A United States Expert Consensus to Standardise Definitions, Follow-Up, and Treatment Targets for Extra-Intestinal Manifestations in Inflammatory Bowel Disease

Benjamin Cohen; Ashwin N. Ananthakrishnan; Edward L. Barnes; Abhik Bhattacharya; Jean-Frederic; Colombel; Raymond K. Cross; Marcia S. Driscoll; Anthony P. Fernandez; Christina Ha; Hans Herfarth; Sara Horst; Jason Hou; M. Elaine Husni; Daniela Kroshinsky; Kristine A. Kuhn; Careen Y. Lowder; George Martin; Deep Parikh; Christopher J. Sayed; Lisa Schocket; Bernadette C. Siaton; Priyanka Vedak; Michael H. Weisman; Florian Rieder

Disclosures

Aliment Pharmacol Ther. 2022;55(9):1179-1191.

Abstract and Introduction

Abstract

Background and Aims: Extra-intestinal manifestations (EIMs) are a common complication of inflammatory bowel diseases (IBD), affecting up to half of the patients. Despite their high prevalence, information on standardised definitions, diagnostic strategies, and treatment targets is limited.

Methods: As a starting point for a national EIM study network, an interdisciplinary expert panel of 12 gastroenterologists, 4 rheumatologists, 3 ophthalmologists, 6 dermatologists, and 4 patient representatives was assembled. Modified Delphi consensus methodology was used. Fifty-four candidate items were derived from the literature review and expert opinion focusing on five major EIMs (erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis) were rated in three voting rounds.

Results: For use in a clinical practice setting and as part of the creation of a prospective registry of patients with EIMs, the panel developed definitions for erythema nodosum, pyoderma gangrenosum, uveitis, peripheral arthritis, and axial arthritis; identified the appropriate and optimal subspecialists to diagnose and manage each; provided methods to monitor disease course; offered guidance regarding monitoring intervals; and defined resolution and recurrence.

Conclusions: Consensus criteria for appropriate and optimal means of diagnosing and monitoring five EIMs have been developed as a starting point to inform clinical practice and future trial design. Key findings include straightforward diagnostic criteria, guidance regarding who can appropriately and optimally diagnose each, and monitoring options that include patient and physician-reported outcomes. These findings will be used in a national multicenter study network to optimise the management of EIMs.

Introduction

Extra-intestinal manifestations (EIMs) represent a significant yet understudied complication of inflammatory bowel diseases (IBD). EIMs are diagnosed in up to 50% of IBD patients^[1] and are associated with morbidity, markedly decreased quality of life, increased complexity of decision-making for providers, and at times even mortality.^[2,3]

Despite their prevalence and significance for patients, the diagnosis and management of EIMs have received only limited attention in the literature, especially in the United States (US). Consistent definitions have yet to be established and can vary widely based on whether the gastroenterology or subspecialty literature is followed.^[4,5] Retrospective studies often rely on metrics like patient reports or the International Classification of Disease (ICD) code for diagnosis and are inherently limited by their retrospective nature.^[6–9] Subanalyses of clinical trials lack standardised definitions of EIMs, are heterogeneous, and are of limited sample size.^[10] There have been few randomised control trials (RCTs), and prospective studies have only been carried out for some of the EIMs, which typically are of small sample size and use widely different definitions of EIMs and treatment success.^[11–16] None of the indices for EIMs in IBD have been developed following accepted methodologies. A 2017 systematic review of the use of biologics to treat all EIMs, including metabolic bone disease and anemia, only identified 22 studies, the majority of which were noninterventional.^[17] The heterogeneity of EIM definitions and outcomes meant that grading studies or conducting a meta-analysis was not possible and led the authors to identify EIMs as a significant unmet need in the literature.^[17]

This scattered and nonsystematic approach has led to conflicting reports and ongoing uncertainties in clinical practice. For example, a retrospective study found a higher rate of EIMs in patients on vedolizumab, whereas a subanalysis of the GEMINI trial reported a decreased likelihood of joint-related EIMs.^[10,12] Diagnosis and management of EIMs is thus largely based on the expert opinion of individual providers as opposed to rational data-driven management, as indicated in the first guideline published in 2015 in Europe.^[13] Although a very important and useful guide, this work does not comment on several items critical for clinical practice. Due to limitations in the literature itself, how and by whom these entities should be diagnosed and treated is often vague, and the means of assessing for improvement or worsening, resolution, and recurrence are not always clearly outlined. In addition, there is little guidance regarding monitoring intervals for EIMs. At the time, this consensus was initiated, no guidelines in the United States had been published.

To address this unmet need, we assembled a multidisciplinary panel of experts across the US and conducted a modified Delphi consensus panel to standardise definitions and treatment targets of five major EIMs in the clinical practice setting. The manifestations included in this study are erythema nodosum (EN), pyoderma gangrenosum (PG), uveitis, peripheral arthritis, and axial arthritis, which were selected based on prevalence and impact on quality of life. This work intends to provide clarity for the practicing provider, set the groundwork for a national multicenter EIM study network, and facilitate future, much-needed prospective studies and clinical trials of EIMs that will impact most IBD patients in their lifetime.

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Table 1. EN items reaching consensus
Item	Responses	Proportion agreement (%)
In a clinical practice setting, IBD-associated EN should be recognised by	Dermatologist	100
	An IBD specialist	100
IBD-associated EN should be clinically diagnosed by	Dermatologist	100
IBD-associated EN should be clinically diagnosed by	An IBD specialist	94
IBD-associated EN should be defined in the clinical practice setting based on	Characteristic appearance of erythematous nodule(s) plus patient report of tenderness	100
	A lesion with features of septal panniculitis on biopsy if there is diagnostic uncertainty on physical exam	100
The average patient with IBD-associated EN can be monitored via	Visits to IBD specialist	88
	Visits to Dermatologist	88
The average patient with IBD-associated EN should be seen	At the time of scheduled assessment of IBD with mild disease and every 1–3 months for moderate to severe disease requiring active intervention	88
Appropriate ways to assess for improvement or worsening in IBD-associated EN include	Patient report of a change in size and/or number of nodules	88
	Patient global assessment	82
	Physician assessment demonstrating change in size	75–83^a
	Physician assessment of change in the number of nodules	76–82^a
	Physician global assessment^b	76–94^a
Resolution of IBD-associated EN is defined as	Patient report of resolution	88
Resolution of IBD-associated EN is defined as	Physician assessment demonstrating no nodule(s)	88
Recurrence of IBD-associated EN is defined as	Nodule(s) that develop anywhere	100
Timeline of recurrence of IBD-associated EN is defined as	Patient report of the nodule(s) returning any time after resolution	82
Timeline of recurrence of IBD-associated EN is defined as	Physician assessment of nodule(s) returning any time after resolution	88
Patients with IBD-associated EN should be monitored for recurrence	As part of standard of care visits with their IBD specialist	94
	As part of standard of care visits with dermatology	88

Abbreviations: EN, erythema nodosum; IBD, inflammatory bowel disease.
^aRange in percentage is due to the inclusion of percentage agreement for improvement and for worsening (see Table S2 for a breakdown of percentages by individual items).
^bPhysician global assessment was defined by our panel with 100% consensus as the overall status of EIM based on patient symptoms, physical exam, and any relevant testing (imaging, laboratory data).

Table 2. PG items reaching consensus
Item	Responses	Proportion agreement (%)
In a clinical practice setting, IBD-associated PG should be recognised by	An IBD specialist	88
	Dermatologist	94
IBD-associated PG should be clinically diagnosed by	Dermatologist	100
IBD-associated PG can be defined in the clinical practice setting via	Expert assessment of ulcerated and tender lesions with the exclusion of other etiologies	94
	Ulcerated lesions with biopsy of edge demonstrating neutrophilic infiltrate AND exclusion of other etiologies	75
	Any lesion meeting either 2018 Modified Delphi Consensus OR Paracelsus score criteria^a	75
The average patient with IBD-associated PG should be monitored via	Visits to IBD specialist	88
	Visits to Dermatologist	88
The average patient with IBD-associated PG should be seen	At the time of scheduled assessment of IBD with mild disease and every 1–3 months for moderate to severe disease requiring active intervention	88
Appropriate ways to assess for improvement or worsening of IBD-associated PG include	Patient report of change in size (measured with a tape measure) and/or degree of ulceration	81
	Physician assessment of subjective change in size	81
	Physician assessment of objective change in size	100
	Physician assessment of change in ulceration	88–94^b
	Physician global assessment^c	76–92^b
	Photographs demonstrating a change in size and/or degree of ulceration as per dermatology	94
Resolution of IBD-associated PG can be defined as	Patient report of absence of ulceration	94
	Physician assessment demonstrating no lesion(s)	100
	Photographs demonstrating no lesions as per dermatology	94
Recurrence of IBD-associated PG is defined as	A lesion that recurs anywhere	100
Timeline of recurrence of IBD-associated PG is defined as	Physician assessment of lesions returning any time after resolution	76
Patients with IBD-associated PG should be monitored for recurrence	As part of the standard of care visits with their IBD specialist	88
	As part of the standard of care visits with dermatology	88

Abbreviations: IBD, inflammatory bowel disease; PG, pyoderma gangrenosum.
^aThe 2018 Modified Delphi criteria are one major criterion – biopsy of ulcer edge demonstrating neutrophilic infiltrate and eight minor criteria: (1) exclusion of infections; (2) pathergy; (3) history of inflammatory bowel disease or inflammatory arthritis; (4) history of papule, pustule, or vesicle ulcerating within 4 days of appearing; (5) peripheral erythema, undermining border, and tenderness at ulceration site; (6) multiple ulcerations at least one on the anterior lower leg; (7) cribriform or "wrinkled paper" scar(s) at healed ulcer sites; and (8) decreasing ulcer size within 1 month of initiation immunosuppressive medication(s).³⁰ The Paracelsus Criteria are Progressing disease (defined as clinically evident ulcer developing within <6 weeks), Assessment of relevant differential diagnoses, Reddish-violaceous wound border, Amelioration by immunosuppressant drugs, Characteristically irregular (bizarre) ulcer shape, Extreme pain >4/10 on the visual analog scale, Localization of lesion at the site of trauma (pathergy phenomenon), Suppurative inflammation in histopathology, Undermined Wound Border, Systemic disease associated.³¹
^bRange in percentage is due to the inclusion of percentage agreement for improvement and for worsening (see Table S2 for a breakdown of percentages by individual items).
^cPhysician global assessment was defined by our panel with 100% consensus as the overall status of EIM based on patient symptoms, physical exam, and any relevant testing (imaging, laboratory data).

Table 3. Uveitis items reaching consensus
Item	Responses	Proportion agreement (%)
In a clinical practice setting, IBD-associated uveitis should be recognised by	An ophthalmologist	100
IBD-associated uveitis should be clinically diagnosed by	An ophthalmologist	100
IBD-associated uveitis should be defined as	More than one cell in the anterior chamber, vitreous haze, or the presence of choroidal or retinal inflammation	75
In a clinical practice setting, IBD-associated uveitis should be monitored by	An ophthalmologist	100
Improvement of IBD-associated uveitis is defined as	Two-step decrease in the level of inflammation or decrease to Grade 0 as per ophthalmologists	77
Worsening of IBD-associated uveitis is defined as	Two-step increase in the level of inflammation or increase from Grade 3 to 4 as per ophthalmologists	86
Recurrence of IBD-associated uveitis is defined as	New episode in either eye	92
Timeframe of recurrence of IBD-associated uveitis is defined as	Inflammation recurring after >3 months regardless of IBD therapy	93
Patients with history of IBD-associated uveitis should be monitored for recurrence	As part of the standard of care visits with ophthalmology	93

Abbreviation: IBD, inflammatory bowel disease.

Table 4. Peripheral arthritis items reaching consensus
Item	Responses	Proportion agreement (%)
In a clinical practice setting, IBD-associated peripheral arthritis should be recognised by	An IBD specialist	92
	A rheumatologist	93
IBD-associated peripheral arthritis should be clinically diagnosed by	An IBD specialist	85
	A rheumatologist	100
In a clinical practice setting, IBD-associated peripheral should be defined as	Joint pain + swollen/tender joints on exam	77
	Morning stiffness + joint pain + swollen/tender joints on exam	85
	Swollen/tender joints on the exam with the exclusion of other etiologies	92
In a clinical practice setting, IBD-associated peripheral can be monitored via	Visits to IBD specialist	85
	Visits to rheumatologist	100
The average patient with IBD-associated peripheral arthritis should be seen	At the time of scheduled assessment of IBD with mild disease and every 1–3 months for moderate to severe disease requiring active intervention	85
Appropriate ways to assess for improvement or worsening in IBD-associated peripheral arthritis include	Patient report of change in morning stiffness	75
	Patient report of the change in joint pain with movement	75
	Patient report of change in swelling/tenderness	81–88^a
	Patient report of change in number of involved joints	75
	Patient report of overall improvement/worsening	75–81^a
	Physician report of change in swelling/tenderness/redness	100
	Physician report of change in number of involved joints	86–100^a
	Physician global assessment^b	86–88^a
Resolution of IBD-associated peripheral arthritis can be defined as	Patient report of resolution	75
	IBD specialist assessment demonstrating resolution	86
	Rheumatology assessment demonstrating resolution	100
Recurrence of IBD-associated peripheral arthritis is defined as	Recurrent joint involvement in the same anatomic location(s)	88
	New joint involvement in any anatomic location	100
Timeline of recurrence of IBD-associated peripheral arthritis is defined as	Patient report of joint symptoms returning any time after resolution	75
	Physician assessment of joint symptoms returning any time after resolution	88
Patients with IBD-associated peripheral arthritis should be monitored for recurrence	As part of the standard of care visits with their IBD specialist	94
	As part of the standard of care visits with rheumatology	100

Abbreviation: IBD, inflammatory bowel disease.
^aRange in percentage is due to the inclusion of percentage agreement for improvement and for worsening (see Table S2 for a breakdown of percentages by individual items).
^bPhysician global assessment was defined by our panel with 100% consensus as the overall status of EIM based on patient symptoms, physical exam, and any relevant testing (imaging, laboratory data).

Table 5. Axial arthritis items reaching consensus
Item	Responses	Proportion agreement (%)
In a clinical practice setting, IBD-associated axial arthritis should be recognised by	An IBD specialist	86
	A rheumatologist	100
IBD-associated axial arthritis should be clinically diagnosed by	A rheumatologist	100
In a clinical practice setting, IBD-associated axial arthritis should be defined as	Patient who meets ASAS classification criteria for axial arthritis as per rheumatologists^c	93
	Patients with IBD, inflammatory back pain, and consistent MRI findings as per rheumatologists	93
In a clinical practice setting, IBD-associated axial arthritis can be monitored via	Visits to rheumatologist	100
The average patient with IBD-associated axial arthritis should be seen	At least every 3 months until symptoms improve or resolve	81
Appropriate ways to assess for improvement or worsening of IBD-associated axial arthritis include	Patient report of change in back pain	75
	Patient report of overall improvement or worsening	75–76^a
	Physician global assessment^b	86
In a clinical practice setting, clinical resolution of symptoms of IBD-associated axial arthritis can be defined as	Rheumatology assessment demonstrating resolution of clinical symptoms	94
In a clinical practice setting, clinical recurrence of symptoms of IBD-associated axial arthritis can be defined as	Rheumatology assessment demonstrating recurrence of clinical symptoms anytime after resolution	88
The average IBD patient with axial arthritis should be seen	As part of the standard of care visits with their IBD specialists	81
The average IBD patient with axial arthritis should be seen	As part of the standard of care visits with rheumatology	100

Abbreviation: IBD, inflammatory bowel disease.
^aASAS criteria for spondyloarthritis include patients with ≥3 months of back pain with or without peripheral manifestations and age at onset <45 years who have sacroiliitis on imaging plus ≥1 spondyloarthritis feature of HLA-B27 plus ≥2 other spondyloarthritis features. Spondyloarthritis features include inflammatory back pain, arthritis, enthesitis (heel), uveitis, dactylitis, psoriasis, Crohn's/Ulcerative colitis, good response to nonsteroidal anti-inflammatory drugs, family history for spondyloarthritis, HLA-B27, and elevated C-reactive protein.⁵
^bRange in percentage is due to the inclusion of percentage agreement for improvement and for worsening (see Table S2 for a breakdown of percentages by individual items).
^cPhysician global assessment was defined by our panel with 100% consensus as the overall status of EIM based on patient symptoms, physical exam, and any relevant testing (imaging, laboratory data).

Authors and Disclosures

Benjamin Cohen¹, Ashwin N. Ananthakrishnan², Edward L. Barnes³, Abhik Bhattacharya⁴, Jean-Frederic Colombel⁴, Raymond K. Cross⁵, Marcia S. Driscoll⁶, Anthony P. Fernandez⁷, Christina Ha⁸, Hans Herfarth³, Sara Horst⁹, Jason Hou¹⁰, M. Elaine Husni¹¹, Daniela Kroshinsky¹², Kristine A. Kuhn¹³, Careen Y. Lowder¹⁴, George Martin¹⁵, Deep Parikh¹⁶, Christopher J. Sayed¹⁷, Lisa Schocket¹⁸, Bernadette C. Siaton¹⁹, Priyanka Vedak¹⁷, Michael H. Weisman²⁰ and Florian Rieder¹

¹Department of Gastroenterology and Hepatology, Cleveland Clinic Foundation, Cleveland, OH, USA
²Department of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
³Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA
⁴Department of Gastroenterology, Mount Sinai, New York, NY, USA
⁵Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
⁶Department of Dermatology, University of Maryland, Baltimore, MD, USA
⁷Department of Dermatology, Cleveland Clinic Foundation, Cleveland, OH, USA
⁸Department of Gastroenterology, Mayo Clinic Arizona, Scottsdale, AZ, USA
⁹Department of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA
¹⁰Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center & Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
¹¹Department of Rheumatologic and Immunologic Disease, Cleveland Clinic Foundation, Cleveland, OH, USA
¹²Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA
¹³Department of Medicine, Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
¹⁴Cleveland Clinic Foundation Cole Eye Institute, Cleveland, OH, USA
¹⁵Dr. George Martin Dermatology Associates, Kihei, HI, USA
¹⁶Department of Ophthalmology New York Eye and Ear Infirmary of Mount Sinai, Department of Ophthalmology, New York University Langone Health, New York, NY, USA
¹⁷Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA
¹⁸Department of Ophthalmology, University of Maryland, Baltimore, MD, USA
¹⁹Division of Rheumatology and Clinical Immunology, University of Maryland, Baltimore, MD, USA
²⁰Department of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA

Correspondence
Florian Rieder, Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, 9500 Euclid Avenue –NC22, Cleveland, OH 44195, USA. Email: riederf@ccf.org

Author Contributions
Katherine Falloon: Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); project administration (equal); validation (equal); visualization (equal); writing – original draft (lead); writing – review and editing (equal). Benjamin L. Cohen: Conceptualization (equal); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); project administration (equal); supervision (equal); validation (equal); visualization (equal); writing – original draft (supporting); writing – review and editing (equal). Ashwin Ananthakrishnan: Data curation (equal); formal analysis (equal); methodology (equal); writing – review and editing (equal). Edward L. Barnes: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Abhik Bhattacharya: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Jean-Frederic Colombel: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Raymond K. Cross: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Marcia S. Driscoll: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Anthony P. Fernandez: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Christina Ha: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Hans Herfarth: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Sara Nicole Horst: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Jason Hou: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). M. Elaine Husni: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Daniela Kroshinsky: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Kristine A. Kuhn: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Careen Y. Lowder: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). George Martin: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Deep Parikh: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Christopher J. Sayed: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Lisa Schocket: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Bernadette C. Siaton: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Priyanka Vedak: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Michael H. Weisman: Data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); writing – review and editing (equal). Florian Rieder: Conceptualization (lead); data curation (equal); formal analysis (equal); investigation (equal); methodology (equal); project administration (equal); resources (equal); supervision (lead); validation (equal); visualization (equal); writing – original draft (equal); writing – review and editing (lead).
All authors participated in the modified Delphi consensus panel. KF and FR wrote the manuscript. All authors revised and edited the manuscript. All authors approved the final version of the article, including the authorship list.

Declaration of personal interests
AA has served on the scientific advisory boards of Gilead, Ikena therapeutics, and Sun Pharma. Ananthakrishnan is supported by grants from the National Institutes of Health, Crohn's and Colitis Foundation, and Chleck Family Foundation. APF is an investigator for Pfizer, Corbus, Mallinckrodt, and Novartis and receives personal research support from Mallinckrodt and Novartis; honorarium from AbbVie, BMS, Novartis, Alexion, UCB, Boeringer-Ingelheim, and Mallinckrodt for consulting and advisory board participation, and honorarium from AbbVie, Novartis, Kyowa Kirin, and Mallinckrodt for teaching and speaking. ELB is a consultant for AbbVie, Gilead, Pfizer, and Target RWE. BLC receives the following financial support: Advisory Boards and Consultant for Abbvie, Celgene-Bristol Myers Squibb, Pfizer, Sublimity Therapeutics, Takeda, TARGET RWE; CME Companies: Cornerstones, Vindico; Speaking: Abbvie; Educational Grant: Pfizer. RKC receives income from consulting and participation in advisory boards from Abbvie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, Samsung Bioepis, and Takeda. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc., Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda, TiGenix; and hold stock options in Intestinal Biotech Development. KF is supported by a grant from the Crohn's and Colitis Foundation. CH is on the advisory board for Abbvie, Janssen, Genentech, InDex Pharmaceuticals, Takeda, Pfizer, and Bristol Myers Squibb. She has research collaborations (nonfunded) with Abbvie, Genentech, Lilly, and Pfizer. She receives grant support from Pfizer. She is on the speakers' bureau for Abbvie. HH receives research support from Allakos, Artizan, NovoNordisk, Pfizer, and consulting fees from Alivio, BMS, Boehringer, ExeGi Pharma, Finch, Gilead, Janssen, Pfizer, Pure Tech, and Otsuka. SH has served as a consultant for Abbvie, Janssen, UCB, Takeda, and Gilead. JH has received research funding from Redhill Biosciences, Janssen, Abbvie, Celgene, Genentech, Eli-Lily, Lycera, and Pfizer Inc. JH is supported in part by resources at the VA HSR&D Center for Innovations in Quality, Effectiveness and Safety (#CIN 13–413), at the Michael E. DeBakey VA Medical Center, Houston, TX. The views expressed in this article are those of the author(s) and do not necessarily represent the views of the Department of Veterans Affairs. GRM serves on Scientific Advisory Boards for Almirall, Incyte, Pfizer, Lilly, UCB, Dermavent, Trevi, Abbvie, Bristol Meyers Squibb (BMS), Celgene, and LEO; is a consultant for Pfizer, Almirall, Abbvie, Lilly, Biofrontera, UCB, Galderma, Scientist, Dermavent, Bausch/Ortho, Incyte, BMS, Celgene, and LEO; is a speaker for Incyte, UCB, LEO; and owns stock in Doc Martins of Maui Sunscreen Company. FR is on the advisory board for or consultant to Adnovate, Agomab, Allergan, AbbVie, Arena, Boehringer Ingelheim, Celgene/BMS, CDISC, Cowen, Ferring, Galmed, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Jannsen, Koutif, Mestag, Metacrine, Morphic, Organovo, Origo, Pfizer, fPliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surmodics, Surrozen, Takeda, Techlab, Theravance, Thetis, UCB, Ysios, and 89Bio. FR is supported by grants from the National Institutes of Health (K08DK110415 and R01DK123233), Crohn's and Colitis Foundation, Rainin Foundation, and the Helmsley Charitable Trust through the Stenosis Therapy and Anti-Fibrotic Research (STAR) Consortium. CS has received honoraria as a speaker from Abbvie and Novartis, honoraria for consulting from Abbvie, Novartis, and UCB. Investigator fees are paid to the institution by Abbvie, Novartis, UCB, InflaRx, Incyte, and Chemocentryx. Consulting fees are paid to the institution by UCB.