Targeting the interleukin-23/17 axis in axial spondyloarthritis

Abstract

Purpose of review To highlight and emphasize how new knowledge of mechanisms linked to the IL-23/IL-17 pathway are relevant to the pathophysiology of axial spondyloarthritis (axSpA) and to demonstrate how molecules in IL-23/IL-17 pathway provide novel therapeutic targets for axSpA patients. Recent findings Similar to AS, the increased frequency of Th17 cells in nr-axSpA patients underscores the concept that these disorders can be viewed on a spectrum. Recent findings suggest that the contribution of IL-23/IL-17 signaling pathways possibly differ in male and female AS patients. The finding that IL-17 and IL-22 secreting type 3 innate lymphoid cells (ILC3), are increased in AS patients point to their potential role in the pathogenesis of axSpA. Reports of dysbiosis in the gut microbiome of AS patients supports previous work indicating a possible causal relationship between altered gut flora, ileocolonic inflammation and axSpA. Of important clinical relevance, are results from clinical trials supporting the efficacy and safety of agents that block IL-12/23 (ustekinumab) and IL-17 (secukinumab and ixekizumab) in AS patients. Summary Recent studies further establish the central position of the IL-23/IL-17 pathway in the pathogenesis of axSpA. Targeting IL-23/IL-17 pathway appears to be a safe and effective strategy for treatment of axSpA patients.

Efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis: 52‐week pooled results from two phase 3 studies

“…Anti-TNFa and anti-IL-17A agents are currently the only approved classes of biologic therapy for the treatment of patients with AS, and they are widely used for patients in whom the disease is not controlled with conventional treatment (NSAIDs). 7,8,[18][19][20][21][22][23] In this pooled subanalysis of Asian patients from two pivotal phase 3 trials, secukinumab provided rapid and sustained improvements in the signs and symptoms of AS, with ASAS20 and ASAS40 responses achieved in 69.6% and 43.5% of Asian patients compared with placebo (26.1% and 17.4%, respectively) at Week 16.…”

“…5 Currently, anti-tumor necrosis factor alpha (anti-TNFa) and anti-interleukin-17A (IL-17A) agents are the only class of biologics approved for the treatment of AS, both in Asia and worldwide. 4,[6][7][8] Up to 40% of AS patients experience an inadequate response or intolerance (IR) to anti-TNFa therapies, 4,9,10 and cases of relapse of disease have been reported specifically in Asian patients after completion of short-term treatment with anti-TNFa therapies. 4 Thus, there is an unmet medical need for additional effective treatments for AS.…”

“…Evidence indicates that IL-17A, a proinflammatory cytokine, plays a role in the pathogenesis of AS. 3,7,11,12 Secukinumab, a human monoclonal immunoglobulin (Ig)G1j antibody that selectively binds and neutralizes IL-17A, 8,13 has demonstrated efficacy in the treatment of psoriasis, 14 psoriatic arthritis (PsA), 15,16 and AS 17 and is approved for the treatment of these conditions in Europe, the United States and Asia. The 150 mg dose of secukinumab is the approved dose in the treatment of AS.…”

Anti-IL17A in Axial Spondyloarthritis—Where Are We At?

“…Previously, the pathogenesis has centered on description of the Th1 pathway and TNF-alpha (16). Knowledge regarding the mechanisms of the IL17–IL23 pathway has increased with genetic, experimental models and functional data suggesting that it plays a crucial role in SpA (16, 17).…”

“…Knowledge regarding the mechanisms of the IL17–IL23 pathway has increased with genetic, experimental models and functional data suggesting that it plays a crucial role in SpA (16, 17). First evidence came from genetic studies that showed protective polymorphisms in the IL-23 receptor gene (rs11209026, Arg381Gln) for AS (18) by impairing function of Th17 cells to produce IL-17 through the IL-23-dependent pathway.…”