121 - Pathogenesis and pathophysiology of axial spondyloarthritis

Abstract

Spondyloarthritis (SpA) is characterized by a triad of inflammation, bone destruction, and osteoproliferation. Despite some fundamental differences between axial and peripheral disease, both subtypes are driven by common autoinflammatory disease mechanisms primarily involving the innate immune system, as supported by histopathologic, molecular, and genetic evidence. Axial SpA is thought to arise from aberrant microbial or biomechanical triggers in the genetically prone, with a prominent role for human leukocyte antigen (HLA) B27. In this regard, entheses are considered to harbor the principal sites of pathologic changes and clinical symptoms. As for the pathophysiology, innate immune cells are the major source of key inflammatory mediators such tumor necrosis factor alpha, interleukin (IL)-1, and IL-23/IL-17. In particular, IL-17 producing innate or innate-like cells such Th17, natural killer, and mucosal-associated invariant T cells may drive SpA pathobiology in an IL-23 dependent or -independent way. Axial inflammation subsequently disturbs skeletal homeostasis, promoting osteoclastogenesis, deposition of repair tissue, and ossification, potentially mediated by hypertrophic chondrocytes. Molecular pathways involved in bone new formation include Wnt signaling, bone morphogenetic proteins (BMP), hedgehog proteins, and lipid inflammatory mediators. Evidence about the temporal relationship between resolution of subchondral inflammation and subsequent new bone formation in SpA is, however, inconclusive. Supported by evidence from animal and human studies and with a particular translational focus, this chapter provides an overview of key molecular and cellular players involved in SpA pathogenesis and pathophysiology.