Treatment Response Biomarkers for Systemic Sclerosis‐Associated Interstitial Lung Disease

Objective This studied investigated whether changes in circulating biomarkers predict progressive pulmonary fibrosis (PFF) in patients with systemic sclerosis‐associated interstitial lung disease (ILD) receiving treatment. Method Participants of Scleroderma Lung Study (SLS) II, which compared mycophenolate (MMF) versus cyclophosphamide (CYC) for SSc‐ILD, who had blood samples at baseline and 12‐months were included. Levels for C‐reactive protein (CRP), interleukin (IL)‐6, chemokine ligand 4 (CXCL4), chemokine ligand 18 (CCL18) and Krebs von den Lungen 6 (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 Ninety‐two of the 142 randomized participants had longitudinal biomarker measurements and the required clinical outcome data, with 19 (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 365.68 [SD 434.41]) vs ‐207.45 [SD 670.26]; P<0.001). In the MMF alone arm, changes in CRP and CXCL4 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 PFF (OR 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 SSc‐ILD.