Nat Rev Gastroenterol Hepatol. 2023 Oct 3. doi: 10.1038/s41575-023-00838-4.Online ahead of print.

Holm H Uhlig ^1 2 3, Claire Booth ^4 5, Judy Cho ⁶, Marla Dubinsky ⁷, Anne M Griffiths ^8 9, Bodo Grimbacher ^10 11 12, Sophie Hambleton ¹³, Ying Huang ¹⁴, Kelsey Jones ^15 16, Jochen Kammermeier ¹⁷, Hirokazu Kanegane ¹⁸, Sibylle Koletzko ^19 20, Daniel Kotlarz ^19 21 22, Christoph Klein ^19 21, Michael J Lenardo ²³, Bernice Lo ^24 25, Dermot P B McGovern ²⁶, Ahmet Özen ²⁷, Lissy de Ridder ²⁸, Frank Ruemmele ²⁹, Dror S Shouval ^30 31, Scott B Snapper ^32 33, Simon P Travis ^34 35 16, Dan Turner ³⁶, David C Wilson ^37 38, Aleixo M Muise ^{8 9 39 40 41}

Author information

¹Translational Gastroenterology Unit, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.

²Department of Paediatrics, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.

³Biomedical Research Centre, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.

⁴UCL Great Ormond Street Institute of Child Health, London, UK.

⁵Department of Paediatric Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

⁶Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

⁷Department of Paediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

⁸SickKids Inflammatory Bowel Disease Centre and Cell Biology Program, Research Institute, Toronto, Canada.

⁹Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, Toronto, Canada.

¹⁰Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.

¹¹Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.

¹²Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, UK.

¹³Primary Immunodeficiency Group, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK.

¹⁴Department of Gastroenterology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China.

¹⁵Paediatric Gastroenterology, Great Ormond Street Hospital, London, UK.

¹⁶Kennedy Institute, University of Oxford, Oxford, UK.

¹⁷Gastroenterology Department, Evelina London Children's Hospital, London, UK.

¹⁸Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

¹⁹Dr. von Hauner Children's Hospital, Department of Paediatrics, University Hospital, LMU Munich, Munich, Germany.

²⁰Department of Paediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland.

²¹German Center for Child and Adolescent Health, Munich, Germany.

²²Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

²³Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

²⁴Research Branch, Sidra Medicine, Doha, Qatar.

²⁵College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.

²⁶F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

²⁷Marmara University Division of Allergy and Immunology, Istanbul, Turkey.

²⁸Department of Paediatric Gastroenterology, Erasmus University Medical Center Sophia Children's Hospital, Rotterdam, Netherlands.

²⁹Université Paris Cité, APHP, Hôpital Necker Enfants Malades, Service de Gastroentérologie pédiatrique, Paris, France.

³⁰Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.

³¹Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

³²Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA.

³³Department of Paediatrics and Department of Medicine, Harvard Medical School, Boston, MA, USA.

³⁴Translational Gastroenterology Unit, University of Oxford, Oxford, UK.

³⁵Biomedical Research Centre, University of Oxford, Oxford, UK.

³⁶Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.

³⁷Child Life and Health, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.

³⁸Department of Paediatric Gastroenterology, The Royal Hospital for Children, and Young People, Edinburgh, UK.

³⁹Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.

⁴⁰Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

⁴¹Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

Abstract

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments) standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians to assess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis.