Gout: Guidance Issued on Treat-to-Target

Janis C. Kelly

October 03, 2016

The first treat-to-target recommendations for gout advise clinicians to focus on specific treatment targets and outcome measures when monitoring gout disease activity, and then adjust treatment regimens for maximal efficacy. However, with few trials available, the new recommendations are based on "highly credible overarching principles" and expert opinion.

The primary treatment goal is to reduce serum uric acid (SUA) levels to lower than 6 mg/dL and to maintain that level. Patients with severe gout, such as tophi or frequent attacks, should aim for SUA levels lower than 5 mg/dL.

The other three treatment targets in the recommendations are amount/reduction/absence of tophi, pain reduction, and presence or absence of attacks. The three outcome measures are clinical (pain, joint count, number of attacks/year), laboratory (serum urate level, C-reactive protein, erythrocyte sedimentation rate, serum creatinine), and patient-reported outcomes (quality of life, short form 36, work status, productivity, work days off, and absenteeism).

Senior author Juergen Braun, MD, medical director of Rheumazentrum Ruhrgebiet, Herne, Germany, told Medscape Medical News, "I think the most important message is that gout is a simple disease in the way that it is easy to define targets such as constantly low uric acid levels. However, there are almost no studies checking whether strategies to reach those targets work and whether we should change our strategies and/or potentially define other targets."

The gout recommendations were developed by an international working group that included 11 rheumatologists, one cardiologist, one nephrologist, one general practitioner, and one patient with gout. Uta Kiltz, MD, from Rheumazentrum Ruhrgebeit Ruhr-University Bochum Herne, Germany, and colleagues published the recommendations online September 22 in the Annals of the Rheumatic Diseases.

Gout Experts Agree on Management Principals, Call for RCTs

The group performed a systematic literature review of 761 papers (55 of which were selected for full-text review), but identified no randomized trials comparing standard treatment with treat-to-target approaches in gout. Therefore, the recommendations were based on indirect evidence and expert recommendations. The final expert group recommendations center on dissolution of crystals and prevention of flares, patient education, ensuring adherence to medications, and monitoring serum urate levels.

The recommendations specifically did not include asymptomatic hyperuricemia because of inadequate evidence of treatment efficacy.

Education, Telephone Access Can Improve Gout Treatment Adherence

The authors note studies showing that "control of [SUA levels] is optimised by providing patient education, enhanced telephone access to expert advice, upward titration of allopurinol, febuxostat or benzbromarone and increased frequency of visits until the target SUA concentration was achieved." Lesinurad and other urate-lowering drugs were not included in the recommendations because of a lack of published strategy trials employing these drugs.

The reviewers also found evidence that tophus size shrinks more quickly when SUA concentration is reduced below the monosodium urate saturation point early in treatment and maintained at that level.

Dr Braun said, "If we manage to implement that basic message that gout is a chronic disease which needs proper and regular management to patients and general practitioners, this would be a major step forward."

The recommendations emphasize the importance of educating both providers and patients about gout and gout treatment and of shared decision-making by patients and providers.

The working group decided not to differentiate between "acute" and "chronic" gout, reasoning that these are parts of the spectrum of a single chronic disease. They recommend that acute attacks be treated promptly with anti-inflammatory drugs and warn that comorbidities should be identified and considered before selecting anti-inflammatory therapy.

Better Disease Activity Measures Needed

The authors write, "[L]ack of evidence supporting how best to treat gout likely is one of the main reasons why it is often difficult to treat the disease successfully and especially to maintain patients free of disease activity over the long term. In the presence of comorbidities, such as renal impairment, the aim of low disease activity is much more complicated to reach which was the basis to recommend assessment of renal function on a regular basis."

Dr Braun told Medscape Medical News that his approach would be to measure renal function every 3 to 6 months, depending on the individual risk and whether there were comorbidities such as diabetes or hypertension. He also would check blood pressure, HbA1, and lipid levels, and provide patient education, including diet recommendations.

This initial work on developing treat-to-target guidance for gout identified a number of major unanswered questions, most prominently the lack of validated measures of disease activity or severity. "The term 'severity' is inexact when referring to patients with gout and reflects a variety of parameters, such as frequency of attacks, number of swollen joints, number and size of tophi and presence of comorbidities. No threshold has been defined to differentiate between severe and mild disease states," the authors write.

Unanswered Question: Can Early SUA Lowering Prevent Symptoms?

Dr Braun said, "There are many unanswered questions in gout. The most important one would be primary prophylaxis; that is, to show that starting from a certain level of hyperuricemia, you would treat to lower the uric acid load. The Japanese recommend starting from 9 mg/dL. We haven't even touched that issue because there are many opinions, but no data, and it is in a way a separate issue. There are many more study questions to answer, including many simple ones on the patient care level. Among many other issues is why the compliance of many patients is limited and how this could be potentially changed."

Recommendations Unlikely to Help Most African Americans With Gout

Bharat Kumar, MD, clinical associate professor of internal medicine, Division of Immunology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, who has studied disparities in gout treatment in African American patients, told Medscape Medical News that he finds the recommendations reasonable, but doubts they will improve the situation for African Americans with gout.

Dr Kumar, who was not involved in the project, said, "The serum uric acid level target of 6 mg/dL (or lower, with optional target of 5 mg/dL) is something that is used very commonly in the United States. The authors acknowledge that they do not address asymptomatic hyperuricemia, which is a contentious issue that needs further investigation. They did not address which of the urate-lowering medications should be used, and how to select them in certain populations (such as those who have a high risk of developing HLA-B5801-associated allopurinol hypersensitivity reactions)."

He continued, "[The recommendations] are unlikely to improve the situation with regard to healthcare delivery for African Americans for a number of reasons. Even though it is very admirable to introduce the treat-to-target strategy, the major issues for African Americans are (1) diet, (2) patient education, and (3) improving adherence. These are only tangentially mentioned in the [Annals of the Rheumatic Diseases] article."

Dr Kumar agreed with Dr Braun that patients with gout need to be regularly monitored, both clinically and through laboratory studies, to maintain SUA goal levels.

Dr Kumar added, "Patients need to be educated about lifestyle modifications and the importance of adherence, even when they don't have flares, in order to reduce their risk of further musculoskeletal, cardiac, and renal disease. Poor adherence is our fault. We don't educate patients about what gout is, how uric acid contributes to disease, and why it is so critical to reduce their risk. We don't speak in their language and often end up talking in a judgmental tone about diet and exercise that they naturally just don't internalize."

When asked about the paucity of trial data, Dr Kumar said there are ethical considerations in performing randomized controlled trials in gout, including possible harm to control groups. "So, even though the level of evidence is low, it is the best that is available. Besides that, the degree of agreement among the raters is fairly high, so I think there is a fair degree of reliability in their recommendations," Dr Kumar said.

The study was supported by Novartis, Berlin-Chemie Menarini, Astra-Zeneca, and Ardea Bioscience. Dr Kiltz has received grant and research support and consultancy fees from AbbVie, Chugai, MSD, Novartis, Pfizer, Roche, and UCB. Dr Braun has received honoraria for talks, advisory boards, paid consultancies and grants from studies from Berlin-Chemie Menarini, and Novartis. Other coauthors reported honoraria, consulting fees, speaker fees, or grants from AbbVie, Astellas, AstraZeneca, BMS, Chugai, Mitsubishi-Tanabe, Pfizer, Takeda, Teijin and UCB. Janssen, Roche, RuiYi, sanofi-aventis, Teijin, Crealta, Cymabay, Fonterra, Nordic Biosciences. Regeneron Pharmaceuticals, and Sobi. The remaining authors and Dr Kumar have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online September 22, 2016. Abstract

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