Background/Purpose: Krebs von den Lungen-6 (KL-6), a marker of lung epithelial and endothelial injury, has been associated with progression of interstitial lung disease associated with systemic sclerosis (SSc-ILD). In the SENSCIS trial, nintedanib, an intracellular inhibitor of tyrosine kinases, slowed the rate of decline in forced vital capacity (FVC) in patients with SSc-ILD compared with placebo. We assessed the associations between levels of KL-6 and clinical variables, and the effect of nintedanib on changes in KL-6 in the SENSCIS trial.

Methods: Patients in the SENSCIS trial had SSc with first non-Raynaud symptom ≤7 years before screening and an extent of fibrotic ILD on HRCT ≥10%. Blood samples for biomarker analysis were taken at baseline and at weeks 4, 24 and 52. Absolute changes from baseline in KL-6 over 52 weeks were analyzed using a mixed model for repeated measures and restricted maximum likelihood approach. Data were log₁₀ transformed prior to analysis and estimates of change from baseline were back-transformed to provide fold changes. Associations between KL-6 levels and age, FVC, DLco, SpO₂, modified Rodnan skin score, St George’s Respiratory Questionnaire total score, and digital ulcer net burden at baseline, and between changes from baseline in KL-6 and each clinical variable over 52 weeks, were assessed using Spearman’s correlation coefficients (rho). Correlations with a coefficient ≥0.25 and a p-value < 0.05 were considered notable.

Results: Of 576 treated patients, 559 (97.0%) had data on KL-6 levels at baseline. At baseline, there was a weak negative correlation between KL-6 levels and DLco % predicted (rho: −0.38 [95% CI: −0.45, −0.31]; nominal p< 0.0001). No notable correlations were observed between KL-6 and other clinical variables at baseline. No notable correlations were observed between changes in KL-6 and changes in other clinical variables over 52 weeks. Fold changes from baseline in adjusted mean KL-6 at week 52 were 0.83 (95% CI: 0.79, 0.88) in the nintedanib group and 0.92 (95% CI: 0.87, 0.97) in the placebo group (ratio of 0.91 [95% CI: 0.84, 0.98]; nominal p=0.01) (Figure). Mean (SE) absolute changes from baseline in KL-6 at week 52 were −202.2 (47.5) U/mL in the nintedanib group and −124.5 (54.8) U/mL in the placebo group. There was no significant difference between the nintedanib and placebo groups in fold change from baseline in adjusted mean KL-6 at week 24.

Conclusion: In the SENSCIS trial in patients with SSc-ILD, higher KL-6 levels at baseline were associated with lower DLco % predicted. KL-6 levels decreased over 52 weeks both in the nintedanib and placebo group, with a larger decrease in the nintedanib group. These data suggest that KL-6 demonstrates a pharmacodynamic response to nintedanib in patients with SSc-ILD over 52 weeks of treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-nintedanib-on-kl-6-in-patients-with-systemic-sclerosis-associated-interstitial-lung-disease/