Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Abstract

The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

TNF-α inhibitor therapy can improve the immune imbalance of CD4+ T cells and negative regulatory cells but not CD8+ T cells in ankylosing spondylitis

“…One of the most specific pathologic features of AS is inflammation at the enthesis [19]. Recent genetic and immunological research has highlighted a key role for IL-17A/ IL-23 cytokine dysregulation of the Th17 immune pathway in AS [1].…”

Regeneration of Damaged Tendon-Bone Junctions (Entheses)—TAK1 as a Potential Node Factor

“…Only a few years ago the scientific community realized that immune cells have a considerable presence in injured as well as in healthy entheses [ 56 , 57 ] although their numbers might be relatively low. The most important types of entheseal immune cells consist of interleukin 23 (IL-23) responsive cells like macrophages [ 58 ], natural killer (NK) cells [ 59 ] and γδ T cells [ 60 ].…”

Loss and gain of bone in spondyloarthritis: what drives these opposing clinical features?

“…Whilst IL-23 clearly induces IL-17 production and many of the murine models show a strong IL-23-depenence, 91 clinical trials evidence shows that IL-23 blockade is less effective that IL-17A inhibition on disease progression in the spine suggesting potential differences between the role of IL-23 in spinal versus peripheral skeleton enthesitis. 92 The weight of evidence is strongly in favour of the IL-17–IL-23 axis as a central component affecting bone in SpA but as evidence evolves it may become clear that effects on bone loss or formation may vary at different bone sites.…”