Understanding the pathogenesis of spondyloarthritis From disease initiation to progression

Spondyloarthritis (SpA) comprises immune-mediated inflammatory disorders affecting axial and/or peripheral joints and is accompanied by extra-articular inflammation and pathological new bone formation. Current therapies reduce disease activity, yet sustained remission is achieved in fewer than one-third of patients. This thesis investigated molecular and cellular pathways underlying inflammation, structural damage, and the preclinical development of SpA using human studies and HLA-B27 transgenic rat model. Dual inhibition of tumor necrosis factor and interleukin-17A effectively reduced clinical inflammation, peripheral arthritis, and structural alterations, with a more pronounced effect on axial new bone formation; however, it was not substantially superior to either single therapy. In patients with peripheral SpA, secukinumab-mediated IL-17A blockade suppressed synovial pathways related to inflammation, stromal activation, and bone remodeling, while producing tissue-specific effects distinct from IL-12/23 pathway inhibition. Therapeutic targeting of HLA-B27 open conformers did not attenuate arthritis or spondylitis in rats, potentially because of insufficient antibody exposure or suboptimal binding characteristics. Studies of first-degree relatives of HLA-B27-positive axial SpA patients identified increased innate immune, antimicrobial, and endoplasmic reticulum stress responses in individuals who subsequently developed disease. Corresponding animal studies demonstrated increased inflammatory cytokines in joints before clinical onset, providing evidence that molecular changes precede symptomatic SpA. Finally, acute imiquimod-induced psoriasis-like skin inflammation was insufficient to trigger SpA manifestations in the experimental model. Collectively, these findings clarify pathways involved in inflammation and bone remodeling, establish the existence of a preclinical disease phase, and identify opportunities for earlier detection and more targeted therapeutic intervention to improve long-term outcomes for patients.