The Effectiveness of Leflunomide Etanercept and Infliximab in the Treatment of Rheumatoid Arthritis:a systematic review

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the diarthrodial (synovial) joint. It has an autoimmune feature, with an unidentified cause, and has a substantial societal effect in terms of cost, disability, and lost productivity. Much emphasis has been geared towards investigating the pathogenesis of RA, and to identify aetiologic markers. Greater insight into the cellular and molecular systems of RA has led to the development of new therapies, and clinical trials have demonstrated the efficacy of such therapies in patients with active disease. Existing management of RA focuses on early use of disease modifying anti-rheumatic drugs (DMARDs), particularly methotrexate and sulfasalazine, to control clinical features and to slow disease progression. However, much of these conventional drugs often produce delayed, inadequate or temporary responses, or troublesome unwanted effects. Several factors are involved in the pathogenesis of RA. T lymphocytes and the cytokines tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) appear particularly important in the development of synovitis and joint destruction. Drugs that target TNF-α, such as etanercept (Enbrel®) and infliximab (Remicade®), and leflunomide (Arava®) that targets proliferating T-cells offer a novel approach. With the approval of marketing these drugs by the Food and Drug Administration (FDA), the safety and efficacy data for these new disease modifying anti-rheumatic agents and combination regimens have come under closer scrutiny. Objective: To assess the evidence for the effectiveness of etanercept, infliximab and leflunomide in the treatment of rheumatoid arthritis (RA). Methods: A systematic review of randomised controlled trials (RCTs) investigating etanercept, infliximab and leflunomide in the treatment of adult RA was carried out. Relevant papers were retrieved through Medline, and the main outcome studied was response defined using the American College of Rheumatology 20 (ACR20) criteria. Other outcomes assessed included the health assessment questionnaire (HAQ) scores and radiographic scores. Where appropriate data were pooled. Results: Twenty-two reports were identified. Seven reports assessed etanercept, six infliximab, and nine leflunomide. Eleven RCTs (fifteen reports) gave data suitable for meta-analysis (5 for etanercept, 1 for infliximab and 5 for leflunomide). All three agents showed significant benefit over placebo in ACR 20 scores, HAQ scores and retardation of joint damage. Anti-TNF therapy appeared to be slightly superior to leflunomide. The differences in efficacy between methotrexate and etanercept or leflunomide were not very considerable. Significant differences, in favour of etanercept (25 mg) were only seen at twenty-four months (RD 0.13 CI: 0.04, 0.22). Leflunomide was also comparable to sulfasalazine. Infliximab mono-therapy was not compared to any other DMARD. Methotrexate combination strategies with all three novel agents resulted in highly significant response rates. Conclusion: International trials have demonstrated that etanercept, infliximab and leflunomide are very effective in lowering disease activity in RA sufferers. All these agents have tolerable side effects, with common unwanted effects for the anti-TNF agents being infection and injection-site reactions. Liver toxicity is the main concern with leflunomide. Infliximab and etanercept are costly, however recent economic evaluations suggest that these agents may well be cost-effective. All three agents have certainly increased the therapeutic repertoire for RA drug therapy. However their risk-benefit profiles with long-term use have yet to be fully established.