Ab0045 cxcl14 in early and established rheumatoid arthritis

Background Single cell sequencings studies have identified a CXCL14+ synovial fibroblast cluster in synovial tissue. This CXCL14+ cluster express CD34 and correlate to lower DAS28 and swollen joint count, while being similar between genders, age or sero status [1]. The biological role of CXCL14 in rheumatoid arthritis (RA) is unknown, but CXCL14+ synovial fibroblasts have been shown to express abundant GAS6, which regulate remission functions in MerTK+CD206+ synovial tissue macrophages [2]. This may suggest an anti-inflammatory or pro-remission role of the CXCL14+ synovial fibroblast cluster in specific RA pathotypes [1]. Objectives Our study aimed to investigate soluble CXCL14 in plasma and synovial fluid and its potential connection to long term joint deterioration and disease activity in RA. Methods We used optimized commercial CXCL14 ELISA kits to investigate CXCL14 levels in 3 cohorts. 1) Plasma samples from patients with early RA (eRA) from the methotrexate arm of the CIMESTRA trial (N=80) [3]. 2) Plasma and synovial fluid from patients with established RA included at time of therapeutic arthrocentesis (the INART cohort) (N=41). 3) Plasma from matched healthy controls (HC) (N=44). Results Plasma CXCL14 was significantly higher compared to synovial fluid, median 2.3 ng/ml. CXCL14 levels in the two compartments corelate. Plasma and synovial fluid CXCL14 were not influenced by gender, ACPA, smoking status, disease duration or time since sampling. Age and rheumatoid factor status may affect plasma CXCL14 levels, but this was not consistent in both RA cohorts. Analysis showed a significant higher amount of plasma CXCL14 in patients with RA from the INART cohort, median 6.9 ng/ml, compared to eRA, median 4.8 ng/ml and HC, median 4.3 ng/ml. Plasma CXCL14 did not change significantly in patients with eRA after 1 year of treatment. Baseline plasma CXCL14 in patients with eRA significantly correlated to baseline tender joint count, but not DSA28, swollen joint count or total sharp score. Baseline plasma CXCL14 correlated to DAS28 after 5 years of treatment. Evaluating DAS28 after 11 years of treatment we observed a difference between patients in remission (DAS<2.6) and patients with active disease (DAS28 ≥ 2.6). For patients in remission, baseline CXCL14 correlated inversely with DAS28, whereas this correlation was positive in patients with active disease (Figure1). No associations were present between CXCL14 and change in total sharp score over a 11-year period. Conclusion Soluble CXCL14 can be measured in both plasma and synovial fluid from patients with RA. Plasma CXCL14 levels are higher compared to synovial fluid but a significant correlation is present between to two compartments. This suggests plasma CXCL14 as a potential proxy for CXCL14 activity in the joint and joint fluid. CXCL14 was not affected by gender, disease duration, smoking or 1 year of cDMARD treatment. Baseline CXCL14 correlated to higher DAS28 in the CIMESTRA cohort after 5 years and in patients with active disease after 11 years. Interestingly, we noticed that baseline CXCL14 may associate to lower DAS28 in patients in remission after 11 years. Together, this may support previous studies associating CXCL14 to an active anti-inflammatory (positive CXCL14/DAS28 correlation in active disease group) and pro-remission (negative CXCL14/DAS28 in remission group) role in RA. References [1]Micheroli, R., et al., Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis. RMD Open, 2022. 8(1). [2]Alivernini, S., et al., Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med, 2020. 26(8): p. 1295-1306. [3]Hetland, M.L., et al., Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum, 2006. 54(5): p. 1401-9. Figure 1. Acknowledgements: NIL. Disclosure of Interests Søren Lomholt: None declared, Louisa Hunskjær: None declared, Stinne Ravn Greisen: None declared, Tue Wenzel Kragstrup Shareholder of: Co-founder and clinical developer in Aptol Pharma., Speakers bureau: Speaking fees from Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, UCB, and Abbvie., Consultant of: Consultancy fees from Bristol-Myers Squibb, UCB, Gilead, and Eli-Lilly., Grant/research support from: Research grants from Gilead.