A recent study published in Rheumatic and Musculoskeletal Diseases Open found that elevated baseline levels of complement activation marker C3dg and complement proteases MASP-1 and MASP-3 predicted new bone formation in axial spondyloarthritis (axSpA) patients after 2 years of TNF inhibitor therapy.
The complement system comprises more than 40 soluble and membrane-bound proteins that play a central role in innate immunity. Complement activation has been implicated in the pathogenesis of axSpA in animal models. Clinical studies have shown that lectin pathway proteins such as H-ficolin and L-ficolin are elevated in patients with axSpA compared with healthy controls, while complement factor C3 decreases during TNF-inhibitor therapy in both axSpA and PsA. In contrast, C3 and C4 levels have not differed significantly across disease activity states in axSpA. Evidence from clinical cohorts has demonstrated links between complement system activation, axSpA diagnosis, and disease activity, and experimental models have further indicated that complement inhibition can attenuate structural damage characteristic of radiographic axSpA.
Despite an expanding range of biological and targeted synthetic DMARDs, radiographic progression continues to occur in a subset of patients. Addressing this persistent progression underscores the unmet need for a deeper understanding of disease pathogenesis. The CONSUL multicentre randomised controlled trial analysed serum samples from 96 patients with active radiographic axial spondyloarthritis before and after 108 weeks of golimumab therapy. Baseline serum levels of C3dg and MASP-1 were elevated in patients who developed new syndesmophytes or experienced growth of existing syndesmophytes during follow-up, while MASP-3 levels were decreased. Univariate logistic regression demonstrated that baseline levels of MASP-1, MASP-3 and C3dg were associated with new bone formation, and these associations remained significant in multivariate analysis. At the 2-year follow-up, serum levels of C3dg and L-ficolin were elevated in patients with new bone formation, with C3dg retaining significance in multivariate logistic regression.
The findings indicated that complement system activation was associated with radiographic spinal progression in this cohort of patients with radiographic axial spondyloarthritis who demonstrated high risk of structural damage progression. Some patients exhibited radiographic progression despite showing clinically favourable responses to TNF inhibitor therapy. The study suggested that complement activation markers, particularly C3dg, MASP-1 and MASP-3 measured prior to initiating biologic therapy, may serve as predictive biomarkers for identifying patients at risk of structural progression. The association between L-ficolin, which recognises acetylated structures, certain bacteria and apoptotic cells, and new bone formation at follow-up raised questions about potential mechanistic links between complement activation and established axial spondyloarthritis risk factors such as HLA-B27 and infections.
These results highlighted a potential unmet clinical need for improved risk stratification tools in the era of precision medicine and suggested that targeting the complement system could represent a therapeutic avenue for preventing pathological bone formation in radiographic axial spondyloarthritis.
References
- Mistegaard C, Troldborg A, Torgutalp M, Loft AG, Thiel S, et al. Complement system activation is associated with spinal radiographic progression in axial spondyloarthritis after 2 years of follow-up: findings from the CONSUL RCT. RMD Open. 2025 Nov 28;11(4):e006087.
- Mistegaard CE, Proft F. The Complement System in Spondyloarthritis: What Do We Know? 1 [Internet]. 2022 Dec 14 [cited 2025 Dec 4]; Available from: https://touchimmunology.com/axial-spondyloarthritis/journal-articles/the-complement-system-in-spondyloarthritis-what-do-we-know/