S4859 A JAK of All Trades: The Novel Use of Upadacitinib in LRBA Deficiency-Related Autoimmune Enterocolitis

Introduction: Very-early-onset inflammatory bowel disease, defined as inflammatory bowel disease diagnosed before the age of 6 years, carries a higher likelihood of an underlying monogenic etiology involving genes critical to immune regulation. There are around 80 known monogenic etiologies of Very-early-onset inflammatory bowel disease 1, including lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency, an autosomal recessive primary immunodeficiency leading to defective regulation of cytotoxic T-lymphocyte antigen 4 (CTLA-4). Case Description/Methods: A 25-year-old woman, diagnosed with Crohn’s disease at age 16, presented after recurrent hospitalizations for severe electrolyte derangements, acidemia, TPN-dependent malnutrition, and multiple infections (labial abscess, dental abscess, pneumonia, and bacteremia). Review of her endoscopic biopsies showed loss of goblet and Paneth cells with abundant apoptosis, and her diagnosis was revised to autoimmune enterocolitis. She was treated with prednisone, budesonide, azathioprine, and sirolimus with limited benefit. Evaluation for a primary immune deficiency revealed compound heterozygosity in the LRBA gene: 1 known pathogenic variant and 1 missense variant of uncertain significance. LRBA protein expression was null by flow cytometry, but CTLA-4 functional testing strongly supported functional LRBA deficiency. She was started on abatacept with marginal improvement. Addition of upadacitinib led to significant improvement in diarrhea and electrolyte derangements. Symptoms briefly returned when upadacitinib was held for a dental abscess, then resolved with reinitiation. Discussion: This case represents the first reported use of combined abatacept and upadacitinib to treat LRBA deficiency–associated autoimmune enterocolitis. While abatacept, a CTLA4-Ig fusion protein, is an established therapy for LRBA deficiency due to its restoration of CTLA4 function, the addition of upadacitinib is novel. Upadacitinib is a selective Janus kinase 1 inhibitor that broadly disrupts pro-inflammatory cytokine signaling central to the pathogenesis of multiple primary immunodeficiencies.