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63 ■ December 2015
update article
Uric Acid
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
erythromycin
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
Allopurinol
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
minute).
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
Lesinurad
are uricosuric
I n h i b i t s U R AT 1 a n d O AT 4
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