Circulating biomarkers in patients with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial

This study aimed to determine the prognostic significance of circulating proteins and the effects of nintedanib on these proteins in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the safety and efficacy of nintedanib in systemic sclerosis study (SENSCIS) trial.

Patients had SSc with ≤7 years since their first non-Raynaud symptom. Candidate biomarkers of inflammation, epithelial dysfunction, extracellular matrix (ECM) synthesis, and ECM turnover were measured in serum/plasma. We assessed associations between baseline biomarker levels and decline in forced vital capacity (FVC) over 52 weeks and change in modified Rodnan Skin Score (mRSS) at week 52 in the placebo group, and changes in biomarker levels in nintedanib and placebo groups.

Baseline Krebs von den Lungen-6 (KL-6) and citrullinated vimentin (VICM) degraded by MMP-2/8 levels were significantly associated with the rate of decline in FVC over 52 weeks in uncorrected analyses. A baseline KL-6 concentration of >1000 vs ≤1000 U/mL was associated with a greater rate of decline in FVC (mL) over 52 weeks (estimates: -132.5 [95% CI: -174.1, -91.0] vs -56.4 [-95.2, -17.6]; P = .009). Higher baseline N-terminal propeptide of type III collagen (Pro-C3), chemokine (C-C motif) ligand 2, and C-reactive protein levels were significantly associated with less improvement in mRSS at week 52 in analyses corrected for multiple comparisons. Decreases in cancer antigen (CA)-125 and N-terminal propeptide of type VI collagen (pro-C6) over 52 weeks were observed in patients who received nintedanib vs placebo. In mediation analysis, 48.0% of the effect of nintedanib on change in FVC at week 52 was attributed to the treatment-related decrease in CA-125 at week 24.

Applying a dichotomised threshold for KL-6 can aid in identifying patients with SSc-ILD with more progressive ILD. Nintedanib reduced levels of the epithelial dysfunction marker, CA-125, and collagen synthesis epitope, pro-C6.