P302 Precision medicine for a case with monogenic inflammatory bowel disease

Abstract Background Here we report the case of a 33-year-old patient suffering from recurring infections since childhood, and Crohn’s disease (CD)-like inflammation in ileum colon for 5 years. The was transferred to our hospital due severe pneumonia with Pseudomonas aeruginosa Mycobacterium chimaera infection, recurrent fever, bronchiectasis, cachexia (BMI 12.9) gastrointestinal symptoms (diarrhoea blood 15 times per day). Colonoscopy revealed peculiar inflammatory pattern without healthy sections deep punched lesions which did not fit diagnosis CD. Methods Exome sequencing performed pathogenic variants identified by silico prediction. Peripheral mononuclear cells (PBMCs) were isolated Signal Transducer And Activator Of Transcription 1 (STAT1) activation assessed immunoblot after treatment JAK-inhibitors. STAT1 quantified leukocytes whole samples flow cytometry. Mucosal used quantify within mucosal multicolour immunofluorescence. Two individuals served as controls. Results mutation (c.1256C>G) gene, predicted cause gain-of-function. is part JAK/STAT1 pathway induced different stimuli orchestrates proliferation responses immune transcription factor. Isolated PBMCs exhibited increased activation, levels particularly observed Monocytes T-helper cells. In activated especially expressed but also epithelial Stimulation Upadacitinib or Tofacitinib partially Filgotinib decreased levels. We initiated vitro results its approval treat ulcerative colitis. After two weeks, clinical improved drastically endoscopy 3 month indicated full remission, paralleled normalisation PBMCs. Conclusion present rare form Inflammatory bowel (IBD) caused gain-of-function affecting gene. IBD-like are unusual mutations, usually immunodeficiency, this specific only twice before listed data bases describing phenotype. Our approach demonstrate how delineating pathomechanism IBD enables targeted precision treatment, currently intensively investigated concept might be implemented into routine future.