Pharmacological strategies for mitigating anti-TNF biologic immunogenicity in rheumatoid arthritis patients

Tumor necrosis factor alpha (TNFa) inhibitors are a mainstay of treatment for rheumatoid arthritis (RA) patients after failed re-sponses to conventional disease-modifying antirheumatic drugs (DMARDs). Despite the clinical efficacy of TNFa in-hibitors (TNFi), many RA patients experience TNFi treatment failure due to the development of anti-drug antibodies (ADAs) that can neutralize drug levels and lead to RA disease relapse. Methotrexate (MTX) therapy with concomitant TNFa inhibitors decreases the risk of TNFi immunogenicity, but additional and/ or alternative strategies are needed to reduce MTX-associated toxicities and to further increase its potency for preventing TNFa inhibitor immunogenicity. In this review, we highlight the limitations of MTX for mitigating TNFa inhibitor immunoge-nicity, and we discuss potential alternative pharmacological targets for decreasing the risk of immunogenicity during TNFa inhibitor therapy based on the key kinases, second messen-gers, and shared signaling mechanisms of lymphocyte re-ceptor signaling.