AB0067 RHEUMATOID ARTHRITIS IS DRIVEN NOT ONLY BY INFLAMMATION BUT ALSO BY FIBROGENESIS
Authors: A. C. Bay-Jensen, S. F. Madsen, K. Gehring, K. Musa, M. Karsdal
Journal: Annals of the Rheumatic Diseases (2021)

Background: Rheumatoid arthritis (RA) is a chronic, autoimmune disease characterized by inflammation of the synovium, cartilage and bone leading to joint swelling, tenderness, and dysfunction. The destruction of the joint tissue involves degradation of the extracellular matrix (ECM). The ECM consist of collagens and other connective proteins 1 . Studies have shown that elevated levels of collagen metabolites, such as those of type I, II, III and VI, are highly elevated in RA, correlated to disease activity and modulated in response to, for example tocilizumab 2 , baricitinib 3 and methotrexate 4 . However, little is known about the formation of collagen, fibroblast activity, the fibrotic component of RA and how this influence likelihood of response to treatment. Objectives: We investigated the level of active fibrogenesis in a population of moderate to severe RA patients (in contrast healthy controls) by assessing blood-levels of PRO-C3 and PRO-C6 (type III and VI collagen formation markers), which have been reported to be associated with the degree and extent of fibrosis5. Methods: PRO-C3 and PRO-C6 was measured in serum of 166 RA patients (age; 54 (20-82), 83 % females, 91% white) at baseline and week 16 after treatment with an anti-IL6 receptor antibody in combination with MTX, as well as in serum of 77 donors (age; 42 (20-69), 51 % females, 66% white). Marker data was LN transformed. A general linear model was used when comparing groups. Results: The serum fibrogenesis marker PRO-C3, but not PRO-C6, was significantly elevated in RA compared to donors (2.1 vs. 2.4 ≈ 30% difference, p&lt;0.0001, fig. 1A). None of the markers were correlated with disease measures such as DAS28, CRP, VASpain. None of the markers were modulated significantly in response to treatment. Interestingly, PRO-C3 levels were significantly higher at in non-responders (resp.) at week 16 compared to resp. (2.8 vs. 2.4 ≈ 40% difference, p=0.0018, fig. 1C). Similar trend was observed for PRO-C6 (2.2 vs. 2.0 ≈ 20% difference, p=0.061 fig. 1D). Conclusion: Active fibrosis, with activated fibroblasts, may play an unseen role in RA. Patients will elevated levels of the fibrosis markers PRO-C3 and PRO-C6 were less likely to respond to an anti-IL6R. This may also give clue why such treatment are less efficacious in diseases with a clear fibrotic component. References: [1] Karsdal et al. Rheumatoid arthritis: A case for personalized health care? ACR 2014; 66: 1273–80. [2] Bay-Jensen et al. Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE study. SAR 2014; 43: 470–8. [3] Thudium et al. The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis. ART 2020; 22. [4] Drobinski et al. Connective tissue remodeling is differently modulated by tocilizumab versus methotrexate monotherapy in patients with early rheumatoid arthritis: the AMBITION study. ART 2021; 23. [5] Karsdal et al. Profiling and targeting connective tissue remodeling in autoimmunity - A novel paradigm for diagnosing and treating chronic diseases. AutoRev 2021; 20. Disclosure of Interests: None declared