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

Tumor necrosis factor alpha (TNFα) inhibitors are a mainstay of treatment for rheumatoid arthritis (RA) patients after failed responses to conventional disease-modifying antirheumatic drugs (DMARDs). Despite the clinical efficacy of TNFα inhibitors (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 TNFα 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 TNFα inhibitor immunogenicity. In this review, we highlight the limitations of MTX for mitigating TNFα inhibitor immunogenicity, and we discuss potential alternative pharmacological targets for decreasing the risk of immunogenicity during TNFα inhibitor therapy based on the key kinases, second messengers, and shared signaling mechanisms of lymphocyte receptor signaling.