Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline

Gout, a common form of inflammatory arthritis, is characterized by acute intermittent episodes of synovitis that cause joint swelling and pain. Approximately 8 million persons in the United States have gout (1). It occurs when excess urate in the body crystalizes (as monosodium urate) in joint fluid, cartilage, bones, tendons, bursas, or other sites. The crystals can directly initiate an acute inflammatory attack. In some patients, acute gout attacks become progressively more frequent, protracted, and severe and may progress to a chronic inflammatory condition. In addition, some patients develop tophi, which are deposits of urate crystals at the surface of joints or in skin or cartilage. This systematic review was proposed by the American College of Physicians (ACP) to support the development of a clinical practice guideline that would aid primary care practitioners in the management of adult patients with gout. Methods We developed a protocol ); followed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines for reporting systematic reviews (2); and detailed search and selection processes, inclusion criteria, and evidence tables in an evidence report (3). Key Questions Key questions proposed by ACP were revised on the basis of input from a group of key informants, a technical expert panel, and the public. Treatment questions addressed benefits and harms of pharmacologic and dietary therapies for adults with acute gout attacks and the intermediate and long-term benefits and harms of therapies for adults with gout and hyperuricemia. Additional management questions addressed monitoring of serum urate levels and whether criteria exist to identify patients who are candidates for discontinuation of urate-lowering therapy or anti-inflammatory prophylaxis. Data Sources and Searches We searched (without language restrictions) for systematic reviews and original research studies in PubMed, EMBASE, the Cochrane Collaboration, and the Web of Science, using the terms gout and gouty and terms for tophi. The start date of the searches was 1 January 2010, which was at least 1 year before the search dates for the most recent systematic reviews, and the end date was 1 March 2016. Relevant references were obtained from 29 recent systematic reviews. We searched ClinicalTrials.gov from inception to 1 March 2016 and the Web of Science from 1 January 2010 through 1 March 2016, and we contacted manufacturers of prescription medications used to treat gout for recently completed studies and unpublished or nonpeer-reviewed study findings in July 2014. Appendix Table 1 provides detailed search methods. Appendix Table 1. Detailed Search Methods Study Selection Two reviewers independently screened records (titles, abstracts, and articles) to identify reviews and studies that reported on the benefits (randomized trials) or harms (observational studies and trials) of treatment and management strategies for gout. We examined only medications approved by the U.S. Food and Drug Administration (FDA), except for nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used to treat gout. As suggested by the ACP Clinical Guidelines Committee, we excluded pegloticase and lesinurad, which primary care physicians are unlikely to prescribe. Studies that enrolled participants with no formal gout diagnosis (based on either synovial fluid analysis or a clinical diagnosis) were excluded. Data Extraction and Quality Assessment Study-level details were abstracted by one reviewer and checked by a second reviewer, with reconciliation of disagreements by group discussion. Risk of bias of individual studies was assessed independently by 2 reviewers using an adapted Cochrane risk-of-bias tool (4), with reconciliation of disagreements by the project lead. A modified AMSTAR (A Measurement Tool to Assess Systematic Reviews) tool was used to assess the quality of systematic reviews (5). Data Synthesis and Grading We deemed studies to be too few in number and too heterogeneous to support new meta-analysis. We assessed the overall strength of evidence as high, moderate, low, or insufficient for each conclusion by using guidance suggested by the Effective Health Care Program (6). We also applied criteria proposed by Bradford Hill for causality when judging strength of evidence (7), including the strength, consistency, and specificity of the association; the temporal relationship; the biologic gradient or doseresponse curve; the biologic plausibility; and coherence. Role of the Funding Source This topic was proposed by the ACP to the Agency for Healthcare Research and Quality (AHRQ) and funded by AHRQ. Staff at AHRQ and ACP helped to develop and refine the scope of the study and reviewed the draft report. Results The Figure shows the search and selection process that identified 155 articles meeting the inclusion criteria. Of these, 22 evaluated dietary therapy or traditional Chinese medicine; details about the inconclusive evidence from those studies are in the evidence report (3). Figure. Literature flow diagram. * The number of included studies for this article differs from the number of included studies in the evidence report (3) because this review did not address all of the key questions addressed in the report. Results for this question are not included in this article. See the evidence report (3). Pharmacologic Treatment for Acute Gout We identified evidence for several pharmacologic treatments for acute gout: colchicine, NSAIDs, corticosteroids, and animal-derived corticotropin formulation (835). None of the studies assessed differences in effectiveness by patient characteristics, such as age, sex, duration of the episode, history, genetic profile, baseline serum urate level, or presence of comorbidities. Colchicine Although colchicine was used to treat gout in the ninth century or earlier (36), its use has been evaluated in only 2 randomized, placebo-controlled trials (12, 14). These trials enrolled 184 and 43 patients, respectively, who had crystal-proven gout or met the American College of Rheumatology criteria and had mean duration of symptoms of 38 hours or less. Both studies found that patients treated with colchicine had better pain relief than placebo recipients (38% vs. 16% achieved a 50% decrease in target joint pain at 24 hours, and 41% vs. 9% achieved a 50% decrease in baseline pain score at 24 hours). The earlier trial, published in 1987, used an initial colchicine dose of 1 mg followed by 0.5 mg every 2 hours until symptom relief or adverse effects occurred (14). All of the colchicine-treated patients had gastrointestinal adverse effects by 24 hours, and 91% reported adverse effects before achieving a 50% reduction in pain intensity. The later trial compared low-dose (an initial dose of 1.2 mg followed by 0.6 mg 1 hour later) versus high-dose (an initial dose of 1.2 mg followed by 0.6 mg per hour for 6 hours) colchicine (12). Low-dose colchicine was as effective as high-dose colchicine compared with placebo and was much better tolerated; for example, 23% versus 77% of patients receiving low- and high-dose therapy reported diarrhea, and 0% versus 19% of these patients reported severe diarrhea (Table 1). Table 1. Key Trials of Treatments for Acute Gout NSAIDs One low-quality, placebo-controlled trial assessed NSAIDs in patients with acute gout (30). This small study assessed the effect of tenoxicam (40 mg once daily) in 30 patients and found that a greater proportion of those receiving tenoxicam than those receiving placebo reported at least 50% improvement at 24 hours. Sixteen randomized trials compared one NSAID with another (8, 9, 11, 1519, 2123, 2729, 31, 32). Most studies found no statistically significant differences in outcomes between treatments, although only 3 studies enrolled more than 100 patients (9, 22, 23), meaning that most studies were small and had limited power to detect differences (Appendix Table 2). Appendix Table 2. Randomized, Controlled Trials of NSAID Versus NSAID for Treatment of Acute Gout Corticosteroids No published placebo-controlled trials assessed oral corticosteroids for acute gout. Six randomized trials compared corticosteroids (3 oral, 2 intramuscular, and 1 intravenous) versus NSAIDs. These studies, which enrolled 27 (20), 60 (13), 90 (24), 92 (33), 120 (10), and 416 (34) patients, found few differences in effectiveness or adverse events between treatments. In one study of oral corticosteroids, 90 patients presenting to the emergency department with acute arthritis suggestive of gout were randomly assigned to receive either prednisolone, 30 mg/d for 5 days, or indomethacin, 50 mg 3 times daily for 2 days and 25 mg/d for the next 3 days; all patients also received paracetamol. No statistically or clinically significant between-group differences were seen at any evaluation point (up to 14 days). More patients in the indomethacin group than the prednisolone group reported adverse events (63% vs. 27%) (24). In another study of oral corticosteroids, 120 patients who presented to family physicians with acute monoarthritis and had monosodium urate crystals on synovial fluid examination were randomly assigned to prednisolone, 35 mg/d, or naproxen, 500 mg twice daily. Over the subsequent 4 days, no statistically significant differences in effectiveness outcomes were observed between groups. Equal proportions of patients in both groups reported an adverse event (66% vs. 63%) (10). The third study of oral corticosteroids randomly assigned 416 patients with a clinical diagnosis of gout with symptoms lasting less than 3 days to indomethacin or prednisolone for 5 days. There were no important statistically or clinically significant differences in pain outcomes or overall adverse events.