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Beyond the TNF-α Inhibitors: New and Emerging Targeted Therapies for Patients with Axial Spondyloarthritis and their Relation to Pathophysiology

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Abstract

Axial spondyloarthritis (axSpA) is a complex disease that affects the joints and entheses of axial and peripheral joints, and is associated with inflammation in extra-articular sites such as the gut. Improved knowledge on genetics and immunology has improved treatment options with the availability of treatments targeting tumor necrosis factor-α (TNF-α) and interleukin (IL)-17. However, these agents do not provide clinical benefit for about 40% of patients, and additional therapeutic options are necessary. Theories on pathogenesis includes misfolding of HLA-B*27 during its assembly leading to endoplasmic reticulum stress and autophagy/unfolded protein response (UPR). HLA-B*27 may express free heavy chain on the cell surface, which activates innate immune receptors on T, natural killer, and myeloid cells with pro-inflammatory effects. Activation of UPR genes is associated with increased TNF-α, interleukin-23 (IL-23), IL-17, interferon-γ expression, and expansion of T helper (Th)-17 cells. Certain genotypes of endoplasmic reticulum aminopeptidase (ERAP) 1 and 2 are associated with ankylosing spondylitis (AS) and functionally interact with the HLA-B27 peptidome. Innate immune cells type 3, which express RORγt, regulate expression of IL-17 and IL-22 in T cells. Stimulation of gamma-delta T cells with IL-23 also induces IL-17. Mucosa-associated invariant T cells residing in the gut mucosa express IL-17 in AS patients after stimulation with IL-7. Prostaglandin E2 induces IL-17A independent of IL-23 via IL-1β and IL-6. The pathogenic role of gut inflammation, zonulin and microbiota, which has a different composition in AS patients, remains to be elucidated. This article also includes a comprehensive review on the mechanism of action and efficacy of the biological treatments currently approved for axSpA (TNF-α inhibitors and IL-17 inhibitors) and future targets for treatment (other IL-17 family member (s), Janus kinase, IL-23, and phosphodiesterase 4).

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Authors and Affiliations

  1. Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Disease, Rigshospitalet, Valdemar Hansens Vej 17, 2600, Glostrup, Denmark

    Susanne Juhl Pedersen

  2. Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada

    Walter P. Maksymowych

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Correspondence to Susanne Juhl Pedersen.

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Walter P. Maksymowych has \received consulting honoraria from Abbvie, Eli-Lilly, Galapagos, Janssen, Novartis, Pfizer, and UCB; grants from Abbvie, Janssen, Novartis, and Pfizer; and holds a position as Chief Medical Officer in Canadian Research Education (CaRE) Arthritis. Susanne Juhl Pedersen has received research grants/honoraria/speaker fee from Abbvie, BMS, MSD, Pfizer, and Novartis.

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Pedersen, S.J., Maksymowych, W.P. Beyond the TNF-α Inhibitors: New and Emerging Targeted Therapies for Patients with Axial Spondyloarthritis and their Relation to Pathophysiology. Drugs 78, 1397–1418 (2018). https://doi.org/10.1007/s40265-018-0971-x

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