Integrated inflammatory-immune-nutritional signatures differentiate lung phenotypes in systemic sclerosis

Background: Systemic sclerosis (SSc) exhibits heterogeneous pulmonary involvement, most commonly interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). How systemic inflammatory, immune, and nutritional states differ across these lung phenotypes remains incompletely understood. Objective: To characterize integrated inflammatory-immune-nutritional signatures across SSc lung phenotypes and validate their robustness using multivariable modeling and unsupervised clustering. Methods: = 12) and sparse-data instability; and (3) k-means clustering of standardized biomarker profiles. Internal validation and clustering stability analyses were performed. Results: = 0.028). In multinomial models, female sex and longer disease duration were associated with both ILD + /PAH- (OR 3.48, 95%CI 1.51-8.04; OR 1.02 per month, 95%CI 1.01-1.04) and ILD + /PAH + (OR 3.49, 95%CI 1.31-9.33; OR 1.03 per month, 95%CI 1.01-1.05). Triglycerides (Z-score) were associated with ILD + /PAH- (OR 1.70, 95%CI 1.05-2.77), while log(ESR) (Z-score) was associated with ILD + /PAH + (OR 1.82, 95%CI 1.01-3.27). Clustering supported a three-cluster structure driven by inflammation (ESR), mucosal immunity (IgA), and metabolic dysregulation (triglycerides), with strong stability (Adjusted Rand Index = 1.00). Internal validation showed stable within-cohort performance (accuracy ∼0.62-0.65). Conclusion: SSc lung phenotypes defined by ILD/PAH co-occurrence display distinct integrated inflammatory-immune-nutritional signatures. The ILD + /PAH + phenotype reflects a high-burden systemic inflammatory state, and a small set of coherent markers (ESR, triglycerides, IgA, and autoantibodies) provides a reproducible framework for phenotype-oriented stratification.