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  • Review Article
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The IL-23–IL-17 pathway as a therapeutic target in axial spondyloarthritis

Nature Reviews Rheumatology volume 15, pages 747–757 (2019)Cite this article

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Abstract

The cytokines IL-23 and IL-17 have an important role in the pathogenesis of, and as a therapeutic target in, both animal models of chronic inflammation and some human chronic inflammatory diseases. The traditional view is that a main source of IL-17 is T cells and that IL-17 production is under the control of IL-23. IL-17 inhibition has shown good efficacy in clinical trials for ankylosing spondylitis (AS), a subtype of axial spondyloarthritis (axSpA) characterized by radiographic evidence of sacroiliitis. On the basis of data from animal models, genetic studies and the investigation of tissue and blood samples from patients with AS, IL-23 had also been predicted to be important in the pathogenesis of this disease and was therefore considered a potential therapeutic target for axSpA. However, two placebo-controlled, double-blind clinical trials in axSpA of monoclonal antibodies directed against either the p40 protein or the p19 protein of the IL-23 molecule had clear negative results. These findings indicate that IL-23 and IL-17 are at least partly uncoupled in axSpA. Reasons as to why, when and how such an uncoupling might occur are discussed in this Review, with special reference to the unique microenvironment of the subchondral bone marrow in axSpA.

Key points

  • The IL-17 pathway has an important role in the pathogenesis of axial spondyloarthritis (axSpA); IL-23 is thought to be involved too as it stimulates the production of IL-17.

  • IL-17 inhibitors and TNF inhibitors are currently the only effective and approved biological DMARDs for axSpA.

  • IL-23 inhibitors are effective against psoriasis and psoriatic arthritis, but not against axSpA; however, IL-23 inhibitors might have an effect on peripheral enthesitis in axSpA, which should be investigated further.

  • On the basis of negative trial data, a role for IL-23 in the pathogenesis of axSpA is uncertain.

  • Whether IL-17 inhibitors have an effect on new bone formation in axSpA has still to be clarified, but an effect of IL-23 inhibitors is unlikely.

  • The discrepancy in efficacy between effective IL-17 inhibitors and non-effective IL-23 inhibitors in axSpA is unique among immune-mediated diseases and might be explained by an uncoupling of IL-17 and IL-23.

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Fig. 1: Potential differences in the IL-23–IL-17 pathway in psoriasis and spondyloarthritis.
Fig. 2: Effects of cytokine exposure on bone and ligaments.

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  1. Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Berlin, Germany

    Joachim Sieper & Denis Poddubnyy

  2. Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany

    Denis Poddubnyy

  3. Immunogenomics and Inflammation Research Unit EA4130, Department of Immunology and Rheumatology, Hôpital Édouard Herriot, University of Lyon, Lyon, France

    Pierre Miossec

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J.S. declares that he has received honoraria for consultancies or for being a member of the speakers’ bureau from Abbvie, Boehringer-Ingelheim, Janssen, Lilly, Merck, Novartis, Pfizer and UCB. D.P. declares that he has received honoraria for consultancies or for being a member of the speakers’ bureau from Abbvie, Celgene, Lilly, Merck, Novartis, Pfizer, Roche and UCB. P.M. declares no competing interests.

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Sieper, J., Poddubnyy, D. & Miossec, P. The IL-23–IL-17 pathway as a therapeutic target in axial spondyloarthritis. Nat Rev Rheumatol 15, 747–757 (2019). https://doi.org/10.1038/s41584-019-0294-7

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