Efficacy and safety implications of molecular constructs of biological agents for rheumatoid arthritis

Targeted biologic immunomodulatory therapies have had a major impact in rheumatoid arthritis (RA) treatment, including tumor necrosis factor (TNF)-α inhibition, B-cell depletion, interference in T-cell costimulation and interleukin (IL)-1 and IL-6 inhibition. Along with the recognition of the importance of early, aggressive disease-modifying antirheumatic drugs (DMARDs) grounded in the use of methotrexate, the introduction of biologic DMARDs (bDMARDs) has provided significantly improved outcomes in patients with RA with a goal of true remission, or at least a state of very low disease activity, now possible in many. There are a number of methods to inhibit cytokines, cellular receptors and pathways of signal transduction that have been used thus far and are in development. In some cases, the method of target inhibition and differences in molecular construct has impacted efficacy and/or safety; whereas, in other cases, similar safety and/or efficacy signals across compounds have demonstrated class- or target-related effects. As the development of targeted therapies moves forward, it is increasingly important to understand the role of the target both in RA disease pathogenesis and normal host defense and the mechanisms of target inhibition.

This review covers the targets of therapy for biologic agents in rheumatic diseases, their molecular constructs and implications on efficacy and safety, with focus on approved treatments for RA.

Advances in molecular biology have provided a number of different ways to impact pathobiologically relevant pathways and targets in terms of the molecular construct of individual compounds. The use of these agents have provided important mechanistic insights into disease pathogenesis, and in some cases are associated with differences in efficacy and safety among agents even with the same downstream target. As bDMARDs identify promising mechanisms, oral agents that target or specifically regulate downstream pathways are made possible.