Chronic gout: Barriers to effective management

Transcription

1 Chronic gout: Barriers to effective management Sylvie Rogenmoser, Mark H Arnold Background Gout is one of the most common inflammatory arthropathies, and the pathogenesis is well understood. In Australia, most patients with chronic tophaceous gout (CTG) are treated by general practitioners (GPs). Urate-lowering therapy, if adhered to continuously, can suppress the disease, reduce the likelihood of flares and prevent long-term complications such as disfiguring tophi and joint damage. Many rheumatology societies recommend a treat-to-target (T2T) approach, lowering serum urate to 0.35 mmol/l or below with urate lowering therapy. Objectives The aim of this article is to discuss inconsistencies in treatment guidelines, identify patient and physician barriers to optimal gout care, explain why a T2T approach is appropriate and make a series of recommendations that are practical for GPs. Discussion Despite an in-depth understanding of this controllable disease and the availability of simple, safe treatments, chronic gout remains poorly managed. The development of Australian gout guidelines that are easily implemented by GPs is vital and overdue. THE PREVALENCE OF medically diagnosed gout in adult Australians may be as high as 5.2%. 1 The pathogenesis of gout is clearly understood. Risk factors include increasing age, genetic factors, purine-rich foods, alcohol, diabetes and diuretic use. 2 Gout often recurs and, when inadequately treated, may progress to chronic tophaceous gout (CTG) and joint damage. Gout is associated with metabolic syndrome, nephrolithiasis, cardiovascular disease and chronic renal impairment. Hyperuricaemia and gout have been associated with increased risk of cardiovascular events in a variety of populations; 3 9 urate-lowering therapy either has no increase in risk, 10 or may lower risk, 4 of cardiovascular events. Treatments indicated in the management of chronic gout include education, diet and lifestyle changes, pharmacotherapy for acute flares and long-term urate-lowering therapy for repeated episodes and CTG. Urate-lowering therapy optimally reduces serum uric acid levels below the solubility constant for urate (48 µmol/l or 6.8 mg/dl) and, with long-term adherence, may place the patient in remission from gout and resolve tophi. 11 Therapy is effective when adhered to; however, adherence in chronic gout is the lowest among seven chronic diseases. 12 Excepting the American College of Physicians statement, 13 evidence-based guidelines for gout are rheumatologistgenerated and disseminated in rheumatology journals. Patients with gout are typically managed longitudinally by general practitioners (GPs), 14 who are often underexposed to this literature. The current article documents: inconsistencies in the levels of evidential support in current guidelines contributing to uncertainty in treatment patient and physician barriers to optimal gout care, and suggested approaches practical for Australian GPs to overcome these barriers. Literature search strategy Searches were performed on Medline and PubMed using the terms gout, hyperuricaemia, hyperuricemia, tophi, monosodium urate, therapy, management, treatment and all possible synonyms. Search strings are detailed in Figure 1. Guidelines analysed in this review included those of the American College of Physicians (ACP), 13 the European League Against Rheumatism (EULAR), 15 the Multinational Evidence, Expertise, Exchange Initiative, 16 the American College of Rheumatology (ACR), 17 the British Society of Rheumatology (BSR) 18 and the 2015 Australian and New Zealand recommendations. 19 The 2017 Australian Therapeutic Guidelines 20 were not accessible in this search strategy but are commented on later. Practice guidelines Major guideline inconsistencies are presented in Table 1. Gaps exist in relation to the definition of severe gout when considering the presence or absence of tophi, frequency of attacks, number of affected joints and the balancing of comorbidities in treatment decisions. The varying levels of evidential strength in existing guidelines led to the proposition in the ACP guidelines that the absence of high-quality evidence supporting a treat-to-target (T2T) approach means a treat-to-avoid-symptoms (TTS) approach is more supportable. This major discrepancy between a generalist versus a The Royal Australian College of General Practitioners 2018 REPRINTED FROM AJGP VOL. 47, NO. 6, JUNE

2 CHRONIC GOUT: BARRIERS TO EFFECTIVE MANAGEMENT sub-speciality perspective implies that the absence of (strong) evidence indicates lack of efficacy; this does not reflect clinical practice realities. Physician barriers to care Although 50% of patients with gout may see a rheumatologist, 14 GPs are mostly responsible for ongoing care. Treatment regimens are often insufficient to control attacks of gout or prevent complications; less than 30% of patients undergo serum uric acid monitoring and of those, only 33% achieve the target serum uric acid. 21,22 Typically, patients remain on the starting dose of allopurinol without titration to achieve the target serum uric acid. 23 To achieve target serum uric acid, the allopurinol dosage can be increased to 600 mg daily (very rarely higher), or a uricosuric agent can be added. Before doing so, it must be ascertained that the patient is adherent; if not adherent to the medication regimen, this approach is futile. Qualitative studies reveal that clinicians believe they have the knowledge and 182 articles identified through database searching 98 articles limited to past five years 98 titles and abstracts screened 28 full-text articles assessed Full-text article reference lists screened; 15 additional references included 43 articles included, seven of which were guidelines or recommendations Figure 1. Search strategy skills to educate patients with gout; however, many patients report uncertainty regarding its causes and treatment. 24 Patient barriers to care Up to 57% of patients with chronic gout are non-adherent to the medication regimen; 70% have interrupted therapy; and long term adherence is lowest in younger males of lower socioeconomic status without comorbidities and with fewer acute flares. 23,25 27 Most non-adherence is purposeful, due to clinical/financial factors rather than forgetfulness. 24 Patients cite concerns regarding side effects and medication interactions; acute attacks and pain are the main drivers for adherence. 28 Patients may believe that without acute flares, urate lowering therapy drugs need not be taken continuously. Patients may also report that potential complications of gout have not been explained, and have a poor understanding that gout is an arthritis. 29 Patients typically believe that gout is a self-inflicted consequence of ageing 70 articles excluded based on title and abstract: Non-English language Non-human studies Paediatric studies Abstract-only reference Opinion pieces Duplicate record and are reluctant to seek medical advice. Qualitative evidence suggests that some men hesitate to seek help despite intense pain. 30 Discussion Most guidelines concur with a serum urate defined T2T approach to eventually suppress gout; the target serum uric acid is defined, yet variable units of measurement add complexity to the implementation of guidelines. Most guidelines endorse a lower target serum uric acid for severe gout without a consensus definition of severity encompassing frequency of attacks, number of joints involved, presence of tophi or comorbidities. Hence, the ACP characterises T2T as unproven/ inappropriate/impractical, contentious and not evidence-based. 31 The ACP suggests a TTS approach for acute flares, without urate-lowering therapy, to correct hyperuricaemia, and fails to acknowledge the potential longterm morbidity of chronic gout, including the potential for tophus development, joint damage and patient suffering. Implementing the ACP guidelines may worsen already suboptimal care. 32 The costs of allopurinol and serum uric acid monitoring are minimal, compared with the potential downstream costs for CTG, without evidence of an unfavourable risk benefit ratio for T2T. Guidelines agree that allopurinol is a first-line urate-lowering therapy, easy to administer, well tolerated, widely available and economical. However, ACP and ACR guidelines also endorse optional first-line febuxostat, which, compared with allopurinol, is significantly more expensive, with less long-term tolerability and cardiovascular safety data. Febuxostat should not be used in Australia as first-line therapy; it is available on Pharmaceutical Benefits Scheme authority when allopurinol is contraindicated, imposing increased taxpayer costs. 33 Lack of clinician education is a significant barrier to optimal gout care. Compared with other arthritides, gout receives less attention in non rheumatological training 352 REPRINTED FROM AJGP VOL. 47, NO. 6, JUNE 2018 The Royal Australian College of General Practitioners 2018

3 CHRONIC GOUT: BARRIERS TO EFFECTIVE MANAGEMENT CLINICAL Table 1. Comparison of published gout guidelines SUA target ACP EULAR Aust & NZ 3e Initiative ACR BSR General <6 mg/dl (0.36 mmol/l) <0.36 mmol/l <0.36 mmol/l (6 mg/dl) <6 mg/dl <300 µmol/l Specified <5 mg/dl (0.30 mmol/l) severe gout <0.30 mmol/l tophaceous gout <0.30 mmol/l (5 mg/dl) tophaceous gout <5 mg/dl severe gout ULT indications Tophi Attacks 2/year Recurrent >2/year >2/year Arthropathy Radiographic evidence Comorbidities ULT initiation Near time of diagnosis During attack 1 2 weeks after attack First-line ULT Allopurinol, febuxostat Allopurinol Allopurinol Allopurinol Allopurinol, febuxostat Allopurinol Starting dose (mg/day) Titration to target SUA 100 mg every 2 4 weeks Gradual increases Slow increases Every 2 5 weeks mg every few weeks ACP, American College of Physicians (2016) guidelines 13 ; EULAR, European League Against Rheumatism (2016) guidelines 15 ; Aust & NZ, Australian and New Zealand (2015) recommendations 19 ; 3e Initiative, Multinational Evidence, Expertise, Exchange Initiative (2013) guidelines 16 ; ACR, American College of Rheumatology (2012) guidelines 17 ; BSR, British Society of Rheumatology (2007) guidelines 18 ; Not specified in guideline; Specified in guideline; SUA, serum uric acid; ULT, urate-lowering therapy programs and is viewed academically as unimportant. 30 The lack of direct GP involvement in guideline development, and limited dissemination, contribute to poor accessibility and use. Many patients receive suboptimal allopurinol dosages if tight serum uric acid control is not correlated with treatment success. 33 Gout recommendations issued by the Australian Therapeutic Guidelines 20 are accessible online and may be used more readily by GPs. However, further discordance exists between these guidelines and those already discussed. The Therapeutic Guidelines advise uratelowering therapy for all patients with diagnosed gout, while most evidencebased recommendations agree that urate-lowering therapy should be reserved for those with recurrent flares or those experiencing more than two attacks per year. Historically, a lower maximal dose of allopurinol was recommended in patients with impaired renal function because of the fear of allopurinol hypersensitivity syndrome (AHS); its incidence is only %, and it is most frequent in Asian peoples and those with HLA-B*5801 mutations. 34 Overestimation of the frequency of AHS may result in suboptimal urate-lowering therapy. Using higher starting doses of allopurinol increases the risk of AHS. 35 Gouty nephropathy is evident postmortem in almost 40% of patients clinically diagnosed with gout. 36 For treating chronic kidney disease, some authors note that control of hyperuricaemia (without incident gout) may slow progression of renal disease. 37 Gout is usually asymptomatic between attacks, so patient-initiated discontinuations are common. Gout must be understood to be a chronic and potentially disabling arthropathy. Patients perceptions of the meaning of the illness are intrinsically related to their resultant behaviour and adherence, and stigma surrounding gout stems from historical portrayals of gout as a disease of affluence, from men overconsuming rich food and excess alcohol, and somehow comical. Recommendations Australian guideline development Broadly disseminated Australian GP-focused, evidence-based guidelines The Royal Australian College of General Practitioners 2018 REPRINTED FROM AJGP VOL. 47, NO. 6, JUNE

4 CHRONIC GOUT: BARRIERS TO EFFECTIVE MANAGEMENT are required. Online or other auditable disease management tools could reinforce guideline usage. Practitioners Gout should be appreciated as a risk for significant comorbidities. Online education models incorporating gout guidelines and case-based scenarios may increase awareness, pragmatism and confidence in treating gout. A practical T2T CTG treatment approach is outlined in Box 1. Patients Patient education may be the most effective means of improving adherence to treatment. Ideally, provision of education by nurse specialists will achieve target serum uric acid levels in more than 90% of patients. 38 Raising public awareness of gout and its consequences may correct misperceptions and stigma regarding gout and improve health-seeking behaviour. Conclusion Multiple barriers to effective management of CTG, a common and arguably curable inflammatory arthritis, still exist. There remains considerable disunity in published guidelines, which are typically not disseminated to GPs. Patient non-adherence is frequent and attributable to lack of knowledge of the disease and cognitive biases towards its causes. Neither physicians nor patients alone are responsible for the suboptimal management of gout. Clear, universally accessible Australian evidence-based guidelines agreed upon through collaboration between GP and speciality groups are necessary to overcome barriers and achieve consensus around the indications for CTG therapy. Key points Target serum uric acid Although <6 mg/dl (360 mmol/l = 0.36 mmol/l) is the most common target serum uric acid, levels differ in value and unit measurement. Some guidelines Box 1. Suggested treatment approach for patients with episodic gout* General approaches Measure SUA out of context of an acute attack. Do not commence allopurinol (or other ULT) in the context of an acute attack. When commencing allopurinol (or other ULT), ensure the patient is taking prophylactic therapy: colchicine, NSAIDs or corticosteroids are appropriate. If diarrhoea occurs, consider: NSAIDs, COX-II inhibitor, or very low-dose corticosteroids, contextualised to patient s overall health. Inform the patient of the objectives of treatment. Consider dietary advice generally, low-urate diets are not complied with. Diets compatible with optimal glycaemic control and primary cardiovascular prevention are usually acceptable. Always assess patients for the presence of manageable comorbidities: hypertension, obesity, type 2 diabetes/metabolic syndrome, cardiovascular disease and renal calculi/renal disease. Allopurinol for ULT Explain that allopurinol is a preventative strategy, not a treatment for an acute attack; the analogy of relievers and preventers in asthma is well understood. Commence with allopurinol 100 mg daily (maximum), or 50 mg daily if egfr 50 ml/min. Consider: HLA-B*5801 mutation genotyping for people of Asian origin. Titrate: increase the dose of allopurinol by mg every 3 4 weeks, monitoring for rash/itch. Target SUA: increase allopurinol to a maintenance dose sufficient to reduce the SUA to <0.35 mmol/l in non-tophaceous disease, or mmol/l in tophaceous disease. Prophylactic therapy: continue for up to three months after a stable dose of ULT sufficient to reach target SUA, or three months after an acute attack has occurred, whichever is longer. Acute attack: if an attack of gout occurs, do not stop allopurinol; treat the acute attack as appropriate. Monitor: monitor SUA when other blood tests are taken, preferably six-monthly for two years after last attack. Continue: do not cease allopurinol (or other ULT) even if the patient has been free of attacks (for years). II *Includes patients with gout that affects quality of life, results in excess time off work, or whose concurrent health conditions pose contraindications to agents used for acute treatment (eg prior upper gastrointestinal tract ulceration/bleeding, anticoagulation, impaired renal function, cardiovascular disease or diabetes). The objectives of treatment are: elimination of attacks which may take months or even years on occasion to achieve. Many patients do not achieve target SUA on allopurinol 300 mg daily; the dose may be increased or a uricosuric agent may be added. Always check for medication adherence prior to increasing/adding medications, as this with have no effect in a non-adherent patient shrinkage of tophi which can be achieved over years and may require combination therapy with the addition of a primary uricosuric agent to a xanthine oxidase inhibitor in certain cases. Explain that though some dietary modifications, such as increased consumption of milk/dairy and cherries, may be helpful, diet alone or the removal or addition of some foodstuffs will almost never be sufficient to control gout. The Mediterranean diet is now mainstream and accepted by many. There are numerous urban myths based on folklore and mistakenly felt to be factual that can be addressed by a dietitian. Patients equate high-protein foods with foods high in purine generally. Avoid idiosyncratic dietary advice. Never commence allopurinol in a person treated with azathioprine or 6-mercaptopurine, which is the pharmacologically effective first metabolite of azathioprine; these agents may cause hyperuricaemia, but the addition of allopurinol will increase the serum level of 6-mercaptopurine threefold to fourfold, often resulting in myelotoxicity. Other first-line options include probenecid (not discussed in this paper) if renal function is sufficient. II When ULT is ceased, the serum urate will simply increase and eventually this may result in recurrence of attacks. Patients often understand the analogy of long-term treatment for hypertension or cholesterol to reduce cardiovascular risks. egfr, estimated glomerular filtration rate; NSAIDs, non-steroidal anti-inflammatory drugs; SUA, serum uric acid; ULT, urate-lowering therapy 354 REPRINTED FROM AJGP VOL. 47, NO. 6, JUNE 2018 The Royal Australian College of General Practitioners 2018

5 CHRONIC GOUT: BARRIERS TO EFFECTIVE MANAGEMENT CLINICAL suggest a lower target serum uric acid for tophaceous or severe gout. Indications for urate-lowering therapy The presence of tophi is the most common indicator for urate-lowering therapy, although this is not universal. Frequency of attacks varies from more than two per year to recurrent flares. The BSR recommends diuretic use as an indicator of the need for treatment; 11 most other guidelines recommend avoiding diuretics in chronic gout. When to initiate urate-lowering therapy The ACP recommends against uratelowering therapy after a first gout attack or in those with infrequent attacks. 5 EULAR guidelines suggest initiating urate-lowering therapy close to the time of diagnosis, 8 and the BSR specifies initiating 1 2 weeks after an acute attack. 11 The ACR guidelines state that urate-lowering therapy can be initiated during an attack, if combined with antiinflammatory management. 10 Choice of urate-lowering therapy All guidelines establish allopurinol as a first-line urate-lowering therapy. ACP and ACR guidelines recommend febuxostat as a comparable first-line agent. Starting doses of urate-lowering therapy vary, or are in some cases not specified, and techniques for titrating doses to target serum uric acid lack detail. Authors Sylvie Rogenmoser BAppSci, MD, Junior Medical Officer, Tweed Hospital, Tweed Heads, NSW Mark H Arnold MBBS, FRACP, MBioethics, Associate Professor of Medicine, Sydney Medical Program; Associate Dean and Head, School of Rural Health, University of Sydney, NSW. mark.arnold@sydney. edu.au Competing interests: None. Provenance and peer review: Not commissioned, externally peer reviewed. References 1. Ting K, Gill TK, Keen H, Tucker GR, Hill CL. Prevalence and associations of gout and hyperuricaemia: Results from an Australian population-based study. Intern Med J 2016;46(5): doi: /imj Doherty M, Jansen TL, Nuki G, et al. Gout: Why is this curable disease so seldom cured? Ann Rheum Dis 2012;71(11): doi: / annrheumdis Schieir O, Tosevski C, Glazier RH, Hogg-Johnson S, Badley EM. Incident myocardial infarction associated with major types of arthritis in the general population: A systematic review and metaanalysis. Ann Rheum Dis 2017;76(8): Su X, Xu B, Yan B, Qiao X, Wang L. 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6 CHRONIC GOUT: BARRIERS TO EFFECTIVE MANAGEMENT 32. FitzGerald JD, Neogi T, Choi HK. Do not let gout apathy lead to gouty arthropathy. Arthritis Rheumatol 2017;69(3): doi: / art Lipworth W, Kerridge I, Brett J, Day R. How clinical and research failures lead to suboptimal prescribing: The example of chronic gout. BMJ 2011;343:d7459. doi: /bmj.d Grainger R, Harrison AA. Rules of engagement: Turning recommendations into results in the diagnosis and management of gout. Int J Rheum Dis 2015;18(3): doi: / X Stamp LK, Taylor WJ, Jones PB, et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: A proposed safe starting dose of allopurinol. Arthritis Rheum 2012;64(8): Nickeleit V, Mihatsch MJ. Uric acid nephropathy and end-stage renal disease Review of a non-disease. Nephrol Dial Transplant 1997;12(9): Krishnamurthy A, Lazaro D, Stefanov DG, Blumenthal D, Gerber D, Patel S. The effect of allopurinol on renal function. J Clin Rheumatol 2017;23(1):1 5. doi: / RHU Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if informed appropriately: Proof-of-concept observational study. Ann Rheum Dis 2013;72(6): doi: /annrheumdis correspondence ajgp@racgp.org.au 356 REPRINTED FROM AJGP VOL. 47, NO. 6, JUNE 2018 The Royal Australian College of General Practitioners 2018