Objective To study the potential role of semaphorins in the pathogenesis of rheumatoid arthritis (RA). Methods Microarray experiments were performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in RA endothelial cells (ECs) and control ECs derived from circulating progenitors. Expression of class 3 and class 4 semaphorins and their receptors in the serum of RA patients and healthy controls was assessed by immunohistochemical analysis in synovial tissue and by enzyme‐linked immunosorbent assay. Results Microarray analysis revealed differential expression of class 3 and class 4 semaphorins and their receptors in RA ECs. Semaphorin 4A (SEMA4A), plexin D1, and neuropilin 1 messenger RNA (mRNA) levels were markedly increased in RA ECs by 1.75‐, 2.21‐, and 1.68‐fold, respectively. Stimulation with tumor necrosis factor (TNF) led to a 2‐fold increase in SEMA4A mRNA levels in RA ECs, and deficient SEMA4A expression modified RA EC angiogenic properties. Class 3 and class 4 semaphorins as well as their receptors were overexpressed in RA synovial tissue. A respective 1.30‐fold increase and 1.54‐fold increase in SEMA4A and SEMA3E, as well as a 24% decrease in SEMA3A, was observed in the serum of RA patients. Serum levels of SEMA4A, SEMA4D, and SEMA3A correlated with levels of inflammation and proangiogenic markers. In 2 independent cohorts of patients with low disease activity or with RA in remission, the presence of SEMA4A identified patients with residual disease activity. Conclusion Gene expression profiling of ECs identified class 3 and class 4 semaphorins as potential biomarkers and therapeutic candidates in RA, with confirmed overexpression in ECs, synovial vessels, and serum, and correlation with validated markers of inflammation and angiogenesis. Thus, semaphorins might be novel and appealing EC‐derived inflammatory and proangiogenic targets in RA.

Objective To identify the factors potentially associated with serum gamma-glutamyltransferase (γGT) elevation in patients with rheumatoid arthritis (RA). Methods Cross-sectional monocentric study including RA patients for a 12-month period. Data on liver function, RA disease activity, 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 DAS28-γGT composite index by replacing ESR by γGT. Results Among the 129 included patients, 32 (25%) had isolated γGT increase. γGT correlated with age, CRP levels, body weight and were significantly increased in patients with alcohol intake, type 2 diabetes mellitus, blood hypertension, dyslipidemia and metabolic syndrome. γGT levels also gradually increased with the number of CV risk factors and correlated with the Framingham CV risk score. The composite index DAS28-γGT 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-γGT 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 >10%. Conclusion γGT may be considered as a marker of systemic inflammation and CV risk in RA patients. Based on these findings, we herein propose an original index, the DAS28-γGT, able to evaluate both joint disease activity and CV risk. This index will deserve further validation in prospective cohorts.