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Objective Sjögren’s disease (SjD) is a chronic systemic autoimmune disease with heterogeneous glandular and extraglandular manifestations. Although aetiology and pathogenesis of SjD remains elusive, emergence of autoreactive T and B lymphocytes is crucial in disease development. In this study, the metabolome of patients with SjD was characterised to improve disease understanding and to identify biomarkers as tools to aid drug development.Method The metabolome was investigated in saliva, tears and plasma samples from two independent cohorts from Poland (PL) and the UK using a mass spectrometry screening platform with 4500 reference metabolites. The PL cohort included 30 healthy subjects and 32 patients with SjD. The UK cohort encompassed longitudinal samples from 13 healthy subjects and 12 patients with SjD.Results Patient heterogeneity was reflected in the metabolome across all three matrices (plasma, saliva and tears) with consistent disturbances in the amino acid metabolism and transport pathway. A biomarker signature was developed using both cohorts, which allowed to characterise patients with milder and more severe disease activity. The relevance of the biomarker signature was supported by the presence of metabolites linked to pathways such as gamma-glutamyl cycle, pyrimidine metabolism and sex steroid hormones, which have previously been described to be deregulated in patients with SjD and other autoimmune diseases.Conclusion A plasma metabolome biomarker signature was developed that can be implemented in clinical studies by simple blood collection. The biomarker signature allows to characterise disease activity of patients with SjD at baseline and provides a basis for future studies to investigate its potential utility in monitoring therapeutic intervention.