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Abstract Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling. Since dephosphorylated-uncarboxylated Matrix Gla-Protein (dp-ucMGP) is associated with cardiovascular mortality in systemic sclerosis, a disease associated with PAH, and immune-system involvement in PAH is increasingly recognized, we investigated the relationship between dp-ucMGP, vascular remodeling and soluble immune-checkpoint proteins in PAH. This prospective cohort study included patients with idiopathic (I)PAH, connective tissue disease (CTD)-PAH, chronic thrombo-embolic PH (CTEPH) and CTD patients without PAH. Patients with IPAH and CTD-PAH were stratified by clinical signs of immune-mediated inflammatory disease (IMID). We measured dp-ucMGP plasma levels, soluble immune-checkpoint proteins (sICPs), and vascular smooth muscle cell (iVSMC) calcification. We found elevated dp-ucMGP levels in all PAH subtypes and CTD patients compared to healthy controls. PAH patients showed increased iVSMC calcification, but no direct correlation was found with dp-ucMGP. IMID-PAH patients had higher dp-ucMGP levels than non-IMID PAH patients. dp-ucMGP correlated with several sICPs in both IPAH and CTD patients; multiple sICPs were elevated in IMID PAH patients. High dp-ucMGP levels in IPAH patients were associated with worse survival. Our findings suggest dp-ucMGP as a potential biomarker of immune-mediated vascular remodeling in PAH. Hence, dp-ucMGP, could help identify PAH patients who might benefit from immunosuppressive therapies.

Objective: Systemic sclerosis (SSc) related mortality and morbidity remains high. Immunosuppressive therapy is considered most effective when immune activity and inflammation but not fibrosis still dominates the disease process. This study evaluated long-term intensified immunosuppression combined with therapeutic plasma exchange (TPE) in early-onset progressive SSc-related interstitial lung disease (ILD). Methods: The study cohort consisted of 161 SSc patients, with a median follow-up time of 8.9 years. The standardized mortality rate (SMR) and overall survival was calculated in patients with and without cardiopulmonary involvement. We used a standardized, pragmatic, non-randomized approach to treat 24 consecutive early progressive SSc-ILD patients with intensified immunosuppressive therapy, including plasma exchange. Outcome measurements were event-free survival (EFS), pulmonary function and safety profile. The outcome was compared with the analyzed data from the other SSc-ILD patients, who did not fulfill the inclusion criteria, and instead were treated with estimated optimal care (EOc). Results: The age-adjusted SMR of all 161 SSc patients was 3.0 (CI95%; 0.32–5.68). EFS at 10 years was 49.9% in the intensified treatment group and 43.3% in the EOc group (p = 0.106). Improvement of the percentage of predicted forced vital capacity (%pFVC) and percentage of predicted diffusing capacity for carbon monoxide (%pDLco) in the intensified treatment group was +10.1% respectively +3.6%, compared to a decrease of respectively 10.8% and 7% in the EOc (p

Background: There is a pressing need to identify early biomarkers of lung involvement in systemic sclerosis (SSc) to start as soon as possible antifibrotic therapy. We aimed to identify extracellular vesicle-derived microRNAs (EV-miRNAs) that are differentially expressed between SSc patients with and without interstitial lung disease (ILD), explore their diagnostic value and investigate their functional properties., Methods: Small EVs (sEVs) derived from plasma were isolated from 91 well-characterised SSc patients with ILD (SSc-ILD, n=45), without ILD (SSc-no ILD, n=46) and 43 matched healthy subjects (HS). Small RNA sequencing followed by quantitative RT-PCR were used to identify and validate sEV-miRNAs associated to SSc-ILD. Correlations between SSc-ILD-associated miRNAs and clinical parameters were assessed, as well as the impact of related miRNAs/sEVs on fibrosis., Results: We identified a 4-miRNA signature associated with ILD in SSc context (miR-584-5p, miR-744-5p, miR-1307-3p and miR-10b-5p) (ROC AUC=0.85, 95% CI 0.76-0.94, p<0.0001). Deeper analysis revealed a correlation of these candidates with pulmonary function tests (DLCO and FVC), highlighting their capacity to monitor lung fibrosis progression in SSc patients. Furthermore, SSc-ILD-associated sEV miRNAs are positively correlated and enriched in circulating lymphocytes, suggesting that these immune cells are their cellular source. Finally, functional studies highlighted an alteration of functional properties of sEVs in SSc-ILD context mainly due to the transfer of profibrotic miR-584-5p in lung fibroblasts., Conclusions: Our sEV-based biomarker approach enabled to identify a promising 4-miRNA signature characteristic of ILD in SSc patients. Furthermore, the profibrotic properties of SSc-ILD-associated sEVs suggest a prominent role of these vesicles on SSc severity., (Copyright ©The authors 2025.)

The syndromes of thrombotic microangiopathy (TMA) are associated with acute kidney injury and end-stage kidney disease. TMAs typically present with thrombocytopenia and microangiopathic hemolytic anemia (ie, systemic TMA). Kidney-limited TMA can occur, although often overlooked and undertreated. In this study, we studied the etiology and outcome of kidney-limited TMA. Patients with TMA on kidney biopsy, either systemic or kidney-limited, were recruited and classified as definite complement-mediated (C-)TMA (ie, ≥1 pathogenic complement gene variant), probable C-TMA (ie, massive ex vivo C5b9 formation without a pathogenic complement gene variant), and non (n)C-TMA (ie, normal ex vivo C5b9 formation). Morphologic features of TMA on kidney biopsy and their clinical correlates were studied. Patients were classified as definite C-TMA (N = 14; 18%), probable C-TMA (N = 21; 27%), or nC-TMA (N = 42; 55%), including 51 (66%) out of 77 patients with kidney-limited TMA. Patients with definite and probable C-TMA often presented with hemolysis (79% and 62% vs 34%; P = .007), glomerular thrombosis (79% and 76% vs 43%), a higher creatinine level (974 and 502 vs 280 μmol/L; P = .001), and a younger age (33 and 33 vs 40 years; P = .029) as compared with nC-TMA. Morphologic features neither defined etiology nor differed between systemic and kidney-limited TMA. Eculizumab improved kidney outcomes in patients with kidney-limited C-TMA but not in those with nC-TMA akin to patients with systemic C-TMA. Kidney outcomes were not affected by chronicity grading on kidney biopsy. Kidney-limited TMA is common in diverse TMAs, including C-TMA. A kidney biopsy is needed to detect TMA at the earliest possible stage of the disease. Morphology does not allow for the identification of etiology, and patients with kidney-limited TMA should therefore be screened for complement dysregulation, having a major impact on treatment and prognosis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Exhaled breath analysis, utilising VOCs, offers promise in identifying SSc-ILD patients, aiding targeted treatment. Further multicentric studies are crucial for validation and exploring longitudinal VOC changes for comprehensive disease management. https://bit.ly/4aKMYif., Competing Interests: Conflict of interest: Outside of this submitted work, B. André reports travel support from Abbvie. Conflict of interest: Outside of this submitted work, R. Louis received unrestricted research grants from GSK, AstraZeneca and Chiesi, and lecture or advisory board fees from GSK and AstraZeneca. Conflict of interest: Outside of this submitted work, J. Guiot received consulting and lectures fees and support for attending meetings from AstraZeneca, Janssens, Chiesi, Roche, GSK and Boehringer Ingelheim, and advisory board fees from GSK, Chiesi, Janssens, AstraZeneca and MSD; and has patents from Radiomics (Oncoradiomics SA). Conflict of interest: The rest of the authors declare that they have no relevant conflicts of interest., (Copyright ©The authors 2024.)

Pulmonary hypertension (PH) is a serious condition linked to immune-system dysfunction. Myositis-specific/associated antibodies (MSAs/MAAs) play a role in idiopathic inflammatory myopathy (IIM) and interstitial lung disease (ILD), but their significance in PH remains unclear. We believe the presence of these antibodies may be underestimated. This study analyzed adult PH patients without pre-existing IIM for MSA/MAA prevalence using a line-blot assay. We compared PH patients with and without ILD signs to a cohort clinically suspected of IIM/ILD ( n = 558). Our PH cohort ( n = 121) showed a significantly higher prevalence of overall weak positive MSAs/MAAs and positive overlap syndrome-associated MAAs than the suspected IIM/ILD group ( p < 0.001). Notably, MSAs/MAAs were found in PH patients both with and without ILD, though more prevalent in those with ILD. Anti-synthetase and anti-overlap syndrome antibodies were the most common. Our study is the first to systematically show a high MSA/MAA prevalence in PH without IIM presentation. This highlights the need to consider PH when diagnosing MSA/MAA-associated conditions. We recommend MSA/MAA screening for newly diagnosed PH, especially in those with ILD, for early detection and potential immunomodulatory treatment. Further research should explore the link between MSAs/MAAs and PH, and the value of monitoring patients with weak MSA/MAA positivity over time.

Background: Systemic sclerosis (SSc) patients face an elevated risk of cardiovascular disease (CVD), even when classic cardiovascular risk factors are considered. Plasma dephosphorylated-uncarboxylated Matrix Gla-protein (dp-ucMGP), an inactive form of MGP, is associated with increased CVD risk. Smooth muscle cells, implicated in SSc's development, are the primary dp-ucMGP producers. This study assessed dp-ucMGP levels and initial CVD events in early-diagnosed SSc patients, investigating its potential as a CVD and all-cause mortality predictor over time., Methods: In a cohort of 87 SSc patients (excluding those with pre-existing CVD or on dialysis), baseline dp-ucMGP levels were measured, along with cardiovascular risk factors. Validation involved assessing dp-ucMGP in a subset of treatment-naive SSc patients., Results: A significantly elevated median dp-ucMGP level of 634 pmol/L (IQR 301) compared with healthy controls (dp-ucMGP < 393 pmol/L; p < 0.001) was observed. Validation in a treatment-naive SSc patient subset yielded similar results (median 589 pmol/L; IQR 370). During a median 10.5-year follow-up among 78 SSc patients, 33.3% experienced their first CVD event, independent of traditional risk factors. Elevated dp-ucMGP levels (>634 pmol/L) correlated with a higher risk of CVD and/or death (log-rank test: p < 0.01)., Conclusions: In summary, dp-ucMGP emerges as a novel biomarker in SSc patients, with elevated levels indicating an increased risk of CVD and/or mortality in this population.

Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Current therapies are mainly focused on vasodilative agents to improve prognosis. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. These include, the B-cell-mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tobal, Potjewijd, Empel, Ysermans, Schurgers, Reutelingsperger, Damoiseaux and Paassen.)