P.240 Deciphering synovitis in systemic sclerosis

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Introduction Synovitis is a common manifestation of systemic sclerosis (SSc), driving disability and predicting disease progression and mortality. Current immunosuppressive strategies, largely extrapolated from rheumatoid arthritis (RA), offer limited efficacy. A deeper understanding of the pathomechanisms underlying SSc synovitis is therefore needed to enable the development of more effective, targeted therapies. Material and Methods Synovial tissue from 11 SSc patients (91% limited cutaneous SSc, excluding overlap syndromes), 7 RA patients (all anti-CCP and RF positive), and 6 non-inflammatory controls (NIC) underwent histological classification. For single-cell RNA sequencing (scRNA-seq), synovium from 6 SSc, 6 RA, and 6 NIC samples was dissociated, yielding 78,128 cells (SSc: 21,248; RA: 32,062; NIC: 24,818). Data were analysed using Seurat (v4.3) and integrated with Harmony and STACAS. Analyses included differential expression (MAST), pathway enrichment, gene module scoring (MSigDB hallmark), and transcription factor activity inference (decoupleR). In vitro qPCR validation was performed on synovial fibroblasts (SF) stimulated with TNF, IFN-a, IFN-b, and IFN-g. Serum IFN-a2a levels were measured in an independent cohort of 156 SSc patients. Results Histology revealed a pauci-immune pathotype in 10/11 SSc synovial biopsies, with lower Krenn scores (p=0.01) and less acute inflammation than RA (p<0.01). Given the stromal predominance in SSc, we focused on SF (n=15,502) and observed reduced expression of invasion-associated genes in PRG4+ lining SF, consistent with fewer radiographic erosions in SSc than RA (36% vs. 50%). Across SF, we identified a strong IFN-a/g signature (FDR<0.05) in SSc versus RA, where TNF responses predominated (FDR<0.001). IFN-associated genes, JAK/STAT signalling, and IFN-related transcription factors were enriched in FOSB+ SF, while MFAP5+/CXCL14+ SF expressed IFN-induced complement components and regulators, a pattern reproduced by in vitro IFN stimulation. Genes upregulated in SSc SF, including canonical ISGs and complement targets, overlapped with transcripts downregulated in Anifrolumab-treated SSc skin, supporting therapeutic relevance. A canonical IFN signature was also evident in endothelial cells, MERTK-/SPP1- macrophages, and S100A12+ monocytes (figure A). Importantly, serum IFN-a2a levels were higher in SSc patients with arthritis and independently predictive for the presence of arthritis (figure B), linking systemic IFN activity to synovial inflammation. Conclusions Our findings provide the first in-depth characterisation of SSc synovitis, revealing a pauci-immune, less-invasive phenotype marked by a dominant IFN signature across stromal, myeloid, and endothelial compartments. Together with the association of serum IFN-a2a with arthritis, these data highlight an IFN axis in SSc synovitis and support IFN blockade as a promising therapeutic strategy.

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