Targeted therapies and their outcomes in monogenic very early onset inflammatory bowel disease: a systematic review

Background: Very early onset inflammatory bowel disease (VEO-IBD) is a rare, severe condition with over 80 monogenic causes. These often resist conventional therapies, necessitating targeted treatments such as biologics and hematopoietic stem cell transplantation (HSCT). This study aimed to systematically review therapeutic outcomes. Methods: This systematic review followed PRISMA guidelines. We searched MEDLINE/PubMed, Web of Science, and Scopus (up to July 25, 2025) for studies on outcomes of targeted therapies in genetically confirmed monogenic VEO-IBD. Eligible studies included case reports, case series, and observational studies reporting remission, exacerbation, or mortality, with quality assessed using Joanna Briggs Institute checklists. Results: Of 447 records, 62 studies (31 case reports, 21 observational studies, 10 case series) involving 355 patients were included. HSCT (4 studies) achieved survival rates of 64%-100% and remission rates up to 92%, with pooled individual-level data indicating 82% survival and 69% remission. Common complications included graft-versus-host disease (46%) and infections (64%). Of 59 patients receiving biologics or small-molecule agents, anti-TNF therapy showed minimal benefit, especially in IL-10 signaling defects, while based on case repots, other targeted therapies demonstrated favorable responses in specific genetic contexts, including ustekinumab (DUOX2, TGFBR2), anakinra (IL10RA), vedolizumab (CYBB), canakinumab (MVK), and abatacept (CTLA4). Conclusions: HSCT is effective for monogenic VEO-IBD, especially IL10R deficiency, with substantial survival and remission rates despite notable risks, while biologics yield inconsistent results. These findings reinforce early genetic diagnosis in guiding treatment and support the integration of precision medicine into the management of monogenic VEO-IBD, but also highlight the need for genotype-stratified prospective studies. Registration: This review was registered on PROSPERO (CRD420251118080).