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Successes and failures of chemokine-pathway targeting in rheumatoid arthritis

Nature Reviews Rheumatology volume 12, pages 5–13 (2016)Cite this article

Subjects

Key Points

  • Chemokines and chemokine receptors have been implicated in leukocyte recruitment and angiogenesis underlying rheumatoid arthritis (RA) and other inflammatory rheumatic diseases

  • Chemokines and chemokine receptors are abundant in the synovium and other inflammatory sites

  • Promising results from preclinical studies of agents targeting chemokines and chemokine receptors in animal models of arthritis have not been replicated in human trials of antibodies and synthetic compounds in RA

  • Possible reasons for the lack of positive results from human trials include pathway redundancy, incomplete antagonism and interspecies differences that limit translation of results from animal models

  • An alternative approach to the targeting of individual chemokines is chemokine-receptor blockade

  • The CCR1 receptor is a potential target, assuming that a high level of receptor occupancy can be maintained throughout treatment

Abstract

Chemokines and chemokine receptors are involved in leukocyte recruitment and angiogenesis underlying the pathogenesis of rheumatoid arthritis (RA) and other inflammatory rheumatic diseases. Numerous chemokines, along with both conventional and atypical cell-surface chemokine receptors, are found in inflamed synovia. Preclinical studies carried out in animal models of arthritis involving agents targeting chemokines and chemokine receptors have yielded promising results. However, most human trials of treatment of RA with antibodies and synthetic compounds targeting chemokine signalling have failed to show clinical improvements. Chemokines can have overlapping actions, and their activities can be altered by chemical modification or proteolytic degradation. Effective targeting of chemokine pathways must take acount of these properties, and can also require high levels of receptor occupancy by therapeutic agents to prevent signalling. CCR1 is a promising target for chemokine-receptor blockade.

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Figure 1: Leukocyte trafficking into the inflamed synovium.
Figure 2: Known interactions between chemokines and their receptors.

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Authors and Affiliations

  1. Department of Rheumatology, Institute of Medicine, University of Debrecen Faculty of Medicine, Nagyerdei Str 98, Debrecen, H-4004, Hungary

    Zoltán Szekanecz

  2. Department of Internal Medicine, Division of Rheumatology, University of Michigan Health System, 1500 East Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Alisa E. Koch

Authors
  1. Zoltán Szekanecz
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  2. Alisa E. Koch
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Both authors contributed to researching data and writing the article, and to reviewing and editing the manuscript before submission.

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Correspondence to Zoltán Szekanecz.

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Szekanecz, Z., Koch, A. Successes and failures of chemokine-pathway targeting in rheumatoid arthritis. Nat Rev Rheumatol 12, 5–13 (2016). https://doi.org/10.1038/nrrheum.2015.157

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