Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards

doi:10.1038/s41575-023-00838-4

Review

. 2023 Dec;20(12):810-828.

doi: 10.1038/s41575-023-00838-4. Epub 2023 Oct 3.

Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards

Holm H Uhlig^{1

2

3}, Claire Booth^{4

5}, Judy Cho⁶, Marla Dubinsky⁷, Anne M Griffiths^{8

9}, Bodo Grimbacher^{10

11

12}, Sophie Hambleton¹³, Ying Huang¹⁴, Kelsey Jones^{15

16}, Jochen Kammermeier¹⁷, Hirokazu Kanegane¹⁸, Sibylle Koletzko^{19

20}, Daniel Kotlarz^{19

21

22}, Christoph Klein^{19

21}, Michael J Lenardo²³, Bernice Lo^{24

25}, Dermot P B McGovern²⁶, Ahmet Özen²⁷, Lissy de Ridder²⁸, Frank Ruemmele²⁹, Dror S Shouval^{30

31}, Scott B Snapper^{32

33}, Simon P Travis^{34

35

16}, Dan Turner³⁶, David C Wilson^{37

38}, Aleixo M Muise^{8

9

39

40

41}

Affiliations

¹ Translational Gastroenterology Unit, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.
² Department of Paediatrics, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.
³ Biomedical Research Centre, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.
⁴ UCL Great Ormond Street Institute of Child Health, London, UK.
⁵ Department of Paediatric Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁶ Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Department of Paediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ SickKids Inflammatory Bowel Disease Centre and Cell Biology Program, Research Institute, Toronto, Canada.
⁹ Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, Toronto, Canada.
¹⁰ Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.
¹¹ Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.
¹² Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, UK.
¹³ Primary Immunodeficiency Group, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK.
¹⁴ Department of Gastroenterology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China.
¹⁵ Paediatric Gastroenterology, Great Ormond Street Hospital, London, UK.
¹⁶ Kennedy Institute, University of Oxford, Oxford, UK.
¹⁷ Gastroenterology Department, Evelina London Children's Hospital, London, UK.
¹⁸ Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁹ Dr. von Hauner Children's Hospital, Department of Paediatrics, University Hospital, LMU Munich, Munich, Germany.
²⁰ Department of Paediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland.
²¹ German Center for Child and Adolescent Health, Munich, Germany.
²² Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²³ Molecular 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.
²⁴ Research Branch, Sidra Medicine, Doha, Qatar.
²⁵ College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
²⁶ F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²⁷ Marmara University Division of Allergy and Immunology, Istanbul, Turkey.
²⁸ Department of Paediatric Gastroenterology, Erasmus University Medical Center Sophia Children's Hospital, Rotterdam, Netherlands.
²⁹ Université Paris Cité, APHP, Hôpital Necker Enfants Malades, Service de Gastroentérologie pédiatrique, Paris, France.
³⁰ Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
³¹ Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³² Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
³³ Department of Paediatrics and Department of Medicine, Harvard Medical School, Boston, MA, USA.
³⁴ Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
³⁵ Biomedical Research Centre, University of Oxford, Oxford, UK.
³⁶ Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.
³⁷ Child Life and Health, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
³⁸ Department of Paediatric Gastroenterology, The Royal Hospital for Children, and Young People, Edinburgh, UK.
³⁹ Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
⁴⁰ Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
⁴¹ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

PMID: 37789059
DOI: 10.1038/s41575-023-00838-4

Review

Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards

Holm H Uhlig et al. Nat Rev Gastroenterol Hepatol. 2023 Dec.

. 2023 Dec;20(12):810-828.

doi: 10.1038/s41575-023-00838-4. Epub 2023 Oct 3.

Authors

Affiliations

¹ Translational Gastroenterology Unit, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.
² Department of Paediatrics, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.
³ Biomedical Research Centre, University of Oxford, Oxford, UK. holm.uhlig@ndm.ox.ac.uk.
⁴ UCL Great Ormond Street Institute of Child Health, London, UK.
⁵ Department of Paediatric Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁶ Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷ Department of Paediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ SickKids Inflammatory Bowel Disease Centre and Cell Biology Program, Research Institute, Toronto, Canada.
⁹ Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, University of Toronto, Toronto, Canada.
¹⁰ Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.
¹¹ Department of Rheumatology and Clinical Immunology, Medical Center, Faculty of Medicine, Albert Ludwig University of Freiburg, Freiburg, Germany.
¹² Institute of Immunology and Transplantation, Royal Free Hospital, University College London, London, UK.
¹³ Primary Immunodeficiency Group, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK.
¹⁴ Department of Gastroenterology, National Children's Medical Center, Children's Hospital of Fudan University, Shanghai, China.
¹⁵ Paediatric Gastroenterology, Great Ormond Street Hospital, London, UK.
¹⁶ Kennedy Institute, University of Oxford, Oxford, UK.
¹⁷ Gastroenterology Department, Evelina London Children's Hospital, London, UK.
¹⁸ Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁹ Dr. von Hauner Children's Hospital, Department of Paediatrics, University Hospital, LMU Munich, Munich, Germany.
²⁰ Department of Paediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland.
²¹ German Center for Child and Adolescent Health, Munich, Germany.
²² Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²³ Molecular 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.
²⁴ Research Branch, Sidra Medicine, Doha, Qatar.
²⁵ College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
²⁶ F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²⁷ Marmara University Division of Allergy and Immunology, Istanbul, Turkey.
²⁸ Department of Paediatric Gastroenterology, Erasmus University Medical Center Sophia Children's Hospital, Rotterdam, Netherlands.
²⁹ Université Paris Cité, APHP, Hôpital Necker Enfants Malades, Service de Gastroentérologie pédiatrique, Paris, France.
³⁰ Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
³¹ Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
³² Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA.
³³ Department of Paediatrics and Department of Medicine, Harvard Medical School, Boston, MA, USA.
³⁴ Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
³⁵ Biomedical Research Centre, University of Oxford, Oxford, UK.
³⁶ Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.
³⁷ Child Life and Health, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
³⁸ Department of Paediatric Gastroenterology, The Royal Hospital for Children, and Young People, Edinburgh, UK.
³⁹ Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
⁴⁰ Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
⁴¹ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

PMID: 37789059
DOI: 10.1038/s41575-023-00838-4

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.

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References

1. Uhlig, H. H. et al. Clinical genomics for the diagnosis of monogenic forms of inflammatory bowel disease: a position paper from the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 72, 456–473 (2021). - PubMed - PMC
1. Bolton, C. et al. An integrated taxonomy for monogenic inflammatory bowel disease. Gastroenterology 122, 859–876 (2022).
1. Uhlig, H. H. & Powrie, F. Translating immunology into therapeutic concepts for inflammatory bowel disease. Annu. Rev. Immunol. 36, 755–781 (2018). - PubMed
1. Charbit-Henrion, F., Parlato, M., Malamut, G., Ruemmele, F. & Cerf-Bensussan, N. Intestinal immunoregulation: lessons from human mendelian diseases. Mucosal Immunol. 14, 1017–1037 (2021). - PubMed
1. Sullivan, K. E., Conrad, M. & Kelsen, J. R. Very early-onset inflammatory bowel disease: an integrated approach. Curr. Opin. Allergy Clin. Immunol. 18, 459–469 (2018). - PubMed - PMC

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[1] Uhlig, H. H. et al. Clinical genomics for the diagnosis of monogenic forms of inflammatory bowel disease: a position paper from the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 72, 456–473 (2021). - PubMed - PMC

[2] Uhlig, H. H. et al. Clinical genomics for the diagnosis of monogenic forms of inflammatory bowel disease: a position paper from the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 72, 456–473 (2021). - PubMed - PMC

[3] Bolton, C. et al. An integrated taxonomy for monogenic inflammatory bowel disease. Gastroenterology 122, 859–876 (2022).

[4] Bolton, C. et al. An integrated taxonomy for monogenic inflammatory bowel disease. Gastroenterology 122, 859–876 (2022).

[5] Uhlig, H. H. & Powrie, F. Translating immunology into therapeutic concepts for inflammatory bowel disease. Annu. Rev. Immunol. 36, 755–781 (2018). - PubMed

[6] Uhlig, H. H. & Powrie, F. Translating immunology into therapeutic concepts for inflammatory bowel disease. Annu. Rev. Immunol. 36, 755–781 (2018). - PubMed

[7] Charbit-Henrion, F., Parlato, M., Malamut, G., Ruemmele, F. & Cerf-Bensussan, N. Intestinal immunoregulation: lessons from human mendelian diseases. Mucosal Immunol. 14, 1017–1037 (2021). - PubMed

[8] Charbit-Henrion, F., Parlato, M., Malamut, G., Ruemmele, F. & Cerf-Bensussan, N. Intestinal immunoregulation: lessons from human mendelian diseases. Mucosal Immunol. 14, 1017–1037 (2021). - PubMed

[9] Sullivan, K. E., Conrad, M. & Kelsen, J. R. Very early-onset inflammatory bowel disease: an integrated approach. Curr. Opin. Allergy Clin. Immunol. 18, 459–469 (2018). - PubMed - PMC

[10] Sullivan, K. E., Conrad, M. & Kelsen, J. R. Very early-onset inflammatory bowel disease: an integrated approach. Curr. Opin. Allergy Clin. Immunol. 18, 459–469 (2018). - PubMed - PMC

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Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards

Affiliations

Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards

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