, Volume 78, Issue 14, pp 1397–1418 | Cite as

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

  • Susanne Juhl PedersenEmail author
  • Walter P. Maksymowych
Leading Article


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).


Compliance with Ethical Standards

Conflicts of Interest

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.


No financial support was received for the preparation of this manuscript.


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Susanne Juhl Pedersen
    • 1
    Email author
  • Walter P. Maksymowych
    • 2
  1. 1.Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine DiseaseRigshospitaletGlostrupDenmark
  2. 2.Department of MedicineUniversity of AlbertaEdmontonCanada

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