You are on page 1of 8

56 Journal of The Association of Physicians of India ■ Vol.

63 ■ December 2015

update article

Pathogenesis and Clinical Management of Gouty

Renu Saigal1, Abhishek Agrawal2

G out, the most common of the

crystal arthritides is a result
of disturbed uric acid metabolism
Gout is three to four times more
common in males than in pre-
menopausal females; incidence in
9, GLUT9, or fructose transporter
encoded by gene on chromosome
4) is involved in voltage-dependent
and precipitation of urate crystals women increases after menopause urate anion reabsorption at
in extra cellular space of joints, and after the age of 60, approaches the proximal tubule.7 Genetic
periarticular tissue, bones and that in men. 3 polymorphisms of SLC2A9 may
other organs. This update aims to highlight point towards the mechanisms by
In the West, gout affects around recent developments in which high fructose intake and
1% of adult men over 45 years of understanding pathogenesis of gout hyperglycemia are linked with
age. The estimated incidence being along with current management hyperuricemia and gout. Single
0.6 to 2.1 per 1000 per year, with a strategies. nucleotide polymorphism (SNP)
prevalence of 9.5 to 13.5 per 1000 of ABCG2 (ATP-binding cassette
persons of all ages. 1 The incidence Pathophysiology of Gout subfamily G member 2), the key
of gout has been on rise globally; transporter for tubular secretion
Uric Acid Metabolism4,5 of urate; is strongly associated
potentially attributable to recent
shifts in diet, lifestyle, medical In humans, uric acid is the end with hyperuricemia in men, post
care, and increased longevity. 2 product of purine metabolism in menopausal women and hormone
the liver (Figure 1). therapy users.
Ribose 5-P + ATP Uric Acid Excretion Hyperuricemia and Gout
(Purines-Endogenous and Dietary)
Humans lack the enzyme The natural history of articular
PRPP Synthetase uricase, which degrades uric acid gout is typically composed of
to highly soluble allantoin. Two four periods: asymptomatic
third of the urate load is excreted hyperuricemia, episodes of acute
5-Phosphoribosyl -1-Pyrophosphate (PRPP)
by the kidneys. Here post-secretary attacks of gout (acute gouty arthritis)
reabsorption in the S3 segment of with asymptomatic intervals
Glutamine proximal renal tubule is the major (intercritical gout), and chronic
contributor for the reabsorption gouty arthritis. Hyperuricemia is a
of filtered urate load. The major major contributor to gout, in 85% to
genes that encode ion transporters 90% of people it develops because
involved in urate renal transport of underexcretion (excretion
HPRT* have been identified. <330 mg/d) of urate while its
The most important among these overproduction (excretion >600
Hypoxanthine is the anion exchanger URAT1 mg/d) accounts for only 10% to 15%
encoded by SLC22A12 (solute of hyperuricemia cases (Table 1).
Xanthine Oxidase carrier family 22 [organic anion/ The common precipitants of
urate transporter ] member 12) an acute attack of gout such as
Xanthine gene on chromosome 11q13 which strenuous exercise, cold, alcoholism
drives urate anions reabsorption. 6 and overeating, act by inducing
Xanthine Oxidase The hexose transporter SLC2A9 accelerated degradation of ATP
(also called the glucose transporter into AMP, (a precursor of uric acid)

Uric Acid

(*Hypoxanthine-guanosine phosphoribosyl transferase)

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
Fig. 1: Urate biosynthesis
Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015 57

Table 1: Causes of Hyperuricemia

Drugs causing hyperuricemia MSU Crystals
Aspirin (low dose) Frusemide
Initiation Phase
Amiloride Levodopa
MSU Crystal Phagocytosis
Alcohol Niacin
Chlorthalidone Pyrazinamide
NALP 3 Inflammosome Acvaon
Cisplatin Parathyroid hormone
Cyclosporine A Tacrolimus
Caspase 1 Cleavage & Acvaon
Ethacrynic acid Thiazide
Ethambutol Theophylline
Overproduction of uric acid Cleavage of Pro IL 1B
Genetic : Inborn error of purine metabolism Monocyte or
↑ Nucleic acid turnover :
Maturaon and Secreon of IL- 1B
Undifferenated Macrophage
– Malignancies : Myelo or
– Excessive alcohol, purine or fructose Amplification Phase Interacon of IL- 1B with IL-1 R-MyD88 Complex
– Psoriasis, hemolytic disorders Endothelial Cells
– Obesity –BMI >30 kg/m2 Endothelial Acvaon and Release of Cytokines
– Heavy exercise
Underexcretion of uric acid Recruitment & Acvaon of Neutrophils and Other Cells
Chronic kidney disease (MSU: Monosodium urate, IL: Interleukin, IL-1R: Interleukein-1 receptor:
Drugs (vide supra) MyD88: Myeloid differentiation factor 88)
HT Fig. 2: Pathogenesis of urate-induced inflammation
Metabolites (lactate and ketones)
Lead intoxication 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
furthermore, ethanol ingestion
endogenous molecules (including release caused vascular endothelial
contributes to hyperuricemia
urate crystals), through recognition cell activation and vasodilatation,
by associated dehydration and
of pathogen-associated molecular increased plasma proteins
metabolic acidosis.
p a t t e r n s ( PA M P s ) o r d a n g e r - permeability and leukocyte
Crystal-Induced Inflammation
associated molecular patterns recruitment. This may require the
Hyperuricemia is necessary but (DAMPs). 9 MSU crystals in the presence of cell surface receptors
not sufficient for the development 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:
of gout. The urate precipitation is endothelial cells followed by the toll-like receptors-1 (TLR -1), TLR-2
modulated by lower temperature recruitment and activation of mast or TLR-4, the TLR adapter protein,
at the foot, intra-articular fluid cells and blood monocytes. 4 Later, myeloid differentiation factor 88
dehydration (onset at night time), neutrophils get recruited, leading (MyD88), or an adapter protein
cation concentration and the to further MSU crystal phagocytosis shared by TLR-2 and TLR-4: CD 14.
presence of various nucleating and cell activation. Normally MSU Triggering receptors expressed on
agents, such as insoluble crystals are coated with serum myeloid cell 1 (TREM-1) present on
collagens, chondroitin sulfate, proteins (apolipoprotein E or monocytes and neutrophils, act as
proteoglycans, cartilage fragments, apolipoprotein B) which inhibits amplifier of the immune response. 11
and other crystals. 4 Among these the binding of MSU crystals to cell Phagocytosis of MSU Crystals
the immunoglobulin G (IgG) is receptors. causes generation of reactive
prominent as monosodium urate Initiation Phase (Figure 2) oxygen species through activation
(MSU) crystals from tophi and
In acute gout, Interleukin-1β of NADPH oxidases leading to
synovial fluid during acute gout
(IL-1β) is the core inflammatory activation of NLRP3 (NACHT,
are found to be coated with IgG. 8
mediator released as a result of LRR and pyrin domain containing
The nucleation and subsequent
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
growth rates of MSU crystals are
and synovial lining cells. 10 IL-1β Inflammasomes are molecular
directly proportional to the degree
can induce the expression of a wide platforms which function as
of MSU supersaturation.
range of inflammatory mediators pathogen sensors similar to TLRs.
MSU crystals are pro- leading to neutrophil influx in the Additional triggers for
inflammatory and can initiate, synovium. provoking inflammation include
amplify and sustain an intense
Phagocytosis of MSU crystals dietary factors such as long-chain
inflammatory response. 5 Innate
58 Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015

activation of endothelium; Accurate Diagnosis of Gout

and chemokines (IL-8, S100 or
macrophage inflammatory protein Typical Clinical Picture
-2) and cytokines (IL-1, TNF-α) The presence of Acute
production. 16 monoarthitis involving first
Spontaneous Resolution of Acute metatarsophalangeal (Podagra),
Attack where inflammation peaks in 24
Subsidence of an acute gout attack hours, and may involve midtarsal,
occurs due to multiple feedback ankle, knee, wrist or elbow joints.
mechanisms, most important being There may be presence of tophi. A
the apoptotic clearance of damaged rapid response to colchicine further
Fig. 3: Needle shaped MSU neutrophils, induced by peroxisome establishes a diagnosis of gout.
crystals (as seen under light proliferator–activated receptor-γ Atypical gout is seen in elderly,
microscope) (PPAR-γ) expression in monocytes. as oligo/polyarticular subacute/
Formation of differentiated persistent arthritis of unusual
free fatty acids or ethanol, which
macrophage with increased anti joints, also affecting bursae, tendon
act by activating TLRs, in particular
inflammatory cytokines IL-10 sheaths making distinction from
TLR4. These TLR ligands include
and transforming growth factor chronic arthritides difficult.
high-mobility group protein B1
(HMGB1), DNA and the calcium- (TGF-β1) in the synovial fluid, Serum Uric Acid Estimation
binding proteins S100A8 and lowering endothelial activation, Serum uric acid (SUA) is usually
S100A9. A rapid change in ATP monocyte and neutrophil adhesion elevated but may be normal in
concentration causes activation of and recruitment, and reduced IL-1 about 30% patients during an
purinergic receptor P2X ligand- and IL-1R expression. 17 acute attack because of IL-6 and
gated ion channel 7 receptor Intercritical Gout endogenous cortisol secretion,
(P2X7R) which leads to rapid Following resolution of an acute which are uricosuric so SUA should
exit of intracellular potassium attack, the MSU crystals still persist be repeated after 2 weeks.
triggering NLRP3 inflammosome either free or as microtophi in the Synovial Fluid (SF) Examination
activation. 13 NLRP3 inflammasome synovium. These crystals promote A fresh sample SF should be
mediates the activation of caspase- a state of low-grade persistent aspirated to demonstrate the
1, causing cleavage of pro-IL-1β inflammation in the synovium. 18 presence of monosodium urate
to the active form of IL-1β and Formation of Tophi and Joint Damage (MSU) crystals for a definite
IL-18. Besides IL-1β, both IL-6 diagnosis of gout. SF if not examined
In patients with repeated attacks
and TNFα are also upregulated. immediately may be refrigerated
of acute gout, tissue deposits
Colchicine is thought to block IL-1β for days to months. MSU crystal
of MSU crystals surrounded by
maturation by inhibition of NLRP3 identification is considered the
granulomatous inflammation
inflammasome activation. 14 gold standard for diagnosis. 19
known as tophi are found in
Novel agents targeting elements numerous tissues besides joint The MSU crystals are needle
of the NLRP3 inflammasome, IL-1β and skin, including the kidney shaped negatively birefringent
or the IL-1R-MyD88 complex may and larynx. Tophi are associated crystals, easily detected by an
provide more directed therapies with destruction of surrounding ordinary polarizing microscope.
for prevention and treatment of cartilage and bone brought about The MSU crystals are yellow
acute gout. by crystal–chondrocyte cell when parallel to slow axis of
In patients with chronic renal membrane interactions. These red compensator and blue when
failure, MSU induced release include chondrocyte activation, perpendicular to red compensator
of IL-1, IL-6, and TNF from the and inducible nitric oxide synthase shining on the dark microscope
monocytes is blunted causing (iNOS), leading to nitric oxide field. Caution should be exercised
reduced gout attacks in spite of release through TLR2 signalling not to take SF in formalin as urate
high degree of hyperuricemia in via MyD88, IRAK1 (IL-1 receptor- crystals dissolve in formalin. Under
these patients. 15 associated kinase 1) and TRAF-6 light microscopy also MSU crystals
Amplification Phase (Figure 2) (TNF receptor associated factor-6) may be seen as needle shaped
resulting in NFκB (nuclear factor crystals (Figure 3).
After being secreted in the
k a p p a B ) a c t i va t i o n a n d o ve r - Ultrasound (US)
extracellular space, IL-1 ß interacts
expression of MMPs (matrix
with IL-1 receptor (IL-1R) complex A short 4-joint (including both
leading to recruitment of MyD88 knees and both first MTP joints)
(an intracellular adaptor protein US screening may be done as a
involved in IL-1R signaling), useful complement to clinical
Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015 59

multifaceted approach. Recently colchicine or corticosteroids,

‘curing’ gout i.e. long-term reduction topical ice and IL-1 inhibitors.
of serum urate concentration < 360 Monotherapy is preferred if
μmol/l (6 mg/dl), thus promoting there is mild to moderate pain (<6
crystal dissolution and preventing on a 1-10 visual analogue scale)
formation of new crystals; has limited to one or two joints. Severe
b e en t he mai n a im of t r eat in g pain or polyarticular involvement
rheumatologists. requires combination therapy.
Fig. 4: Double Contour Sign in Diet and Lifestyle Changes 19,20 NSAIDs
Gout. White arrow: anechoic 1. Achieve ideal body weight The choice amongst NSAID
cartilage, black arrow: MSU depends on the patients response
2. Cessation of smoking
crystal deposition over
3. H e a l t h y d i e t a n d o p t i m a l and tolerability. In patients with
cartilage. (Image courtesy:
Dr. P.D. Rath, Senior exercise gastrointestinal intolerance to
Consultant Rheumatologist, NSAIDs, cyclooxygenase-2 (COX-2)
4. Good hydration
Max Hospital, Delhi) inhibitors e.g. etoricoxib may be
Avoid20 used.
examination. 20 Double contour Purine-rich organ meat (liver Topical Ice Application
(DC) sign on US (Figure 4) is very and kidney, thymus and pancreas
In addition to pharmacologic
specific for non-tophaceous urate of calf and lamb, seafood), fructose-
therapy this is an important
crystal deposition on articular rich drinks (corn syrup, sweetened
relieving measure in acute attack.
cartilage. soft drinks, ice cream) and fruits
The sensitivity and specificity (apples, oranges); alcohol use
of the DC in diagnosing gout is especially during attacks of gout Oral colchicine is first-line
estimated to be 43.7% and 99%, and large, rich meals. treatment for acute gout attacks
respectively. 21 Erosions are most Limit20 along with oral NSAIDs.
commonly found in the first MTP Beef, lamb, pork, and sea food It works best when commenced
j o i n t ( m e d i a l s u r f a c e ) . 22 O t h e r (shellfish and sardines); natural within 36 hours of first symptoms
synovial signs on US specific for sugars, sweetened beverags, of an acute attack. A loading dose
gout are erosions, intrasynovial desserts and table salts. Limit of 1 mg followed one hour later
hyperechogenicity, hyperechoic alcohol (esp. beer, also wine and by 0.5 mg and then continued (up
areas and brightly stippled foci spirits) in all gout patients to <2 to 0.5 mg 3 times daily) until the
(snowstorm). 23 servings/day for males and <1 acute attack resolves or the patient
Dual-Energy Computerized serving/day for females. develops vomiting. A reduced dose
Tomography (DECT) of 0.5 mg daily or on alternate days
This modality can quantify the is used in elderly or those with
Low fat or non-fat dairy hepatic or renal dysfunction.
burden of tophi as it can detect products and vegetable intake.
clinical as well as subclinical tophi Colchicine has a narrow
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
and it has high specificity (93%) therapeutic index and dose-
uricosuric effect. The dairy fractions
and moderate sensitivity (78- dependent gastrointestinal toxicity
glycomacropeptide and G600 milk
84%). 24 is common.
fat extract might inhibit triggering
As soon as the diagnosis of of the inflammasome by urate Colchicine myopathy may
gout is established patient should crystals thus may also have anti- rarely be seen in elderly with
be evaluated for the presence of inflammatory effects. 25 renal impairment. Serum creatine
secondary causes of hyperuricemia kinase monitoring is recommended
Dietary intake of vegetables,
(Table 1). in these patients every six months.
vitamin C and coffee has been
There is an increased prevalence associated with lowered serum Colchicine should be used at
of comorbidities like hypertension, urate levels and reduction of risk low doses and with caution in
obesity, type 2 diabetes mellitus, factors for urate urolithiasis. patients taking a cytochrome P450
hyperlipidemia and chronic kidney 3A4 inhibitor and P-glycoprotein
disease (CKD) which promotes Management of Acute inhibitors (Table 2). 26
hyperuricemia. Gouty Arthritis Corticosteroids (CS)
Aspiration of an affected
Treatment of Gout and Acute gouty attacks should be 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
Hyperuricemia managed with non-steroidal anti- corticosteroids is ideal treatment
inflammatory drugs (NSAIDs), of acute monoarticular gout
Management of gout requires a
60 Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015

Table 2: Colchicine dosing recommendation (Modified according to availability in Prophylaxis of Acute Gout Attacks
India) during ULT
Normal renal / Gout flares Prophylaxis against U LT i s p r e c e d e d b y a n t i -
hepatic function flares inflammatory measures as during
General dose 1 mg stat followed by 0.5 mg 0.5 mg once or twice t h e i n i t i a l p h a se o f ULT t h e r e
1 hr later then 0.5 mg tid daily
may be an early increase in acute
CYP3A4 inhibitors* Clarithromycin, Half the dose as in general 0.25 mg daily or every
gout attacks. Anti-inflammatory
ketaconazole, dose other day
itraconazole, measures are usually given for
telithromycin 3 months in patients without
Diltiazem, 1 mg single dose, repeat dose 0.25 mg once or twice tophi and 6 months in patients
verapamil, not earlier than 3 days daily with tophi, after target SUA is
achieved. 29
P-glycoprotein Cyclosporine A 0.5 mg stat; dose to be 0.25 mg daily or every
inhibitors* repeated not earlier than other day Colchicine is currently
3 days considered the standard of care for
CYP3A4 is involved in the metabolism of colchicine to its inactive metabolites, thus co-administration flare prophylaxis during initiation
of CYP3A4 inhibitors can result in colchicine accumulation and toxicity. P-glycoprotein is thought to of ULT, alternatively, low-dose
limit gastrointestinal absorption of colchicine, thus P-glycoprotein inhibitors may lead to accumulation
steroids and IL-1β inhibitors might
of colchicine.
be used.
when colchicine, NSAIDs or oral subcutaneously) 28 are beneficial in XOI
corticosteroids are contraindicated. patients with frequent gout attacks
XOI are the first-line ULT. XOIs
Where NSAIDs or colchicine cannot (≥ 3 attacks in previous 12 months)
reduce endogenous production
be used or are ineffective, oral in whom NSAIDs and colchicine
of uric acid by inhibiting the
prednisolone (0.5 mg /kg/day for are not tolerated, or are ineffective
conversion of hypoxanthine to
five days) is preferred. or contraindicated.
xanthine and of xanthine to uric
A single dose of depot Urate Lowering Therapy (ULT) During acid.
methylprednisolone acetate Acute Attack
Indications of XOI
80 mg or triamcinolone 40-80 Current recommendation is that
Any confirmed patient of gout
mg intramuscularly or methyl- ULT can be started during an acute
with: (i) two or more attacks of
prednisolone succinate (0.5-2.0 mg/ gout attack in low dosage, along
gout, (ii) presence of tophi on
kg) intravenously may also be given. with effective anti-inflammatory
clinical or imaging study, (iii)
ACTH 25-40 IU subcutaneously/ management which is contrary to
joint damage (erosive gout) due
intramuscularly every 8 hours for the earlier practice when ULT was
to chronic gouty arthritis, (iv)
1-14 days, is another option. ACTH contraindicated in acute attack. 19
CKD stage 2 or worse, and (v) past
may inhibit gouty inflammation
Long-Term Management of history of urolithiasis.
by activating melanocortin type 3
receptor peripherally. Gout
Biologic Response Modifiers The most commonly used XOI,
The aim of long-term therapy allopurinol should be started
IL-1 inhibition has been shown
is to ‘cure’ gout by lowering SUA with 100 mg/day, to reduce early
to be an effective first-line therapy
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 gout flares after ULT initiation,
for acute gout attacks when
point for urate (<360 μmol/l or 6 and to reduce the potential for
NSAIDs, colchicine or CS are
mg/dl); in the presence of tophi, severe hypersensitivity reactions. 30
contraindicated. 27
target SUA level should be <5 mg%. Allopurinol may be titrated up
Three biologic agents are Regular monitoring of SUA (every (up to 900 mg/day) till the target
available that bind and inactivate 2–5 weeks) during urate loweing SUA is reached. In stage 4 CKD
extracellular IL-lß: Anakinra; therapy (ULT) should be done, once starting dose is 50 mg/day which
the IL-1 receptor antagonist that the serum urate target is achieved may be titrated up to 300 mg/
inhibits the activity of both IL-1α then SUA should be measured day if target SUA is not achieved,
and IL-1β; rilonacept, a soluble e ve r y s i x m o n t h s t o k n o w t h e with regular monitoring for drug
decoy receptor fusion protein that adherence. hypersensitivity.
binds IL-1α and IL-1β receptors; Urate-lowering Therapy (ULT) Adverse Events
and canakinumab, a fully human
anti-IL-1β monoclonal antibody. • Xanthine oxidase inhibitors I t i s u s u a l l y we l l t o l e r a t e d ,
(XOI) rash (3%), gastrointestinal events
Anakinra (100 mg
• Uricosuric drugs (2%), allopurinol hypersensitivity
subcutaneously daily for 3 days);
• Pegloticase syndrome (AHS) (1%), fever (1%)
or rilonacept (80-160 mg weekly);
and musculoskeletal events (1%)
and canakinumab (150 mg
Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015 61

have been reported. 31 AHS includes it is not recommended for use in hours, so given as twice or thrice a
Stevens Johnson syndrome those with an estimated glomerular day therapy.
and toxic epidermal necrolysis filtration rate <30 ml/min/1.73 m 2. Benzbromarone
with mortality of 20-25%. Drug If one XOI is ineffective to achieve
It may be used in those with
rash, eosinophilia and systemic target level of SUA or intolerance
mild to moderate renal impairment.
symptoms (DRESS) can also occur develops to it then second XOI may
The availability of benzbromarone
with allopurinol. 32 Pruritic rash, be substituted.
became limited mainly due to
eosinophilia and elevated hepatic Drug Interactions of XOI reports of hepatotoxicity,
transaminases may be the first
X O I h a ve i n t e r a c t i o n s w i t h particularly in Asia.Liver function
signs of impending AHS or DRESS.
drugs metabolized by xanthine should be frequently checked. 34
Risk factors for AHS include high
oxidase enzyme e.g. azathioprine, Other available uricosuric drugs
initial dose, presence of renal
6-mercaptopurine and theophylline
impairment, concomitant use of L o s a r t a n 3 5 i n h i b i t s U R AT 1
thus increasing their concentration
thiazide diuretics, presence of HLA and GLUT9, while fenofibrate
and hence toxicity. Similarly,
B5801 allele, concomitant use of inhibits only URAT1. These two
warfarin may have increased anti-
colchicine and statins. drugs can be considered as useful
coagulant effect with allopurinol.
Febuxostat adjunctive therapy if hypertension
ACE inhibitors may increase risk
or hyperlipidemia are coexistent.
Febuxostat, a non-purine, of allergic reactions to allopurinol.
Other drugs include vitamin C
highly specific XOI, had been Uricosuric Drugs (Table 3) supplements and corticosteroids.
shown to be more effective than
Uricosuric drugs act Pegloticase
fixed-dose (300 mg) allopurinol
p r e d o m i n a n t l y o n U R AT 1 t o
as ULT. 33 However, febuxostat It is polyethylene glycol uricase
prevent reuptake of uric acid at
should be used in patients who are preparation i.e. pegylated form of
the proximal renal tubule and
intolerant of allopurinol or when it recombinant uricase. Pegloticase
thus increase renal excretion of
is contraindicated. Starting dose of therapy is not recommended as
uric acid. The resulting higher
febuxostat is 40 mg/day, after two first-line ULT agent.
concentration of uric acid in the
weeks if target level is not achieved It reduces SUA by enzymatic
collecting tubules can predispose
it may be increased to 80 mg then degradation of uric acid to more
to uric acid stone formation, so
to 120 mg/day. wa t e r s o l u b l e a n d e x c r e t a b l e
the patient should remain well-
Adverse effects hydrated. Urine should be made allantoin. It is approved by USFDA
Include abnormal liver alkaline by potassium citrate to for use in patients with severe
function tests, diarrhoea and dissolve uric acid crystals. gout disease burden, in actively
musculoskeletal symptoms. Liver symptomatic patients and in those
These drugs should be given to
function should be assessed at who are refractory to, or intolerant
those patients who cannot tolerate
two and four months. Febuxostat of, conventional and appropriately
allopurinol or as an adjunctive
also has cardiovascular toxicity dosed ULT.
therapy with XOI where SUA target
like AV blocks, atrial fibrillation, is not achieved. Uricosuric drugs Pegloticase (8 mg intravenously
cardiovascular thromboembolic should be added and gradually every 2 weeks) can bring about
events. It should be used with the dose should be increased every rapid tophus burden reduction and
caution in patients with congestive 2-5 weeks till the target SUA is can achieve rapid improvements
heart failure stage III or IV, hepatic achieved. Most of the uricosuric in clinical outcomes sometimes in
dysfunction and in patients drugs are either not available or months only whereas oral agents
with GFR less than 30 ml/min. have limited availability in India. may take years. 36
hypersensitivity is rarely reported. Most common adverse reactions
Pre-requisites of using Uricosuric ULT
Febuxostat Versus Allopurinol are gout flares, infusion related
Renal function should be normal
As a non-competitive XOI, reactions, headache (11%) and
(creatinine clearance >50 ml/
Febuxostat has several theoretical nausea (7%). Antibody develop in
advantages over the competitive nearly 90 percent of those receiving
Urate excretion should be <800 the active drug associated with loss
XOI allopurinol, including greater
mg/24 hours. of efficacy and increased infusion
potency, specificity and a reduced
reliance on renal excretion. There should be no evidence of reactions.
urolithiasis. Other ULT, such as
Advantage of febuxostat over
allopurinol is that it can be used Probenecid allopurinol and febuxostat, should
without dose-adjustment or concern It is drug of choice among all the not be given to patients receiving
over toxicity in patients with CKD uricosuric drugs. Its half life is 3-8 pegloticase, because they may
with GFR >30 ml/min although mask recognition of rising SUA
62 Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015

Table 3: Uricosuric Drugs Table 4: Modifications in the treatment of gout according to co-morbid conditions
Uricosuric Starting Maximum Co-morbid conditions Contraindication/caution
drug dose/day dose/day Moderate to severe CKD NSAIDs, COX-2 inhibitors, colchicines
Probenecid 500 mg 2000 mg Congestive heart failure NSAIDs, COX-2 inhibitors
Benzbromarone 50 mg 200 mg Peptic ulcer diseas NSAIDs, COX-2 inhibitors, CS
Sulfinpyrazone 200 mg 800 mg Diabetes mellitus Corticosteroids
Losartan 50 mg 100 mg Ongoing infection or high risk of Corticosteroids
Fenofibrate 200 mg infection
Hepatic disease NSAIDs, COX-2 inhibitors, colchicines, febuxostat
levels which suggests antibody With anticoagulants/antiplatelet therapy NSAIDs
formation. Hypertension β Blockers, ACE inhibitors and ARB (other than
Newer Urate Lowering Drugs losartan)
Prefer losartan or calcium channel blockers as these
are uricosuric
I n h i b i t s U R AT 1 a n d O AT 4
(organic anionic transporter 4) suffered a stroke; the prevalence References
in renal tubule. Phase III studies of these comorbidities increased
with the degree of hyperuricemia, 1. Saag KG, Mikuls TR, Abbott J. The
have shown that it can be given Epidemiology of Gout and Calcium
as monotherapy to those who are supporting the notion that serum
Pyrophosphate Dihydrate Deposition
intolerant to XOI, or in combination urate is related to the presence Disease in: Wortmann RL ed. Crystal-
with allopurinol or febuxostat. 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 , induced arthropathies: gout, pseudogout
either as a marker of disease or and apatite-associated syndromes. Taylor
Ulodesine and Francis 2006; 7-36.
perhaps by itself exacerbating other
Oral, once daily novel purine diseases. 37 These co-morbidities 2. Aromdee E, Michet C, Crowson C, O’Fallon
nucleoside phosphorylase inhibitor should be managed judiciously M, Gabriel S. Epidemiology of gout: is
which blocks production of uric (Table 4).
the incidence rising? J Rheumatol 2002;
acid at the step higher than xanthine 29:2403–2406.
Hypertension should be
oxidase inhibition. Phase 2 trials 3. Wallace KL, Riedel AA, Joseph-Ridge N,
managed preferably by Losartan Wortmann R. Increasing prevalence of gout
have been going on with this drug.
and calcium channel blockers as and hyperuricemia over 10 years among
both increase uric acid excretion. older adults in a managed care population.
T h i s U LT h a s a l s o b e e n Other antihypertensives like J Rheumatol 2004; 31:1582–7.
undergoing phase 2 trial. β-adrenergic blocking agents, 4. Choi HK , Mount DB, Reginato AM.
Pathogenesis of gout. Ann Intern Med
Arhalofenate and Tranilast angiotensin-converting enzyme
2005; 143:499.
Inhibits URAT1 and other urate inhibitors and angiotensin
5. Becker MA,  Jolly M. Clinical gout and
exchanger molecules and are II receptor blockers other than
the pathogenesis of hyperuricemia. In:
undergoing Phase I and II trials. losartan, increase SUA by reduced Koopman W.J., Moreland L.W., ed. Arthritis
Novel intestinal transporters of uric acid renal excretion. and Allied Conditions: A Textbook of
Rheumatology, (ed. 15) Lippincott Williams
In patients with CKD, total Hyperlipidemia and
and Wilkins Philadelphia, PA2005: 2303-39.
urinary uric acid falls and the hyperglycemia need to be managed
6. Anzai N, Jutabha P, Amonpatumrat-
principal burden of elimination aggressively as tight control of
Takahashi S, Sakurai H. Recent advances
shifts from the kidney to the each can independently reduce in renal urate transport: characterization
gut, there is upregulation of S U A l e ve l s t h r o u g h i m p r o ve d of candidate transporters indicated by
intestinal ABCG2 exporters, this renal excretion of uric acid. Agents genome-wide association studies. Clin Exp
decreasing insulin resistance also Nephrol 2012; 16:89-95.
has become an important area of
study to develop novel intestinal tend to reduce SUA levels. 38 7. Anzai, N Ichida K, Jutabha P, Kimura T, et al.
Plasma urate level is directly regulated by
transporters which may become
Conclusion a voltage-driven urate efflux transporter
an alternative for those at risk of URATv1 (SLC2A9) in humans. J Biol Chem
developing uric acid kidney stones Management of gout has 2008; 283:26834–26838.
with uricosuric agents. undergone major change in the last 8. Kam M, Perl-Treves D, Caspi D, Addadi L.
Managing Comorbidities couple of years. Proper control of Antibodies against crystals. FASEB J 1992;
In NHANES study of 5,707 SUA to less than 6.0 mg% (or lower
9. Russell IJ, Mansen C, Kolb LM, Kolb WP:
participants in the 2007-2008, 74% in presence of tophi) is the main aim
Activation of the fifth component of
had HTN, 71% had CKD stage 2 or with optimum management of co- human complement (C5) induced by
higher, 53% were obese, 26% had morbidities and patient education monosodium urate crystals: C5 convertase
diabetes, 24% had nephrolithiasis, are of paramount importance. assembly on the crystal surface. Clin
Immunol Immunopathol 1982; 24:239-250.
14% had myocardial infarction,
11% had heart failure, and 10% had 10. Po p e R M , Ts c h o p p J. Th e ro l e o f
interleukin-1 and the inflammasome in
Journal of The Association of Physicians of India ■ Vol. 63 ■ December 2015 63

gout: implications for therapy. Arthritis 2012 American College of Rheumatology 2012 American College of Rheumatology
Rheum 2007; 56:3183–3188. Guidelines for management of gout. Part guidelines for management of gout. Part 2:
11. Terkeltaub R, Zachariae C, Santoro D, Martin 1: Systematic nonpharmacologic and therapy and antiinflammatory prophylaxis
J, Peveri P, Matsushima K. Monocyte- pharmacologic therapeutic approaches of acute gouty arthritis. Arthritis Care Res
derived neutrophil chemotactic factor/ to hyperuricemia. Arthritis Care Res 2012; (Hoboken) 2012; 64:1447–1461.
interleukin-8 is a potential mediator of 64:1431-46.) 30. Stamp LK, Taylor WJ, Jones PB, et al.
crystal-induced inflammation. Arthritis 21. Filippucci E, Riveros MG, Georgescu Starting dose is a risk factor for allopurinol
Rheum 1991; 34:894-903. D, Salaffi F, Grassi W. Hyaline cartilage hypersensitivity syndrome: a proposed safe
12. Roberge CJ, de Medicis R, Dayer JM, Rola- involvement in patients with gout and starting dose of allopurinol. Arthritis Rheum
Pleszczynski M, Naccache PH, Poubelle calcium pyrophosphate deposition 2012; 64:2529–36.
PE. Crystal-induced neutrophil activation. disease: an ultrasound study. Osteoarthritis 31. Ryu H, Song R, Kim HW, Kim JH et al.
V. Differential production of biologically Cartilage 2009; 17:178–81. Clinical Risk Factors for adverse events in
active IL-1 and IL-1 receptor antagonist. J 22. Wright SA, Filippucci E, McVeigh C, Grey allopurinol users. J Clin Pharmacol 2012;
Immunol 1994; 152:5485-94. A, et al. High-resolution ultrasonography 53:211–216.
13. Tao JH, Zhang Y, Li XP. P2X7R: a potential of the first metatarsal phalangeal joint in 32. Arellano F, Sacristan J. Allopurinol
key regulator of acute gouty arthritis. Semin gout: a controlled study. Ann Rheum Dis hypersensitivity syndrome: a review. Ann
Arthritis Rheum 2013; 43:376-80. 2007; 66:859–64. Pharmacother 1993; 27:337–43.
14. Busso N, So A. Mechanisms of inflammation 23. Rettenbacher T, Ennemoser S, Weirich H, et 33. Becker MA, Schumacher HR Jr, Wortmann
in gout. Arthritis Res Ther 2010; 12:206. al. Diagnostic imaging of gout. Comparison RL, et al. Febuxostat compared with
of high-resolution US versus conventional allopurinol in patients with hyperuricemia
15. Schreiner, O, Wandel, E, Himmelsbach, X-ray. Eur Radiol 2008; 18:621–30.
F, Galle PR, Märker-Hermann E. Reduced and gout. N Engl J Med 2005; 353:2450-61.
secretion of proinflammatory cytokines 24. Choi HK, Burns LC, Shojania K, et al. Dual 34. Ogino, K Kato M, Furuse Y, et al. Uric acid-
of monosodium urate crystal-stimulated energy CT in gout: a prospective validation lowering treatment with benzbromarone in
monocytes in chronic renal failure: an study. Ann Rheum Dis 2012; 71:1466–1471. patients with heart failure: a double-blind
explanation for infrequent gout episodes 25. Singh JA, Reddy SG, Kundukulam J. placebo-controlled crossover preliminary
in chronic renal failure patients?. Nephrol Risk factors for gout and prevention: a study. Circ Heart Fail 2010; 3:73–81.
Dial Transplant 2000; 15:644. systematic review of the literature. Curr 35. Zhu X, Chen J, Han F, et al. Efficacy and safety
16. Chen CJ, Shi Y, Hearn A, et al. MyD88- Opin Rheumatol 2011; 23:192–202. of losartan in treatment of hyperuricemia
dependent IL-1 receptor signaling is 26. Terkeltaub RA. Novel evidence-based and posttransplantation erythrocytosis:
e s s e nt i a l fo r g o u t y i n f l a m m at i o n colchicine dose-reduction algorithm to results of a prospective, open, randomized,
stimulated by monosodium urate crystals. predict and prevent colchicine toxicity in case–control study. Transplant Proc 2009;
J Clin Invest 2006; 116:2262. the presence of cytochrome P450 3A4/P- 41:3736–3742.
17. Dalbeth N, Haskard D. Mechanisms of glycoprotein inhibitors. Arthritis Rheum 36. Sundy JS, Baraf HS, Yood RA, et al. Efficacy
inflammation in gout. Rheumatology 2005; 2011; 63:2226–37. and tolerability of pegloticase for the
44:1090–1096. 27. Schlesinger N. Treatment of chronic gouty treatment of chronic gout in patients
18. Pascual E, Battle-Gualda E, Martinez A, et arthritis: it is not just about urate-lowering refractory to conventional treatment: two
al. Synovial fluid analysis for diagnosis of therapy. Semin. Arthritis Rheum 2012; randomized controlled trials. JAMA 2011;
intercritical gout. Ann Intern Med 1999; 42:155–165. 306:711–20.
131:756–759. 28. Schlesinger N, De Meulemeester M, Pikhlak 37. Zhu Y, Pandya BJ, Choi HK. Comorbidities of
19. Zhang W, Doherty M, Pascual E, et al. A, et al. Canakinumab relieves symptoms gout and hyperuricemia in the US general
EULAR evidence based recommendations of acute flares and improves health-related population: NHANES 2007-2008. Am J Med
for gout. Part I: Diagnosis. Report of a quality of life in patients with difficult- 2012; 125:679-87.
task force of the Standing Committee for to-treat gouty arthritis by suppressing 38. Li C, Hsieh MC, Chang SJ. Metabolic
International Clinical Studies Including inflammation: results of a randomized, syndrome, diabetes, and hyperuricaemia.
Therapeutics (ESCISIT). Ann Rheum Dis dose-ranging study. Arthritis Res Ther Curr Opin Rheumatol 2013; 25: 210–216.
2006; 65:1301-11. 2011; 13:R53.

20. Khanna D, Fitzgerald JD, Khanna PP, et al. 29. Khanna D, Khanna PP, Fitzgerald JD, et al.