Monotherapies With Disease-Modifying Antirheumatic Drugs Comparable in RA

November 28, 2007 — Of several monotherapies with disease-modifying antirheumatic drugs (DMARDs) for adults with rheumatoid arthritis, no regimen is clearly superior, according to a review published in the November 19 Rapid Access issue and will appear in the January 15, 2008, issue of the Annals of Internal Medicine. The reviewers also note that combination therapies improve response rates in some patients who were previously taking monotherapy.

In the United States, available agents for treatment of rheumatoid arthritis include corticosteroids; synthetic DMARDs, including hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine; and biological DMARDs, including abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab. The American College of Rheumatology recommends starting treatment with DMARDs within 3 months of diagnosis.

"Often, treatment with a single DMARD does not adequately control symptoms, leading clinicians to consider various combination strategies," write Katrina E. Donahue, MD, MPH, from the University of North Carolina and Cecil G. Sheps Center for Health Services Research, Chapel Hill, and colleagues. "Many questions remain about the risks of these agents across a spectrum of adverse events from relatively minor side effects to severe and possibly life-threatening problems. Given this uncertainty, the Agency for Healthcare Research and Quality (AHRQ) commissioned a systematic review to compare the benefits and safety of rheumatoid arthritis drugs."

To evaluate the risks and harms of DMARD therapy for adults with rheumatoid arthritis, the reviewers searched MEDLINE, EMBASE, The Cochrane Library, and International Pharmaceutical Abstracts from 1980 to September 2007 for English-language reports of studies in adults. Relevant studies were independently selected by 2 reviewers, and a standard protocol was used to extract study design, interventions, outcomes, and quality.

Criteria for inclusion of reports in the analysis were head-to-head trials and prospective cohort studies with at least 100 participants and 12-week follow-up, relevant good- or fair-quality meta-analyses comparing benefits or harms of 11 drug treatments, and retrospective cohort studies reporting on harms.

There were 23 head-to-head trials, which demonstrated no clinically significant differences in efficacy among the synthetic DMARDs evaluated (methotrexate, leflunomide, and sulfasalazine) or among the antitumor necrosis factor drugs tested (adalimumab, etanercept, and infliximab).

Compared with methotrexate monotherapy, antitumor necrosis factor monotherapy was associated with better radiographic outcomes. However, no important differences in clinical outcomes were demonstrated, such as 20%, 50%, or 70% improvement by response criteria from the American College of Rheumatology.

Compared with monotherapy with either methotrexate or biological DMARDs, various combinations of biological DMARDs plus methotrexate were more effective at improving clinical response rates and functional outcomes. Patients who did not respond to monotherapy had better response rates when treated with a combination of synthetic DMARDs.

Use of biological and synthetic DMARDs gave rise to similar numbers and types of short-term adverse events. For biological DMARDs, however, the evidence was insufficient to make definitive conclusions regarding differences for rare but serious adverse events. The reviewers note that long-term safety issues may considerably shift the balance between benefits and harms for some of these drugs.

"Limited available comparative evidence does not support one monotherapy over another for adults with rheumatoid arthritis," the review authors write. "Although combination therapy is more effective for patients whose monotherapy fails, the evidence is insufficient to draw firm conclusions about whether one combination or treatment strategy is better than another or is the best treatment for early rheumatoid arthritis."

Limitations of this review were that most of the studies included in the analysis were short-term efficacy trials performed in selected populations of patients with few comorbid conditions, limiting generalizability; low number of studies per drug comparison; publication bias; and selection bias.

"Several therapies are available for persons with rheumatoid arthritis; no regimen is clearly better than another," the review authors conclude. "Future studies, including those with good applicability to patients seen in community practices, will be useful; researchers should plan to perform subgroup analyses a priori in older patients and patients with comorbid conditions. Long-term adverse event studies, particularly with the newer agents, will help clinicians and patients better weigh the benefits of these drugs."

The Agency for Healthcare Research and Quality, US Department of Health and Human Services, supported this review. Coauthor Beth L. Jonas, MD, has disclosed receiving honoraria.

Ann Intern Med. Published online November 19, 2007.

Source: http://www.medscape.com/viewarticle/566560?src=mpnews