The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies

Abstract

Although the pathogenic mechanisms underlying axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) are not fully elucidated, several lines of evidence suggest that immune responses mediated by interleukin 17A (IL-17A) play a pivotal role in both diseases. This is best highlighted by the significant clinical efficacy shown with inhibitors of IL-17A in treating axSpA and PsA. Nevertheless, a number of knowledge gaps exist regarding the role of IL-17A in the pathophysiology of spondyloarthritis in man, including its cellular origin, its precise role in discrete disease processes such enthesitis, bone erosion, and bone formation, and the reasons for the discrepant responses to IL-17A inhibition observed in certain other spondyloarthritis manifestations. In this review, we focus on the latest data from studies investigating the role of IL-17A in ankylosing spondylitis (AS) and PsA that build on existing and emerging scientific knowledge in the field. Key remaining research questions are also highlighted to guide future research.

Keywords: ankylosing spondylitis; inflammation; psoriatic arthritis; spondyloarthritis.

Figure 1

Single nucleotide polymorphisms identified in the IL-17 signalling pathway that have been linked to axial spondyloarthritis and psoriatic arthritis. ^aSignificant association shown in European but not Asian populations; ^bNo risk associated with this SNP shown in certain studies; ^cNo risk associated with this SNP shown in certain studies; ^dSNP can be associated with risk or protection depending on the specific mutation. AS, ankylosing spondylitis; IL-1R2, interleukin 1 receptor; IL-6R, interleukin 6 receptor; IL17R, interleukin receptors; PsA, psoriatic arthritis; SNP, single nucleotide polymorphism.

Figure 2

Key sources of IL-17A in spondyloarthritis. AS, ankylosing spondylitis; ILC3, type 3 innate lymphoid cell; iNKT, innate natural killer T cell; MAIT, mucosal-associated invariant T cell; PsA, psoriatic arthritis; SpA, spondyloarthritis; Th17, T helper 17 cell; T_RM, resident memory T cell.

Figure 3

The role of IL-17A in bone erosion and bone formation in spondyloarthritis. Adapted from Schett et al and Gravallese et al[59 223 231]. BMP, bone morphogenetic protein; ILC3, type 3 innate lymphoid cell; RANKL, receptor activator of nuclear factor kappa-Β ligand; Th17, T helper 17 cell.

Figure 4

Summary of clinical efficacy with IL-17A inhibitors in spondyloarthritis. ^aNo efficacy shown with secukinumab in non-infectious uveitis; not investigated in anterior uveitis, the form of the disease most common in patients with spondyloarthritis. AS, ankylosing spondylitis; PsA, psoriatic arthritis; SpA, spondyloarthritis.

Figure 5

Emergent scheme to explain IL-23/–17 axis pathway divergence in PsA and AS. IL-23 pathway blockade is highly effective in psoriasis but not in AS, which is unexpected given the IL-23 SNPs and related gene SNPs associated with AS. Anatomical differences between entheses in the spine versus peripheral joints could play a role (A). The peripheral skeleton has numerous synovio-entheseal complexes, which contain abundant myeloid cells, while these cells are rare in the spine. Spinal enthesitis is also associated with peri-entheseal bone disease and osteitis. The role of inflammatory cytokines, namely IL-23, IL-17A and TNFα, also differs across the spondyloarthritidies (B). IL-17A can be produced by several different sources in spinal entheses (C). Emerging evidence supports the cellular basis for IL-17 production that is independent of IL-23. Animal models also show that IL-23 has a redundant role once adaptive immunity is primed. Where ++, strong involvement; +, involvement; –, no involvement. AS, ankylosing spondylitis; γδT, gamma delta T cells; HLA-B27, human leucocyte antigen B27; IL-17A, interleukin 17A; IL-23, interleukin 23; ILC3, Type three innate lymphoid cells; iNKT, innate natural killer T cell; MAIT, mucosal associated invariant T cell; MSCs, mesenchymal stem cells; PsA, psoriatic arthritis; PsO, psoriasis; Tc17, CD8+T cells; Th17, T helper 17 cells; TNF, tumour necrosis factor α.