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Background: The lack of validated tools to predict rheumatoid arthritis (RA) disease course warrants the development of new reliable biomarkers. We have previously detected increased semaphorin 4A (SEMA4A) expression in endothelial cells, synovial tissue, and serum of patients with RA. In addition, SEMA4A serum levels correlated with multiple clinical, biological, and power doppler ultrasound markers of disease activity. Our aim was to evaluate circulating SEMA4A for the prediction of outcomes in patients with RA.Methods: A first cohort included between May 2016 and February 2018 101 consecutive RA patients followed up on an annual basis until August 2021. Baseline SEMA4A concentrations were analyzed according to disease progression defined for the purpose of this study by the occurrence of patient-reported flares and initiation or change of targeted therapy. A second cohort included 40 consecutive RA patients who initiated new therapy because of insufficient disease control. The course of SEMA4A levels was studied between baseline and month 3 according to treatment response. Results: During a follow-up period of 41±15 months, disease progression occurred in 26/101 patients in the first cohort. Increased baseline SEMA4A levels were identified as an independent predictor of disease progression (hazard ratio, HR: 2.71, 95%CI 1.14-6.43). The highest predictive value of disease progression was obtained with the combination of increased circulating SEMA4A and/or DAS28-CRP>3.2 and/or synovial hyperemia on doppler ultrasound (HR: 10.42, 95%CI 1.41-76.94). SEMA4A was also predictive of disease progression in patients with a DAS28 Conclusion: circulating SEMA4A appears as an appealing biomarker in RA with ability to predict disease progression, and with association with response to therapy.

ObjectiveTo identify the factors potentially associated with serum gamma-glutamyltransferase (GGT) elevation in patients with rheumatoid arthritis (RA).MethodsThis is a cross-sectional monocentric study including RA patients over a 12-month period. Data on liver function, RA disease activity, and hepatotoxic and cardiovascular (CV) risk factors were systematically collected. To provide a simple tool to evaluate both joint disease activity and CV risk factors, we constructed the Disease Activity Score in 28 joints (DAS28)-GGT composite index by replacing erythrocyte sedimentation rate (ESR) with GGT.ResultsAmong the 129 included patients, 32 (25%) had isolated GGT increase. GGT correlated with age, C-reactive protein (CRP) levels, and body weight and were significantly increased in patients with alcohol intake, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome. GGT levels also gradually increased with the number of CV risk factors and correlated with the Framingham CV risk score. The composite index DAS28-GGT remained a reliable marker of RA disease activity and accurately detected patients with CV risk factors. Conversely to the DAS28 and the DAS28-CRP, the DAS28-GGT steadily increased according to the number of CV risk factors and had an increased diagnostic value compared to the DAS28 and DAS28-CRP for the presence of at least 2 CV risk factors and a Framingham CV risk score greater than 10%.ConclusionGGT may be considered as a marker of systemic inflammation and CV risk in patients with RA. Based on these findings, we herein propose an original index, the DAS28-GGT, which is able to evaluate both joint disease activity and CV risk. This index will deserve further validation in prospective cohorts.