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.

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Purpose of review To review susceptibility genes and how they could integrate in systemic sclerosis (SSc) pathophysiology providing insight and perspectives for innovative therapies. Recent findings SSc is a rare disease characterized by vasculopathy, dysregulated immunity and fibrosis. Genome-Wide association studies and ImmunoChip studies performed in recent years revealed associated genetic variants mainly localized in noncoding regions and mostly affecting the immune system of SSc patients. Gene variants were described in innate immunity (IRF5, IRF7 and TLR2), T and B cells activation (CD247, TNFAIP3, STAT4 and BLK) and NF-κB pathway (TNFAIP3 and TNIP1) confirming previous biological data. In addition to impacting immune response, CSK, DDX6, DNASE1L3 and GSDMA/B could also act in the vascular and fibrotic components of SSc. Summary Although genetic studies highlighted the dysregulated immune response in SSc, future research must focus on a deeper characterization of these variants with determination of their functional effects. Moreover, the role of these genes or others on specific vasculopathy and fibrosis would provide insight. Establishment of polygenic score or integrated genome approaches could identify new targets specific of SSc clinical features. This will allow physicians to propose new therapies to SSc patients.