Allanore, Y. | Search bioRxiv

bioRxiv2026

Synovitis in systemic sclerosis is an interferon-driven stromal condition distinct from rheumatoid arthritis

Joint involvement is a major driver of disability in systemic sclerosis (SSc), yet its pathophysiology remains poorly understood. In the absence of specific evidence, SSc synovitis is treated by analogy with rheumatoid arthritis (RA). Here, we present the first comprehensive molecular characterization of SSc synovitis, integrating histology, single-cell RNA sequencing, and spatial multi-omics of synovial biopsies from SSc patients, RA patients, and non-inflammatory controls with in vitro validation. We show that SSc synovitis is characterized by distinct pathomechanisms from RA. Histologically, most SSc biopsies displayed a pauci-immune pathotype with sparse immune infiltrates and predominant stromal cells. At molecular level, synovial fibroblasts in SSc were characterized by a disease-specific type I interferon (IFN) response program, in contrast to the TNF-dominant profile of RA, accompanied by dysregulation of the complement cascade. This IFN program extended across multiple synovial cell types, including monocyte-derived macrophages and endothelial cells, and was spatially organized into focal myeloid niches and a diffuse stromal program. Systemically, elevated serum IFN-2a levels were associated with the presence of clinical synovitis in an independent cohort of SSc patients. We furthermore show that similar IFN-driven programs are shared between skin and synovium in SSc. Genes downregulated by IFNAR1 blockade in SSc skin were enriched in SSc synovium, supporting IFN receptor blockade as a multi-organ target therapeutic strategy. These findings reframe SSc synovitis as a less destructive, IFN-driven stromal condition distinct from RA and provide a mechanistic basis for dedicated clinical trials for joint inflammation in SSc. One Sentence SummarySSc synovitis is a pauci-immune, IFN-driven stromal condition distinct from RA, supporting IFNAR1 blockade as a therapeutic strategy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/733140v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@d85bb5org.highwire.dtl.DTLVardef@6cffe6org.highwire.dtl.DTLVardef@148eb4org.highwire.dtl.DTLVardef@1a4cd83_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Soquelitinb, A selective inhibitor of interleukin-2-inducible kinase (ITK), is active in several murine models of T cell-mediated inflammatory disease

Interleukin-2-inducible T cell kinase (or ITK) is a tyrosine kinase predominantly expressed by T lymphocytes. It plays a major role in T cell activation, differentiation, and receptor signaling. Studies in mouse models have established that the absence or inhibition of ITK reduces the secretion of Th2 and Th17 cytokines, while favoring the production of Th1 cytokines and the differentiation of T cells to regulatory T cells (T regs). We recently characterized the activity of soquelitinib (SQL), a selective, covalent inhibitor of ITK in vitro using mouse or human T cells and in vivo in murine models of cancer. We hypothesized that selective pharmacologic blockade of ITK could attenuate a variety of T cell-mediated inflammatory diseases including murine models that resemble asthma, pulmonary fibrosis, systemic sclerosis, psoriasis, and acute graft versus host disease. In each model, SQL demonstrated substantial ability to ameliorate the disease process along with effects on cytokines and/or T cell subsets consistent with the reported function of ITK. Our studies demonstrate that selective inhibition of ITK by SQL is potentially a novel therapeutic approach for several forms of T cell-mediated, inflammatory diseases.

immunology↗