Cytokine dysregulation is hypothesized to play a key role in the pathogenesis of interstitial lung disease (ILD) associated with anti-synthetase syndrome (ASyS). However, the temporal dynamics of cytokine profiles and their relationship with ILD progression remain poorly characterized. This study aimed to characterize longitudinal cytokine trajectories and evaluate their association with disease progression in patients with ASyS-ILD.

We conducted a retrospective longitudinal analysis of 54 patients diagnosed with ASyS-ILD between June 2020 and February 2023. Clinical, serological, and cytokine data were collected alongside high-resolution computed tomography (HRCT) scores. Linear mixed-effects models were used to assess longitudinal changes in cytokine levels. Cox proportional hazards models and Kaplan–Meier analysis were applied to identify baseline predictors of ILD progression and all-cause mortality.

Among the 54 participants (mean age 52.75 ± 10.53 years; 81.5% female), 94.4% had ILD at baseline, and 35.2% (n = 19) developed progressive ILD during follow-up. Elevated baseline interferon-alpha (IFN-α) levels were observed exclusively in progressors (15.8% vs. 0.0%, p = 0.039), and median interleukin-6 (IL-6) levels were significantly higher in this group (5.74 vs. 3.36 pg/mL, p = 0.013). During follow-up, elevated IFN-γ levels were more frequently detected in progressors (21.1% vs. 2.9%, p = 0.047). Notably, IL-6 levels exhibited a sharp increase within the first 12 months in progressors (slope difference: 5.00 ± 2.50 pg/mL; 95% CI 0.10–9.91; p = 0.049), followed by a gradual decline, whereas levels remained stable in non-progressors. Elevated baseline IFN-α was associated with higher mortality risk (p = 0.018). Multivariable Cox regression identified baseline IL-6 (HR 1.045; 95% CI 1.011–1.080; p = 0.010) and complement C4 (HR 1.011; 95% CI 1.001–1.022; p = 0.026) as independent predictors of ILD progression.

 A distinct early surge in IL-6 levels predicts subsequent ILD progression in ASyS, while elevated baseline IFN-α levels are associated with increased mortality. These findings highlight the potential of cytokine profiling for risk stratification and suggest a therapeutic window for IL-6-targeted interventions in high-risk patients.