Volume 68, February 2023, 102320Author links open overlay panelAbstract

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.

Section snippetsBackground

Rheumatoid arthritis (RA) is the most common type of chronic inflammatory disease affecting the joints. The goals of RA treatment are to achieve disease remission by attenuating joint inflammation and damage [1]. Low-dose methotrexate (MTX, 5–25 mg/week) is the first-line therapy for RA [2], whereas biological disease-modifying antirheumatic drugs (DMARDs), such as tumor necrosis factor alpha (TNFα) inhibitors are effective in reducing inflammation after failed or inadequate responses to

Strategies for mitigating biologic immunogenicity require attenuating antigen-specific CD4+ T- and B-cell activation

Because CD4+ T and B cells are essential for the development of biologic immunogenicity, suppressing their activation and proliferation during biologic exposure is essential for attenuating drug-induced immunogenicity. Unlike immunosuppressive agents used for the prevention of graft-versus-host-disease (e.g., tacrolimus and cyclosporine A or CsA), optimal immunosuppressive strategies will have minimal toxicities, limit the risk of neutropenia and infections, and will not attenuate RA efficacy.

Conclusions and future perspectives

The success of MTX in reducing TNFi immunogenicity has indicated that strategies leading to adenosine signaling can protect from this toxicity, presumably via attenuating NF-κB. Mechanistically, strategies that can attenuate the transcriptional activity of NFAT and/or AP-1 should enhance the anti-inflammatory properties of MTX. It is also possible that adenosine receptor agonist or inhibitors that increase extracellular adenosine levels may lead to similar effects as MTX or allow for lower MTX

Conflict of interest statement

Nothing declared.

Acknowledgments

This work was supported by the University of Pittsburgh School of Pharmacy and NIH Grant R01 CA216815.

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