Elsevier

Joint Bone Spine

Volume 69, Issue 1, January 2002, Pages 12-18
Joint Bone Spine

REVIEW
Discovery of TNF-α as a therapeutic target in rheumatoid arthritis: preclinical and clinical studies

https://doi.org/10.1016/S1297-319X(01)00335-9Get rights and content

Abstract

The development of effective new treatments is greatly facilitated by the understanding of the mechanisms of disease. In rheumatoid arthritis, there has been progress in understanding its immunology, the HLA class II predisposition including the ‘shared epitope’ and more recently in understanding the importance of proinflammatory cytokines. Here we review our work in defining TNFα as a therapeutic target in rheumatoid arthritis, from an understanding of molecular pathogenesis in vitro, to formal proof in the clinic in vivo. There is now extensive clinical use of anti-TNFα biologicals for severe rheumatoid arthritis in the US and Europe.

Section snippets

Preclinical studies

The progress in defining the nature of the soluble protein mediators of inflammation, immunity, tissue growth, repair, fibrosis, which are now collectively termed cytokines (reviewed in 1, 2, 3), prompted several groups in the mid-80s to investigate their possible role in various diseases (e.g., 4, 5, 6, 7). Our interest in this field was stimulated by awareness that a number of disease features of human autoimmune sites were possibly dependent on cytokines. Thus human thyroid Grave’s disease

Clinical studies

Our work in defining TNFα as a therapeutic target from 1988 to 1991 led us to seek an industrial partner who could provide us with an anti-TNFα antibody for clinical use to help us verify our ideas. Eventually we found a willing company, Centocor, Inc., who had produced a chimaeric (mouse Fv, human IgG1) neutralizing antibody with high affinity for TNFα for clinical trials in sepsis from a murine anti-TNF hybridoma produced in Jan Vilcek’s laboratory 〚32〛. It was termed cA2, subsequently known

Mechanism of action studies

The efficacy of infliximab prompted us to try to ascertain the important pathways controlled by TNFα in RA, and thus learn more about the pathogenesis of RA. For this purpose we used blood and sometimes synovial samples from patients in the clinical trials. We were able to establish the following:

  • •

    TNFα regulates a cytokine cascade in vivo. Blockade of TNFα leads to a rapid diminution in the serum levels of IL-6, IL-1, IL-8, MCP-1, VEGF, etc. This confirmation in vivo is important, as in vitro

Conclusion

Clinical science moves slowly. It does so because of the paramount concern over safety, from the Hippocratic tradition, of doing no harm to patients. As TNFα is an important component of host defence, we and others had major worries about the safety of anti-TNFα therapy, especially in the long term. Thankfully, these concerns are not major, and the overall safety of anti-TNFα therapies, be it infliximab (Remicade™) or etanercept (Enbrel™), is at least as good as that of any other anti-rheumatic

Acknowledgements

The work described here would not have been possible without the financial support of the Arthritis Research Campaign, nor the dedication of many colleagues and collaborators in an increasing network. Involved in preclinical studies include F. Brennan, G. Buchan, R. Williams, C. Haworth, E. Paleolog, C. Chu, M. Field, P. Gray, M. Shepard, T. Taniguchi, T. Kishimoto.

Of importance in clinical studies include F. Breedveld, J. Kalden, J. Smolen, P. Lipsky, M. Elliott, P. Taylor, and from Centocor,

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