Treatment Response Biomarkers for Systemic Sclerosis-Associated Interstitial Lung Disease

Abstract

Objective: This study investigated whether changes in circulating biomarkers predict progressive pulmonary fibrosis (PPF) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) receiving treatment.

Methods: Participants of the Scleroderma Lung Study II, which compared receiving mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) for treating SSc-ILD, who had blood samples at baseline and 12 months were included. Levels for C-reactive protein (CRP), interleukin-6, C-X-C motif chemokine ligand (CXCL) 4, CCL18, and Krebs von den Lungen (KL)-6 were measured, and a logistic regression model evaluated relationships between changes in these biomarkers and the development of PPF by 24 months.

Results: A total of 92 of the 142 randomized participants had longitudinal biomarker measurements and the required clinical outcome data, with 19 participants (21%) meeting criteria for PPF. In the whole cohort, changes in KL-6 levels were significantly correlated with PPF. KL-6 increased in patients who developed PPF and decreased in patients who did not (mean change ± SD 365.68 ± 434.41 vs -207.45 ± 670.26; P < 0.001). In the arm of participants who received MMF alone, changes in CRP and CXCL4 levels were also significantly correlated with PPF. When added to an existing prediction model based on baseline factors associated with PPF in this cohort (sex, baseline reflux severity, and CXCL4 levels), the change in KL-6 remained significantly associated with PPF (odds ratio 1.4; P = 0.0002).

Conclusion: Changes in the circulating levels of KL-6 after treatment with MMF or CYC predicted PPF, even after adjusting for baseline factors associated with PPF. Measuring longitudinal KL-6 in patients with SSc-ILD may improve how we personalize therapy in patients with SSc-ILD.