Background Immune pathways have been implicated in both systemic sclerosis (SSc)-related interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). Determination of blood cytokine differences in these two disorders need to be elucidated to better understand potential biological processes and common pathogenic pathways.

Objectives This study compared 87 circulating cytokine levels amongst healthy controls and both SSc-ILD and IPF. There was also exploration of the association between cytokine levels and disease progression based on the annualized rate of decline of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO).

Methods Levels of 87 plasma cytokines were measured using commercial panels for consecutive SSc-ILD, IPF, and healthy individuals recruited at a Canadian tertiary-care center. Pulmonary function tests were performed as clinically indicated every 3-12 months. Cytokine levels are compared using the Wilcoxon rank sum test for two samples pairwise. The association between differentially expressed cytokines with both percent predicted annualized FVC and DLCO change was assessed within each disease group using multiple linear models adjusted for age, sex, baseline FVC, and immunosuppressive or anti-fibrotic treatment at sampling. Correction for multiplicity of testing was by Holm’s method.

Results There were 19 healthy controls, 40 SSc-ILD, and 17 IPF participants with clinical features shown in Table 1. Eotaxin-1 and interleukin 6 (IL-6) were significantly elevated in both SSc-ILD and IPF compared to healthy controls (Figure 1). SSc-ILD had significantly lower soluble epidermal growth factor receptor (sEGFR) and higher levels of both soluble tumor necrosis factor receptor type II (sTNFRII) and soluble vascular endothelial growth factor receptor-1 (sVEGFR1) compared to healthy controls. IPF cases were distinguished from healthy controls by significantly higher monocyte chemoattractant protein-1 (MCP-1) and monokine induced by gamma interferon (MIG, also known as CXCL9) levels. No significant association was found for any of the cytokines with ILD progression based on annualized rates of either FVC or DLCO change.

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Figure 1.

Notched box plots of cytokine differences between disease groups. All cytokine levels are shown on a log scale. Overlap of notches indicates lack of a statistically significant difference in medians in a pairwise comparison. P-values are for SSc-ILD or IPF compared to healthy controls using Wilcoxon rank sum two-sample test corrected for multiple testing using Holms method.

Conclusion Differences in seven circulating cytokines between healthy controls with both SSc-ILD and IPF show evidence of systemic cytokine activation. All seven cytokines have a role in immune cell extravasation and pro-fibrotic signaling, which provides further evidence of immune pathways involved in pulmonary fibrosis. Further studies will be pursued of longitudinal change of these biomarkers for halting or slowing disease progression and improving response to treatment.

Disclosure of Interests Boyang Zheng: None declared, Kevin Keen Grant/research support from: Merck Canada Inc, Marvin Fritzler Shareholder of: Abbott Laboratories; Roche Holdings; Abcellera; Moderna, Speakers bureau: For diagnostic company: Werfen, Consultant of: For diagnostic company: Werfen; Aesku, Employee of: Medical Director of Mitogen Diagnostics, Christopher Ryerson Speakers bureau: Boehringer Ingelheim, Hoffmann-La Roche, Consultant of: Boehringer Ingelheim, Hoffmann-La Roche, Veracyte, Astra Zeneca, Grant/research support from: Boehringer Ingelheim, Hoffmann-La Roche, Pearce Wilcox Speakers bureau: Vertex, Valeo, Boehringer, Beth Whalen: None declared, Basak Sahin: None declared, Haiyan Hou Employee of: Mitogen Diagnostics, Penny Latham Employee of: Eve technologies, Mei Feng Zhang Employee of: Mitogen diagnostics, Iris Yao: None declared, James Dunne: None declared