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Introduction Effective resolution of inflammation is a critical process to ensure normal tissue repair and avoid fibrosis. It depends on macrophage (M) clearance of apoptotic cells by the process called efferocytosis. The aim of the present work was to study perivascular Macro efferocytosis in Systemic Sclerosis (SSc), a prototypic vascular and fibrotic autoimmune disease.Material and Methods Transcriptomic analysis was performed in 24 SSc and 10 HD skin biopsies using Nanostring technology. Multiparametric immunofluorescence (IF) staining using cyclic IF (MACSIMA) and Tyramide were performed on FFPE skin biopsies from HD and SSc patients. Macro were generated from healthy monocytes in the presence of SSc or HD medium or IL-1b-activated cutaneous primary MVEC conditioned medium. Macro efferocytosis was evaluated with pH-Rhodo-stained apoptotic Jurkat cells (apoJK) for 24 hours using the live cell imager. Efferocytosis-associated receptors expression was analyzed by flow cytometry. Macro’s lipidic mediators and cytokines were measured by Mass Spectrometry and multiplex assays respectively. Fibroblast activation and EndoMT were assessed using RT-qPCR.Results Transcriptomic analysis revealed altered efferocytosis-related genes expression in SSc skin, along with increased apoptosis and IL-1b signaling, notably in dcSSc patients with high fibrotic score. CycIF and Tyramide stainings showed increased vascular apoptosis together with altered perivascular MERTK+ Macro phenotype characterized by increased in CD209 and CD14 expression together with decreased MERTK expression and alteration in efferocytosis-associated markers. In vitro analysis shows that irrespective of the origin of the MVEC, IL-1b and MVEC secretome act synergically to induce a significant decrease of Macro apoJK phagocytosis and altered apoptotic cells receptors. When MVEC were from SSc origin, IL-1b-MVEC Macro post efferocytosis secretome exhibited altered lipids content characterized by increased TXB2, maresin and resolvins. Post-efferocytic MEVC- Macro secretome synergizes with TGF-b to promote extra-cellular matrix production by fibroblasts. In sharp contrast, IL-1b-MVEC induced-Macro post efferocytosis secretome induced pro-remodeling phenotype that was more pronounced when MVEC were from SSc origin. Finally, in SSc settings, IL-1b-MVEC induced-Macro post efferocytosis secretome led to a significant increase of MVEC aSMA and fibronectin expression, suggestive of endoMT.Conclusions Altogether, these data suggest that depending on the cytokine milieu, perivascular Macro efferocytosis alteration might have a double-edge sword effect in SSc. IL-1b contributing to sustained inflammation through increased apoptotic load, pro-inflammatory and remodeling fibroblasts induction and endoMT, while associated with TGFb favoring direct MEC deposition. Hence, restoring proper efferocytosis function might be a new avenue for limiting inflammation and fibrosis in SSc.Conclusions Initial therapy was associated with improved survival and reduced PAH progression in SSc-PAH, with consistent effects across haemodynamic thresholds and risk strata. These findings support guideline-recommended early intervention, highlight the importance of high-quality observational data in rare diseases, and underscore the need for RCTs to clarify treatment effects in patients with milder haemodynamic impairment.