Interstitial lung disease (ILD) has emerged as a lethal complication of systemic juvenile idiopathic arthritis (sJIA), often characterized by a clinical "phenotypic dissociation" between intense systemic inflammation and minimal articular involvement. This study aimed to delineate the clinical endotype of sJIA-ILD and investigate the pathogenic role of Oncostatin M (OSM) and its regulation under diverse therapeutic pressures.

We conducted a retrospective study of 202 sJIA patients (ILD+, n=64; ILD-, n=138) to define clinical and radiological signatures. Independent risk factors were identified via multivariate logistic regression. Circulating biomarkers were screened using Olink® high-dimensional proteomics. Mechanistic validation was performed in a TLR9-induced Macrophage Activation Syndrome (MAS) mouse model. We evaluated compartmentalized OSM regulation by IFN-γ and compared the efficacy of Janus kinase (JAK) inhibition (ruxolitinib) against divergent Interleukin-6 receptor (IL-6R) blockade regimens: single high-dose (SD, 20 mg/kg) versus multiple low-dose (MD, 10 mg/kg ×3).

Patients with sJIA-ILD exhibited a "systemic-dominant" phenotype, characterized by a significantly higher MAS incidence (67.2% vs. 29.0%, P < 0.001) despite a paradoxically lower active joint count (P = 0.020). LDH (OR=2.69 per 1-SD increase) and CRP (OR=1.85 per 1-SD increase) were identified as independent predictors of ILD. A significant sexual dimorphism was observed in radiological manifestations, with male gender conferring a 4.05-fold increased risk of pleural effusion (P = 0.019). Proteomic profiling identified OSM as a specific hallmark of ILD. In the MAS model, induction triggered massive surges in systemic and pulmonary OSM. Mechanistically, exogenous IFN-γ paradoxically suppressed pulmonary OSM (72.9% reduction) while leaving systemic levels elevated, revealing a distinct compartmentalized regulation. Therapeutically, ruxolitinib robustly normalized OSM levels across both compartments. Conversely, while single high-dose IL-6R blockade was effective, the multiple low-dose regimen precipitated a systemic hyperinflammatory rebound, with plasma OSM levels surging 6.6-fold compared to the high-dose group (P = 0.029).

sJIA-ILD represents a distinct hyperinflammatory endotype driven by OSM, characterized by a visceral-dominant clinical profile and radiological sexual dimorphism. The observed compartmentalized regulation and the risk of paradoxical exacerbation under suboptimal IL-6R blockade emphasize the critical impact of dosing strategies. These findings support JAK inhibition as a mechanistically superior therapeutic approach for this refractory complication.