Elsevier

The Lancet

Volume 370, Issue 9602, 1–7 December 2007, Pages 1861-1874
The Lancet

New Drug Class
New therapies for treatment of rheumatoid arthritis

https://doi.org/10.1016/S0140-6736(07)60784-3Get rights and content

Summary

Rheumatoid arthritis is characterised by pain, swelling, and destruction of joints, with resultant disability. Only disease-modifying antirheumatic drugs can interfere with the disease process. In the past few years, biological agents, especially inhibitors of tumour necrosis factor, have allowed for hitherto unseen therapeutic benefit, although even with these drugs the frequency and degree of responses are restricted. Therefore, new agents are needed, and three novel biological compounds for treatment of rheumatoid arthritis have already been used in practice or are on the horizon: rituximab (anti-CD20), abatacept (cytotoxic T-lymphocyte antigen 4 immunoglobulin), and tocilizumab (anti-interleukin 6 receptor). We discuss the targets of these drugs, the roles of these targets in the pathogenesis of rheumatoid arthritis, and the efficacy and adverse effects of these agents from clinical trial data. Novel therapeutic strategies in conjunction with optimised disease assessment for better treatment of rheumatoid arthritis and an outlook into potential future targets are also presented.

Section snippets

Pathogenesis of rheumatoid arthritis

The cause of rheumatoid arthritis remains unknown, but insights into pathogenic pathways have accumulated over the past two decades (figure 1). A plethora of cells enter the synovium via activated endothelial cells expressing various adhesion molecules. Several cell types, especially dendritic cells, express pattern-recognition molecules such as Toll-like receptors, which bind to various foreign and self structures as part of their innate immune response activity, become activated subsequently,

Assessment of disease activity and outcome

Rheumatoid arthritis is a heterogeneous disorder. Its many clinical features—differing between, and even within, individuals—make assessment of any one variable, such as joint count, morning stiffness, acute-phase response, or fatigue, unreliable for groups of patients.37, 38 Therefore, composite indices have been developed and shown to reliably indicate disease activity and response to treatment (table 1).39 American College of Rheumatology (ACR) response criteria40 are categorical in nature

Limitations of disease-modifying antirheumatic drugs, including targeted treatments

Traditionally, rheumatoid arthritis has been treated with non-steroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying antirheumatic drugs (figure 2). Only disease-modifying agents—and to some extent glucocorticoids—can impede or halt the inflammatory and destructive disease processes. The most widely used small-molecule disease-modifying antirheumatic drug is methotrexate, a cornerstone of most treatment regimens for rheumatoid arthritis,58, 59, 60 with the highest retention

New classes of targeted treatments

Two new classes of biological agents have been approved for the treatment of rheumatoid arthritis—rituximab and abatacept. A third compound, tocilizumab, is in phase III trials.

Other novel agents in early trial phases

Since neither established nor new treatments—as effective as they are in various clinical situations—cure rheumatoid arthritis or remit the disease in most patients, the search for better drugs (or strategies) goes on, and various novel targets are currently being intensively studied. These include interleukins 15, 17, 18 and 32 and chemokines or chemokine receptors.34, 129, 130, 131, 132 Similarly, interference with Toll-like receptor pathways might constitute a novel approach.36, 133, 134

Recommendations and outlook

All three agents—rituximab (approved for combination therapy with methotrexate in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to disease-modifying antirheumatic drugs including TNF inhibitors), abatacept (approved in the USA for rheumatoid arthritis patients who failed any other type of disease-modifying drug and in Europe for patients who failed other disease-modifying drugs including TNF inhibitors), and tocilizumab (licensed for

Search strategy and selection criteria

We searched the Cochrane Library, Medline, and Embase from 1995 to 2007. We used the following generic drug names as search terms: “abatacept”, “CTLA4Ig”, “rituximab”, “anti-CD20”, “tocilizumab”, “MRA”, and “anti-IL-6R”. We limited the results to randomised trials and selected studies on rheumatoid arthritis. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Our reference list was modified on the basis of comments

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