Managing gout needs more than drugs: ‘Il faut le savoir-faire, l’Art et la manière’ Frédéric Lioté, 1,2,3 Hyon Choi 4 Gout management has recently been a topic of active discussion, prompted by several European and international recom- mendations. 1–3 Nevertheless, a number of studies have reported a suboptimal level of current gout care, including even poorer adherence to prescribed drugs, 4 than in patients with diabetes or hypertension. 5 Quality indicators for the treatment of gout developed to date have focused pri- marily on the use of allopurinol as the most frequently prescribed urate lowering therapy (ULT), adjustment of the maximal dose according to renal function and serum uric acid (SUA) level measurement. 67 In their provocative, proof-of-concept study, Rees et al 8 provide important pre- liminary evidence that treating gout effectively is not just a matter of initiating ULT, but rather of implementing a proper approach that combines patient educa- tion, individualised lifestyle advice, and appropriate use of ULTs to achieve and sustain treatment targets (eg, SUA level <360–300 μmol/l). 7 Over the 1-year trial period, this approach led to more than 90% of patients achieving the primary treatment target of SUA of <360 μmol/l recommended by Eular League Against Rheumatism (EULAR), 2 and to 85% achieving an SUA of <300 μmol/l, the target level recommended by the British Society for Rheumatology. 3 Although the trial was an open-label, proof-of-concept study without randomisa- tion or a control group, the effect sizes appear large enough to overcome potential regression to the mean or placebo effects. Furthermore, previous randomised gout trial experience suggests that SUA levels below 6.0 mg/dl are not attained in placebo- treated patients. So these findings do suggest substantial potential benefits from the proposed approach. While the next step of a controlled trial of the approach is cur- rently underway, the proof-of-concept study findings appear instructive in their own right in several ways. IS GOUT SUCH A DIFFICULT DISEASE TO TREAT? Despite the recent publications challenging the quality of current gout care, gout has long been considered potentially ‘curable’ with a well-characterised pathogenesis and the availability of effective antigout mea- sures. Gout attacks (or acute joint inflam- mation, if preferred) can result at any time from the deposited urate (monosodium urate; MSU) crystals that form as a conse- quence of hyperuricaemia; a low grade crystal associated subclinical inflammation occurs continuously. SUA serves as a clear biomarker, which is readily available, affordable and easy to use. With use of ULT options to reduce SUA levels below the crystallisation threshold (eg, lower than 360 μmol/l, or even 300 μmol/l in advanced cases), one can reduce gout flares and tophi, 9 10 and even heal bone lesions in some patients. 11 To this effect, the study by Rees et al 8 provides key initial evidence that an appropriate comprehensive approach can meaningfully improve gout care, as was long thought possible. The target-guided approach adopted by the study of Rees et al 8 should be viewed analogous to the treat-to-target paradigm in rheumatoid arthritis (RA). In RA, this approach strives for targets, aiming at quick remission, based upon clinical and inflammatory biomarkers and with absence of synovitis by ultrasound exam- ination. A higher goal can be pursued in gout since it is a potentially ‘curable’ rheumatic disease. ‘ GO SLOWLY’ AND ‘ GO EFFECTIVELY’ TO AVOID THERAPEUTIC INERTIA Among ULT options, allopurinol, a xan- thine oxidase inhibitor, is the leading choice worldwide. 2 3 12 Optimal dosing is guided by renal function to help avoid side effects that range from mild rashes (∼2%) to rare, but serious hypersensitivity syndromes. While there are some differ- ences of opinion regarding the maximal doses of allopurinol that should be employed, 13–15 current guideline recom- mendations suggest that maximal dosages of 800 or 900 mg/day can be safely used if required in patients with normal renal function. 2 3 Alternative available ULT includes febuxostat, another xanthine oxidase inhibitor, 12 pegloticase (a uricase) and uricosurics such as probenecid, sulfinpyrazone and benzbromarone, while several other potential ULT options are being developed. 16 17 Allopurinol, when appropriately dosed, is an effective gout treatment as demon- strated by Dutch rheumatologists. 16 17 Nevertheless, many randomised control trials, mostly conducted in the US gout population, have notably employed the so-called ‘usual’ allopurinol dosage of 300 mg, which appears to be insufficient in many instances. 12 In a recent survey from UK, 16 44 out of 164 cases were receiving allopurinol, with 70% at 300 mg daily, and only 4 (10%) taking a dose >300 mg daily. Despite this, 23% of treated patients had SUA >360 mmol/l, indicating that the therapeutic target was not reached. Renal impairment was the most frequent reason for not escalading allopurinol. By contrast, in the study of Rees et al 8 , only 28% received allopurinol 300 mg daily, while 25% received 400 mg/day, 25% 500 mg/day and 13% needed higher doses. The median dose was 400 mg daily in the 80 patients taking allopurinol at final visit. Other patients received febuxo- stat or benzbromarone as alternative ULT after treatment failure. The uptitration of allopurinol was slow and accompanied by close monitoring and patient education. In addition to this leading to the high success rates of meeting the predefined SUA targets, 65% of patients had fewer gout flares over the 1-year period and a third of the patients had a reduction in number and size of tophi. This ‘go slowly ’ and ‘go effectively ’ approach is consistent with EULAR recommendation #9 and other studies 18 to start allopurinol at a low dose (100 mg daily) and increase by 100 mg every 2–4 weeks. 2 This gradual and stepwise approach also appears to have helped to avoid hypersensitivity skin reactions, 18 and the gout flares that are well known to follow the initiation of ULT despite the fact that only 4% of 1 Department of Rheumatology, University Paris Diderot, Paris, France 2 Service de Rhumatologie, AP-HP , Hôpital Lariboisière, Centre Viggo Petersen, Paris, France 3 Inserm, UMR 606, Hôpital Lariboisière, Centre Viggo Petersen, Paris, France 4 Department of Medicine, Section of Rheumatology and the Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USA Correspondence to Professor Frédéric Lioté, Service de Rhumatologie, AP-HP , Centre Viggo Petersen, Hôpital Lariboisière, 2, rue Ambroise Paré, Paris F-75010, France; frederic.liote@lrb.aphp.fr Ann Rheum Dis June 2013 Vol 72 No 6 791 Editorial group.bmj.com on May 11, 2013 - Published by ard.bmj.com Downloaded from