MEETING SUMMARIES

Challenges in the Pathophysiology, Diagnosis, and Management

of Intestinal Fibrosis in Inflammatory Bowel Disease
Geert D’Haens,1 Florian Rieder,2,3 Brian G. Feagan,4 Peter D. R. Higgins,5 Julian Panés,6
Christian Maaser,7 Gerhard Rogler,8 Mark Löwenberg,1 Robbert van der Voort,9
Massimo Pinzani,10 Laurent Peyrin-Biroulet,11 Silvio Danese,12 and the International
Organization for Inflammatory Bowel Disease Fibrosis Working Group
1
Amsterdam University Medical Center, Academic Medical Center, Department of Gastroenterology and Hepatology,
Amsterdam, The Netherlands; 2Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic
Foundation, Cleveland, Ohio; 3Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery
Institute, Cleveland Clinic Foundation, Cleveland, Ohio; 4Western University, Department of Medicine, London, Ontario,
Canada; 5University of Michigan Medical School, Department of Internal Medicine, Ann Arbor, Michigan; 6Hospital Clínic de
Barcelona, August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive
Diseases, Barcelona, Spain; 7University Teaching Hospital Lüneburg, Outpatients Department of Gastroenterology, Lüneburg,
Germany; 8University Hospital Zurich, Department of Gastroenterology and Hepatology, and University of Zurich, Zurich,
Switzerland; 9Vision Medical Communications, Nijmegen, The Netherlands; 10University College London, Institute for Liver and
Digestive Health, Division of Medicine, Royal Free Hospital, London, UK; 11University Hospital of Nancy, University of Lorraine,
Department of Hepato-Gastroenterology and INSERM U954, Vandoeuvre-lès-Nancy, France; and 12Inflammatory Bowel
Disease Center, Humanitas Clinical and Research Hospital, Humanitas University, Milan, Italy

I ntestinal fibrosis is a common complication of in-

flammatory bowel disease (IBD) that is usually the
consequence of chronic inflammation. Although the anti-
cells (Figure 1).1 Luminal microorganisms and bacterial
products, in addition to growth factors and cytokines
released from immune and nonimmune cells, are the main
inflammatory therapies currently available have had little drivers of mesenchymal cell activation and differentiation
impact on intestinal fibrosis in Crohn’s disease (CD), that ultimately result in fibrosis.
increased understanding of the pathophysiology and the Preclinical models of intestinal fibrosis have been
development of therapies targeting fibrogenic pathways developed to better understand the pathophysiology,
hold promise for the future. One of the critical challenges is including a heterologous transplant model in rats and mice.
how reduction or reversal of intestinal fibrosis should be For example, it was demonstrated that the bacteria-
defined and measured in the setting of clinical trials and responsive adaptor protein MYD88 (myeloid differentiation
drug approval. primary response 88) and the cytokine interleukin 10 do
The International Organization for Inflammatory Bowel not play critical roles in intestinal fibrosis, despite the
Disease organized a workshop in Amsterdam, The theoretical plausibility of this interaction. Pirfenidone and
Netherlands, on December 19–20, 2018 in an attempt to antibodies against matrix metalloproteinase 9, agents
review the current knowledge of the biological background, currently approved for the treatment of idiopathic pulmo-
diagnosis, treatment of intestinal fibrosis, and clinical trial nary fibrosis, prevented the development of experimental
end points. Basic and clinical scientists discussed the patho- intestinal fibrosis. Other translational studies indicated
physiology of intestinal fibrosis, the current status of bio- that inhibition of the pH-sensing OGR1 (ovarian cancer
markers and imaging modalities in stenosing CD, and recent G-protein-coupled receptor 1) and the apoptosis regulator
clinical studies in this area. Researchers from outside the IBD BCL2 (B-cell lymphoma 2) are potential approaches to
field presented advances in the understanding of fibrotic prevent fibrosis in IBD.
processes in other organs, such as the skin, liver, and lungs.
Lastly, the design of clinical trials with antifibrotic therapy for Biomarkers For Intestinal Fibrosis
IBD was discussed, with priority on patient populations, pa- Prediction of the development and progression of
tient-reported outcomes (PROs), and imaging. intestinal fibrosis and stricture formation is of great
This report summarizes the key findings, discussions,
and conclusions of the workshop.
Abbreviations used in this paper: CD, Crohn’s disease; ECM, extracellular
Pathophysiology of Intestinal Fibrosis matrix; IBD, inflammatory bowel disease; MRI, magnetic resonance im-
aging; PRO, patient-reported outcome; SSc, systemic sclerosis.
Fibrosis represents excessive production of extracellular
matrix (ECM) by activated mesenchymal cells. ECM-
Most current article
producing cells are predominantly myofibroblasts that
© 2022 by the AGA Institute
differentiate from epithelial, endothelial, and stellate cells, 0016-5085/$36.00
as well as from fibroblasts and bone marrow–derived stem https://doi.org/10.1053/j.gastro.2019.05.072

Gastroenterology 2022;162:26–31
 MEETING SUMMARIES

Figure 1. Pathophysiology of intestinal fibrosis: Soluble factors (red) and different origins of mesenchymal cells (blue).1 CTGF,
connective tissue growth factor; EGF, epidermal growth factor; EndoMT, endothelial-to-mesenchymal transition; ET, endo-
thelins; PDGF, platelet-derived growth factor.

importance in the management of IBD. Multiple studies have In the RISK (Risk Stratification and Identification of
tried to identify markers that can stratify patients in fibrotic Immunogenetic and Microbial Markers of Rapid Disease
risk groups, detect early stages of fibrosis before the onset Progression in Children with Crohn’s Disease) study, which
of symptoms, and predict the outcomes of therapy. This included more than 900 children and adolescents with
search resulted in the identification of several phenotypic newly diagnosed IBD, a competing-risk model based on
characteristics and serologic and genetic markers associated demographic characteristics, clinical, serologic, and genetic
with stenotic complications. markers could predict a complicated disease course and
Of the more than 200 genes connected to IBD, several response to anti-tumor necrosis factor therapy.2 Other risk
have been associated with fibrostenotic CD, such as variants models, such as the Bacardi model, have been developed to
of NOD 2 (nucleotide-binding oligomerization domain- facilitate therapeutic decisions.
containing protein 2) gene and matrix metalloproteinase 3. Histopathologic analysis of intestinal fibrosis may pro-
Epigenetic regulation of the genes encoding WNT2B vide critical information beyond that available from these
(wingless-type mouse mammary tumor virus integration clinical phenotype-based instruments. Smooth muscle hy-
site family 2B) and 2 eicosanoid synthesis pathway enzymes perplasia of the submucosa, hypertrophy of the muscularis
was also associated with CD fibrosis. In addition, several propria, and chronic inflammation are the most prominent
serologic parameters, including ECM molecules; growth changes in CD strictures.3 Because the overall muscular
factors; and antibodies against microbial products, are hyperplasia and hypertrophy correlated positively with
associated with the development of IBD and, in some cases, chronic inflammation and negatively with fibrosis, the
with fibrosis. “inflammation-smooth muscle hyperplasia axis” appears to

27
MEETING SUMMARIES
play a dominant role in the pathogenesis of CD-associated developed currently as a tool to quantify intestinal inflam-
strictures. mation and fibrosis.

Evaluation of Stenosis in Crohn’s Disease Lessons From Fibrosis in Other Organs

Sensitive and specific diagnostic methods, including im- Fibrosis is a complication of many chronic diseases and
aging modalities and biomarkers, are required to quantify aging, and occurs in virtually all organs. Accumulating
different components of stenosis. An ideal instrument must evidence indicates that the pathogenic pathways involved in
be valid, reliable, and responsive. Outcome measures in systemic sclerosis (SSc) and hepatic fibrosis display simi-
clinical trials should also be noninvasive, widely available, larities with intestinal fibrosis.
inexpensive, and, if possible, radiation-free. An instrument
with all of these desirable properties could become vali-
dated as a surrogate end point in clinical trials in stenosing Systemic Sclerosis
CD. A number of tools are currently available as potential SSc is an autoimmune disorder characterized by exten-
outcome measures in stenosing CD, each of which has sive fibrosis, vasculopathy, and immune dysfunction.
specific advantages and disadvantages. Critical components Although the pathogenesis of SSc is largely unknown,
are the assessment of bowel wall thickness, mechanical and translational studies have revealed altered fibroblast
vascular characteristics, infiltration of immune cells, and biology, in addition to activation and accumulation of
expression of genes and proteins. However, it should be immune cells. CXC-chemokine ligand 4, a chemokine
recognized that none of these candidate modalities has un- secreted by plasmacytoid dendritic cells, is highly overex-
dergone the comprehensive validation process required for pressed in SSc, and correlates with the severity of pulmo-
a robust outcome measure. nary fibrosis and pulmonary arterial hypertension, the 2
Cross-sectional imaging techniques, such as magnetic most serious complications of the disease.
resonance imaging (MRI) and computer tomography scan- Transforming growth factor b–dependent signaling
ning, are the most widely explored methods to differentiate through STAT3 (signal transducer and activator of tran-
fibrosis and inflammation. For instance, whereas inflam- scription 3) is also up-regulated in SSc. STAT3 inhibitors,
mation in CD is associated with increased T2 hyperintensity, which are currently being tested for other indications, offer
mucosal enhancement, ulcerations, and blurred margins, an attractive approach in SSc and other fibrotic conditions.
fibrosis is rather characterized by abnormalities in contrast The inhibition of serotonin signaling is another potential
uptake (“enhancement”). Diffusion-weighted MRI and approach, given that inhibition of serotonin receptors pre-
magnetization transfer MRI are potentially useful for vents the onset of experimental fibrosis and reduces
quantification of fibrosis. Other promising modalities established fibrosis in animal models.
include T2* mapping, intravoxel incoherent motion diffu- Clinical trials in SSc assess disease modification in skin
sion-weighted MRI, MRI-defined motility, and magnetic or lungs, using both composite clinical end points and other
resonance elastography. organ-specific readouts. For instance, the modified Rodnan
Intestinal ultrasound is being used increasingly for the skin score is used for the clinical assessment of skin scle-
evaluation of CD and assessment of complications and rosis, the forced vital capacity measures lung function in
treatment response. Intestinal ultrasound is noninvasive, pulmonary fibrosis, and the Composite Response Index in
convenient for the patient and physician, inexpensive, and Systemic Sclerosis is used commonly to evaluate disease
associated with overall sensitivity and specificity for stric- activity in early diffuse cutaneous SSc.
tures of 80% and 95%, respectively.4 The use of contrast At present, tocilizumab, nintedanib, riociguat, and aba-
media can further increase the sensitivity and specificity. tacept have been approved in various jurisdictions for the
Limitations of intestinal ultrasound include the lack of a treatment of SSc. In addition, many other agents, including
“panoramic” view of the whole bowel, the currently missing inhibitors of adhesion molecules, growth factors, and cyto-
standard for image documentation, and the difficulty kines and their receptors, are being evaluated as mono-
assessing the proximal ileum and jejunum. therapy or combination therapy. Myeloablative autologous
Innovative imaging modalities are contrast-enhanced hematopoietic stem cell transplantation has also been of
ultrasonography and elastography. Contrast-enhanced ul- benefit to patients with severe SSc.
trasonography is time-consuming, relatively expensive, and
not yet validated. Hepatic Fibrosis
Elastography, including quantitative shear wave elas- Hepatic fibrosis is characterized by excessive accumu-
tography and qualitative strain elastography, might be lation of ECM components, resulting from chronic liver
especially useful to distinguish fibrotic from inflammatory injury associated with nonalcoholic steatohepatitis, viral
stenosis, and to discriminate low-grade from high-grade hepatitis, or alcoholic liver disease. Several methods are
fibrosis. Limitations include variability in manual compres- available to quantify the degree of hepatic fibrosis in
sion and lack of standardization. nonalcoholic fatty liver disease, of which nonalcoholic
Photoacoustic imaging, which uses specific laser wave- steatohepatitis is the advanced stage. These include the
lengths to produce detectable vibrations in specific mole- Fibrosis-4 score, the enhanced liver fibrosis test, FibroScan,
cules, such as hemoglobin and collagen, is also being serum biomarkers, and magnetic resonance elastography.

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 MEETING SUMMARIES
A central factor in the pathobiology of hepatic fibrosis is Table 1.Potential Agents for the Treatment of Intestinal
the activation of hepatic stellate cells with subsequent Fibrosis
transformation into myofibroblasts, cells that have both
Agent Class Original indication Status
fibrogenic and immunomodulatory capacity. Antifibrotic
therapies that deactivate, silence, or eliminate hepatic stel- Spesolimab IL-36Ri UC Phase 2
late cells that have been explored include the peroxisome
PF-06480605 TL1Ai UC Phase 2
proliferator-activated receptor-g agonist pioglitazone and
the farnesoid X receptor agonist obeticholic acid. Alternative GSK2330811 Oncostatin Mi Cut SSc Phase 2
strategies have interfered with biogenesis, remodeling of Pirfenidone unknown IPF Registereda
connective tissue or specific inflammatory processes.
Although no antifibrotic agents have been approved for Nintedanib TKI IPF Registereda
nonalcoholic steatohepatitis, a number of agents have FG-3019 CTGFi IPF Phase 2b
shown encouraging results in phase 2 and 3 trials. Examples
PRM-151 rhPTX-2 IPF, HF Phase 2
include the farnesoid X receptor agonist cilofexor, the anti-
oxidant vitamin E, the chemokine receptor inhibitor cen- Lebrikizumab IL-13i IPF Phase 2
icriviroc, and the ASK-1 (apoptosis signal–regulating kinase SAR-156597 IL-4/13i IPF Phase 2
1) inhibitor selonsertib. Innovative 3-dimensional models
BG-00011 avb6i IPF Phase 2
composed of human liver tissue or cells are anticipated to
boost the development of effective and clinically relevant BMS-986020 LPARi IPF Phase 2
therapies for liver fibrosis. Pioglitazone PPARga NASH Phase 3
Elafibranor PPARga NASH Phase 3
Idiopathic Pulmonary Fibrosis
GS-9674 FXRa NASH Phase 2
In idiopathic pulmonary fibrosis, agents that inhibit
activation or differentiation of fibroblasts or immune cells Vitamin E anti-oxidant NASH Phase 3
or decrease the production of ECM molecules have shown Emricasan caspase i NASH Phase 2b
promising results. Of these, the immunosuppressive agent
pirfenidone and the tyrosine kinase inhibitor nintedanib Cenicriviroc CCR2/5i NASH Phase 3
have been approved in selected jurisdictions. Although Selonsertib ASK-1i NASH Phase 3
treatment with these agents resulted in short-term
GR-MD-02 galectin 3i NASH Phase 2b
improvement in lung function, existing data do not support
a benefit on overall prognosis. Other effective agents in
development include the connective tissue growth factor a, agonist; ASK-1, apoptotic signal regulating kinase 1; CCR,
inhibitor FG3019, recombinant pentraxin 2, the lysophos- CC chemokine receptor; CTGF, connective tissue growth
phatidic acid receptor antagonist BMS-986020, and the factor; cut SSc, cutaneous systemic sclerosis; FXR, farnesoid
X receptor; HF, hepatic fibrosis; i, inhibitor; IL, interleukin; IPF,
avb6 integrin inhibitor BG00011.
idiopathic pulmonary fibrosis; LPAR, lysophosphatidic acid
receptor; NASH, nonalcoholic steatohepatitis; PTX-2, pen-
traxin 2; R, receptor; rh, recombinant human; TKI, tyrosine
Treatment of Intestinal Fibrosis kinase inhibitor; TL1A, tumor necrosis factor-like cytokine 1A.
No antifibrotic therapies have been approved for IBD, a
Registered by the US Food and Drug Administration and the
but several agents showed promising results in preclinical European Medicines Agency.
studies. A recent study demonstrated that an antibody to the
interleukin-36 receptor reduced fibrosis in a murine model
of chronic intestinal inflammation (Table 1).5 Other poten- Stricture Therapies) group used a modified RAND Corpo-
tially interesting agents include inhibitors of antibodies ration and University of California Los Angeles appropri-
against tumor necrosis factor–like cytokine 1A and agents ateness methodology trying to reach consensus definitions
that are used for the treatment of fibrosis in other organs for small bowel strictures, outcome measures, and treat-
(Table 1). Blockade of the fibrosis-inducing cytokine ment end points in stricturing CD.6 Consensus was reached
Oncostatin M with the monoclonal GSK2330811 offers an on MRI as the preferred imaging technique to define stric-
attractive strategy as well. Topical Rho kinase inhibition tures and assess response to therapy, and 24–48 weeks of
may also be effective by reducing myocardin-related tran- therapy was considered appropriate for pharmacologic
scription factor and p38 mitogen-activated protein kinase trials.
activation and activation of fibroblast autophagy. The only large prospective trial that evaluated the effi-
cacy of treatment for stenosing CD was the CREOLE study.
This cohort study assessed the efficacy of adalimumab in
Clinical Trial Design symptomatic CD small bowel strictures using a composite
No antifibrotic agents have been approved for CD, which end point of treatment success at week 24, defined as
is partially due to a lack of standardized definitions, diag- continuation of adalimumab without prohibited treatment,
nostic modalities, and validated treatment end points. The endoscopic dilation, or bowel resection.7 However, the
interdisciplinary CONSTRICT (Crohn’s Disease Anti-fibrotic Crohn’s disease obstructive score used was designed by

29
MEETING SUMMARIES
physicians and not a valid PRO. Sixty-four percent of the optimal evaluation of antifibrotic agents in IBD. Progress in
patients met the end point. A prognostic score was proposed the development of a PRO for stricturing CD is anticipated to
to define patients with a good, intermediate, and poor further facilitate clinical studies in this field. Although in-
prognosis. testinal fibrosis is a complex and challenging disorder,
For trials in symptomatic CD patients with fibrosis, the numerous preclinical and clinical efforts have resulted in
identification of the most optimal study population with promising advances.
radiologic confirmation will be essential.
Measurement of stenotic fibrosis by validated magnetic
resonance and computed tomography criteria is likely to be References
preferred for assessment of treatment efficacy. Neverthe- 1. Rieder F, Fiocchi C, Rogler G. Mechanisms, manage-
less, evaluation of symptoms by rigorously developed PROs ment, and treatment of fibrosis in patients with inflam-
is also necessary to show the value of new treatments to matory bowel diseases. Gastroenterology 2017;
patients’ well-being and for regulatory approval. Expert 152:340–350.
members of the International Organization for Inflammatory 2. Kugathasan S, Denson LA, Walters TD, et al. Predic-
Bowel Disease recently proposed 13 end points for use in tion of complicated disease course for children newly
clinical trials that assess the efficacy and safety of anti- diagnosed with Crohn’s disease: a multicentre inception
fibrotic agents in CD.8 cohort study. Lancet 2017;389:1710–1718.
Currently, the international STAR (Stenosis Therapy and 3. Chen W, Lu C, Hirota C, et al. Smooth muscle hyper-
Anti-Fibrotic Research) consortium is developing a PRO plasia/hypertrophy is the most prominent histological
instrument for stricturing CD according to US Food and change in Crohn’s fibrostenosing bowel strictures: a
Drug Administration–recommended methodology and semiquantitative analysis by using a novel histological
internationally developed best practices. grading scheme. J Crohns Colitis 2017;11:92–104.
4. Kucharzik T, Maaser C. Intestinal ultrasound and man-
agement of small bowel Crohn’s disease. Therap Adv
Discussion and Disagreement Gastroenterol 2018;11:1756284818771367.
Most likely, antifibrotic treatment in isolation has rela- 5. Scheibe K, Kersten C, Schmied A, et al. Inhibiting inter-
tively little chance of success if not combined with anti-in- leukin 36 receptor signaling reduces fibrosis in mice with
chronic intestinal inflammation. Gastroenterology 2019;
flammatory treatment. It remains unclear and a matter of
156:1082–1097.
discussion what this component of a “combined interven-
6. Rieder F, Bettenworth D, Ma C, et al. An expert
tion” should look like. Moreover, it remains unclear whether
consensus to standardise definitions, diagnosis and
smooth muscle hyperplasia observed in the submucosa and
treatment targets for anti-fibrotic stricture therapies in
hypertrophy of the muscularis propria would need different
Crohn’s disease. Aliment Pharmacol Ther 2018;
targeted treatment.
48:347–357.
Also, the ideal study population remains uncertain:
7. Bouhnik Y, Carbonnel F, Laharie D, et al. Efficacy of
should it be patients who have had a complete bowel
adalimumab in patients with Crohn’s disease and
obstruction? Can they have a balloon dilatation or strictur- symptomatic small bowel stricture: a multicentre, pro-
oplasty before entering an antifibrotic trial? How can di- spective, observational cohort (CREOLE) study. Gut
etary changes be controlled? Patients tend to alter their 2018;67:53–60.
intake based on symptoms caused by specific food products, 8. Danese S, Bonovas S, Lopez A, et al. Identification of
which may interfere with subjective wellbeing and even endpoints for development of antifibrosis drugs for
with prestenotic dilatation as documented on imaging. treatment of Crohn’s disease. Gastroenterology 2018;
Although MR enterography was proposed as the most 155:76–87.
attractive imaging modality, validated and reliable scores
for fibrostenotic IBD are lacking. In addition, waiting times
for MR can be challenging and, therefore, less invasive ul- Author names in bold designate shared co-first authorship.
trasound-based technologies warrant further investigation. Received April 25, 2020. Accepted October 3, 2020.

Correspondence
Address correspondence to: Geert D’Haens, MD, PhD, Department of
Conclusions Gastroenterology, Amsterdam University Medical Center, Academic Medical
During this International Organization for Inflammatory Center, Meibergdreef 9, 1100 DZ Amsterdam, The Netherlands. e-mail:
[email protected].
Bowel Disease workshop, the pathophysiology, diagnosis,
and potential therapies for intestinal fibrosis and other International Organization for Inflammatory Bowel Disease Fibrosis
chronic fibrotic diseases were reviewed. The pathways of Working Group
Mariangela Allocca, IBD Center, Humanitas Clinical and Research
fibrosis were analyzed and compared, and potential thera- Hospital, Humanitas University, Milan, Italy; Gert De Hertogh, University
peutic targets were identified. Currently approved and Hospitals Leuven, Department of Pathology, Leuven, Belgium; Chris Denton,
Royal Free Hospital, Centre for Rheumatology and Connective Tissue
investigational therapies for systemic sclerosis and pulmo- Diseases, University College London, London, UK; Jörg Distler, Friedrich-
nary and hepatic fibrosis were discussed. The workshop Alexander-University, Erlangen-Nürnberg and Universitätsklinikum Erlangen,
Department of Internal Medicine 3, Rheumatology and Immunology,
fueled continuing efforts to formulate definitions, end Erlangen, Germany; Kelly McCarrier, Pharmerit, Bethesda, Maryland; Dermot
points, and trial designs that are highly needed for the McGovern, Cedars-Sinai Medical Center, Medical Genetics Research

30
 MEETING SUMMARIES
Institute, Department of Medicine, Los Angeles, California; Tim Radstake, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd, and Zyngenia;
University Medical Center Utrecht, Utrecht University, Laboratory of is affiliated with the speakers bureau of Abbott/AbbVie, JnJ/Janssen, Lilly,
Translational Immunology, and Department of Rheumatology and Clinical Takeda, Tillotts, UCB Pharma; is a member of the scientific advisory board
Immunology, Utrecht, The Netherlands; Daniel Serrano, Pharmerit, Bethesda, of Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia
Maryland; and Jaap Stoker, Cancer Center Amsterdam, Amsterdam Biologics Inc, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene,
University Medical Center, Academic Medical Center, Departments of Centocor Inc, Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen,
Radiology and Nuclear Medicine, Amsterdam, The Netherlands. Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories,
Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts
Author Contributions Pharma AG, and UCB Pharma; and is a Senior Scientific Officer of Robarts
Geert D’Haens and Robbert van der Voort drafted the manuscript. All Clinical Trials Inc (London). Peter Higgins has served as a consultant for
authors revised the manuscript critically and contributed important Abbvie, Genentech, UCB, and Takeda, and has received educational grants
intellectual content. and research grants from Abbvie, Janssen, Pfizer, and Takeda. Julian Panés
received consulting fees from AbbVie, Arena Pharmaceuticals, Boehringer
Conflicts of interest Ingelheim, Celgene, Ferring, Genentech, GlaxoSmithKline, Janssen, MSD,
These authors disclose the following: Geert D’Haens has served as advisor for Nestle, Oppilan, Pfizer, Progenity, Robarts, Roche, Takeda, Theravance, and
Abbvie, Ablynx, Allergan, Alphabiomics, Amakem, Amgen, AM Pharma, Arena TiGenix; speaker fees from AbbVie, Janssen, MSD, and Takeda; and
Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meiers Squibb, research funding from AbbVie and MSD. Christian Maaser has served as a
Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Echo speaker, consultant and/or advisory board member for Abbvie, Celgene, Falk
Pharmaceuticals, Eli Lilly, Engene, Ferring, DrFALK Pharma, Galapagos, Foundation, Ferring, Janssen, MSD, Pfizer, Takeda, and Vifor. Gerhard
Genentech/Roche, Gilead, Glaxo Smith Kline, Gossamerbio, Hospira/Pfizer, Rogler has consulted to Abbvie, Augurix, BMS, Boehringer, Calypso,
Immunic, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Celgene, FALK, Ferring, Fisher, Genentech, Gilead, Janssen, MSD, Novartis,
Millenium/Takeda, Medtronics, Mitsubishi Pharma, Merck Sharp Dome, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions and Zeller;
Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Photopill, received speaker’s honoraria from Astra Zeneca, Abbvie, FALK, Janssen,
Prodigest, Prometheus Laboratories/Nestle, Progenity, Protagonist, RedHill, MSD, Pfizer, Phadia, Takeda, Tillots, UCB, Vifor, and Zeller; and educational
Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, grants and research grants from Abbvie, Ardeypharm, Augurix, Calypso,
Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor; and FALK, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Tillots, UCB, and
received speaker fees from Abbvie, Biogen, Ferring, Johnson & Johnson, Zeller. Mark Löwenberg has served as speaker, consultant, or principal
Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, investigator for Abbvie, Celgene, Covidien, Dr Falk, Ferring Pharmaceuticals,
Millenium/Takeda, Tillotts, and Vifor. Florian Rieder received consulting fees Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer,
from Allergan, AbbVie, Boehringer Ingelheim, Celgene, Cowen, Gilead, Protagonist therapeutics, Receptos, Takeda, Tillotts, and Tramedico; and
Gossamer, Helmsley, Janssen, Koutif, Metacrine, Pliant, Pfizer, Receptos, received research grants from AbbVie, Merck Sharp & Dohme, Achmea
RedX, Roche, Samsung, Takeda, Thetis, and UCB; and research funding Healthcare, Dr Falk, and ZonMW. Massimo Pinzani is an inventor and patent
from Boehringer Ingelheim, UCB, Celgene, and Pliant. Brian Feagan received holder (ELF test) for Siemens; and served as a speaker or consultant for
grants and/or research support from AbbVie Inc, Amgen Inc, AstraZeneca/ Echosens, Promethera, Neurovive, Chemomab, Median Technology, UCB
MedImmune Ltd, Atlantic Pharmaceuticals Ltd, Boehringer-Ingelheim, Cell Tech, Boehringer Ingelheim, Engitix Ltd, 3P-Sense Ltd, and
Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd, Hepatotargets. Laurent Peyrin-Biroulet has served as a speaker for Merck,
Gilead Sciences Inc, GlaxoSmithKline, Janssen Research & Development Abbvie, Janssen, Genentech, Ferring, Tillots, Vifor, Pharmacosmos, Celltrion,
LLC, Pfizer Inc, Receptos Inc/Celgene International, Sanofi, Santarus Inc, Takeda, Boerhinger-Ingelheim, Pfizer, Amgen, Biogen, and Samsung Bioepis;
Takeda Development Center Americas Inc, Tillotts Pharma AG, and UCB; is and as a consultant for Merck, Abbvie, Janssen, Genentech, Ferring, Tillots,
a consultant for Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Vifor, Pharmacosmos, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim,
Applied Molecular Transport Inc, Aptevo Therapeutics, Astra Zeneca, Atlantic Lilly, Pfizer, Index Pharmaceuticals, Amgen, Sandoz, Celgene, Biogen,
Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Samsung Bioepis, Alma, Sterna, Nestlé, Enterome, Mylan, and HAC-Pharma.
Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Silvio Danese has served as a speaker, a consultant, and an advisory board
Ferring Pharma, Roche/Genentech, Galapagos, Galen/Atlantica, GiCare member for Abbvie, Allergan, Biogen, Boehringer Ingelheim, Celgene,
Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, Intact Celltrion, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda,
Therapeutics, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd, Lexicon, Lilly, Lycera Mundipharma, Pfizer, Sandoz, Tigenix, UCB Pharma, and Vifor. The
BioTech, Merck, Mesoblast Pharma, Millennium, Nestles, Nextbiotix, remaining author discloses no conflicts.
Novonordisk, ParImmune, Parvus Therapeutics Inc, Pfizer, Prometheus
Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Funding
Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna This meeting was supported through unrestricted grants from Celgene, Gilead,
Biologicals, Synergy Pharma Inc, Takeda, Teva Pharma, TiGenix, Tillotts, GlaxoSmithKline, Pfizer, Roche, and Union Chimique Belge (UCB) Pharma.

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