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Published on: October 31, 2025
Inflammatory Biomarkers and Outcome Heterogeneity in Anti-MDA5 Antibody-Associated Interstitial Lung Disease: A
Akina Nigi1, Keisuke Iwamoto1, Hidetoshi Itani1
1Department of Respiratory Medicine, Japanese Red Cross Ise Hospital, 471-2 Funae, Ise 516-8512, Mie, Japan.
Background:
Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive interstitial lung disease (ILD) is associated with high mortality. While inflammatory markers have been linked to poor outcomes, clinical heterogeneity remains evident, as some patients survive despite marked hyperinflammation.
Methods:
We retrospectively analyzed consecutive patients with anti-MDA5 antibody-positive ILD treated at our institution between May 2017 and November 2025. In-hospital mortality was assessed in relation to clinical characteristics and laboratory markers, including peak anti-MDA5 antibody titers, ferritin, C-reactive protein (CRP), lactate dehydrogenase (LDH), and KL-6. Analyses were exploratory and hypothesis-generating. Continuous variables were compared using Mann-Whitney U tests, and categorical variables using Fisher's exact test. Principal component analysis (PCA) and receiver operating characteristic (ROC) analyses were performed for descriptive purposes.
Results:
Seventeen patients were included (10 survivors and 7 non-survivors). Peak ferritin, C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels were significantly higher in non-survivors, whereas peak anti-MDA5 antibody titers showed a non-significant trend toward higher values in non-survivors (p = 0.057). KL-6 levels did not differ significantly between groups. In ROC analyses, LDH and CRP showed the highest discriminative performance for in-hospital mortality, followed by ferritin, whereas KL-6 showed the lowest discriminative performance. Despite these overall trends, substantial overlap between survivors and non-survivors remained across all biomarkers. Principal component analysis (PCA) demonstrated partial separation of outcomes along an inflammation-dominant axis, but with persistent overlap, indicating marked outcome heterogeneity.
Conclusions:
Inflammatory biomarkers, particularly LDH, CRP, and ferritin, were associated with in-hospital mortality in anti-MDA5 antibody-associated ILD. However, persistent overlap between survivors and non-survivors suggests that single-biomarker assessment is insufficient for precise prognostication. These findings should be interpreted as hypothesis-generating and require validation in larger multicenter cohorts.