Mediators of systemic sclerosis-associated interstitial lung disease (SSc-ILD): systematic review and meta-analyses

Abstract

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is rare, poorly understood, with heterogeneous characteristics resulting in difficult diagnosis. We aimed to systematically review evidence of soluble markers in peripheral blood or bronchoalveolar lavage fluid (BALF) as biomarkers in SSc-ILD.MethodFive databases were screened for observational or interventional, peer-reviewed studies in adults published between January 2000 and September 2021 that assessed levels of biomarkers in peripheral blood or BALF of SSc-ILD patients compared with healthy controls. Qualitative assessment was performed using Critical Appraisal Skills Programme (CASP) checklists. Standardised mean difference (SMD) in biomarkers were combined in random-effects meta-analyses where multiple independent studies reported quantitative data.Results768 published studies were identified; 38 articles were included in the qualitative synthesis. Thirteen studies were included in the meta-analyses representing three biomarkers: KL6, SP-D and IL-8. Greater IL-8 levels were associated with SSc-ILD in both peripheral blood and BALF, overall SMD 0.88 (95% CI 0.61 to 1.15; I2=1%). Greater levels of SP-D and KL-6 were both estimated in SSc-ILD peripheral blood compared with healthy controls, at an SMD of 1.78 (95% CI 1.50 to 2.17; I2=8%) and 1.66 (95% CI 1.17 to 2.14; I2=76%), respectively.ConclusionWe provide robust evidence that KL-6, SP-D and IL-8 have the potential to serve as reliable biomarkers in blood/BALF for supporting the diagnosis of SSc-ILD. However, while several other biomarkers have been proposed, the evidence of their independent value in diagnosis and prognosis is currently lacking and needs further investigation.PROSPERO registration numberCRD42021282452.

Alveolar epithelial-to-mesenchymal transition in scleroderma interstitial lung disease: Technical challenges, available evidence and therapeutic perspectives

“…A causal relationship between microcirculation abnormalities and pulmonary fibrosis could be driven by the clinical association of SSc-ILD with digital ulcers, 41 capillaroscopy structural changes, 42 anti-endothelium antibody positivity 43 and increased serum markers of endothelial dysfunction such as E-selectin, P-selectin, von Willebrand Factor Antigen and ICAM1. 44 , 45 Furthermore, the available BALF characterization data consistently show increased levels of endothelin-1 46 and thrombin 47 in SSc-ILD patients. Of note, even if endothelial cells are known to be major players in the synthesis or activation of the above paracrine mediators, these can also derive from epithelial cells, macrophages or mesenchymal cells as a part of a complex cellular crosstalk.…”

Acute Exacerbations of Interstitial Lung Diseases: Focus on Biomarkers

“…In a recent meta-analysis, KL-6, SP-D, and IL-8 in blood and BALF were the best biomarkers of SSc-ILD [ 123 ]. Patients with SSc-ILD have higher serum SP-D levels than those without [ 124 ].…”

Editorial: Cellular and molecular mechanisms of lung regeneration, repair, and fibrosis

“…IPF and scleroderma-associated interstitial lung disease (SSc-ILD) are chronic fibrotic diseases that share common fibrosis pathways. SSc-ILD occurs in individuals with scleroderma, an autoimmune disease, and affects the lungs ( Fields et al, 2023 ). It is characterized by inflammation and fibrosis in the lungs, resulting in progressive scarring and impaired lung function.…”