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Gout management has recently been a topic of active discussion, prompted by several European and international recommendations.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 primarily 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.6 ,7
In their provocative, proof-of-concept study, Rees et al8 provide important preliminary evidence that treating gout effectively is not just a matter of initiating ULT, but rather of implementing a proper approach that combines patient education, 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 randomisation 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 currently 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 measures. Gout attacks (or acute joint inflammation, if preferred) can result at any time from the deposited urate (monosodium urate; MSU) crystals that form as a consequence 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 al8 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 al8 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 examination. 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 xanthine 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 differences of opinion regarding the maximal doses of allopurinol that should be employed,13–15 current guideline recommendations 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 demonstrated 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 µmol/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 al8, 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 febuxostat 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 studies18 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 patients were given gout flare prophylaxis during the trial.8 This challenges current practice recommendations for the need for prophylaxis during initiation of ULT,2 and suggests that there is a need for further studies to clarify whether prophylaxis with low dose colchicine or NSAIDs is always really necessary.
This ‘go slowly’ and ‘go effectively’ approach would also help to avoid ‘therapeutic inertia’ in gout management.19 Although not widely considered in the gout literature, this phenomenon of therapeutic inertia20 has been well known in the management of diabetes for decades, with at least 108 PubMed references relating to its occurrence. In this field, it has been well established that despite the observation of insufficient glycaemic control, physicians do not systematically increase drug treatments,21 and this has been attributed to ‘clinical inertia’.22
How can we do better? Are new drugs or modalities the solution?
In this study, Rees et al8 evaluated a whole strategy as a ‘package deal’ that consisted of several components: information, tight monitoring and reassurance. The study has been designed to evaluate the effectiveness of the whole approach, but does not allow one to draw inferences about the effects of individual components of the strategy. Nevertheless, it is entirely conceivable, and even likely, that all the involved components are necessary for the strategy to work. Notably, the management included initial patient education by an experienced specialist, which may be a key to its success. The gout specialist performed arthrocentesis and synovial fluid examination for MSU identification to confirm the diagnosis in all patients. Thus, the ‘gold standard’1 was established without a need for additional imaging modalities such as ultrasound. Other notable components included communication with the patient, and taking sufficient time to explain the meaning and significance of hyperuricaemia, in relation to crystal formation, and the clinical manifestations of gout, as well as the importance of treating-to-target when using ULT and the need for treating flares. The online booklet devoted to gout, patient education and regular contacts with nurses also provided additional information to patients.
Overall, these findings suggest that gout can be treated effectively by optimal use of the well established treatment options coupled with better patient education and communication, while there is only a sparing need for the more recently introduced drugs. It remains to be seen whether this approach is feasible in other practice settings, including primary care.7 For example, it is unclear whether this approach would be successful if the initial 1 h consultation with the gout expert and the subsequent follow-up by the trained nurse specialist were substituted by medical and nursing staff in primary care. The potential selection bias acknowledged by the authors calls for future studies with more generalisable patient populations and appropriate comparison groups.
How to ensure patient compliance and physician education?
There are numerous barriers to the implementation of universal quality care involving attitudes and beliefs of physicians and patients. Many physicians think that gout is of little importance,23 ,24 and they are not aware that persistent gout inflammation and association with cardiovascular diseases is an indicator of gout severity. In a small prospective survey on patient and provider expectations in gout, most providers concluded they had adequate skills to teach disease self-management behaviours.25 Interestingly, patients requested more information and longer visit times. The latter is in keeping with the study of Rees et al8 and provides evidence that health management should not be reduced to drug prescription, but must also include patient education. Regular phone calls or direct face-to-face meetings with clinical nurses allowed a slow increase of the chosen ULT to achieve the SUA target, while maintaining high compliance rate.8 Indeed, diet changes are not so difficult to manage since only few drinks should be totally avoided such as beers, including non-alcoholic beers, high fructose soft drinks, and spirits. High protein, lipid and calories intake should be reduced. Individualised lifestyle and pharmacological management was another notable component that could be evaluated in other studies since busy clinics may be a target setting for this approach.26 Overall, however, the direct cost associated with initial monthly monitoring followed by follow-up every 3 months should be readily acceptable.
For physician education, there have been a number of recent national and international recommendations developed on gout management.2 ,3 ,27 ,28 Other education modalities have included articles in general or specialty journals, pamphlets, booklets dedicated to patients and physicians, industry sponsored symposia with various size audiences, and head-to-head or small group interactive meetings. However, quality indicators derived from recommendations may not have been satisfactorily reached.
Despite its specialty care setting and lack of control group, the proof-of-concept study indeed provides strong evidence for its predefined concept that implementing key elements of best practice recommendations can lead to a remarkable success rate in achieving the therapeutic target and maintaining high adherence to ULT over a 12-month period.8 We are awaiting replication of these findings in different settings and/or with a longer follow-up. Anyway, the demonstrated considerable benefits appear enough to recommend the same or a similar approach in the current gout management wherever feasible.
Contributors Both authors have contributed to the draft, discussion and final version of the paper.
Funding This work was supported in part by grants from the National Institutes of Health (R01AR056291 and P60AR047785), from Inserm and University Paris Diderot, Sorbonne Paris Cité. The funding sources had no role in the reporting of the study or in the decision to submit the manuscript for publication.
Competing interests FL has received educational grants from several pharmaceutical companies (Novartis Global, Novartis France, Savient, SOBI, Mayoly-Spindler, Ipsen Pharma, Menarini France, Menarini Global), the INSERM and Paris Diderot University, Sorbonne Paris Cité (UFR de médecine) for organising several European Workshops on crystal-induced inflammation and human diseases since 2010;have served on advisory boards for Novartis Global & Novartis France, Ipsen Pharma and Menarini France, Mayoly-Spindler, Savient, Astra-Zeneca & Ardea. HKC has received research funding for other projects from Takeda Pharmaceuticals and Savient Pharmaceuticals, has served on advisory boards for Takeda Pharmaceuticals, Savient Pharmaceuticals, Novartis, AstraZeneca, and URL Pharma.
Provenance and peer review Commissioned; externally peer reviewed.
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