Outcomes and Endpoints of Postoperative Recurrence in Crohn’s Disease: Systematic Review and Consensus Conference

Abstract

Background

Outcomes after ileocolonic resection in Crohn’s disease [CD] are heterogeneous, and a clear definition of postoperative recurrence remains to be determined. Our Endpoints Working Group of the International Organization for the study of Inflammatory Bowel Disease [IOIBD] aimed to standardise postoperative outcomes, to discuss which endpoints should be used for postoperative clinical trials, and to define those which could be used in trials or registries.

Methods

Based on a systematic review of the literature, recommendations and statements were drafted and sent to all IOIBD members for a first round of voting. Recommendations and statements were revised based on the voters’ comments during a consensus hybrid conference open to all IOIBD members. If no agreement was reached after two rounds of voting, the statement was excluded.

Results

In the systematic review, 3071 manuscripts were screened of which 434 were included. Sixteen recommendations were identified, of which 11 were endorsed. Recommendations and statements include that endoscopy remains the gold standard and should be used as a short-term primary endpoint in both observational cohorts and randomised controlled trials. Clinical symptoms classically used in clinical trials for luminal CD are not reliable in this specific situation. For that reason, longer-term endpoints should be based on the evidence of macroscopic inflammation assessed by imaging techniques, endoscopy, or as reflected by the presence of complications.

Conclusions

Agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognise primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy-based and/or imaging-based endpoints.

1. Introduction

Despite the recent and upcoming expansion of the therapeutic arsenal for the medical treatment of Crohn’s disease [CD], ileocolonic resection remains frequent in the management of a patient with CD. However, postoperative recurrence is the rule and not the exception for the further course of CD. Cohort studies reported endoscopic recurrence rates between 50% and 80% at 1 year, with clinical recurrence in at least half of them within 5 years post-surgery despite postoperative treatment.^1–7

These results are consistently in line with rates reported in the landmark study by Rutgeerts et al.⁸ 30 years ago, and should therefore lead to a reconsideration of our postoperative management, including a clear definition of the objectives to be achieved.

Rutgeerts et al. demonstrated that recurrence of CD in the neoterminal ileum after curative ileocolonic resection is dependent on exposure to faecal stream.⁹ There is evidence of activation of the mucosal immune system and the epithelium in the neo-terminal ileum already as early as 8 days after restoration of the faecal stream.¹⁰ In fact, surgery does not correspond to a complete resetting in many patients. There is evidence of histological inflammation at the ileal margin of surgical specimens in 15–20% of patients¹¹ and expanded T cell clones with pro-inflammatory characteristics may be present.¹² Furthermore the microbiome, which appears as a key player in recurrence,¹³ has the same characteristics in non-inflamed areas of the surgical specimen, suggesting that a potentially pathogenic microbiome may persist after surgery.¹⁴

Clinical recurrence during the first 2 years after surgery is uncommon. In fact, many patients present symptoms related to surgical resection and which have non-inflammatory causes. Regueiro et al. showed a poor correlation between Crohn’s Disease Activity Index [CDAI] and endoscopic recurrence 1 year after intestinal resection.¹⁵ Thus, diagnosis of postoperative recurrence cannot rely only on clinical symptoms but must be supported by biological and/or morphological assessment.

Aiming at the development of a prognostic score for postoperative endoscopic recurrence, Rutgeerts et al. defined the combination of several elementary lesions, including: the number, size, and distribution of ulcerations; and diffuseness of mucosal inflammation between ulcers; at the ileocolonic anastomosis and neo-terminal ileum, and incorporated these into a prognostic score known as the 'Rutgeerts score'.⁸ In the 30 years since its publication, the Rutgeerts score has become almost universally adopted as the 'gold standard' for studies of postoperative recurrence and was used for the identification of risk factors for postoperative recurrence. The ECCO-IBD guidelines in 2016, based on the existing literature, identified: active smoking at surgery; prior intestinal resection; perforating phenotype of the disease; perianal disease; absence of prophylactic treatment; and histological features at the ileal resection margin; as predictors of endoscopic recurrence.¹⁶ Different histological features at the ileal margin may have an impact.^11,17 Several studies have also suggested a role of type of surgery and anastomosis.^18–20 Moreover, based on the results of a randomised study,²¹ all international guidelines recommend an ileocolonoscopy within the year following surgery, to adjust/optimise treatment based on the endoscopic appearance.¹⁶

Even though the Rutgeerts score is widely used in clinical practice and in clinical trials, some limitations have also been reported, including moderate inter-observer reliability,²² and the differential impact of lesions limited to the anastomosis versus lesions more proximal in the neoterminal ileum.^2,23 Based on this, the modified Rutgeerts score splits the i2 score into i2a [lesions confined to the anastomosis] and i2b [lesions affecting both the anastomosis and the neoterminal ileum]. However, ‘i4’ still pools severe diffuse ulceration and stenosis, which are two completely different endoscopic entities.

Regulatory guidelines do not specifically mention the situation of postoperative CD recurrence, and advise to use the endpoints defined for luminal CD.²⁴ The Endpoints Working Group of the International Organization for the study of Inflammatory Bowel Disease [IOIBD] decided to address this question, to discuss and to define specific endpoints which should be used for postoperative recurrence. Hence, we performed a systematic literature review on postoperative outcomes, from which we generated several proposed consensus recommendations and statements. Our objectives were to describe short and long-term postoperative outcomes, to discuss which endpoints should be used for postoperative clinical trials, and to define long-term endpoints which could be used in clinical trials or registries. These recommendations and statements have been discussed in a hybrid conference open to all IOIBD members, held in November 2022.

2. Methods

This project has been developed as part of the IOIBD endpoints cluster initiative, and followed several stages to reach consensus among international Inflammatory Bowel Diseases [IBD] experts after careful review of existing evidence. A steering committee of four IOIBD [MA, WR, DS, GH] members formulated the search questions and scope. A systematic review of the literature was performed in May 2021. PubMed, EMBASE, the Cochrane Library, and congress abstracts were searched. No search limits were set for full publications, other than specifying articles published in English. The key words used for this systematic review were 'Ileal Crohn’s Disease', 'Surgery', 'Ileocolonic Resection', and 'Postoperative Recurrence’. These key words were sought in article titles and abstracts and separated with the logical operator 'OR'.

This literature review was performed by two authors [NH and MA]. These authors reviewed all identified abstracts, and potentially eligible studies were retrieved in full text. This review led to the selection of original articles and congress abstracts assessing: the natural history of postoperative ileal CD; clinical and biological risk factors for recurrence; clinical, endoscopic, biological, and imaging endpoints; as well as clinical trials on potential treatments to prevent recurrence. Based on this literature review, the steering committee of IOIBD members reformulated the main goals and topics to be questioned in the manuscript and consensus conference. A first draft of a manuscript was written with the following sections: endpoints used in clinical trials; clinical recurrence and means to assess it; biological biomarkers; endoscopic scores and validation; imaging strategies to assess recurrence.

Based on the above, consensus recommendations and statements were drafted by the steering committee and then sent to all IOIBD members [n = 90] for voting, along with the literature review. Identical to the methodology used in STRIDE-I and STRIDE-II,²⁵ agreement was achieved if at least 75% of participants scored the statement as 7 to 10 on a 10-point rating scale [1, do not agree at all; 10, agree completely]. For those recommendations or statements where no consensus was achieved, these were revised based on the voters’ comments during a consensus hybrid [in person and virtual] conference open to all IOIBD members, held in California, USA, in November 2022. This was followed by a second round of voting. If no agreement was reached after two rounds of voting, then the recommendation or statement was excluded.

3. Results

3.1. Literature research

Based on the literature research criteria, 3071 articles or congress abstracts from the literature were selected. In all, 2452 studies were excluded either because they were not in English language or they were not assessing postoperative recurrence in CD. After the exclusion of 185 abstracts and manuscripts, 434 studies were finally selected for this work [Figure 1—Flowchart].

Among these 434 studies, 207 [48%] were cohort studies assessing natural history and risk factors for recurrence in ileal CD. A total of 111 [26%] studies focused on therapeutic interventions of the postoperative period, including 42 [38%] randomised, controlled trials and 69 [62%] cohort studies. Further, 86 studies [20%] were specifically focused on postoperative endpoints, including meta-analyses or clinical, biological, endoscopic, or imaging endpoints, with a large overlap between the aims of these studies. Finally, 30 [7%] meta-analyses assessing postoperative treatments or predictors of recurrence at baseline were found [Figure 1—Flowchart].

3.2. Consensus conference

Overall, 16 recommendations or statements were pre-defined by the steering committee of four IOIBD members and were sent out to a first round of voting. In this first round, 53 IOIBD members participated. Then, each recommendation or statement was discussed at the hybrid conference consensus. Among these 16 statements, 11 were endorsed after revision. In a second round of voting, 39 IOIBD members participated, leading to the validation of all these 11 recommendations and statements. Results of the second round of voting are listed in Table 1.

3.3. Endpoints used in randomised controlled trials

Since 1992, 42 randomised, controlled trials [RCTs] assessing postoperative management strategies were published. Of these, 35 [83%] evaluated medical treatments in the prevention of postoperative recurrence, three [7%] surgical procedures, two [5%] nutritional management pre- or postoperatively, and two [5%] global management strategies [Tables 2 and 3; all references are listed in the Supplementary data].

Among the 35 RCTs on the effect of medical treatments, 27 [77%] used endoscopic evaluation by the Rutgeerts score as a primary outcome. For 17 [45%] of those, the Rutgeerts score was the only endpoint assessed, and the other 10 used a composite endpoint mainly in combination with clinical criteria. The duration between surgery and postoperative endoscopy varied across studies [from 3 months to 24 months]. Likewise, different definitions of endoscopic recurrence were used, such as a Rutgeerts score >i1 for 17 RCTs or >i2 in two [8%]. The modified Rutgeerts score^23,26 was rarely used in these studies. Among the studies which included endoscopy in their primary endpoint, 10 [37%] used central reading to assess the Rutgeerts score: six of them with video recordings and four with photos of the anastomosis and neoterminal ileum.

Of the 10 RCTs with a non-exclusive, endoscopic, primary endpoint, clinical evaluation was included in all. In eight RCTs, the primary endpoint was based on clinical evaluation, most frequently by means of the Crohn’s Disease Activity Index [CDAI]. In three studies, change in CD-specific treatment [optimisation, switch to another treatment, etc] was considered as a criterion for recurrence.

Various secondary endpoints were included in all these studies: adverse events, clinical recurrence [mainly by using the CDAI], biological recurrence, radiology (either computed tomography [CT] scan or magnetic resonance imaging [MRI]), histology, or subsequent surgery. Quality of life was progressively included in both primary and secondary endpoints.

These findings exemplify the high heterogeneity of the endpoints chosen and the necessity for better standardisation.

3.4. Endpoints used in observational studies

Prior to the publication of the Rutgeerts score in 1990, several observational studies defined postoperative recurrence as the need for reoperation, named 'surgical recurrence'.^27–29 In 1975, a team at the Mount Sinai Hospital in New York quantified and distinguished rates of clinical recurrence from rates of reoperation.³⁰ In the 1990s, surgical recurrence still amounted to 20–30% at 5 years, with statistically significant differences between study cohorts.⁸ A reduction in the rate of surgical recurrence has been observed over the past two decades,^31,32 probably reflecting progress in medical management, rendering it more difficult to compare cohorts using this endpoint. The definition of recurrence has thus evolved over time. The Rutgeerts score has by now become largely used to define endoscopic recurrence. The most widely used definition of endoscopic recurrence is a score of >i1, although in some studies, notably those exploring cellular or molecular mechanisms, any lesions at all [>i0] was used as definition of recurrence.¹²

Since endoscopic recurrence is an early postoperative phenomenon, appearing within 3–12 months, the longer-term endpoint chosen is mainly clinical recurrence. Definitions of clinical recurrence, however, tend to be highly heterogeneous. These clinical definitions have often been based on the CDAI, the presence of symptoms [usually but not always confirmed by imaging or biomarkers], or the need for introduction or change of therapy.^{1,2,5,33–36}

In the following sections, we shall focus more specifically on the use of clinical, endoscopic, biological, and imaging endpoints in observational studies of postoperative CD recurrence.

 

3.5. Clinical endpoints

Surgery establishes a post-surgical anatomy with functional consequences, the magnitude of which depends upon location and extent of removed tissue. Symptoms due to intestinal resection are difficult to discriminate from those caused by CD-related inflammation.³⁷ Typical symptoms of recurrence include diarrhoea and abdominal pain. To standardise the evaluation of clinical symptoms associated with CD, a score [the CDAI] was developed in 1976³⁸ from the prospective follow-up of 112 patients. This score, useful in therapeutic trials during active CD, is not correlated with postoperative endoscopic recurrence.¹⁵ Although many studies have used the CDAI as the criterion for postoperative recurrence, it is highly debatable whether this measurement is suitable for the purpose. Relying solely on clinical symptoms to define recurrence and possibly adapt disease-specific treatment exposes patients to the risk of under- or over-treatment.³⁹

After multiple surgeries, functional sequelae can be pervasive by impairment of peristalsis, loss of absorption, metabolic, microbial, and neuroendocrine capacities [best known by vitamin B12 deficiency], bile salt diarrhoea, or oxalate kidney stone formation.^40,41 In 1994, a study correlated a handicap index based on the length of cumulative resection and the site of these resections in CD patients with clinical symptoms.⁴² Faecal weight and faecal fat were highly correlated with this index, showing that the characteristics of the cumulative resections could be predictive of the functional long-term consequences for patients. Another study confirmed that a combination of anastomotic width and extent of resection was better correlated with clinical symptoms than endoscopic recurrence itself.⁴³

These symptoms and long-term functional consequences may have a major impact on the quality of life of patients.⁴⁴ Specific CD indexes have been developed to evaluate these consequences.^45,46 Patient-reported outcomes are increasingly considered as therapeutic targets in CD.²⁵ In therapeutic trials in postoperative management, only the L!RIC study defined quality of life as a primary endpoint because of its design comparing two different therapeutic strategies.⁴⁷ Overall, in the evaluation of postoperative recurrence, quality of life remains rarely reported.

  

3.6. Endoscopic endpoints

Recurrence typically occurs at the ileocolonic anastomosis and in the neoterminal ileum and is most frequently scored with the Rutgeerts score, which has been shown to predict clinical recurrence and need for surgery.^8,48 Based on the results of a randomised study,²¹ international guidelines recommend an ileocolonoscopy within 1 year post-surgery, to assess recurrence and adjust/intensify treatment accordingly.¹⁶ A longer period between surgery and endoscopy seems to reduce the predictive value of the endoscopy.⁴⁹ In any event, endoscopy is supposed to be the examination that allows reassessment of disease postoperatively with the highest level of confidence, and is the most widely used method of assessing recurrence in both clinical trials and observational cohorts. Its use has also been evaluated in patients with terminal ileostoma, and its predictive value of long-term clinical recurrence in this case has been reported as good.⁵⁰ In a recent Swiss cohort, however, postoperative endoscopy was under-used in routine practice, with only 55% of patients undergoing this examination.⁵¹

Some specific limitations to the use of the Rutgeerts score have been raised. First, its inter-observer reproducibility is limited.^22,52–54 Four independent studies found low agreement between different endoscopists, including in the distinction between lesions <i2 and ≥i2, the cut-off point usually used to decide on the initiation or optimisation of treatment. This can lead to suboptimal therapeutic decisions in up to 10% of patients. These discrepancies could be due to ambiguity in the definition of certain lesions, to a lack of clear identification of anastomosis, poor video/photo quality, or inconsistent training of the endoscopists. Hence, a training programme and centralised reading with good-quality videos could lead to fewer inconsistencies in the scoring.⁵⁵

Different locations of the lesions could have different implications for the outcome of the disease, depending on whether they involve the anastomosis or the neo-terminal ileum. Lesions confined to the area of the anastomosis are more common in CD than in patients undergoing resection for other indications,⁵⁶ but they may not be as predictive of subsequent clinical recurrence as those extending higher up in the neoterminal ileum.^3,53–57 Reinisch et al. proposed a split between lesions confined to the anastomosis and those involving the anastomosis and the neo-terminal ileum.²⁵ A 'modified' Rutgeerts score has thus been proposed, dividing i2 lesions accordingly.²³ Three studies, including one prospective study, showed that patients with endoscopic lesions confined to the anastomosis have a long-term outcome comparable to patients in endoscopic remission.^2,57,58 Conversely, several retrospective cohorts found that anastomotic lesions were similarly associated with a poor clinical outcome.^59–62 Hence, the REMIND group proposed a new modified Rutgeerts score distinguishing anastomotic from neo-terminal ileal lesions.² This could help to better explore the prognostic value of these endoscopic lesions.

In one prospective study, specific early endoscopic findings at the anastomosis were evaluated for their association with subsequent disease course. Anastomotic ulcer depth [superficial vs deep] and circumferential extent of ulceration [<25%, ≥25%], combined in a 'POCER' index, had high specificity for subsequent endoscopic recurrence. These two key endoscopic factors, comprising the adverse prognostic factors of deep or circumferentially-extensive anastomotic ulceration, need to be evaluated further.⁶³ Of note, the prognostic value of lesions confined to the ileal blind loop [lateral anastomosis] is not well known. One study suggested a poor outcome.⁶⁴

Video capsule endoscopy has also been evaluated in this indication. Beyond a more or less important correlation to the evaluation of the Rutgeerts score, it allowed the visualisation of small lesions not accessible to conventional endoscopy and which could be underestimated.^65,66 It may be prudent to use a patency capsule before the examination, because of the risk of subclinical small bowel/anastomotic stenosis. Likewise, balloon enteroscopy has also detected occult lesions in the upper ileum, particularly in patients with ileo-ileal anastomosis.⁶⁷

   

3.7. Histological endpoints

In 1998, D’Haens et al. reported the effects of infusion of intestinal luminal contents into excluded ileum of three patients with CD who had undergone ileocolonic resection with temporary ileostomy.¹⁰ Eight days after this infusion, histological lesions were found in the excluded neoterminal ileum. A scoring system was proposed to grade these lesions, including epithelial damage, architectural changes, infiltration of mononuclear cells in the lamina propria, infiltration of polymorphonuclear cells in the lamina propria, polymorphonuclear cells in epithelium, ulcers, and granulomas. In RCTs or cohort studies [Table 2], histology was never considered as a primary endpoint to define recurrence. However, in several RCTs evaluation of histological activity was included as a secondary endpoint by applying various scores and definitions to grade histological involvement. Histological recurrence could be of specific interest in patients without macroscopic lesions in the neo-terminal ileum. Patchy distributions of lesions in CD may, however, represent a limitation. Confocal laser endomicroscopy has been evaluated for the assessment of postoperative recurrence. Using a specific score adapted to grade the lesions, Auzoux et al. showed that, in patients in endoscopic remission, those with lesions detected by confocal endomicroscopy had a higher risk of subsequent endoscopic recurrence.⁶⁸ Another potential application of histological examination could be to discriminate between active CD lesions and ischaemic features at the anastomosis. Indeed, it has been suggested that anastomotic inflammation is predominantly a manifestation of recurrent CD rather than of postoperative ischaemia, based on the examination of 29 histological specimens from the ileocolonic anastomosis.⁶⁹

3.8. Biomarker endpoints

We found 24 studies that specifically assessed the association of biological markers with postoperative recurrence. Of these, 20 evaluated the value of faecal calprotectin [FC], seven of C-reactive protein [CRP], and nine of other biomarkers. Most of the studies evaluating FC aimed to correlate its values with endoscopic recurrence. Eleven of these studies found a direct correlation of the FC with the Rutgeerts score.^70–74 However, no consensus was achieved concerning the specific FC threshold denoting recurrence, with suggested levels ranging from 50 to 264 μg/g. Nonetheless, particular thresholds recommended in each study had good specificity and negative predictive value, but the sensitivity was highly variable, depending on the study considered. Four additional studies, although not defining a specific cut-off, found that the FC values in patients with recurrence were higher than in patients in remission.⁷⁵

Three studies evaluated the predictive value for recurrence of an FC evolution in the perioperative period, more precisely within the 3 months following surgery.^76–78 Two of them showed that an increase of FC within the weeks following surgery was associated with endoscopic recurrence at 6 months.⁷⁸ Two particularly interesting studies are to be noted. In 2016, a prospective study included patients in endoscopic remission at 1 year with FC testing every 2 months during 2 years of follow-up. In case of elevation of the latter above 140 μg/g, an endoscopy was performed.⁷⁹ If not, the endoscopy was performed systematically at the end of the follow-up. The patients who reached the end of the follow-up without an elevated FC had fewer endoscopic lesions, unlike those with an elevated FC. Moreover, analysis of the POCER study showed that an FC value below 50 at 6 months was predictive of endoscopic remission at 18 months.⁷³ These data remain to be confirmed.

Almost no correlation was found between CRP and endoscopic recurrence.^71,73,76,80 A study performed in 2009 also showed that FC and lactoferrin correlated better with clinical symptoms than CRP.⁸¹ Among other biomarkers studied, serum IL6 and lactoferrin were also associated with endoscopic recurrence, with a lower level of evidence than for FC.^75,80,82,83

3.9. Imaging endpoints

Of 25 studies evaluating the association of imaging procedures with postoperative recurrence, 13 evaluated the performance of ultrasound, six CT or CT enterography, five MR enterography, three small bowel follow-through, and two Tc99M-HMPAO scintigraphy.

Ultrasound performed by experienced investigators has been the most frequent imaging technique studied, and showed a significant association with endoscopic postoperative recurrence.^84,85 In several studies, wall thickness was consistently correlated with postoperative endoscopic recurrence.^86–92 Interestingly, this correlation was particularly strong with moderate to severe postoperative recurrence [ie, Rutgeerts score >i2]. Hence, one prospective cohort including 40 patients found that a wall thickness >5 mm was significantly correlated with a Rutgeerts score >i2.⁹³ This correlation needs, however, further confirmation, since a recent cohort including 108 patients showed that almost a third of patients with a Rutgeerts score of i3 had a wall thickness lower than 5 mm. Oral or intravenous [IV] contrast enhancement techniques could be promising to improve the performance of ultrasonography examination.⁸⁸ One study also associated wall thickness >5 mm with clinical recurrence⁹⁴ and another with surgical recurrence.⁹⁵

CT and MR enterography have also showed a consistent correlation between wall thickness on imaging and mucosal lesions on endoscopy.^{70,84,96–99} On MRI, scores have been developed, three of which are correlated with endoscopy.^70,97,98,100 The value of CT, MR enterography, and ultrasound as a complement to endoscopy also lies in their better performance in the detection of certain complications [fistulas or abscesses] and in their capacity to detect lesions beyond the scope of endoscopy [lesions above the terminal ileum]. Small bowel follow-through and scintigraphy are infrequently used in practice, and the level of evidence for their utility is low.^85,101 Of note, we found no study evaluating the evolution of tissue damage based on imaging techniques in the context of postoperative follow-up.

 

3.10. Global assessment of long-term recurrence—composite endpoints

As discussed previously, clinical symptoms after surgery may be related to altered anatomy rather than genuine CD recurrence.³⁷ A question still up for debate is whether the presence of objective signs [indicative of active inflammation or tissue damage] is of itself sufficient for a biological definition of 'recurrence'. Conversely, objective postoperative recurrence may occur long before the onset of symptoms, and few patients show clinical activity related to the disease within 1 year of resection . These findings are also true in the long term, where symptoms remain poorly correlated with the results of complementary examinations. Thus, the absence of symptoms is not a guarantee of the absence of disease progression, and the most recent studies on the objectives to be reached in the treatment of CD are not limited to obtaining clinical remission.²⁵

   

3.11. Proposal of a definition of postoperative recurrence

Endoscopy remains the gold standard and should be used as a short-term, primary endpoint in both observational cohorts and randomised controlled trials. Clinical symptoms classically used in clinical trials for luminal CD are not reliable in this specific situation. For that reason, longer-term endpoints should be based on the evidence of macroscopic inflammation assessed by imaging techniques or endoscopy or reflected by the presence of complications.

 

Several limitations must be acknowledged. This work represents a consensus conference and should be seen as the best we have, reflecting the experts’ positions on postoperative recurrence endpoints. These opinions may obviously vary across regions and centres outside this group.

Despite the efforts of academic centres and research groups in this field, there are still few randomised clinical trials evaluating the efficacy of prophylactic treatment after surgery. This is because the agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognise primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy-based and/or imaging-based endpoints, whereas clinical relapses appear as late events that cannot be used as primary endpoints.

Supplementary Data

Supplementary data are available at ECCO-JCC online.

Funding

No specific funding has been received for this work.

Conflict of Interest

DS, JS, MK, and CO have no disclosures. NH has served as a consultant/advisory board member to Abbvie, Janssen, and Lilly and as speaker for Galapagos and Takeda. GD has served as adviser and/or speaker for Abbvie, Alimentiv, Astrazeneca, Bristol Meyers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Landos, Polpharm, Prometheus biosciences, Prometheus laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx. WR has served as a speaker for AbbVie, Celltrion, Falk Pharma GmbH, Ferring, Janssen, Galapagos Medice, MSD, Roche, Pfizer, Pharmacosmos, Shire, Takeda, Therakos; as a consultant for AbbVie, Amgen, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Bioclinica, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celgene, Celltrion, Eli Lilly, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Teva Pharma, Therakos, Theravance, Zealand; as an advisory board member for AbbVie, Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe Pharma Corporation, MSD, Pharmacosmos, Pfizer, Sandoz, Takeda; and has received research funding from AbbVie, Janssen, MSD, Sandoz, Sanofi, Takeda. PK has received consultancy and speaking honoraria from Abbvie, Janssen, Pfizer, and Takeda; and received scientific grants from Takeda and Pfizer. SV has received grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; has received consulting and/or speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma. AG has served as consultant/advisory board member for Abbvie, Amgen, BMS, Janssen, Lilly, Pfizer, Takeda; has received speaker fees from Abbvie, Alimentiv, Janssen, Takeda; investigator-initiated grant support from Abbvie. JP has received financial support for research from AbbVie and Pfizer; consultancy fees/honoraria from AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Robarts, Sanofi, Takeda, Theravance, and Wasserman; reports payment for lectures including service on speaker bureau from Abbott, Ferring, Janssen, Pfizer, and Takeda; and reports payment for development of educational presentations from Abbott, Janssen, Pfizer Roche, and Takeda. SG has served as steering committee member of Janssen, BMS, Receptos, Abbvie; Drug Monitoring Committee for Janssen; advisory board member for Abbvie, Janssen, Ferring, Takeda, Pfizer, Galapagos, Gilead, Pfizer, Celltrion; speaker for CME activities for Janssen, Pfizer, Takeda, Celltrion, Abbvie, Falk Pharma. CS has served as a consultant/advisory board member to Abbvie, BMS, Fresnius, Lilly, Janssen, Napo Pharmaceuticals, Pfizer, ProciseDx, Prometheus Bioscience, Prometheus Labs, Takeda, Trellus Health; speaker for CME activities for Abbvie, Janssen, Pfizer, Takeda; grant support from Abbvie, Janssen, Pfizer, Takeda. WB has served as consultant for Braun; received research grants from Braun and VIFOR; and speaker fees from Janssen, Takeda, and Medtronic. FS has served as consultant/advisory board member to Abbvie, Amgen, Eurofarma, Ferring, Janssen, Pfizer, Sandoz, Takeda. Speaker for Amgen, Ferring, Janssen, Pfizer, Sandoz, Takeda; grant support from Janssen, Pfizer. PF has served as a consultant for Takeda. GM has served as consultant/advisory board member and/or speaker for AbbVie, Aenorasis, Dr Falk, Ferring, Hospira, Janssen, Merck Sharp & Dohme, MYLAN, Pfizer, Takeda, Vianex; and has received research grants from: AbbVie, Genesis, Merck Sharp & Dohme, Takeda. BS has received consulting fees from Abbvie, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech [Roche], Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting, and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock options from Ventyx Biopharma. MTA has received research funding from the National Institute of Health, Department of Defense, charities including the Leona M. and Harry B. Helmsley Charitable Trust, Crohn’s and Colitis Foundation, and Kenneth Rainin Foundation; is a consultant or served on advisory boards for AbbVie, Arena Pharmaceuticals [now Pfizer], Bristol Myers Squibb, Celsius Therapeutics, Eli Lilly, Gilead Sciences, Janssen Pharmaceuticals, Janssen Global Services, Pfizer Pharmaceutical, Prometheus Biosciences, UCB Biopharma SRL; has received fees for lecturing from Alimentiv, Janssen Pharmaceuticals, Prime CME, and WebMD Global LLC. ID has received grants/research support from Altman Research, Pfizer, BMS; honoraria or consultation fees from Abbott, Abbvie, Athos, Arena, Cambridge Healthcare, Celltrion, Celgene/BMS, Ferring, Food Industries Organization, Gilead, Galapagos, Iterative Scopes, Integra Holdings, Janssen, Pfizer, Roche/Genentech, Sangamo, Sublimity, Sandoz, Takeda, Wildbio, Prometheus; has participated in a company-sponsored speaker’s bureau for Abbvie, Celltrion, Celgene/BMS, Ferring, Food Industries Organization, Gilead, Galapagos, Janssen, Pfizer, Roche/Genentech, Sandoz, Takeda; and stock shareholder: Harp Diagnostics. DT received consultation fees, research grants, royalties, or honoraria from Janssen, Pfizer, Shaare Zedek Medical Center, Hospital for Sick Children, Ferring, Abbvie, Takeda, Prometheus Biosciences, Shire, Celgene, Lilly, Roche, ThermoFisher, BMS, SorrisoPharma. AD reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis, and endpoint committees from Abivax, AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb/Celgene, Dr Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Roche/Genentech, Sandoz/Hexal, Takeda, Tillotts, and Vifor Pharma; payment for lectures including service on speaker bureaus from AbbVie, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Streamed-Up, Takeda, Tillotts, and Vifor Pharma; payment for manuscript preparation from Falk Foundation, Takeda, Thieme, and UniMed. MA has served as a consultant/advisory board member to Abbvie, Amgen, Biogen, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Celsius, Celltrion, Egle Therapeutics, Endpoint health, Ferring, Galapagos, Genentech, IQVIA, Janssen, Lilly, Novartis, Pfizer, Roche, Takeda, Tillots; speaker for CME activities for Abbvie, Galapagos, Genentech, Janssen, Pfizer, Roche, Takeda, Tillots; grant support from Janssen, Takeda, Genentech/Roche.

Author Contributions

NH: data curation: lead; formal analysis: equal; investigation: lead; writing—original draft: lead; writing—review and editing: equal. MA: conceptualisation: lead; investigation: equal; supervision: lead; writing—original draft: supporting; writing—review and editing: lead. DS, GD, WR: conceptualisation: equal; writing—review and editing: equal; all other authors: writing—review and editing: equal.

Acknowledgements

Marischka Konings for technical support, and to all other IOIBD members who participated in the consensus: Vineet Ahuja, Willem Bemelman, Charles Bernstein, Johan Burisch, Jean-Frédéric Colombel, André D’Hoore, Marla Dubinsky, Jonas Halfvarsson, Ailsa Hart, Stephen Hanauer, Toshifumi Hibi, Arthur Kaser, Ioannis Koutoubrakis, Wolfgang Kruis, Peter Lakatos, James D. Lewis, James Lindsay, Milan Lukas, Fernando Magro, Uma Mahadevan, Bjorn Moum, Siew Ng, Colm O’Morain, Tom Oresland, Yves Panis, John Pemberton, Daniel Rachmilewitz, Feza Remzi, Robert Riddell, Gerhard Rogler, Rupa Benerjee, Bruce Sands, Stefan Schreiber, Britta Siegmund, Mark Silverberg, Johan Soderholm, Harry Sokol, Ajit Sood, Antonino Spinelli, Simon Travis, Curt Tysk, Morten H Vatn, Gillian Watermeyer, Takayuki Yamamoto.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

References