout. White arrow: anechoic
cartilage, black arrow: MSU
crystal deposition over
cartilage. (Image courtesy:
Dr. P.D. Rath, Senior
Consultant Rheumatologist,
Max Hospital, Delhi)
examination. 20 Double contour
(DC) sign on US (Figure 4) is very
specific for non-tophaceous urate
crystal deposition on articular
cartilage.
The sensitivity and specificity
of the DC in diagnosing gout is
estimated to be 43.7% and 99%,
respectively. 21 Erosions are most
commonly found in the first MTP
j o i n t ( m e d i a l s u r f a c e ) . 22 O t h e r
synovial signs on US specific for
gout are erosions, intrasynovial
hyperechogenicity, hyperechoic
areas and brightly stippled foci
(snowstorm). 23
Dual-Energy Computerized
Tomography (DECT)
This modality can quantify the
burden of tophi as it can detect
clinical as well as subclinical tophi
and it has high specificity (93%)
and moderate sensitivity (78-
84%). 24
As soon as the diagnosis of
gout is established patient should
be evaluated for the presence of
secondary causes of hyperuricemia
(Table 1).
There is an increased prevalence
of comorbidities like hypertension,
obesity, type 2 diabetes mellitus,
hyperlipidemia and chronic kidney
disease (CKD) which promotes
hyperuricemia.
Treatment of Gout and
Hyperuricemia
Management of gout requires a
Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015
multifaceted approach. Recently
‘curing’ gout i.e. long-term reduction
of serum urate concentration < 360
μmol/l (6 mg/dl), thus promoting
crystal dissolution and preventing
formation of new crystals; has
b e en t he mai n a im of t r eat in g
rheumatologists.
Diet and Lifestyle Changes 19,20
1. Achieve ideal body weight
2. Cessation of smoking
3. H e a l t h y d i e t a n d o p t i m a l
exercise
4. Good hydration
Avoid20
Purine-rich organ meat (liver
and kidney, thymus and pancreas
of calf and lamb, seafood), fructose-
rich drinks (corn syrup, sweetened
soft drinks, ice cream) and fruits
(apples, oranges); alcohol use
especially during attacks of gout
and large, rich meals.
Limit20
Beef, lamb, pork, and sea food
(shellfish and sardines); natural
sugars, sweetened beverags,
desserts and table salts. Limit
alcohol (esp. beer, also wine and
spirits) in all gout patients to <2
servings/day for males and <1
serving/day for females.
Encourage20
Low fat or non-fat dairy
products and vegetable intake.
D a i r y p r o d u c t s d e c r e a s e S UA b y
uricosuric effect. The dairy fractions
glycomacropeptide and G600 milk
fat extract might inhibit triggering
of the inflammasome by urate
crystals thus may also have anti-
inflammatory effects. 25
Dietary intake of vegetables,
vitamin C and coffee has been
associated with lowered serum
urate levels and reduction of risk
factors for urate urolithiasis.
Management of Acute
Gouty Arthritis
Acute gouty attacks should be
managed with non-steroidal anti-
inflammatory drugs (NSAIDs),
59
colchicine or corticosteroids,
topical ice and IL-1 inhibitors.
Monotherapy is preferred if
there is mild to moderate pain (<6
on a 1-10 visual analogue scale)
limited to one or two joints. Severe
pain or polyarticular involvement
requires combination therapy.
NSAIDs
The choice amongst NSAID
depends on the patients response
and tolerability. In patients with
gastrointestinal intolerance to
NSAIDs, cyclooxygenase-2 (COX-2)
inhibitors e.g. etoricoxib may be
used.
Topical Ice Application
In addition to pharmacologic
therapy this is an important
relieving measure in acute attack.
Colchicine
Oral colchicine is first-line
treatment for acute gout attacks
along with oral NSAIDs.
It works best when commenced
within 36 hours of first symptoms
of an acute attack. A loading dose
of 1 mg followed one hour later
by 0.5 mg and then continued (up
to 0.5 mg 3 times daily) until the
acute attack resolves or the patient
develops vomiting. A reduced dose
of 0.5 mg daily or on alternate days
is used in elderly or those with
hepatic or renal dysfunction.
Colchicine has a narrow
therapeutic index and dose-
dependent gastrointestinal toxicity
is common.
Colchicine myopathy may
rarely be seen in elderly with
renal impairment. Serum creatine
kinase monitoring is recommended
in these patients every six months.
Colchicine should be used at
low doses and with caution in
patients taking a cytochrome P450
3A4 inhibitor and P-glycoprotein
inhibitors (Table 2). 26
Corticosteroids (CS)
Aspiration of an affected
j o i n t f o l l o we d b y i n j e c t i o n o f
corticosteroids is ideal treatment
of acute monoarticular gout
60 Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015
Table 2: Colchicine dosing recommendation (Modified according to availability in
India)
Normal renal /
hepatic function
General dose
CYP3A4 inhibitors* Clarithromycin, Half the dose as in general
ketaconazole,
itraconazole,
telithromycin
Diltiazem,
verapamil,
erythromycin
P-glycoprotein Cyclosporine A 0.5 mg stat; dose to be
inhibitors*
*
CYP3A4 is involved in the metabolism of colchicine to its inactive metabolites, thus co-administration
of CYP3A4 inhibitors can result in colchicine accumulation and toxicity. P-glycoprotein is thought to
limit gastrointestinal absorption of colchicine, thus P-glycoprotein inhibitors may lead to accumulation
of colchicine.
when colchicine, NSAIDs or oral
corticosteroids are contraindicated.
Where NSAIDs or colchicine cannot
be used or are ineffective, oral
prednisolone (0.5 mg /kg/day for
five days) is preferred.
A single dose of depot
methylprednisolone acetate
80 mg or triamcinolone 40-80
mg intramuscularly or methyl-
prednisolone succinate (0.5-2.0 mg/
kg) intravenously may also be given.
ACTH 25-40 IU subcutaneously/
intramuscularly every 8 hours for
1-14 days, is another option. ACTH
may inhibit gouty inflammation
by activating melanocortin type 3
receptor peripherally.
Biologic Response Modifiers
IL-1 inhibition has been shown
to be an effective first-line therapy
for acute gout attacks when
NSAIDs, colchicine or CS are
contraindicated. 27
Three biologic agents are
available that bind and inactivate
extracellular IL-lß: Anakinra;
the IL-1 receptor antagonist that
inhibits the activity of both IL-1α
and IL-1β; rilonacept, a soluble
decoy receptor fusion protein that
binds IL-1α and IL-1β receptors;
and canakinumab, a fully human
anti-IL-1β monoclonal antibody.
Anakinra (100 mg
subcutaneously daily for 3 days);
or rilonacept (80-160 mg weekly);
and canakinumab (150 mg
Gout flares Prophylaxis against
flares
1 mg stat followed by 0.5 mg 0.5 mg once or twice
1 hr later then 0.5 mg tid daily
0.25 mg daily or every
dose other day
1 mg single dose, repeat dose 0.25 mg once or twice
not earlier than 3 days daily
0.25 mg daily or every
repeated not earlier than other day
3 days
subcutaneously) 28 are beneficial in
patients with frequent gout attacks
(≥ 3 attacks in previous 12 months)
in whom NSAIDs and colchicine
are not tolerated, or are ineffective
or contraindicated.
Urate Lowering Therapy (ULT) During
Acute Attack
Current recommendation is that
ULT can be started during an acute
gout attack in low dosage, along
with effective anti-inflammatory
management which is contrary to
the earlier practice when ULT was
contraindicated in acute attack. 19
Long-Term Management of
Gout
The aim of long-term therapy
is to ‘cure’ gout by lowering SUA
l e ve l s t o b e l o w t h e s a t u r a t i o n
point for urate (<360 μmol/l or 6
mg/dl); in the presence of tophi,
target SUA level should be <5 mg%.
Regular monitoring of SUA (every
2–5 weeks) during urate loweing
therapy (ULT) should be done, once
the serum urate target is achieved
then SUA should be measured
e ve r y s i x m o n t h s t o k n o w t h e
adherence.
Urate-lowering Therapy (ULT)
• Xanthine oxidase inhibitors
(XOI)
• Uricosuric drugs
• Pegloticase
Prophylaxis of Acute Gout Attacks
during ULT
U LT i s p r e c e d e d b y a n t i -
inflammatory measures as during
t h e i n i t i a l p h a se o f ULT t h e r e
may be an early increase in acute
gout attacks. Anti-inflammatory
measures are usually given for
3 months in patients without
tophi and 6 months in patients
with tophi, after target SUA is
achieved. 29
Colchicine is currently
considered the standard of care for
flare prophylaxis during initiation
of ULT, alternatively, low-dose
steroids and IL-1β inhibitors might
be used.
XOI
XOI are the first-line ULT. XOIs
reduce endogenous production
of uric acid by inhibiting the
conversion of hypoxanthine to
xanthine and of xanthine to uric
acid.
Indications of XOI
Any confirmed patient of gout
with: (i) two or more attacks of
gout, (ii) presence of tophi on
clinical or imaging study, (iii)
joint damage (erosive gout) due
to chronic gouty arthritis, (iv)
CKD stage 2 or worse, and (v) past
history of urolithiasis.
Allopurinol
The most commonly used XOI,
allopurinol should be started
with 100 mg/day, to reduce early
gout flares after ULT initiation,
and to reduce the potential for
severe hypersensitivity reactions. 30
Allopurinol may be titrated up
(up to 900 mg/day) till the target
SUA is reached. In stage 4 CKD
starting dose is 50 mg/day which
may be titrated up to 300 mg/
day if target SUA is not achieved,
with regular monitoring for drug
hypersensitivity.
Adverse Events
I t i s u s u a l l y we l l t o l e r a t e d ,
rash (3%), gastrointestinal events
(2%), allopurinol hypersensitivity
syndrome (AHS) (1%), fever (1%)
and musculoskeletal events (1%)

have been reported. 31 AHS includes
Stevens Johnson syndrome
and toxic epidermal necrolysis
with mortality of 20-25%. Drug
rash, eosinophilia and systemic
symptoms (DRESS) can also occur
with allopurinol. 32 Pruritic rash,
eosinophilia and elevated hepatic
transaminases may be the first
signs of impending AHS or DRESS.
Risk factors for AHS include high
initial dose, presence of renal
impairment, concomitant use of
thiazide diuretics, presence of HLA
B5801 allele, concomitant use of
colchicine and statins.
Febuxostat
Febuxostat, a non-purine,
highly specific XOI, had been
shown to be more effective than
fixed-dose (300 mg) allopurinol
as ULT. 33 However, febuxostat
should be used in patients who are
intolerant of allopurinol or when it
is contraindicated. Starting dose of
febuxostat is 40 mg/day, after two
weeks if target level is not achieved
it may be increased to 80 mg then
to 120 mg/day.
Adverse effects
Include abnormal liver
function tests, diarrhoea and
musculoskeletal symptoms. Liver
function should be assessed at
two and four months. Febuxostat
also has cardiovascular toxicity
like AV blocks, atrial fibrillation,
cardiovascular thromboembolic
events. It should be used with
caution in patients with congestive
heart failure stage III or IV, hepatic
dysfunction and in patients
with GFR less than 30 ml/min.
hypersensitivity is rarely reported.
Febuxostat Versus Allopurinol
As a non-competitive XOI,
Febuxostat has several theoretical
advantages over the competitive
XOI allopurinol, including greater
potency, specificity and a reduced
reliance on renal excretion.
Advantage of febuxostat over
allopurinol is that it can be used
without dose-adjustment or concern
over toxicity in patients with CKD
with GFR >30 ml/min although
Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015
it is not recommended for use in
those with an estimated glomerular
filtration rate <30 ml/min/1.73 m 2.
If one XOI is ineffective to achieve
target level of SUA or intolerance
develops to it then second XOI may
be substituted.
Drug Interactions of XOI
X O I h a ve i n t e r a c t i o n s w i t h
drugs metabolized by xanthine
oxidase enzyme e.g. azathioprine,
6-mercaptopurine and theophylline
thus increasing their concentration
and hence toxicity. Similarly,
warfarin may have increased anti-
coagulant effect with allopurinol.
ACE inhibitors may increase risk
of allergic reactions to allopurinol.
Uricosuric Drugs (Table 3)
Uricosuric drugs act
p r e d o m i n a n t l y o n U R AT 1 t o
prevent reuptake of uric acid at
the proximal renal tubule and
thus increase renal excretion of
uric acid. The resulting higher
concentration of uric acid in the
collecting tubules can predispose
to uric acid stone formation, so
the patient should remain well-
hydrated. Urine should be made
alkaline by potassium citrate to
dissolve uric acid crystals.
These drugs should be given to
those patients who cannot tolerate
allopurinol or as an adjunctive
therapy with XOI where SUA target
is not achieved. Uricosuric drugs
should be added and gradually
the dose should be increased every
2-5 weeks till the target SUA is
achieved. Most of the uricosuric
drugs are either not available or
have limited availability in India.
Pre-requisites of using Uricosuric ULT
Renal function should be normal
(creatinine clearance >50 ml/
minute).
Urate excretion should be <800
mg/24 hours.
There should be no evidence of
urolithiasis.
Probenecid
It is drug of choice among all the
uricosuric drugs. Its half life is 3-8
61
hours, so given as twice or thrice a
day therapy.
Benzbromarone
It may be used in those with
mild to moderate renal impairment.
The availability of benzbromarone
became limited mainly due to
reports of hepatotoxicity,
particularly in Asia.Liver function
should be frequently checked. 34
Other available uricosuric drugs
L o s a r t a n 3 5 i n h i b i t s U R AT 1
and GLUT9, while fenofibrate
inhibits only URAT1. These two
drugs can be considered as useful
adjunctive therapy if hypertension
or hyperlipidemia are coexistent.
Other drugs include vitamin C
supplements and corticosteroids.
Pegloticase
It is polyethylene glycol uricase
preparation i.e. pegylated form of
recombinant uricase. Pegloticase
therapy is not recommended as
first-line ULT agent.
It reduces SUA by enzymatic
degradation of uric acid to more
wa t e r s o l u b l e a n d e x c r e t a b l e
allantoin. It is approved by USFDA
for use in patients with severe
gout disease burden, in actively
symptomatic patients and in those
who are refractory to, or intolerant
of, conventional and appropriately
dosed ULT.
Pegloticase (8 mg intravenously
every 2 weeks) can bring about
rapid tophus burden reduction and
can achieve rapid improvements
in clinical outcomes sometimes in
months only whereas oral agents
may take years. 36
Most common adverse reactions
are gout flares, infusion related
reactions, headache (11%) and
nausea (7%). Antibody develop in
nearly 90 percent of those receiving
the active drug associated with loss
of efficacy and increased infusion
reactions.
Other ULT, such as
allopurinol and febuxostat, should
not be given to patients receiving
pegloticase, because they may
mask recognition of rising SUA
62 Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015
Table 3: Uricosuric Drugs
Uricosuric Starting Maximum
drug dose/day dose/day
Probenecid 500 mg 2000 mg
Benzbromarone 50 mg 200 mg
Sulfinpyrazone 200 mg 800 mg
Losartan 50 mg 100 mg
Fenofibrate 200 mg
levels which suggests antibody
formation.
Newer Urate Lowering Drugs
Lesinurad
I n h i b i t s U R AT 1 a n d O AT 4
(organic anionic transporter 4)
in renal tubule. Phase III studies
have shown that it can be given
as monotherapy to those who are
intolerant to XOI, or in combination
with allopurinol or febuxostat.
Ulodesine
Oral, once daily novel purine
nucleoside phosphorylase inhibitor
which blocks production of uric
acid at the step higher than xanthine
oxidase inhibition. Phase 2 trials
have been going on with this drug.
Levotofisopam
T h i s U LT h a s a l s o b e e n
undergoing phase 2 trial.
Arhalofenate and Tranilast
Inhibits URAT1 and other urate
exchanger molecules and are
undergoing Phase I and II trials.
Novel intestinal transporters of uric acid
In patients with CKD, total
urinary uric acid falls and the
principal burden of elimination
shifts from the kidney to the
gut, there is upregulation of
intestinal ABCG2 exporters, this
has become an important area of
study to develop novel intestinal
transporters which may become
an alternative for those at risk of
developing uric acid kidney stones
with uricosuric agents.
Managing Comorbidities
In NHANES study of 5,707
participants in the 2007-2008, 74%
had HTN, 71% had CKD stage 2 or
higher, 53% were obese, 26% had
diabetes, 24% had nephrolithiasis,
14% had myocardial infarction,
11% had heart failure, and 10% had
Table 4: Modifications in the treatment of gout according to co-morbid conditions
Co-morbid conditions
Moderate to severe CKD
Congestive heart failure
Peptic ulcer diseas
Diabetes mellitus
Ongoing infection or high risk of
infection
Hepatic disease
With anticoagulants/antiplatelet therapy
Hypertension
suffered a stroke; the prevalence
of these comorbidities increased
with the degree of hyperuricemia,
supporting the notion that serum
urate is related to the presence
o f s e ve r a l g o u t c o m o r b i d i t i e s ,
either as a marker of disease or
perhaps by itself exacerbating other
diseases. 37 These co-morbidities
should be managed judiciously
(Table 4).
Hypertension should be
managed preferably by Losartan
and calcium channel blockers as
both increase uric acid excretion.
Other antihypertensives like
β-adrenergic blocking agents,
angiotensin-converting enzyme
inhibitors and angiotensin
II receptor blockers other than
losartan, increase SUA by reduced
renal excretion.
Hyperlipidemia and
hyperglycemia need to be managed
aggressively as tight control of
each can independently reduce
S U A l e ve l s t h r o u g h i m p r o ve d
renal excretion of uric acid. Agents
decreasing insulin resistance also
tend to reduce SUA levels. 38
Conclusion
Management of gout has
undergone major change in the last
couple of years. Proper control of
SUA to less than 6.0 mg% (or lower
in presence of tophi) is the main aim
with optimum management of co-
morbidities and patient education
are of paramount importance.
Contraindication/caution
NSAIDs, COX-2 inhibitors, colchicines
NSAIDs, COX-2 inhibitors
NSAIDs, COX-2 inhibitors, CS
Corticosteroids
Corticosteroids
NSAIDs, COX-2 inhibitors, colchicines, febuxostat
NSAIDs
β Blockers, ACE inhibitors and ARB (other than
losartan)
Prefer losartan or calcium channel blockers as these
are uricosuric
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