Definition:

Gout is a clinical disease associated with hyperuricemia and caused by the deposition of monosodium urate (MSU) crystals in and around the tissues, resulting in one or more of the following manifestations:

I- Acute gouty arthritis

II - Tophaceous gout

III- Gouty nephropathy

IV- Uric acid stones

Pathophysiology:

Because uric acid has limited solubility in bodily fluids, monosodium urate crystal formation occurs above the solubility threshold

Urate crystals are deposited preferentially in and around peripheral joints in the feet, knees, hands and elbows, especially those

affected by osteoarthritis

Metabolism of uric acid and risk factors for gout:

Pathogenesis

Pathophysiology:

Hyperuricaemia and gout: time for a new staging system?

Diagnosis:

Gout tophi :

X-ray of Gout:

US of Gout:

DECT of Gout:

The fundamental aims of gout treatment:

Improve outcomes by

short-term suppression

long-term elimination of gout flares

induce durable resolution of tophi

identify and effectively manage

comorbidities

2012 American College of Rheumatology

Guidelines for Management of Gout

(A)

Systematic Nonpharmacologic and Pharmacologic

Therapeutic Approaches to Hyperuricemia

Systematic Non pharmacologic & Pharmacologic therapeutic Approaches to Hyperuricemia:

Patient education on diet, lifestyle, treatment objectives,and management of comorbidities is a recommended core therapeutic measure in gout.

Xanthine oxidase inhibitor (XOI) therapy with either allopurinol or febuxostat is recommended as the first-line pharmacologicurate-lowering therapy (ULT).

The starting dosage of allopurinol should be no greater than 100 mg/day and less than that in moderate to severe chronic kidney disease (CKD), followed by gradual upward titration of the maintenance dose, which can exceed 300

Systematic Non pharmacologic and Pharmacologic therapeutic Approaches to Hyperuricemia:

Probenecid is the first choice among uricosuricagents for ULT monotherapy.

Use of agents other than probenecid with clinically significant uricosuric effects, such as fenofibrate andlosartan, can be therapeutically useful as components of a comprehensive ULT.

History of urolithiasis contraindicates first-line uricosuric urate-lowering monotherapy.

Combination oral ULT with XOI agent and uricosuricagent is appropriate when the target has not been met by appropriate dosing of an XOI.

Pegloticase is appropriate for patients with severe gout disease burden and refractoriness to, or

intolerance of, appropriately dosed oral ULT options

Serum urate lowering

agents:Xanthine oxidase inhibitors Allopurinol

Febuxostat

uricosuric agents: benzbromarone,

probenecid

sulfinpyrazone

Uricase therapies:

rasburicase, pegloticase

Xanthine oxidase inhibitors: The usual first-choice ULT, with allopurinol favoured over

febuxostat due to cost considerations and long-term safety data.

XOIs reduce endogenous production of uric acid by inhibiting the conversion of hypoxanthine to xanthine and of xanthine to uric acid.

Uricosuric drugs:

Act predominantly on urate anion exchanger 1 (URAT1) an organic anion transporter to 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 be advised to drink plenty of fluids and remain well-hydrated

Three uricosuric drugs are licenced and well-established as ULT: benzbromarone (50–200 mg daily), probenecid(250–500 mg twice daily) and sulfinpyrazone (200–800 mg daily)

Probenecid and sulfinpyrazone are contraindicated in patients with severe renal impairment or nephrolithiasis.

The availability of benzbromarone became limitedmainly due to concerns over reports of hepatotoxicity.

Uricase therapies:Uricase an enzyme that converts uric acid to highly soluble allantoin.

Pegloticase :

is a pegylated uricase that was recently licenced(2010 in the USA, 2013 in Europe) for use in ‘treatment-refractory’ gout. This drug is administered by repeated intravenous infusion (8 mg every 2 weeks )

Pegloticase is extremely effective at rapidly reducing SUA to very low levels for several weeks. However it is antigenic, with a risk of anaphylaxis and infusion reaction, so premedication with antihistamine and corticosteroids in an appropriately staffed facility is recommended. Concerns also remain over cardiovascular risk, and

Uricase therapies:Although pegloticase is seemingly very efficient at inducing rapid regression of tophi, the number of patients who are truly refractory to other standard ULTs is likely to be extremely small, and because of safety and tolerability concerns, and the cost and logistics of delivery of this drug, its use is likely to be very restricted.

Rasburicase: a uricase that has been licenced

for many years for tumour lysis prophylaxis, has also been used to treat ‘refractory’ gout where intolerance or renal impairment precludes the use of other ULTs.

However, although some patients seem to tolerate repeated doses, rasburicase is unlicenced for goutand is more antigenic than pegloticase

ULTs in development:

Other drugs that are undergoing clinical investigation as potential ULTs include

RDEA594 (lesinurad), which is a uricosuric,

BCX4208 (ulodesine), which is a purine nucleoside phosphorylaseinhibitor.

However, these agents are not yet available or licenced for use in gout, either as monotherapy or in

combination with an XOI

Asymptomatic hyperuricemia :

Asymptomatic hyperuricemia is the term applied to settings in which the serum urateconcentration is elevated but in which neither symptoms nor signs of urate crystal deposition (gout) have occurred.

Although gout may develop in a hyperuricemic individual at any point, it is likely that two-thirds or more of hyperuricemic individuals will remain asymptomatic

Antihyperuricemic drug therapy for the great majority of individuals with asymptomatic hyperuricemia is not justifiable by risk/benefit analysis

Treatment of Asymptomatic hyperuricemia : Persistent hyperuricemia in the infrequent

patients with sustained serum urateconcentrations greater than 13 mg/dL in men and 10 mg/dL in women .

This recommendation does not generally apply to patients with heart failure who may develop marked hyperuricemia due to renal hypoperfusion and to reduced urate excretion. Such patients typically have advanced heart failure with limited life expectancy and are, therefore, at low risk for chronic urate nephropathy.

Treatment of Asymptomatic hyperuricemia: Excretion of urinary uric acid in excess of

1100 mg (6.5 mmol) daily is associated with a 50 percent risk of uric acid calculi. Management of these individuals should begin with dietary purine restriction. Allopurinol should be used if dietary restriction does not reduce uric acid excretion to less than 1000 mg/day.

Patients about to receive radiotherapy or chemotherapy that is likely to result in extensive tumor cytolysis should be treated to prevent acute uric acid nephropathy and other manifestations of tumor lysis syndrome . Preventive therapy in patients at risk includes intravenous hydration and either

Diuretic-induced hyperuricemia&gout : Hyperuricemia is a relatively common finding in

patients treated with a loop or thiazide diuretic and may, over a period of time, lead to gouty arthritis. The degree of urate retention caused by diuretics is dose dependent .

Loop and thiazide diuretics decrease urateexcretion by increasing net urate reabsorption; this can occur either by :

1. A direct effect of diuretics on promoting uratereabsorption by the proximal tubule.

2. An indirect effect of diuretic-induced volume depletion on increasing urate reabsorption by the proximal tubule.

Diuretic-induced hyperuricemia&gout :

Diuretics may increase the relative risk of gout by nearly 80 percent; the absolute incidence of gout in patients taking diuretics may be close to 3 percent.

Treatment of diuretic-induced asymptomatic hyperuricemia is not necessary, even though the plasma urate concentration may exceed 15 mg/dL particularly in patients with reduced renal perfusion due to underlying advanced heart failure . These patients are not at risk of uric acid nephropathy since the elevation in the plasma urate level is due to an initial decrease in the rate of urate excretion.

Diuretic-induced hyperuricemia&gout : A diagnosis of gout is not necessarily an

indication for discontinuation of the diuretic, particularly if diuretic therapy is required for management of edema. However, if blood pressure control can be effectively and affordably achieved with an appropriate alternative agent, such as an angiotensin inhibitor or a dihydropyridine calcium channel blocker, then the diuretic can be stopped.

Most patients with diuretic-induced gout are treated with a urate-lowering drug such as allopurinol.

Among patients with hypertension, the concurrent administration of an ACE inhibitor or ARB can minimize the diuretic-induced rise in plasma urate concentration . This has been thought to be mediated by reversal of the stimulatory effect of angiotensin II on proximal sodium and urate reabsorption.

In addition, losartan may have a more direct uricosuriceffect, thereby inhibiting urate reabsorption and lowering the plasma urate concentration.

The combination of losartan or an ACE inhibitor with a thiazide has the added advantages of a more potent antihypertensive effect than seen with either drug alone and of minimizing other metabolic effects of the diuretic, such as hypokalemia and hyperlipidemia.

(B)

Therapy and anti-inflammatory Prophylaxis of Acute Gouty Arthritis

NSAID: An oral NSAID is by far the most commonly used

treatment for acute gout in general practice.

Because of the severity of pain experienced in acute gout, the NSAID should be commenced at its maximum dose, rather than titrating upwards from the lower end of the dose range.

Although some doctors still hold the traditional belief that indomethacin is more effective than other NSAIDs, studies comparing different quick-acting NSAIDs demonstrate their equal efficacy in acute gout.

Selective (COX)-2 inhibitors compare favourablywith nonselective NSAIDs for the treatment of acute gout in terms of similar efficacy but lower

incidence of serious gastrointestinal events.

Colchicine:

Colchicine: oral NSAIDs+ oral colchicine is recommended as a first-line

treatment for acute gout attacks.

current EULAR guidelines recommend a maximum dose of 0.5 mg colchicine three times a day

ACR guidelines recommend a regimen involving a loading dose of 1.2 mg then 0.6 mg 1 h later, followed after a further 12 h by 0.6 mg once or twice daily. Such low doses seem to be effective and well-tolerated in clinical practice. Even lower doses (0.5 mg once or twice daily) can be tried in patients with persistent adverse effects and in those with moderate to severe CKD.

Colchicine is considered to work best when commenced within 24 h of first symptoms of an acute attack

ACR guidelines recommend that colchicine is not initiated more than 36 h after symptom onset. Treatment is usually continued until the acute attack has subsided.

Corticosteroids :

Intra-articular corticosteroids Aspiration of an affected joint followed by injection of corticosteroids is ideal for treatment of acute gout attacks, particularly in a hospital setting where first-line use of this intervention can provide prompt relief with minimal adverse effects. This treatment is a particularly useful option where colchicine, NSAIDs or oral corticosteroids are contraindicated.

Oral corticosteroids :Oral prednisolone can be used where colchicine or NSAIDs are contraindicated or have failed to provide sufficient relief, this method of delivery of corticosteroids is the one most commonly used in general practice.

Intramuscular corticosteroids:single injection but, but there is no consensus on dose.

Biologic agents : Available biologic agents that inhibit IL-1 and

which have been assessed in treatment of acute attacks of gout specifically anakinra, canakinumaband rilonacept have either had no comparator or have been compared to a possibly suboptimal dose of triamcinolone (40 mg intramuscularly) rather than a more commonly used short course of oral prednisolone (for example, 30–35 mg prednisolone daily).

Modest advantages of biologic agents have been reported, but these treatments remain comparatively very expensive, and as yet are largely unlicenced for acute gout in most countries (canakinumab is now licenced for use in

europe, but not in the UK or USA).

Long-term management:

The aim of long-term therapy is to ‘cure’ gout by lowering SUA levels to below the saturation point for urate that is, to at least below (6 mg/dl)thus promoting crystal dissolution and preventing formation of new crystals.

The most effective method of achieving this SUA level is the use of urate-lowering therapy (ULT).

Indications for ULT include recurrent attacks of gout, clinically detectable tophi, joint damage or nephrolithiasis in other words, well-established and relatively severe gout.

References:

New Gout Management Guidelines: A Quick and Easy Guide Bret S. Stetka, MD; Jonathan Kay, November 19, 2012.

Optimizing current treatment of gout Rees, F. et al. Nat. Rev. Rheumatol. 10, 271–283 (2014)

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