Therapeutic strategies for rheumatoid arthritis

Key Points Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease that affects 0.5–1% of the population in the industrialized world and commonly leads to significant disability and consequently a reduction in quality of life. Drug therapy for RA rests on two bases: symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). Whereas NSAIDs do not interfere with the underlying immuno-inflammatory events or retard joint destruction, DMARDs, the focus of this review, 'modify' the disease process in all these respects. DMARDs are divided into small-molecule drugs and biological therapies. Approved agents, such as the small molecules methotrexate and leflunomide, and biological therapies, such as tumour-necrosis-factor (TNF) blockers and IL-1 blockers, are briefly reviewed, before considering approaches that could lead to novel agents. Most new candidate small-molecule DMARDs are enzyme inhibitors, which target either secreted enzymes involved in tissue destruction, such as matrix metalloproteinases, enzymes liberating active cytokines from their precursor or membrane-associated forms, or kinases of various signal transduction cascades leading to the activation of transcription factors. Potential approaches to developing novel biological agents that are discussed include targeting TNF, other proinflammatory cytokines and lymphokines; blocking chemokines and angiogenesis; anti-inflammatory cytokines; targeting T cells; targeting B cells and complement; targeting adhesion molecules; targeting Toll-like receptors; and targeting osteoclasts. Recent years have seen considerable advances in our understanding of both the clinical and basic-research aspects of rheumatoid arthritis. Clinical progress has come from a better recognition of the natural history of the disease, the development and validation of outcome measures for clinical trials and, consequently, innovative trial designs. In parallel, basic research has provided clues to the pathogenic events underlying rheumatoid arthritis, and advances in biotechnology have facilitated the development of new classes of therapeutics. Here, we summarize the fruits of these advances: innovative approaches to the use of existing, traditional disease-modifying antirheumatic drugs; novel agents approved very recently; and further avenues that are presently under investigation or which are of more distant promise.