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Introduction Interstitial lung disease (ILD) represents a significant contributor to the morbidity and mortality associated with SSc. The ability to detect and monitor ILD early is crucial for initiating effective treatments and improving patient outcomes. Emerging evidence highlights the potential of serum biomarkers as non-invasive indicators for diagnosing, tracking progression, and predicting prognosis in ILD. However, their specific role in SSc-ILD requires further elucidation. This study sought to investigate the utility of serum biomarkers—KL-6, IL-18, and IL-18 binding protein (IL-18BP)—as tools for diagnosing ILD and predicting its progression in patients with SSc.Material and Methods This 24-month prospective cohort study included 74 SSc patients, stratified based on the presence of ILD using high-resolution computed tomography (HRCT). Clinical evaluations, pulmonary function tests (PFTs), and serum biomarker measurements (KL-6, IL-18, and IL-18BP) were conducted. ILD severity was assessed using HRCT and the modified Goh scoring system. Disease activity and damage were evaluated using the 2017 EUSTAR Activity Index (EScSG-AI) and the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI). Pearson’s correlation was employed to examine associations between biomarkers, lung function, and ILD severity.Results At baseline, 38% of patients had ILD, which increased to 54% over two years. The proportion of patients with lung involvement equal or more than 20% rose from 32% to 43%. Serum KL-6 and IL-18 levels were significantly elevated in patients with ILD, showing strong negative correlations with %FVC and %DLCO. ROC analysis identified serum KL-6 ( equal or more than 273.8 U/mL) and IL-18 (equal or more than 290.83 U/mL) as effective for ILD diagnosis. During follow-up, annual changes in KL-6 were closely associated with lung function decline and ILD severity on HRCT. In the first year, KL-6 changes negatively correlated with FVC (r = -0,51, p = 0.0007) and DLCO (r = -0,21, p = 0.003) while positively correlating with semiquantitative CT grades (rs = 0,30, p = 0.01). These correlations persisted in the second year, with changes in KL-6 correlating with FVC (r = -0.47, p = 0.0007) and DLCO (r = -0.38, p = 0.001).Conclusions KL-6 and IL-18, have significant diagnostic and prognostic value in SSc-ILD. Elevated baseline levels of these biomarkers correlate with ILD presence, severity, and lung function decline, while annual changes in KL-6 provide critical insights into disease progression. These findings underscore the potential of serum biomarkers as non-invasive tools for risk stratification, disease monitoring, and informing therapeutic strategies in SSc-ILD.Abstract P.085 Figure 1