**7. Future Prospective**

While the targeting IL-23 and IL-17 have shown good results for the patients with AS and PsA, it was also effective in the treatment of IBD [143,144]. This finding suggests that the IL-23/ IL-17 pathway isn't specific in the development of SpA

There remains an unclear mechanism that is not fully explained by only IL-23 and IL-17 in the pathogenesis of SpA. According to the results of clinical trials, anti-IL-23 antibody showed significant efficacy in the patients with peripheral SpA, but not in the patients with AS. Besides, only IL-23 and IL-17 cannot explain the different sites of manifestations between axial SpA and peripheral SpA, implying the contribution of the mechanisms that are independent of the IL-23/IL-17 pathway. However, different action mechanisms of IL-23/IL-17 pathway between axial SpA and peripheral SpA remains unknown.

The evidence has been insufficient about the efficacy of targeting IL-23 and IL-17 for the patients with other subtypes of SpA, such as re-SpA, IBD-associated spondylitis, and unclassifiable spondylitis.

Further research is required to elucidate underlying mechanism for the difference between axial SpA and peripheral SpA including the mechanism other than IL-23/IL-17 pathway and to evaluate the therapeutic effects of targeting the IL-23/IL-17 in each subtype of SpA.

#### **8. Conclusions**

Recent studies have clarified the essential roles of IL-23 and IL-17 in SpA. Although clinical and genetic evidence has demonstrated the involvement of IL-23 and IL-17 in the various tissues from patients with SpA, this IL-23/IL-17 pathway cannot explain the whole range of pathogenic conditions in SpA, which suggests the involvement of unknown pathways or mechanisms for the development of SpA. IL-17 originally acts only during an immune response, yet genetic and environmental conditions such as HLA-B27, mechanical stress, and dysbiosis can cause a pathological up-regulation of IL-23 and/or IL-17 and lead to the development of SpA. Indeed, specific inhibition of IL-23 and/or IL-17 by monoclonal antibodies have shown the effects on the control of the disease activity of SpA. The IL-17-producing cells such as Th17, Tc17, and γδT cells and ILC3 were newly identified. However, whether the IL-17 from different cellular sources exerts a different immunopathological response remains to be determined. Further understanding of cellular and molecular regulatory mechanisms of the IL-23/IL-17 axis and other inflammatory cytokines may provide a promising strategy in the treatment of SpA.

**Author Contributions:** H.T. provided overall direction, final editing, and contributed to original writing. T.K. provided overall direction and final editing and supervised this work. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding

**Conflicts of Interest:** The authors declare no conflict of interest.
