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Getting a grip on gout

Gout is the most common form of inflammatory arthritis in men over 40 years of age, often presenting initially in the form of podagra (acute onset of pain, erythema and swelling of the first metatarsophalangeal joint). Women may develop gout later in life, and in women it is more likely to involve the upper extremities.

The lifetime prevalence of gout in the United States has been estimated at 6.1 million and studies in the UK have reported a prevalence approaching 7 per cent. Hyperuricaemia is significantly more prevalent. For example, it is now present in as many as 25 per cent of people (defined as serum urate >360μmol/l in men and women, respectively). The prevalence of gout and hyperuricaemia has been increasing over the past few decades in response to a number of factors.

An elevated serum uric acid (SUA) level is perhaps the most highly correlated laboratory value with the metabolic syndrome, which is a concern with global westernisation of diet, increasing access to high-calorie foods and greater prevalence of obesity. Increasing life expectancy and use of predisposing medications, such as diuretics, may also contribute to this trend. Recent evidence suggests that the intake of fructose in beverages and foods, which has also increased worldwide, may increase the risk of both metabolic syndrome and gout.

As a result of this global trend, it will be important to establish the wide use of safe, inexpensive and effective approaches to prevent and treat gout worldwide. Close attention to risk factors for gout such as a high-purine diet, alcohol use, obesity, diabetes and kidney disease will be important in preventing and controlling an epidemic of hyperuricaemia and gout, but it is unlikely to be sufficient.

Quality of life

Patients with acute gout experience significant pain and swelling, which can severely impair quality of life (QoL). Long-term complications from gout can also impair QoL, as patients may develop chronic, debilitating arthritis and loss of function. Using a variety of distinct validated measures, patients with gout have been shown to experience a significant overall reduction in QoL.

Gout is also associated with healthcare and economic costs. Care of chronic gout represents approximately 6 per cent of a patient’s all-cause yearly healthcare costs. A diagnosis of gout is independently associated with higher medical and arthritic comorbidity, as well as higher utilisation of healthcare. Gout is also associated with significant costs to employers. Patients with gout use more absence days and are less productive. This observation again underscores the need for inexpensive but effective means of prevention and treatment.

Recommendations

This situation prompted the elaboration of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006, which were based on a systematic literature review (SLR) and expert opinion.

Since 2006, our knowledge of the pathophysiology of the disease has improved greatly and the field of gout management has advanced quickly. When the first EULAR recommendations were produced, the number of drugs available for gout treatment was limited and the main urate-lowering therapy (ULT) was allopurinol. Since then, a number of new drugs have become available or are in late-stage development, including febuxostat, pegloticase, interleukin-1 (IL-1) blockers and lesinurad.  Moreover, additional data on established drugs such as colchicine and allopurinol have been published and studies have repeatedly identified increased cardiovascular mortality with gout.

Therefore, the indications for old and new drugs needed to be clarified and novel therapeutic strategies recommended on the basis of their availability, the patient profile, previous drug failure and benefit/risk ratio, as well as the cost of the various drugs now available for the treatment of flare and for lowering urate levels. For this purpose, a taskforce was convened to update the 2006 EULAR recommendations for the management of gout, with the objective of addressing all overarching principles and individual recommendations by expert and patient opinion.

Final set of 11 recommendations on treating patients with gout

Acute flares of gout should be treated as early as possible. Fully informed patients should be educated to self-medicate at the first warning symptoms. The choice of drug(s) should be based on the presence of contraindications, the patient’s previous experience with treatments, time of initiation after flare onset and the number and type of joint(s) involved.

Recommended first-line options for acute flare are colchicine (within 12 hours of flare onset) at a loading dose of 1mg, followed one hour later by 0.5mg on day one and/or an NSAID (plus a proton pump inhibitor if appropriate), oral corticosteroids (30-35mg/day of equivalent prednisolone for three-to-five days) or articular aspiration and injection of corticosteroids. Colchicine and NSAIDs should be avoided in patients with severe renal impairment. Colchicine should not be given to patients receiving strong P-glycoprotein and/or CYP3A4 inhibitors, such as cyclosporin or clarithromycin.

In patients with frequent flares and contraindications to colchicine, NSAIDs and corticosteroids (oral and injectable) IL-1 blockers should be considered for treating flares. Current infection is a contraindication to the use of IL-1 blockers. ULT should be adjusted to achieve the uricaemia target following IL-1 blocker treatment for flare.

Prophylaxis against flares should be fully explained and discussed with the patient. Prophylaxis is recommended during the first six months of ULT. Recommended prophylactic treatment is colchicine, 0.5-1mg/day, a dose that should be reduced in patients with renal impairment. In cases of renal impairment or statin treatment, patients and physicians should be aware of potential neurotoxicity and/or muscular toxicity with prophylactic colchicine. Co-prescription of colchicine with strong P-glycoprotein and/or CYP3A4 inhibitors should be avoided. If colchicine is not tolerated or is contraindicated, prophylaxis with NSAIDs at a low dosage, if not contraindicated, should be considered.

ULT should be considered and discussed with every patient with a definite diagnosis of gout from the first presentation. ULT is indicated in all patients with recurrent flare (twice or more per year), tophi, urate arthropathy and/or renal stones. Initiation of ULT is recommended close to the time of first diagnosis in patients presenting at a young age (less than 40 years), or with a very high SUA level (>8mg/dL; 480µmol/L) and/or comorbidities (renal impairment, hypertension, ischaemic heart disease, heart failure). Patients with gout should receive full information and be fully involved in decision-making concerning the use of ULT.

For patients on ULT, SUA level should be monitored and maintained to <6mg/dL (360µmol/L). A lower SUA target (<5mg/dL; 300µmol/L) to facilitate faster dissolution of crystals is recommended for patients with severe gout (tophi, chronic arthropathy, frequent attacks) until total crystal dissolution and resolution of gout. SUA level <3mg/dL is not recommended in the long term.

All ULTs should be started at a low dose and then titrated upward until the SUA target is reached. SUA <6mg/dL (360µmol/L) should be maintained life-long.

In patients with normal kidney function, allopurinol is recommended for first-line ULT, starting at a low dose (100mg/day) and increasing by 100mg increments every two-to-four weeks, if required, to reach the uricaemic target. If the SUA target cannot be reached by an appropriate dose of allopurinol, allopurinol should be switched to febuxostat or a uricosuric, or combined with a uricosuric. Febuxostat or a uricosuric are also indicated if allopurinol cannot be tolerated.

In patients with renal impairment, the allopurinol maximum dosage should be adjusted to creatinine clearance. If the SUA target cannot be achieved at this dose, the patient should be switched to febuxostat or given benzbromarone with or without allopurinol, except in patients with eGFR <30mL/min.

In patients with crystal-proven, severe, debilitating chronic tophaceous gout and poor quality of life, in whom the SUA target cannot be reached with any other available drug at the maximal dosage (including combinations), pegloticase is indicated.

When gout occurs in a patient receiving loop or thiazide diuretics, substitute the diuretic if possible; for hypertension, consider losartan or calcium channel blockers; for hyperlipidaemia, consider a statin or fenofibrate.

Overarching principles

A. Every person with gout should be fully informed about the pathophysiology of the disease, the existence of effective treatments, associated comorbidities and the principles of managing acute attacks and eliminating urate crystals through life-long lowering of SUA below a target level.

B.  Every person with gout should receive advice regarding lifestyle — weight loss if appropriate and avoidance of alcohol (especially beer and spirits) and sugar-sweetened drinks, heavy meals and excessive intake of meat and seafood. Low-fat dairy products should be encouraged. Regular exercise should be advised.

C.  Every person with gout should be systematically screened for associated comorbidities and cardiovascular risk factors, including renal impairment, coronary heart disease, heart failure, stroke, peripheral arterial disease, obesity, hyperlipidaemia, hypertension, diabetes and smoking, which should be addressed as an integral part of the management of gout.

Proposals for future research

Investigating the ability of low-dose NSAIDs or prednisone to prevent ULT-induced flares.

A head-to-head trial of anakinra versus a conventional anti-inflammatory agent for the treatment of flares.

A controlled trial of early low-dose colchicine versus early NSAIDs or oral corticosteroids or potential new drugs for flares over one week.

The optimal combined therapy for treatment of an acute attack.

The optimal duration for prophylaxis of acute attacks when starting ULT.

Risk factors for flares when initiating ULT.

The long-term impact of very low urate levels on the central nervous system.

The possible benefits of XO inhibition and/or lowering serum uric acid levels for cardiovascular diseases.

The impact of ULT on kidney function.

The best strategy in patients with tophaceous gout.

Direct comparison (efficacy, side-effects, cost utility) between emerging uricosurics and allopurinol or febuxostat.

The cost-utility of HLA-B*58:01 (an allele) determination before initiating allopurinol in patients not of Asian descent.

Imaging to visualise crystal dissolution during ULT.

More research should be conducted in primary care.

These updated EULAR recommendations aim to provide physicians — rheumatologists, GPs and others — with the best pragmatic strategies to manage hyperuricaemia and flare in patients with gout.

As first-line care providers, GPs have a predominant role in gout treatment. Likewise, the involvement of patients in the management of chronic diseases is crucial. Overall, this set of recommendations was well graded by external GPs and rheumatologists.

These novel EULAR recommendations will undoubtedly require updating over the next few years. Indeed, it is anticipated that new data on existing drugs or emerging drugs, in particular novel uricosurics, will be available soon. In addition, studies of therapeutic strategies are likely to emerge. Hopefully, these pragmatic recommendations will improve the current quality of gout care.

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