The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

Douglas J Veale, Dennis McGonagle, Iain B McInnes, James G Krueger, Christopher T Ritchlin, Dirk Elewaut, Keith S Kanik, Thijs Hendrikx, Gabriel Berstein, Jennifer Hodge, Jean-Baptiste Telliez, Douglas J Veale, Dennis McGonagle, Iain B McInnes, James G Krueger, Christopher T Ritchlin, Dirk Elewaut, Keith S Kanik, Thijs Hendrikx, Gabriel Berstein, Jennifer Hodge, Jean-Baptiste Telliez

Abstract

The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.

Figures

Fig . 1
Fig. 1
Innate and adaptive immune responses in the initiation and perpetuation of SpA The JAK pathway sits at the crossroads of both key innate and adaptive immune cell populations that are thought to be important in SpA pathogenesis. The tissue-specific targets of SpA-related disease, including the skeleton, skin and gut, interact with diverse innate immune cells to maintain tissue homeostasis. Although SpA is immunologically heterogeneous, there is strong evidence for adaptive immune responses that could be due to autoantigens or to other antigens that breech tissue barriers. JAK: Janus kinase; Tc: cytotoxic T cell; Th: T helper; TYK: tyrosine kinase.
Fig . 2
Fig. 2
JAK inhibition of cytokine pathways involved in the pathogenesis of SpA Cytokine signaling and production at the enthesis: signaling for a number of key cytokine pathways implicated in the pathogenesis of SpA is blocked through direct inhibition of JAKs, including IFNγ, IL-7, IL-12, IL-15, IL-22 and IL-23. Other important cytokines, such as TNFα, IL-1 and IL-17, signal independently of JAKs, but their expression is regulated by JAK-dependent cytokines and, therefore, may be blocked indirectly via JAK inhibition. These cytokines influence cellular function for a broad range of innate and adaptive cell types, including many of those shown in Fig. 1. JAK, Janus kinase; TYK, tyrosine kinase.

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