Efficacy was maintained at 48 weeks, and 58.6% patients in the BKZ 160mg Q4W arm and 62.3% patients in the BKZ 320mg Q4W arm achieved the ASAS40 response. well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular KPT276 manifestations were limited to psoriasis and did not lengthen to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on indicators, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is obvious in many different KPT276 cell types with functions in innate KPT276 as well as adaptive immunity. Moreover, evidence has emerged for the presence of both IL-23-dependent and IL-23-impartial pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation. mutation) have defects in IL-6, IL-23 and IL-22 signaling with reduced TH17 cells, and are prone to have mucocutaneous candidiasis, staphylococcus aureus infection, and probably viral infections (27). IL-17/IL-23 Pathway in Axial Spondyloarthritis Human genome wide association analyses (GWAS) KPT276 and studies in animal models and human tissues have implicated a pivotal role of IL-23/IL-17 pathway in the disease pathogenesis of ankylosing spondylitis (AS, a.k.a. radiographic axSpA, r-axSpA). GWAS showed that (rs11209026, rs1004819, rs10489629, rs11465804, rs1343151, rs10889677, rs11209032, rs1495965) and (rs6556416, rs10045431) Igf1 single nuclear polymorphism (SNPs) are associated with the susceptibility to AS, as well as SpA related conditions, such as psoriasis and inflammatory bowel disease (IBD) (28C30). In addition, GWAS of Vogt-Koyanagi-Harada (VKH) syndrome, a condition KPT276 that primarily manifests as pan-uveitis, also showed that the SNP is associated with increased disease susceptibility (31). Apart from these two genes, genes that modulate the IL-23/IL-17 pathway, such as (rs6503695, rs744166), (rs2310173), (rs10781500), have been reported to be associated with the risk of having AS and IBD (32). The SNP of over-expression of IL-23 in mouse models induces enthesitis, the pathologic hallmark of axSpA. In B10.RIII mice, IL-23 overexpression acts on a group of ROR-t+ entheseal resident CD4 and CD8 negative T cells, and induces expression of IL-17 and IL-22, as well as IL-6 and Chemokine Ligand 1 (34). Additional features resembling the human axSpA phenotype included psoriasiform skin lesions, aortitis, uveitis, peripheral arthritis, and spondylitis. A subsequent report demonstrated that T cells are the major cells producing IL17 in the enthesis of this IL-23 overexpressing model and that 50-80% of these cells are of the V6+ phenotype?(35). Furthermore, these cells also accumulate in the aortic valve and root as well as the ciliary body of the eye. However, this model has proven difficult to reproduce in other labs. In one report, over-expression of IL-23 using minicircle DNA led to chronic arthritis, severe bone loss, and myelopoiesis associated with the expansion of a myeloid lineage osteoclast precursor. This was partly dependent on TNF and IL-17A but could not be reproduced by overexpression of IL-17A (36). In SKG mice, after injection of curdlan, the mice developed IL-23 and T cell dependent arthritis and spondylitis, and the phenotype was transferrable by CD4+ T cells (37). Interestingly, a study in the HLA-B27 transgenic rat model with arthritis and spondylitis showed that IL-23R inhibition is effective for disease prevention when given prior to clinical onset, but when used for treatment of established disease, anti-IL-23R did not reduce clinical features or levels of IL-17 and IL-22 (38). Instead, when treated with anti-IL17A, the axial and peripheral joint inflammation were significantly reduced (39), suggesting IL-23 might be responsible for the onset of axSpA, but not for maintenance of the phenotype. Immunohistochemical analysis of.
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