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Tumour Necrosis Factor α Antagonists in the Treatment of Rheumatoid Arthritis: An Immunological Perspective

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Abstract

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune conditions, affecting approximately 1 % of the adult population. It is associated with decreased quality of life and considerable morbidity and mortality. Various inflammatory cells, including macrophages, neutrophils, mast cells, natural killer cells, B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression. Several cytokines, including interleukin (IL)-1α and/or IL-1β, and tumour necrosis factor (TNF)-α, are involved at each stage of RA pathogenesis; namely, by augmenting autoimmunity, sustaining long-term inflammatory synovitis and promoting joint damage. Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro-inflammatory mediators. As early as the late 1980s, TNF had been identified as a potential target in RA. Five anti-TNF drugs, infliximab, adalimumab, certolizumab pegol, etanercept and golimumab, are now approved for the treatment of RA in various countries. All are bivalent monoclonal antibodies, with the exception of the monovalent certolizumab and etanercept, which is an engineered dimeric receptor. Although all react with and neutralise soluble TNF in vitro, structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects. Pegylated certolizumab permits once-monthly dosing. Other mechanisms of action proposed to be important for the efficacy of anti-TNF agents are as follows: induction of apoptosis of both monocytes and T cells; neutralization of membrane TNF; antibody-dependent cell-mediated and complement-dependent cytotoxicity; and reverse signaling via membrane TNF.

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Acknowledgments

This manuscript was prepared with financial assistance from UCB Pharma SpA, Milan, Italy. The authors would like to thank Jane Caple and David Murdoch, inScience Communications, Springer Healthcare, for their assistance in the preparation of the manuscript. Assistance with post-submission requirements was provided by Sheridan Henness, PhD, inScience Communications, Springer Healthcare. This article was published in a supplement sponsored by UCB Pharma SpA, Italy. The supplement was guest edited by Daniel Aletaha and peer reviewed by Leonard H. Calabrese who both received a small honorarium from Springer Healthcare to cover out-of-pocket expenses. D.A. has received honoraria and research grants from UCB, and honoraria from Abbvie, Grünenthal, Janssen, Merck, Medac, Mitsubishi Tanabe, Pfizer, AstraZeneca, Eli Lilly, Novo Nordisk, and Sanofi/Regeneron. L.H.C. has consulted for UCB, Roche, Janssen, Pfizer and BMS.

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  1. Divisione di Reumatologia, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Pier-Luigi Meroni

  2. Department of Internal Medicine and Medical Specialties, University of Rome “La Sapienza”, Rome, Italy

    Guido Valesini

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Meroni, PL., Valesini, G. Tumour Necrosis Factor α Antagonists in the Treatment of Rheumatoid Arthritis: An Immunological Perspective. BioDrugs 28 (Suppl 1), 5–13 (2014). https://doi.org/10.1007/s40259-013-0063-0

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