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Emerging targets of biologic therapies for rheumatoid arthritis

Nature Clinical Practice Rheumatology volume 3, pages 336–345 (2007)Cite this article

Abstract

Advances in molecular biology and the clinical success of strategies that target tumor necrosis factor (TNF) have led to further research into the pathophysiology of human rheumatoid arthritis. Several novel therapeutic targets have emerged from these efforts, including not only molecules that regulate TNF (e.g. TNF-α converting enzyme), the complex cytokine network (e.g. interleukin [IL]-6, IL-15, IL-17) and several adipokines, but also targets that originate from cellular and subcellular components of the disease. Strategies that aim at cellular targets include antibodies to CD20 or BLyS (also known as TNF ligand family member 13b), which deplete or inhibit B cells, as well as approaches that interfere with membrane-derived microparticles. Components of subcellular pathways, which are predominantly upstream of the central regulator of transcription nuclear factor κB, have also been studied. Of these, strategies that target mitogen-activated protein kinases have a leading role and are on the verge of clinical use; approaches that target specific molecules such as Janus kinases, signal transducer and activator of transcription proteins, and suppressor of cytokine signaling proteins also seem to show promise and might have a clinical application in the future.

Key Points

  • Biologics are a novel class of agents that are designed to target defined pathogenetic mechanisms and molecules with high specificity

  • Interleukin (IL)-6, IL-15, IL-17 and receptor activator of nuclear factor κB ligand form a complex cytokine network with IL-1 and tumor necrosis factor that promotes joint inflammation and joint destruction

  • Adipokines and microparticles are intriguing targets for new biologics

  • The mitogen-activated protein kinases and transcription factors such as nuclear factor κB are essential intracellular mediators of inflammation and, therefore, are potentially powerful targets, but must be selected carefully because of possible adverse effects

  • Components of intracellular signaling pathways upstream of nuclear factor κB seem to be safer, although potentially less effective, than downstream targets

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Figure 1: Potential intercellular targets for biologic therapy of RA
Figure 2: Potential intracellular targets for biologic therapy of RA

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Acknowledgements

IH Tarner was funded in part by the Deutsche Forschungsgemeinschaft. U Müller-Ladner was funded by the Deutsche Forschungsgemeinschaft. S Gay was funded by the Swiss National Science Foundation.

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Authors and Affiliations

  1. IH Tarner is a Rheumatology Fellow in the Department of Internal Medicine and Rheumatology at the Justus-Liebig-University of Gießen. U Müller-Ladner is a Professor of Medicine and Chair of the Department of Internal Medicine and Rheumatology at the Justus-Liebig-University of Gießen, as well as Director of the Division of Rheumatology and Clinical Immunology at the Kerckhoff-Klinik Bad Nauheim, Germany.,

    Ingo H Tarner & Ulf Müller-Ladner

  2. S Gay is Professor and Director of the WHO Collaborating Center for Molecular Biology and Novel Therapeutic Strategies at the Department of Rheumatology of the University Hospital Zurich, Switzerland.,

    Steffen Gay

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Correspondence to Steffen Gay.

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Tarner, I., Müller-Ladner, U. & Gay, S. Emerging targets of biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 3, 336–345 (2007). https://doi.org/10.1038/ncprheum0506

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