Serum Interleukin 6 Is Predictive of Early Functional Decline and Mortality in Interstitial Lung Disease Associated with Systemic Sclerosis

Abstract

Objective.Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD).Methods.A panel of 8 serum cytokines [interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1] was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline [forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15%] from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD.Results.In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC < 70%), serum IL-6 > 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4–7.2, p = 0.007), but not in those with severe ILD.Conclusion.In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.

NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung

“…Interestingly, it has been suggested that altered IL-6 signalling in IPF primary fibroblast culture may enhance the resistance of these cells to apoptosis and contribute to a pro-fibrotic effect of IL-6 in IPF [27]. In addition, IL-6 serum levels are suggested to be predictive of early disease progression in patients with systemic sclerosis-associated interstitial lung disease [28].…”

Cellular interactions in the pathogenesis of interstitial lung diseases

“…Experimental data demonstrated that treatment with anti-topoisomerase I antibody induces skin and lung fibrosis stimulating IL-6 production [108]. Moreover, IL-6 is an independent predictor of decline in diffusing capacity of the lung for carbon monoxide (DLCO), in both IPF and SSc-ILD patients [109]. Oncostatin M, an IL-6 family cytokine, has been implicated in a number of biological processes, including the modulation of ECM and the induction of pulmonary inflammation and fibrosis, both in SSc-ILD and IPF [110], through an IL-4/IL-13 and TGF-β-independent mechanism.…”

Interstitial lung disease in systemic sclerosis: where do we stand?

“…Recently, a loss of density on capillaroscopy was shown to be associated with worse FVC and DLCO [40] and biomarkers that correlate with the severity of fibrosis have been proposed: elevated levels of chitinase [41], tenascin C [42], growth differentiation protein 15 [43], cartilage oligomeric matrix protein, alveolar epithelial cell antigen, KL-6 [44] and the chemokine CXCL4 [45]. Serum IL-6 predicted early disease progression and IL-6 values >767 pg·mL −1 were predictive of risk of death within the first 30 months in patients with mild SSc-ILD [46].…”