Review: The Interleukin‐23/Interleukin‐17 Axis in Spondyloarthritis Pathogenesis: Th17 and Beyond

Abstract

Spondyloarthritis (SpA) represents a group of immune-mediated inflammatory diseases that exhibit overlapping clinical features, genetic predisposition, and pathogenic mechanisms (1), and affect 0.5–1.5% of the population (2). Disease can be undifferentiated, or manifest as reactive arthritis, psoriatic arthritis (PsA), arthritis associated with inflammatory bowel disease (IBD), or ankylosing spondylitis (AS). Enthesitis is an important pathologic feature of SpA, and contributes to both axial and peripheral arthritis, although synovitis also occurs. Structural damage in AS is dominated by new bone formation that can result in spinal fusion and marked functional limitation. Trabecular bone loss is also prominent, and paradoxically, occurs in close proximity to vertebral osteoproliferation. It can take years from the onset of symptoms to fulfill modified New York criteria for AS. Consequently, newer classification systems have been developed to identify individuals with early axial SpA (3,4) who may benefit from aggressive treatment. Tumor necrosis factor inhibitors (TNFi) have had a major impact on the treatment of SpA (5). Their ability to reduce new bone formation in AS continues to be debated (6), although recent results are encouraging (7). TNFi are not beneficial in all patients, and thus there is a need for greater understanding of pathogenic mechanisms and translation of this knowledge into more effective therapies. Over the last decade our knowledge of the role of IL-23 and IL-17 cytokine pathways in immunity and immune-mediated inflammatory diseases, from multiple sclerosis (MS) to IBD, arthritis, and psoriasis has grown exponentially (8–11). For SpA, there has been a striking convergence of evidence from genetic studies (12–15), animal models (16–19), translational studies (20–23), and now a therapeutic trial (24) firmly implicating the IL-23/IL-17 axis in pathogenesis (25). In this review we outline key evidence accumulated over the last several years that forms the basis for this conclusion, and provides a background on which to build and refine models of pathogenesis, from inflammation to dysregulated bone formation. These developments, together with the availability of biologics and small molecules that target the IL-23/IL-17 axis, provide an unprecedented opportunity for advances in the treatment of SpA.