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Gout is a common, chronic condition with an estimated prevalence of 2.5 per cent in the United Kingdom, almost 4 per cent in the United States, and epidemiological studies indicate that the global prevalence is increasing. The prevalence in Ireland has not been established but can be inferred from other populations. Effective therapeutic options are available for this condition, which are effectively curative when used correctly. Despite this, management is suboptimal internationally. In this article, we will discuss the diagnosis and treatment of gout and key areas for practice change.
The key pathophysiological process responsible for the clinical features of gout is the deposition of monosodium urate (MSU) crystals in the presence of hyperuricaemia (defined as a serum urate concentration (408μmol/L [6.8 mg/dL]), above which monosodium urate crystals form in vitro at physiological pH and temperature). After a period of asymptomatic hyperuricaemia, crystal deposition occurs in joints and other tissues. An acute flare may occur due to an inflammatory response initiated by resident macrophages. Chronic tophaceous gout occurs after years of untreated hyperuricaemia. Tophi represent a chronic granulomatous response to MSU crystals. Progression throughout these stages is not inevitable.
Most people with hyperuricaemia do not have gout and one study reported visible tophi in only 55 per cent after 20 years of gout.
A 43-year-old male presented to our rheumatology outpatient clinic for assessment. He had been diagnosed with gout nine years previously at another rheumatology clinic following an episode of podagra. He was prescribed allopurinol at that time, but took it only briefly and did not present for follow-up. In the subsequent years, he experienced recurrent gouty attacks, which increased in frequency and severity with time. During the preceding four months, he had required three courses of oral steroids for acute flares of gout. He began taking his father’s allopurinol two weeks prior to presentation at our clinic.
His current drug therapy was allopurinol at an unknown dose and diclofenac 50 milligrams three times daily. He had a positive family history of gout and drank 15 pints of beer every Sunday. He expressed dissatisfaction with his previous rheumatologist for having not helped him. Examination revealed numerous tophaceous deposits on the fingers, grossly enlarged olecranon bursae, restricted movement of the subtalar joints and bilateral hallux rigidus.
Diagnosis was confirmed by aspiration of a tophus and visualisation of numerous negatively bifringent crystals by polarised light microscopy. The serum urate was 550μmol/L. He was advised that he needed to adhere to urate-lowering therapy indefinitely and that the target serum urate should be, in his case, approximately 300μmol/L. He was also advised that he should take colchicine 0.5mg twice daily for a minimum of six months as prophylaxis against acute gout attacks in the short term. He was advised to avoid binge-drinking alcohol.
Presentation and diagnosis
Gout presents with an acutely painful inflamed joint, typically of the foot or ankle. Pain is severe, and usually peaks within 24 hours and physical examination will reveal a swollen, erythematous and extremely tender joint. Flares may be triggered by acute medical illness, surgical procedures, dehydration, use of diuretics or excess alcohol intake. Patients who present later in the course of disease may have polyarticular flares or chronic joint pain with tophi or joint deformity on examination. Some patients will experience a polyarticular attack at their first presentation. Tophi are generally painless but can become acutely inflamed, ulcerate or discharge a chalky white substance.
There are both genetic and environmental risk factors for gout, which relate to urate metabolism and resultant hyperuricaemia. These include male sex, increasing age, drugs such as thiazide diuretics, low-dose aspirin, angiotensin-converting enzyme inhibitors, cyclosporine and tacrolimus, high dietary intake of red meat, seafood, alcohol or fructose. Under-excretion is the dominant cause of hyperuricaemia in patients with gout. Patients will often report a positive family history of gout and a number of genetic loci that affect urate level have been identified through genome-wide studies. The factors which dictate why hyperuricaemia leads to crystal deposition, acute flares and tophi development in some individuals but not others remain poorly understood.
Accurate diagnosis is the first element of adequate gout care. The gold standard is the visualisation of negatively birefringent, needle-shaped crystals on polarised light microscopy, usually in synovial fluid aspirated from an inflamed joint but may also be found in fluid from a previously inflamed joint or tophaceous material. In practice, joint aspiration is not always feasible, particularly for primary care practitioners who may not have access to polarising light microscopy. Serum urate level should be measured in all cases. Importantly, serum urate concentrations can fall into the normal range during an acute flare and if gout diagnosis is uncertain, serum urate should be retested after the flare has resolved. Plain radiographs are generally unremarkable in early disease, with the exception of soft tissue swelling. Characteristic ‘punched-out’ lesions with an overhanging rim are a sign of bony erosion and more advanced disease. Ultrasound and dual energy CT are more useful modalities but still have limited sensitivity and specificity.
The most important differential diagnosis to consider is septic arthritis, and if this is clinically suspect, patients should be referred for aspiration with gram stain and culture. Other differential diagnoses to consider are calcium pyrophosphate crystal arthritis, psoriatic arthritis and reactive arthritis. Misdiagnosis does occur and referral to a specialist clinic should be considered, especially where there are atypical features. A diagnostic rule has been developed and validated to assist those without access to joint fluid analysis in accurate diagnosis.
Optimal gout management involves the treatment and prevention of acute flares, administration of urate-lowering therapy (ULT), monitoring of serum urate level, screening and treatment of comorbid conditions and patient education.
Options for treatment of an acute flare are colchicine, NSAIDs or intra-articular or systemic corticosteroids. Treatment should ideally be commenced within 24 hours of onset of the flare. American College of Rheumatology (ACR) guidelines do not rank one class above the other.
Lowering the serum urate to a level at which dissolution of MSU crystals can occur is essential in treating and preventing progression of gout. ACR guidelines recommend commencing ULT in those with more than one acute attack per year, tophi, chronic kidney disease stage 2 or worse, or those with previous urate kidney stones.
Recurrent attacks are common, —one study found approximately two-thirds of patients with documented gout had recurrent attacks, but studies have shown ULT is prescribed only in a minority of patients, indicating gaps in healthcare provider knowledge of this disease. In a nationwide UK cohort study, only one-third of those with prevalent gout were prescribed ULT. Both ACR and the European League against Rheumatism (EULAR) guidelines recommend achieving a serum urate level of <360μmol per litre, a level at which crystal dissolution can occur, in all patients and state that lower targets (300μmol/L) may be beneficial in severe disease to promote more rapid tophi regression.
Treating-to-target requires regular monitoring and appropriate titration of ULT dose. Suggested monitoring intervals are every two-to-five weeks until target serum urate level is achieved, and six-monthly thereafter. Annemans et al found that less than 1 per cent of patients in both German and UK primary care cohorts had testing performed annually. In a survey of Irish GPs, only 32 per cent reported routinely monitoring urate levels. In the United States, 49 per cent of those receiving ULT had serum urate levels >360μmol/litre.
A xanthine oxidase inhibitor is recommended as first-line therapy and in practice, allopurinol is the drug of choice. The most potentially serious adverse effect of therapy is allopurinol hypersensitivity syndrome (AHS), a rare complication whose spectrum of disease includes eosinophilia, hepatitis, Stephen’s Johnson syndrome, toxic epidermal necrolysis, renal impairment and vasculitis. The syndrome usually occurs within the first eight weeks of treatment and risk factors include renal impairment, diuretic use and the HLA-B*5801 allele.
Due to an association between high starting doses and AHS, consensus guidelines advocate a starting dose of no more than 100mg once daily or 50mg once daily in Stage 4 renal failure or above and increasing the dose every two-to-five weeks. Providing ongoing monitoring for drug hypersensitivity, elevated transaminases and eosinophilia, dosing can be increased beyond standard 300mg/day maintenance dosing in those who fail to reach treatment target at this dose, even in the setting of renal impairment.
Febuxostat is an alternate xanthine oxidase inhibitor that may be used, especially in those that do not tolerate allopurinol. Second-line treatments are uricosurics probenecid and benzbromarone, and recombinant uricase pegloticase. Neither benzbromarone or pegloticase are available in Ireland.
Prophylactic therapy is necessary when commencing ULT, as there is an increased risk of acute flares. A minimum of six months of prophylaxis should be used, but in advanced disease, much longer may be required and treatment should continue while there is any ongoing evidence of active disease, such as tophi or recent flares. Colchicine is the first-line treatment for prophylaxis.
A low-dose regimen of 0.5mg twice daily is preferred, as there are lower rates of gastrointestinal disturbance. Dose reduction should be considered in renal impairment and caution used in hepatic impairment or with concomitant use of CYP34A inhibitors (diltiazem, clarithromycin) or p glycoprotein inhibitors (cyclosporin).
In addition to suboptimal prescribing practices, patient adherence to gout therapy is poor and worse than many other common chronic diseases. Kuo et al estimated patient adherence to ULT at 40 per cent, and similar rates have been found in other studies. Promotion of patient adherence is a further benefit of serum urate monitoring, but patient understanding of the rationale of long-term ULT, prophylactic therapy and prompt treatment of flares are crucial. Gaps in patient knowledge have been identified and there is evidence that treatment targets can be met when patients are adequately informed. Further trials of multidisciplinary-led programmes for gout management, including cost-benefit analysis, are warranted.
Gout is associated with a number of diseases including diabetes, hypertension, chronic kidney disease and obesity. Gout in itself is associated with an increased risk of mortality. Screening tests including serum creatinine, fasting glucose, HbA1c and lipid profile, and subsequent appropriate treatment are important in improving patient outcome. However, experts caution against an undue emphasis on the role of lifestyle changes in treating gout itself, as this can take away from the importance of ULT and reinforce negative stereotypes of the disease. While dietary interventions have shown positive effects in serum urate in healthy controls, there is no evidence of benefit in established gout.
Despite major progress in the understanding of pathogenesis and therapeutic advances, the prevalence of gout is increasing and many patients have poorly-controlled disease. Gout is a treatable disease and the strategy of long-term lowering of serum urate concentrations is highly effective in removing monosodium urate crystals. Furthermore, current evidence suggests that effective treatment of gout can reduce mortality and improve quality of life. Enhanced physician and patient education in relation to gout are needed.
References available on request