Comparative Effectiveness of Drug Therapy for Rheumatoid Arthritis and Psoriatic Arthritis in Adults

Rheumatoid and psoriatic arthritis are among the most disabling forms of arthritis. Rheumatoid arthritis (RA), which affects 1 percent of the U.S. adult population (or upwards of 2 million individuals), is an autoimmune disease that involves inflammation of the synovium (a thin layer of tissue lining a joint space) with progressive erosion of bone, leading in most cases to misalignment of the joint, loss of function, and disability. The disease tends to affect the small joints of the hands and feet in a symmetric pattern, but other joint patterns are often seen. The diagnosis is based primarily on the clinical history and physical examination. Psoriatic arthritis (PsA) affects fewer people than RA (approximately 1 million people in the United States). PsA is associated with the skin disease psoriasis. It has a highly variable presentation, which generally involves pain and inflammation in joints and progressive joint involvement and damage. Like RA, PsA can be disabling.

Treatment of patients with RA and PsA aims to control pain and inflammation and, ultimately, to slow the progression of joint destruction and disability. Available therapies for RA include corticosteroids; synthetic disease-modifying antirheumatic drugs, or DMARDs (hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine); and biologic DMARDs (abatacept, adalimumab, anakinra, etanercept, infliximab, rituximab). Three biologics (adalimumab, etanercept, and infliximab) are also classified as anti-tumor necrosis factor (anti-TNF) drugs.

Experts have not arrived at a consensus about the comparative efficacy of different types of combination therapy--synthetic DMARDs, synthetic DMARDs with corticosteroids, or synthetic DMARDs with biologic DMARDs--all often in combination with the synthetic DMARD methotrexate. In addition, there is debate about how early in the disease process combination therapy should be initiated and whether patients will respond to a biologic agent if they have previously failed a different biologic agent. Many questions remain about the risks of these agents across a spectrum of adverse events from relatively minor side effects, such as injection site reactions, to severe and possibly lifethreatening problems, such as severe infections or infusion reactions. Finally, very little is known about the benefits or risks of these drugs in different patient subgroups, including ethnic minorities, the elderly, pregnant women, and patients with other comorbidities.

Historically, few trials have been conducted on patients with PsA, with only minimal research conducted before biologic agents were introduced; management options tended to be adapted from RA trial evidence. All the same issues noted for RA of short- and long-term risks and safety, as well as performance in populationsubgroups, have been only minimally addressed to date for PsA.

This report from the RTI-University of North Carolina Evidence-based Practice Center summarizes the evidence on the comparative efficacy, effectiveness, and harms of corticosteroids, synthetic DMARDs, and biologic DMARDs in the treatment of patients with either RA or PsA. The key questions (KQs) were developed through a public process in conjunction with the Scientific Resource Center at the Oregon Health and Science University. The KQs are as follows:

KQ 1. For patients with rheumatoid arthritis or psoriatic arthritis, do drug therapies differ in

their ability to reduce patient-reported symptoms, to slow or limit progression of radiographic joint damage, or to maintain remission?

KQ 2. For patients with rheumatoid arthritis or psoriatic arthritis, do drug therapies differ in their ability to improve functional capacity or quality of life?

KQ 3. For patients with rheumatoid arthritis or psoriatic arthritis, do drug therapies differ in harms, tolerability, adherence, or adverse effects?

KQ 4. What are the comparative benefits and harms of drug therapies for rheumatoid arthritis and psoriatic arthritis in subgroups of patients based on stage of disease, history of prior therapy, demographics, concomitant therapies, or comorbidities?

We identified 2,153 citations from our searches.

Working from 619 articles retrieved for full review, we included 156 published articles reporting on 103 studies: 22 head-to-head randomized controlled trials (RCTs), 1 head-to-head nonrandomized controlled trial, 13 placebo-controlled trials, 10 meta-analyses or systematic reviews, 55 observational studies, and 2 poor-quality pooled data analyses on subgroups. Of the

103 included studies, 51 (50 percent) were supported by pharmaceutical companies, 21 (20 percent) were funded by governmental or independent funds, and 11 (11 percent) were supported by a combination of pharmaceutical and government funding. We could not determine the source of support for 20 studies (19 percent). One-quarter of the individual trials were rated good quality; most were found to be fair quality.

Conclusions

We present our major findings in this section by type of drug comparison and important outcomes (both benefits and harms). We limit our findings in the Executive Summary to RA because no comparative evidence exists on PsA for any drugs. We also have not presented findings from subpopulation analyses for RA because the strength of evidence for age, sex, and comorbidities is very weak.

Monotherapy vs. Monotherapy Synthetic DMARDs

The data show no differences in radiographic outcomes over 2 years for leflunomide and methotrexate. One systematic review that included a meta-analysis of two RCTs suggested that higher proportions of patients on methotrexate than on

leflunomide met the American College of Rheumatology (ACR) 20-percent improvement criteria

at 1 year (odds ratio [OR], 1.43; 95-percent confidence interval [CI], 1.15-1.77, P = 0.001), but statistical significance was lost at 2 years (OR, 1.28; 95-percent CI, 0.98-1.67). However, patients on methotrexate had less improvement in functional status and health-related quality of life than patients taking leflunomide (Short Form [SF]-36 physical component: 4.6 vs. 7.6, P