Targeting the Janus kinase (JAK) TYK2 could have disease-modifying effects in spondyloarthritis (SpA) by halting inflammation and bone erosion, according to new research. In the study, a novel small-molecule inhibitor of TYK2 blocked IL-23 signalling in vitro and inhibited disease progression in mouse models of SpA.
The researchers first showed that the selective TYK2 inhibitor NDI-031407 inhibited IL-23-induced IL-17A production as well as IL-23-induced STAT3 phosphorylation in a dose-dependent manner in human CD4+ T cells. In vivo, in the β-1,3-glucan (curdlan)-triggered SKG mouse model of SpA, treatment with orally delivered NDI-031407 prevented disease progression, as reflected by lower clinical scores for SpA symptoms. Bone erosion, joint space narrowing and bone marrow oedema were also prevented in NDI-031407-treated as compared with vehicle-treated mice. The SpA-associated expansion and activation of TH17 cells in the draining lymph nodes and arthritic joints of mice was reduced in NDI-031407-treated mice. In a different model of SpA, induced by delivery of minicircle DNA expressing IL23, the TYK2 inhibitor also protected against clinical disease driven by systemic IL-23 expression.
Addressing the biologic relevance of TYK2 single-nucleotide polymorphisms (SNPs) that have been associated with ankylosing spondylitis (AS) in genome-wide association studies, the researchers found that carriage of certain TYK2 SNPs was associated with a decreased TH1 cell frequency and a progressive AS phenotype characterized by a high rate of vertebral fusion.
Previous studies have suggested that pan-JAK inhibitors, such as tofacitinib, could be useful for the treatment of SpA. These latest findings suggest that TYK2 has a role in the pathogenesis of AS, and that specific inhibition of TYK2 inhibits disease progression in animal models of SpA. The researchers propose that a small-molecule TYK2 inhibitor could be explored as a potential disease-modifying therapy for AS.
References
Original article
Gracey, E. et al. TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis. J. Clin. Invest. https://doi.org/10.1172/JCI126567 (2020)
Related article
Ranganathan, V. et al. Pathogenesis of ankylosing spondylitis — recent advances and future directions. Nat. Rev. Rheumatol. 13, 359–367 (2017)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Onuora, S. TYK2 inhibition halts SpA. Nat Rev Rheumatol 16, 248 (2020). https://doi.org/10.1038/s41584-020-0417-1
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41584-020-0417-1