Advances in rheumatology: new targeted therapeutics

Abstract

Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.

Figure 1

Relationships between cytokines. The cascade and network of cellular responses mediated by TNF common to inflammatory arthritides: rheumatoid arthritis (RA), Crohn’s disease (CD) and psoriasis (Ps). Chond, chondrocyte; COX-2, cyclooxygenase-2; CRP, C-reactive protein; DC, dendritic cell; EC, endothelial cell; E-sel, E-selectin; GM-CSF, granulocyte–macrophage colony-stimulating factor; Hep, hepatoxyte; ICAM-1, intercellular adhesion molecule-1; IL, interleukin; INOS, inducible nitric oxide synthase; Mac, macrophage; MCP-1, monocyte chemotactic protein-1; MMP, matrix metalloproteinase; NO, nitric oxide; OC, osteoclast; OPG, osteoprotegerin; PGE2, prostaglandin E₂; RANKL, receptor activator of NF-κB ligand; RANTES, regulated on activation normal T-cell expressed and secreted; ROI, reactive oxygen intermediates; SOD, superoxide dismutase; Treg supp, suppression of T regulatory cells; VCAM-1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor. Reproduced with permission from [1].