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Introduction This study aims to investigate metabolic and lipidic alterations and pathways linked to systemic sclerosis (SSc) and its disease severity, with a focus on interstitial lung disease (ILD).Material and Methods The Western Sweden Systemic Sclerosis Project (WESST) is a longitudinal cohort study of SSc patients at Sahlgrenska University Hospital, Gothenburg, Sweden, and healthy controls. All patients met the 2013 ACR-EULAR criteria at inclusion. Nineteen patients with SSc and ILD were matched with 19 without ILD using propensity scores (age, sex, disease duration, Rodnan score). Additionally, 18 healthy controls were matched by age and sex. LC-MS based plasma metabolomics and lipidomics were performed at the Swedish Metabolomics Center, and data were analysed using MetaboAnalyst 6.0.Results Clinical characteristics of the study cohort are shown in table 1. In total, 287 metabolites and 181 lipids (belonging to 4 lipid classes) were annotated. Patients with SSc showed distinct plasma metabolic and lipidic profiles compared to healthy controls (figure 1A and 1B). Results from univariate analysis in metabolomics combining the outcomes from t-test (p < 0.05) and fold-change (1.5) analyses in a volcano plot showed an enrichment in cis-4-decenoylcarnitine, 4-acetamidobutanoic acid, 4-hydroxyhippuric acid, inosine, and hypoxanthine in patients with SSc compared to healthy controls (figure 1C). At FDR q <0.05, cis-4-decenoylcarnitine, 4-acetamidobutanoic acid and 4-hydroxyhippuric acid remained significant. Patients with SSc also showed lower levels of caffeine, and two metabolites derived from caffeine: theophylline and paraxanthine. Pathway enrichment analysis indicated several metabolic pathways potentially associated with SSc, including purine synthesis, caffein metabolism, arginine and proline metabolism, and tryptophan metabolism. When comparing patients with SSc with and without ILD, alterations in purine metabolism were detected, with an enrichment in xanthine, hypoxanthine, and inosine in SSc with ILD.Univariate analysis in lipidomics showed little difference in lipid profile between healthy controls and patients withSSc. There was a trend for downregulated sphingomyelins and phosphatidylcholines in SSc with ILD compared to SSc without ILD.Conclusions The distinct plasma metabolic and lipidic profiles between patients with SSc and healthy controls highlighted alterations in purine metabolism, caffeine metabolism, and amino acid pathways. Reduced caffeine and metabolites derived from it might indicate lower coffee consumption in patients with SSc, possibly related to gastroesophageal reflux commonly seen in SSc. When comparing patients with SSc with and without ILD, alterations in purine metabolism were observed, likely reflecting the higher prevalence of anti-rheumatic treatment among patients with SSc-ILD.Abstract P.224 Figure 1Abstract P.224 Table 1