The Interleukin-23/Interleukin-17 Axis in Spondyloarthritis Pathogenesis Th17 and Beyond

Compelling evidence from genetics studies, translational research, and animal models implicates the IL-23/IL-17 axis and related cytokines in the pathogenesis of SpA. Predisposing genes including HLA-B27 may contribute to excess innate immune activation and IL-23 production, altered IL-23 responses, and increased production of IL-17 and related cytokines. Recognition of the importance of these pathways has spawned the development of biologic agents and small molecules that offer unique opportunities to advance the treatment of several immune-mediated diseases (11,118,119). For example, ustekinumab, which blocks IL-23 and IL-12 by binding to the common p40 subunit, is beneficial for plaque psoriasis (120,121), psoriatic arthritis (122,123), and TNF inhibitor-refractory Crohn's disease (124). However, trials targeting IL-17 have yielded mixed results. While there is clear evidence that IL-17 inhibition is effective in psoriasis (125,126), a surprising lack of benefit was found in Crohn's disease (127,128). For RA and PsA, although results are promising, primary end points of the studies were not met (129,130). The first trial of IL-17 inhibition in SpA has shown evidence of benefit in active AS after 6 weeks of treatment (25). This is encouraging and consistent with evidence of IL-23/IL-17 axis activation, but larger studies of longer duration are needed (131). There may be several reasons for varying efficacy of IL-17 inhibition in immune-mediated diseases in which there is evidence of IL-23/IL-17 dysregulation. The majority of IL-17 production is downstream of IL-23, and there is heterogeneity in the IL-17-producing cells that may underlie differences in pathogenicity (132). In addition, there may be tissue-dependent differences in the effects of cytokines in this axis. For example, IL-22 can be protective in the gut (79,80) but promote bone formation in skeletal tissue (19). While there is considerable optimism that these insights into pathogenesis will translate into better treatments for AS and related diseases, there is also cause to proceed with caution.