JAK inhibition and axial spondyloarthritis: new steps on the path to understanding pathophysiology

Abstract

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the sacroiliac joints and spine. Tumor necrosis factor (TNF) and interleukin (IL)-17A are key cytokines in disease pathogenesis and are established axSpA treatment targets. Recently, axSpA treatment options have been complemented by Janus kinase inhibitors (JAKi), which inhibit various cytokines without directly impacting TNF or IL-17 signaling. The effect of JAKi on axSpA remains under investigation: besides a JAK2-mediated (and potentially tyrosine kinase 2 [TYK2]-mediated) effect on the IL-23/IL-17 axis, emerging evidence suggests γδ T cells, type 3 innate lymphoid cells, and mucosa-associated invariant T cells, which are dependent on IL-7 and/or IL-15 and thus on JAK1, are strongly inhibited by JAKi used to treat axSpA. This review summarizes potential effects of JAKi on axSpA and shows evidence from pre-clinical/clinical studies. Greater understanding of the mechanisms of action of available treatments may improve knowledge of axSpA and pave the road for future therapies.

Keywords: Axial spondyloarthritis; JAK-STAT pathway; Janus kinase inhibitor; gut-joint axis; pathophysiology.

Figure 1

Schematic overview of the link between JAK-dependent cytokines and axSpA pathophysiology. Adapted from Felice C, et al. Int J Mol Sci. 2023;24:3957 (Copyright: ^© 2023 by the authors. Licensee MDPI, Basel, Switzerland; open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license [https://creativecommons.org/licenses/by/4.0/]). AxSpA development is associated with several genetic factors, of which HLA-B27 is the most prominent. Abnormalities and dysbiosis in the gut can lead to the activation of local immune cells. Subsequent cytokine production, including IL-7 and IL-23, further activate tissue-resident cells, such as MAIT, γδ T and Th17 cells, and ILC3. These cells can produce IL-17 that, together with TNF, play a major role in driving entheseal and bone inflammation, leading to axSpA-specific tissue damage. AxSpA, axial spondyloarthritis; FLS, fibroblast-like synoviocytes; ILC3, type 3 innate lymphoid cells; MAIT, mucosa-associated invariant T; NF-κB, nuclear factor-κB.

Figure 2

JAK–STAT-dependent transmission of cytokine signaling and respective JAKi. Adapted from Choy EH. Rheumatology. 2018;58(6):953-962 (^© The Author[s] 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology; open access article distributed under the terms of the Creative Commons Attribution License [http://creativecommons.org/licenses/by/4.0/], which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited). GM-CSF, granulocyte–macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; JAKi, Janus kinase inhibitors; P, phosphorylation, STAT, signal transducer and activator of transcription; TYK, tyrosine kinase.

Figure 3

Effects of JAK inhibition on pathophysiology of axSpA animal models (A-D). Schematic overview of the prominent animal studies with JAKi in animal models of axSpA and their main findings (further description can be found in the text) (–5). AxSpA, axial spondyloarthritis; JAK, Janus kinase; JAKi, Janus kinase inhibitors; MDSC, myeloid-derived suppressor cell; mNRA, messenger ribonucleic acid; NF-κB, nuclear factor-κB; STAT1, signal transducer and activator of transcription 1; TYK2i, tyrosine kinase 2 inhibitors.

Figure 4

JAKi cellular selectivity for JAK heterodimeric cytokine signaling. Mean fold JAKi selectivity of each JAK pair versus inhibition of JAK1/TYK2 pathway in monocytes. A higher value denotes higher selectivity versus JAK1/TYK2-dependent signaling. Adapted from Traves PG. Ann Rheum Dis. 2021;80:865-875 (^© The Author[s] [or their employer(s)] 2021. Published by BMJ; open access article distributed in accordance with the Creative Commons Attribution Non Commercial License (CC BY- NC 4.0; http://creativecommons.org/licenses/by/4.0/), which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial). G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte–macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; JAKi, JAK inhibitor; TYK, tyrosine kinase.