Type I interferon is raised across connective tissue diseases and is associated with haematological abnormalities and specific autoantibody profiles

Background/Aims The overlapping clinical and serological features among connective tissue diseases (CTDs) suggest a shared molecular aetiology. A molecular taxonomy of CTDs offers new opportunities in clinical trial design, which can potentially be translated into targeted treatment. In a previous study of 164 patients, we identified a type I interferon (IFN) positive subgroup within an unselected CTD cohort associated with specific clinical and serological features. Here, we aim to investigate the relationship between type I IFN and the clinical and immunological phenotype in a larger CTD cohort and determine whether a distinct subpopulation of patients can be identified. Methods Adult patients with at least 1 CTD clinical feature and CTD-related autoantibody were recruited from five rheumatology centres in North West England into the Lupus Extended Autoimmune Phenotype (LEAP) cohort. A 24-gene interferon-stimulated gene (ISG) score was calculated using NanoString as described by Neasens et al. 2022. Results Most patients had lupus (36%). 160 of 344 (46.5%) patients had a positive ISG score across all CTDs with 64/125 (51%) of lupus patients (Fig.1). Patients with positive ISG score were younger and had longer disease duration (p<0.005 for both). There were no differences in mucocutaneous or internal organ involvement between the ISG subgroups. The ISG-positive group had significantly increased frequency of specific autoantibodies (anti-Smith, anti-Chromatin, anti-RNP, anti-Ro) and Rheumatoid Factor, and haematological abnormalities (lower haemoglobin, and lower total white cell and neutrophil counts) in an adjusted model including the CTD subtype. Conclusion In CTD patients, IFN type I positivity was identified across a subset of patients of all CTDs and is associated with specific autoantibodies and haematological parameters; these results support the findings of our previous smaller study. The identification of an IFN I-positive subgroup within an unselected CTD regardless of clinical diagnosis supports a molecular-based approach to treatment. Disclosure A. Madenidou: Grants/research support; Janssen and UCB. G.I. Rice: None. S. Dyball: Grants/research support; UCB, Novartis,Eli Lilly. B. Parker: Honoraria; Fresenius-Kabi and AbbVie. Member of speakers' bureau; Eli Lilly and Roche. Grants/research support; Genzyme/Sanofi and GlaxoSmithKline. T.A. Briggs: Grants/research support; Janssen. I.N. Bruce: Consultancies; AstraZeneca, Eli Lilly, GlaxoSmithKline, Merck Serono and UCB. Member of speakers' bureau; AstraZeneca, GlaxoSmithKline and UCB. Grants/research support; Genzyme/Sanofi, GlaxoSmithKline, Roche, Novartis, Janssen and UCB.