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.
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)
Ranganathan, V. et al. Pathogenesis of ankylosing spondylitis — recent advances and future directions. Nat. Rev. Rheumatol. 13, 359–367 (2017)