Samuel Wilcox, MD1, Reid Herran, MD1, Haley Mertens, MD2, Shrinivas Bishu, MD1, Peter D. R.. Higgins, MD, PhD, MSc1, Samuel Chiang, PhD3, Kelly Walkovich, MD4, Jeffrey Berinstein, MD, MS1 1University of Michigan, Ann Arbor, MI; 2University of Michigan, Chelsea, MI; 3Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 4Michigan Medicine, Ann Arbor, MI Introduction: Very-early-onset inflammatory bowel disease (VEO-IBD), defined as IBD 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 VEO-IBD1, 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 female, 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: one known pathogenic variant and one missense variant of uncertain significance. LRBA protein expression was null by flow cytometry, but CTLA-4 functional testing (Figure 1) 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 function2, the addition of upadacitinib is novel. Upadacitinib is a selective Janus kinase 1 (JAK1) inhibitor that broadly disrupts pro-inflammatory cytokine signaling central to the pathogenesis of multiple primary immunodeficiencies.
References: Hall CHT, de Zoeten EF. Understanding very early onset inflammatory bowel disease (VEOIBD) in relation to inborn errors of immunity. Immunol Rev. 2024 Mar;322(1):329-338. Lo B, Zhang K, Lu W, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436-440.
Figure: Figure 1. A. Mouse monoclonal anti-LRBA staining on various lymphocyte populations show null LRBA protein expression in the patient as compared to control. B. CTLA-4 expression on Treg cell surface and intracellularly upon mock or CD3/CD28 bead stimulation. Values in blue represent the percentage of Tregs expressing CTLA-4 upon stimulation. Median fluorescence intensity when mock stimulated in red, while upon stimulation in black. The patient shows lowered resting state intracellular CTLA-4 levels (401 vs 1049), lowered upregulated intracellular CTLA-4 levels upon stimulation (2685 vs 9529), and lowered cell surface CTLA-4 expression upon stimulation compared to control (138 vs 509).
Disclosures: Samuel Wilcox indicated no relevant financial relationships. Reid Herran indicated no relevant financial relationships. Haley Mertens indicated no relevant financial relationships. Shrinivas Bishu indicated no relevant financial relationships. Peter Higgins: AbbVie – Consultant. Samuel Chiang indicated no relevant financial relationships. Kelly Walkovich indicated no relevant financial relationships. Jeffrey Berinstein indicated no relevant financial relationships.
Samuel Wilcox, MD1, Reid Herran, MD1, Haley Mertens, MD2, Shrinivas Bishu, MD1, Peter D. R.. Higgins, MD, PhD, MSc1, Samuel Chiang, PhD3, Kelly Walkovich, MD4, Jeffrey Berinstein, MD, MS1. P1229 - A JAK of All Trades: The Novel Use of Upadacitinib in LRBA Deficiency-Related Autoimmune Enterocolitis, ACG 2025 Annual Scientific Meeting Abstracts. Phoenix, AZ: American College of Gastroenterology.
