Systemic sclerosis
TRANSLATIONAL SCIENCE Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis Sébastien Sanges , 1,2,3,4,5,6 Lisa Rice, 1 Ly Tu, 7,8 Eleanor Valenzi , 9 Jean-Luc Cracowski, 10 David Montani , 7,8,11 Julio C Mantero, 1 Camille Ternynck, 12 Guillemette Marot, 12,13,14 Andreea M Bujor, 1 Eric Hachulla , 2,3,4,5,6 David Launay, 2,3,4,5,6 Marc Humbert, 7,8,11 Christophe Guignabert, 7,8 Robert Lafyatis 15
ABSTRACT Objectives To mine the serum proteome of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) and to detect biomarkers that may assist in earlier and more effective diagnosis and treatment. Methods Patients with limited cutaneous SSc, no extensive interstitial lung disease and no PAH-specific therapy were included. They were classified as cases if they had PAH confirmed by right heart catheterisation (RHC) and serum collected on the same day as RHC; and as controls if they had no clinical evidence of PAH. Results Patients were mostly middle-aged females with anticentromere-associated SSc. Among 1129 proteins assessed by a high-throughput proteomic assay (SOMAscan), only 2 were differentially expressed and correlated significantly with pulmonary vascular resistance (PVR) in SSc-PAH patients (n=15): chemerin ( ρ =0.62, p=0.01) and SET ( ρ =0.62, p=0.01). To validate these results, serum levels of chemerin were measured by ELISA in an independent cohort. Chemerin levels were confirmed to be significantly higher (p=0.01) and correlate with PVR ( ρ =0.42, p=0.04) in SSc-PAH patients (n=24). Chemerin mRNA expression was detected in fibroblasts, pulmonary artery smooth muscle cells (PA-SMCs)/pericytes and mesothelial cells in SSc- PAH lungs by single-cell RNA-sequencing. Confocal immunofluorescence revealed increased expression of a chemerin receptor, CMKLR1, on SSc-PAH PA-SMCs. SSc-PAH serum seemed to induce higher PA-SMC proliferation than serum from SSc patients without PAH. This difference appeared neutralised when adding the CMKLR1 inhibitor α -NETA. Conclusion Chemerin seems an interesting surrogate biomarker for PVR in SSc-PAH. Increased chemerin serum levels and CMKLR1 expression by PA-SMCs may contribute to SSc-PAH pathogenesis by inducing PA-SMC proliferation. INTRODUCTION Pulmonary arterial hypertension (PAH) is the most devastating complication of systemic sclerosis (SSc). 1 A common pathological hallmark of PAH is remodelling of precapillary pulmonary arteries (PAs), manifested by pulmonary vasoconstriction and medial thickening due to increased expansion of PA smooth muscle cells (SMCs). 2 This alteration
Handling editor Josef S Smolen
of the small/medium-sized PAs contributes to the progressive and rapid increase in pulmonary vascular resistance (PVR) that eventually lead to right ventricular failure. 3 Right heart catheterisa- tion (RHC) is required to confirm the diagnosis of PAH, to assess the severity of the haemodynamic impairment and the response to treatment. 4 PAH has become a leading cause of death in SSc, with a standardised mortality ratio of 5.27 and a median survival of 3 years. 1 5 Improving its prog- nosis is thus a major challenge when managing SSc patients, 3 requiring early diagnosis to allow for timely initiation of treatment, as well as rapid detec- tion of treatment failure to allow for the immediate adjustment of medications. However, since diag- nosis and disease progression in PAH have haemo- dynamic definitions, this supposes performing iterative RHCs, highlighting the need to identify HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY ⇒ Chemerin could be used as a non-invasive assessment of haemodynamic severity in SSc- PAH patients. ⇒ Further studies could evaluate the ability of chemerin to assess treatment response during follow-up, as well as the efficacy of therapeutic strategies targeting the chemerin-CMKLR1 axis. WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒ Invasive assessment of pulmonary vascular resistance (PVR) by right heart catheterisation is essential in the therapeutic and risk stratification strategies for patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). WHAT THIS STUDY ADDS ⇒ Using a wide-scale proteomic approach, we identified chemerin as a potential non-invasive surrogate for PVR in SSc-PAH patients. ⇒ Chemerin seems to induce pulmonary arterial smooth muscle cell proliferation and contribute to the progression of SSc-PAH through binding with its cognate receptor chemokine-like receptor 1 (CMKLR1).
► Additional supplemental material is published online only. To view, please visit the journal online (http://dx. doi.o rg/10.1 136/ard-2 022- 223237). For numbered affiliations see end of article. Correspondence to Dr Sébastien Sanges, Département de Médecine Interne et Immunologie Clinique, CHU Lille, F-59037 Lille Cedex, France; s ebastien.sanges@u niv-lille.fr
SS and LR contributed equally.
Received 16 August 2022 Accepted 21 November 2022 Published Online First 5 December 2022
© Author(s) (or their employer(s)) 2023. No
To cite: Sanges S, Rice L, Tu L, et al . Ann Rheum Dis 2023; 82 :365–373. commercial re-use. See rights and permissions. Published by BMJ.
Sanges S, et al . Ann Rheum Dis 2023; 82 :365–373. doi:10.1136/ard-2022-223237
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