Rules of engagement: turning recommendations into results in the diagnosis and management of gout

Gout is one of the first recognizable diseases to appear in medical writing,1 and one of the earliest in which the pathological basis was characterised,2 yet the management of this disease is still fraught with out-dated practices, often based more on tradition than empirical evidence. Recent clinical research is beginning to cast light on this therapeutic area, with an evidence-based colchicine regimen replacing its toxic predecessor3 and treat-to-target approaches to the prescription of allopurinol that are not hamstrung by arbitrary restrictions based on renal function.4 Allopurinol is a xanthine oxidase inhibitor (XOI) used as a urate-lowering therapy (ULT) for over 40 years and remains a first-line and the most widely used ULT. Febuxostat is a non-purine selective XOI, approved for use as a ULT in 2009. Febuxostat is more effective than fixed-dose allopurinol in reaching target serum urate5 and is also recommended as first-line ULT.6, 7 In practice, people with gout are frequently not prescribed ULT or, if treated, fail to reach target serum urate of < 0.36 mmol/L.8-10 Failure to reach urate targets is influenced by both prescriber and patient behaviors but inadequate dosing of allopurinol is a major contributor.11, 12 Historically, a reduced maximal dose of allopurinol was recommended in people with renal impairment due to perceived risk of allopurinol hypersensitivity syndrome (AHS). AHS is a rare severe cutaneous and systemic adverse reaction with an incidence of 0.1–0.4% but has an estimated mortality of 25%.13 A large case-control study has demonstrated that the starting dose of allopurinol is the key risk factor for AHS14 and all guidelines now recommend starting allopurinol at a low dose with titration until target serum urate is reached. Furthermore, an allopurinol dose escalation study has shown that, even in renal impairment, a cautious increase in allopurinol dose beyond the previously recommended maximum is generally well tolerated, safe and beneficial.4 Carriage of the human leukocyte antigen (HLA)-B*5801 allele has been identified as markedly increasing the risk of AHS.15 Therefore, testing for HLA-B*5801 has been recommended before treatment with allopurinol in population groups with higher allele frequencies, including Han Chinese, Thai and Koreans with stage 3 or worse renal impairment and, if positive, an alternative ULT should be used.6 Probenecid, a uricosuric agent, is an alternate first-line ULT where renal function is preserved, XOIs are contraindicated or not tolerated, and there is no history of nephrolithiasis.6, 7, 16 Used optimally these three ULT alternatives are likely to provide effective serum urate control in the majority of cases. There are a number of ULT agents under development, which include lesinurad (selective inhibitor of the URAT1 transporter in the distal renal tubule), RLBN1001 (mixed actions of moderate XOI and potent inhibitor of URAT1) and arhalofenate (a uricosuric agent with possible anti-inflammatory actions), which may ultimately provide alternative strategies for ULT suitable for all patients.17 The demonstration of monosodium urate crystals in synovial fluid or tissue deposits remains the gold standard of diagnosis, and point-of-care ultrasound has been shown to improve the diagnostic yield of arthrocentesis.18 The ultrasonographic features of gout are being validated and dual-energy computed tomography shows promise as a means of imaging urate crystal deposits.19 These imaging modalities have the potential to improve the accuracy of diagnosis and to allow quantification and monitoring of tophus burden during ULT. In spite of these advances, observational studies of the management of gout in primary and secondary care have shown that there is discordance between recommendations and practice.9, 20 Given that the majority of gout cases are seen outside rheumatology services, the value of these advances may not be realised unless they are adopted by the wider medical community. Leadership from rheumatologists will help disseminate these messages, and guidelines are good reference points for educating clinicians. A number of guidelines for management of gout have been published over recent years by the major rheumatology professional bodies, including the British Society of Rheumatology 2007,21 the European League Against Rheumatism (EULAR) in 200616 and the American College of Rheumatology (ACR) in 2012.6, 22 These have been evidence-based and the recommendations based on the literature have been made by expert groups, appointed by the professional societies. In this issue, Graf et al.23 report on the Australia and New Zealand component of the Multinational Evidence, Expertise, Exchange Initiative (3e initiative) to develop evidence-based recommendations for the diagnosis and management of gout. These recommendations were generated by the 47 participating Australian and New Zealand rheumatologists using a systematic literature review and a Delphi process. They provide a concise summary of best practice management of gout in the form of 11 recommendations: the 10 identified questions from the international gout 3e initiative and an additional question of local relevance. Two recommendations refer to the diagnosis of gout, six focus on different aspects of the management of gout (including drug treatment and monitoring), one recommendation refers to the management of asymptomatic hyperuricemia, one is related to lifestyle advice, and the local recommendation addresses screening for co-morbidities.23 Overall the Australian and New Zealand gout 3e recommendations do not differ markedly from the earlier professional society guidelines. The key messages across all guidelines include: the demonstration of urate crystals in synovial fluid or tophi for a definitive diagnosis of gout; nonsteroidal anti-inflammatory drugs, colchicine or glucocorticoids for treatment of acute gout according to patient co-morbidities and preference; initiation of allopurinol at low doses in individuals with gout, in combination with prophylaxis against gout flare; and optimisation of ULT until a target serum urate is achieved. The Australian and New Zealand 3e guidelines clearly recommend against ULT in people with asymptomatic hyperuricemia and strongly recommend ULT in individuals with tophi but give no definite guidance about when ULT should be initiated between those extremes of the natural history. Perhaps the 3e guidelines are wise to leave the exact timing of initiation of ULT to a decision between doctor and patient. The EULAR guidelines encourage negotiation of timing of initiation ULT in intercritical gout16 while the ACR guidelines do suggest ULT is initiated when gout attacks occur more than twice per year,6 as do the British Society for Rheumatology guidelines.21 Guidelines and recommendations are useful resources, but adherence to treatment is critical to successful treatment and patient behavior is at least as important as prescriber behavior. Poor adherence to treatment is a particular problem in gout,24 and gout patients report low levels of knowledge about treatment rationale and desire for more information and longer interactions with their doctors.25, 26 In a cross–sectional study, adherence with ULT was positively associated with a greater perceived understanding of gout.27 Significant progress has been made in the management of this ‘treatable’ disease, and yet gout continues to be a common reason for hospital admission and a significant cause of disability. Considerable time and effort will need to be invested in the education of clinicians and patients before we will come close to mastering this ancient disease.