Deconvolution of the interleukin-17 pathway in the pathobiology of spondyloarthritis

Spondyloarthritis (SpA) is the second most prevalent form of chronic inflammatory arthritis. There is an unmet clinical need for the treatment of inflammation and bone pathology in SpA patients. Inflammation affects the axial and peripheral joints and may additionally occur in the skin, eye, and gut. SpA is also characterized by pathologic bone formation in peripheral and axial skeletal sites. The ultimate therapeutic goal for SpA would be to develop interventions that suppress both inflammation and pathologic bone formation, and to bring patients into remission. Recent evidence indicates that Interleukin (IL)-17A is a key proinflammatory cytokine in SpA. This thesis presents novel insights on the biology of the IL-17-pathway in SpA, and suggestions for improving the therapeutic efficacy of targeting this pathway.
The novel findings include the tissue-specificity of IL-17A and IL-17F expression in skin and joint inflammation, and the observation that IL-17A+ mast cells can serve as cellular reservoirs of IL-17A. We present preclinical rationales for two novel small molecule treatments that are aimed at targeting cellular sources of IL-17A and modifying pathologic bone formation. Additionally, we identified the function of a previously unexplored IL-17 family cytokine in the disease-context of SpA. This thesis provides the basis for the continued exploration of the tissue-specific differences in the expression and function of IL-17 family members that may underlie the tissue-dependent responses to therapy. Altogether, these novel insights into IL-17 biology in SpA have potential implications for future therapeutic development in SpA.