Anti-IL-17A treatment reduces serum inflammatory, angiogenic and tissue remodeling biomarkers accompanied by less synovial high endothelial venules in peripheral spondyloarthritis

Abstract

Spondyloarthritis (SpA) is characterized by inflammation and new bone formation. The exact pathophysiology underlying these processes remains elusive. We propose that the extensive neoangiogenesis in SpA could play a role both in sustaining/enhancing inflammation and in new bone formation. While ample data is available on effects of anti-TNF on angiogenesis, effects of IL-17A blockade on serum markers are largely unknown. We aimed to assess the impact of secukinumab (anti-IL-17A) on synovial neoangiogenesis in peripheral SpA, and how this related to changes in inflammatory and tissue remodeling biomarkers. Serum samples from 20 active peripheral SpA patients included in a 12 week open-label trial with secukinumab were analyzed for several markers of angiogenesis and tissue remodeling. Synovial biopsies taken before and after treatment were stained for vascular markers. Serum levels of MMP-3, osteopontin, IL-6 (all P < 0.001), IL-31, S100A8, S100A9, Vascular Endothelial Growth Factor A (VEGF-A), IL-33, TNF-α (all P < 0.05) decreased significantly upon anti-IL17A treatment. Secukinumab treatment resulted in a decrease in the number of synovial high endothelial venules and lymphoid aggregate score. These results indicate that anti-IL-17A not only diminishes inflammation, but also impacts angiogenesis and tissue remodeling/new bone formation. This may have important implications for disease progression and/or structural damage.

Vascular Endothelial Growth Factor Biology and Its Potential as a Therapeutic Target in Rheumatic Diseases

“…VEGF also correlates with bone mineral density in AS treatment with infliximab [99]. VEGF levels decrease sharply in AS treated with secukinumab (Anti-IL-17A monoclonal antibody), and decreases in VEGF levels also correlate with inflammatory osteogenic biomarkers [100]. Additionally, VEGF also associates with extra joints and spine manifestations in spondyloarthritis such as subclinical gut inflammation.…”

Juvenile Spondyloarthritis: What More Do We Know About HLA-B27, Enthesitis, and New Bone Formation?

“…IL-17A knockout mice models displayed impaired bone regeneration and fracture repair at the femur when compared to wild-type mice (46). IL-17A inhibition concurrently reduced synovial inflammation (peripheral more than axial) and bone formation in animal models and peripheral SpA patients (51,52). Surprisingly, in AS clinical trials, IL-17A inhibition (secukinumab, ixekizumab) was more effective than IL-23 blockade (ustekinumab, risankizumab) on spinal disease progression (42,53,54).…”

“…A series of recent studies using another preclinical mouse model of TNF overexpression have shed light on how the structure of TNF may contribute to SpA pathogenesis ( 52 , 67 ). The TgA86 mice systemically overexpress a mutant murine TNF gene that is defective at the ADAM17 cleavage site, thereby causing a specific increase of transmembrane-bound TNF (tmTNF) but not soluble TNF (sTNF) ( 68 ).…”

“…The same studies also demonstrated relative overexpression of tmTNF over sTNF in the synovial environment of SpA vs. RA patients, thereby hinting at probable mechanistic relevance. Indeed, it was found that stromal tmTNF overexpression could drive inflammation, especially at peripheral sites ( 52 ). Moreover, tmTNF-driven inflammation and bone erosion seemed to precede new bone formation, which involved both endochondral and membranous ossification ( 67 ).…”

“…The HLA-B27 + transgenic arthritic/colitis rat model persistently developed SpA-like features even after the depletion of CD8 + T cells with either anti-CD8α monoclonal antibodies or CD8α knockout ( 86 , 87 ). Many murine models are also capable of phenocopying SpA to varying degrees in the absence of human HLA-B27, notably through the overexpression of human TNF ( 25 , 26 , 34 , 52 , 67 ). IL-23 overexpression alone in an HLA-B27 − background was also sufficient to drive murine SpA-like disease by activating IL-17-producing entheseal resident non-αβ T cells ( 48 ).…”