Categorising Endoscopic Severity of Crohn’s Disease Using the Modified Multiplier SES-CD [MM-SES-CD]

Abstract

Background and Aims

Current endoscopic scoring indices such as the Simple Endoscopic Score for Crohn’s Disease [SES-CD] quantify the degree of mucosal inflammation in Crohn’s disease [CD] but lack prognostic potential. The Modified Multiplier of the SES-CD [MM-SES-CD] quantifies the endoscopic burden of CD and can be accessed online [https://www.mcmasteribd.com/mm-ses-cd]. This analysis aims to establish MM-SES-CD thresholds that classify CD endoscopic burden into inactive/very mild, mild, moderate, and severe disease based on the probability of achieving endoscopic remission [ER] on active therapy at 1 year.

Methods

This post-hoc analysis included pooled data from three CD clinical trials [n = 350 patients, baseline SES-CD ≥3 with ulceration]. Disease category severity was determined using the maximum Youden Index. Achievement of ER between severity categories was compared using chi square tests. Time to clinical remission [CR] was compared using Kaplan-Meier survival curves.

Results

MM-SES-CD severity categories were established as very mild/remission [score <14], mild [≥14 to <31], moderate [≥31 to <45], and severe [≥45], which were predictive of 1-year ER [50%, 30.3%, 21.7%, 8.8%, respectively, p <0.001]. Lower MM-SES-CD scores had numerically higher rates of 1-year clinical remission [CR], and time to 1-year CR was superior to those with higher scores [p = 0.0492]. MM-SES-CD thresholds for achieving 1-year ileal ER among 75 patients with isolated ileal disease were established as mild [score <14], moderate [≥14 to <33], and severe [≥33], which were predictive of 1-year ER [66.7%, 33.3%, 13.3%, respectively, p = 0.027].

Conclusions

We have established numerical MM-SES-CD cut-offs that categorise endoscopic disease severity and have demonstrated that they are prognostic for 1-year ER and CR.

1. Introduction

Crohn’s Disease [CD] is chronic inflammatory condition of the gastrointestinal tract characterised by transmural inflammation of any portion of the luminal tract from the oral cavity to the rectum. The progressive nature of CD necessitates interventions to prevent irreversible mucosal injury and it has been consistently demonstrated that the healing of intestinal ulcerations and achievement of endoscopic remission [ER] are associated with improved short-term and long-term disease outcomes.^1–3 Therefore ER of CD is recommended as a treatment target in clinical trials and clinical practice.^4,5

Multiple endoscopic scoring indices exist to quantify the degree of luminal inflammation and disease in CD. The Simple Endoscopic Score for Crohn’s disease [SES-CD] is commonly used in both clinical practice and clinical trials, to quantify CD activity and to evaluate treatment response. The SES-CD was designed to be a user-friendly and efficient endoscopic scoring system that detects variations in disease activity and has acceptable intra-observer and inter-observer agreement.⁶

The SES-CD considers four parameters including presence and size of ulcers, extent of ulcerated surface, extent of affected surface, and the presence of strictures. A score of 0-3 is assigned to each parameter in five anatomical segments of the ileum and colon. Severity categories have been proposed by categorising lesions felt to reflect increasing severity of disease, and then creating cut-off values to differentiate such groups with a score of 0-2 indicating CD in remission, 3-6 mild disease, 7-15 moderate, and ≥16 severe disease.^6,7 Defining CD based on severity categories is necessary to objectively quantify disease burden, monitor progression, and assess for treatment response in clinical practice and in clinical trials. Although the SES-CD severity categories are widely used to quantify CD endoscopic burden, the strata of inactive, mild, moderate, and severe disease have not been validated beyond cross-sectional analysis, nor have they been shown to be prognostic for long-term clinical outcomes.

The modified multiplier of the SES-CD [MM-SES-CD] is a novel internally validated endoscopic scoring tool that better accounts for the heterogeneity of CD burden, and can predict 1-year ER.⁸ The MM-SES-CD considers the same endoscopic parameters and anatomical locations as the SES-CD, but acknowledges the different prognostic value of each parameter by assigning an individual weight to each category based on its impact on probability of achieving ER. A scoring tool that incorporates CD heterogeneity is salient, as distinct disease phenotypes based on disease location have been increasingly recognised to behave differently in terms of natural history, and response to therapy.⁹ The MM-SES-CD is accessible online [https://www.mcmasteribd.com/mm-ses-cd], and requires identical effort as does the SES-CD to calculate a score.

The purpose of this paper is to establish cut-off values of the MM-SES-CD score that classify CD endoscopic severity into mild, moderate, and severe, based on the probability of achieving clinical remission [CR] and ER on active therapy at 1 year.

2. Methods

This was a post-hoc analysis of three clinical trial data sets, including the UNITI studies, the EXTEND study, and a biosimilar infliximab study referred to as ‘CT-P13 study’. All three studies investigated individuals with moderate to severe CD. Permission from Janssen Inc. was obtained to use data from the UNITI studies [ClinicalTrials.gov identifiers NCT01369329, NCT01369342, NCT01369355] via the YODA Project [Yale Open Data Access 2021-4684]. Permission was obtained from Abbvie Inc. to access data from the EXTEND study via VIVLI [Protocol #00007077]. Last, Celltrion Inc. permitted the data from the CT-P13 study to be used for this analysis [Clinicaltrials.gov: NCT02096861].^10–13 A local ethics review was deemed not necessary by the Hamilton Integrated Research Ethics Board as data used in this study were previously collected and de-identified. By virtue of this, no informed consent was needed from participants.

2.1.Data availability statement

Data can be made available by permission from third parties.

2.2. Participants

The UNITI studies comprise three trials, UNITI-1, UNITI-2, and IM-UNITI, that enrolled patients with moderate to severe CD based on the Crohn’s Disease Activity Index [CDAI] scores ranging from 220-450. These studies evaluated CD induction and maintenance with ustekinumab. Details with regards to study design and eligibility criteria have been previously published.¹¹ Inclusion criteria of each study required those recruited to have at least one objective measure of active inflammation, which was defined as either C-reactive protein [CRP] >3 mg/L, faecal calprotectin >250 mg/kg, or endoscopic ulceration in the ileum and/or colon. UNITI-1 and UNITI-2 investigated ustekinumab induction therapy, and IM-UNITI examined ustekinumab maintenance therapy in those who responded to induction. Specifically, UNITI-1 included patients who had primary or secondary non-response or unacceptable side effects to tumour necrosis factor [TNF] antagonists, and UNITI-2 included patients who failed conventional therapy [immunosuppressants or glucocorticoids] or had unacceptable side effects with conventional therapy. IM-UNITI re-randomised participants who responded to induction therapy and compared placebo with subcutaneous injections of 90 mg of ustekinumab every 8 weeks or every 12 weeks. The duration of the induction studies was 8 weeks, and maintenance study was 44 weeks, for an entire study duration of 52 weeks. Endoscopy was not required for enrolment in UNITI; however in a subset of patients, a colonoscopy was performed at baseline, Week 8 [completion of induction], and Week 52 [Week 44 of maintenance study]. All colonoscopies were centrally read. There was an additional subset of participants that did not meet inclusion of IM-UNITI, but these individuals were offered open label ustekinumab and were included in the endoscopy sub-study.

The EXTEND trial enrolled patients with CD who had a CDAI score of 220-450 and evidence of mucosal disease established via ileocolonoscopy during study recruitment. Detailed study design and inclusion criteria have been previously published.¹² In brief, adults who previously had poor response to conventional therapy including immunomodulators, glucocorticoids, or previous TNF antagonists [excluding primary non-responders], were recruited to participate in a 52-week trial comparing adalimumab with placebo. All participants received 4-week induction therapy with adalimumab, and were then randomised to either placebo or 40 mg adalimumab every 2 weeks. Endoscopies were performed at baseline, Week 8 or 12, and Week 52. All endoscopies were centrally read.

Last, the CT-P13 study included adults with CD and a CDAI of 220-450 with prior non-response, intolerance, or contraindications for non-biologic therapies for CD.¹³ Eligibility criteria and study design have been previously published but, in short, patients were randomised to one of four experimental arms including: CT-P13 followed by CT-P13 at Week 30; CT-P13 followed by innovator infliximab at Week 30; innovator infliximab followed by innovator infliximab at Week 30; and innovator infliximab followed by CT-P13 at Week 30. Those in the infliximab arms received standard induction and maintenance protocols every 8 weeks with a 5-mg/kg intravenous dose. Those recruited underwent a baseline and end of study [Week 54] colonoscopy. All endoscopies were read centrally.

2.3. Variables

The three trials that were included in this analysis provided a total of 350 participants who had endoscopic assessment prior to study intervention, confirming mucosal ulceration and minimum SES-CD score of 3 or more. There were 334 patients in the endoscopic sub-study of the UNITI studies, though the population who crossed over between ustekinumab and placebo were excluded from this analysis. As such, a total of 80 patients received continuous ustekinumab throughout the 52-week study period and were included in this study. This included both responders and non-responders to induction therapy. Of the EXTEND population, all 129 individuals fulfilled inclusion criteria for this analysis as all had baseline endoscopic assessments. Finally from the CT-P13 study, of the 220 patients randomised, 141 had baseline and Week 54 endoscopies and were included in this analysis. Within the three trials included, 75 individuals had isolated ileal disease. All analyses were completed on an intention to treat basis, and all studies used the SES-CD to quantify endoscopic inflammation.

2.4. Endoscopic activity measurements using the MM-SES-CD

The SES-CD was used in all included studies to quantify CD endoscopic activity. This score takes into account four endoscopic variables in five bowel segments. Each endoscopic variable is scored from 0-3 including: size of ulcers [score of 0 if no ulcers, 1 if diameter <0.5cm, 2 if diameter 0.5cm-2cm, and 3 if diameter >2cm]; extent of ulcerated surface [0 if no ulcers, 1 if extent <10%, 2 if extent 10-30%, and 3 if >30%]; affected surface [0 if not affected, 1 if extent <50%, 2 if extent 50-70%, and 3 if extent >70%]; and presence of narrowing [0 if no narrowing, 1 if single narrowing that can be passed, 2 if multiple narrowings that can be passed, and 3 if narrowing cannot be passed].⁶ The final SES-CD score is derived from the sum of each variable in all five bowel segments and provides a proposed severity spectrum including ≥16 representing severely active disease, 7-15 moderately active, 3-6 mildly active, and ≤3 inactive disease.¹⁴ The MM-SES-CD values were calculated based on the SES-CD scores obtained from UNITI, EXTEND, and the CT-P13 studies. Table 1 outlines the method of MM-SES-CD calculation, and an online calculator is available to clinicians and trialists at [https://www.mcmasteribd.com/mm-ses-cd].

2.5.Outcomes of interest

The purpose of this analysis was to assess for numerical cut-offs of baseline MM-SES-CD to distinguish between mild, moderate, and severe endoscopic CD activity based on the likelihood of 1-year ER. Additionally, the relationship between baseline MM-SES-CD score and likelihood of 1-year CR [CDAI <150] was evaluated. We also planned to evaluate the relationship between baseline SES-CD categories and 1-year ER and CR, and post-induction MM-SES-CD categories with 1-year ER and CR. Following the IOIBD recommendations, ER was defined as SES-CD <3, but in sensitivity analysis we considered an alternative definition of ER as absence of mucosal ulcerations [ER-1].¹⁵

2.6.Statistical analysis

This analysis pooled data from the UNITI, EXTEND, and CT-P13 trials. This same dataset was previously used to define baseline MM-SES-CD values associated with low and high probability of achieving ER. It was previously demonstrated that a baseline score of ≥45 had low probability of ER at 1 year [8.2%] and that a score of <14 had a high probability of ER at 1 year [55.0%].⁸ To further categorise the remainder of patients with scores between 14 and 45, the maximum Youden Index was calculated for thresholds of both low and high probability of ER and CR.¹⁶ Furthermore, separate MM-SES-CD severity categories were established using the maximum Youden index in those with isolated ileal disease, to predict probability of achievement of ileal ER at 1 year.

Continuous variables were described using means with standard deviations, and categorical variables were described as proportions. To compare categorical variables, chi square tests of trend were used. Kaplan-Meier survival curve analysis was employed to compare time to clinical remission within the MM-SES-CD severity categories, the process of establishing these categories described above, and log-rank statistics were performed to compare these groups. We did not perform survival curve analysis for ER as the CT-P13 study included only two endoscopic assessments, one of which at study participant enrolment and the second at Week 54.

The reporting of this analysis follows recommendations from the TRIPOD statement.¹⁷ Statistical analyses were performed using the Python programming language [version 3.8.3] and open-source Python packages, including pandas, NumPy, scikit-learn, seaborn, and imblearn.

3. Results

Baseline characteristics of the 350 participants that were included in this post-hoc analysis are outlined in Table 2. It should be noted that participant demographics are generally consistent with the overall demographics for those enrolled in the UNITI, EXTEND, and CT-P13 studies [data not shown]. The mean MM-SES-CD and SES-CD baseline scores were 37.9 [SD±18.5] and 14.1 [SD±8.1] respectively. The average disease duration was 6.0 years [SD±6.8], and 78 [22.3%] patients in this cohort achieved 1-year ER. There were 203 individuals [58%] who at baseline had an MM-SES-CD of >1 in the ileum, and 75 participants had isolated ileal disease [21%]. Baseline colonic involvement was as follows: 156 [44.6%] had right colon involvement, 151 [43.1%] transverse colon, 210 [60.0%] left colon, and 167 [47.7%] rectal disease. There were 90 individuals [25.7%] who had previous anti-TNF failure. Of the 350 participants in this analysis, 80 [22.9%] were treated with ustekinumab, 141 [40.3%] with infliximab, and 129 [36.9%] with adalimumab.

3.1. One-year endoscopic and clinical remission stratified by baseline MM-SES-CD scores

Prior analyses established MM-SES-CD cut-off values for severe disease as ≥45, and very mild disease or CD in remission as <14.⁸ To establish mild and moderate MM-SES-CD cut-off values based on likelihood of ER and CR, the maximum Youden Index for both parameters was calculated. The maximum Youden index for 1-year ER was 0.139, which corresponded to a cut-off value of 30.5. The maximum Youden index for 1-year CR was 0.137, which corresponded to a cut-off value of 32. As such, a cut-off of 31 was used to distinguish between patients with mild and moderate disease based on baseline MM-SES-CD score.

Table 3 outlines the probability of achieving 1-year ER and CR as stratified by baseline MM-SES-CD severity categories. Of the 350 individuals included in this analysis, 22 had very mild disease or disease in remission, 122 had mild disease, 92 had moderate disease, and 114 had severe disease as defined by the MM-SES-CD. At 1 year, ER was attained by 11/22 [50.0%] individuals with very mild or inactive disease, 37/122 [30.3%] with mild disease, 20/92 [21.7%] with moderate disease, and 10/114 [8.8%] with severe disease [p <0.001]. Sensitivity analysis found 1-year ER-1 was achieved by 13/22 [59.1%] participants with very mild or inactive disease, 43/122 [35.3%] with mild disease, 23/92 [25.0%] with moderate disease, and 16/114 [14.0%] with severe disease [p <0.001]. Figure 1 demonstrates the probability and time to CR [CDAI <150] of patients stratified by MM-SES-CD severity, and illustrates that individuals with lower MM-SES-CD scores had numerically higher rates of 1-year CR [p = not significant: ns], and improved time to CR over 52 weeks compared with those with higher MM-SES-CD scores [log rank p = 0.0492].

3.2. One-year endoscopic and clinical remission stratified by baseline SES-CD scores

The prognostic value of previously established SES-CD categories were also analysed to investigate whether severity cut-offs were associated with 1-year ER and CR [Table 4]. Of the 350 individuals included in this analysis, 63 had mild disease, 153 had moderate disease, and 134 had severe disease, as categorised by the SES-CD score. At 1 year, ER was attained by 24/63 [38.1%] of patients with mild disease, 40/153 [26.1%] with moderate disease, and 14/134 [10.5%] with severe disease [p <0.001]. ER-1 was achieved by 27/63 [42.9%] individuals with mild disease, 45/153 [29.4%] with moderate disease, and 23/134 [17.2%] with severe disease [p = 0.001]. Finally, CR was achieved by 32/63 [50.8%] of individuals with mild disease, 64/153 [41.8%] with moderate disease, and 53/134 [39.6%] with severe disease [p = 0.320].

3.3. One-year endoscopic and clinical remission stratified by post-induction MM-SES-CD scores

We examined the prognostic values of MM-SES-CD severity categories at post-induction assessment to determine whether there was an association with 1-year ER and CR. For this analysis, 99 participants from the UNITI and EXTEND studies who had endoscopy conducted at 8 weeks were used. Results are outlined in Table 5. In total, six individuals in this subgroup had a post-induction MM-SES-CD score that corresponds to very mild disease or in remission, 26 had mild disease, 29 moderate, and 38 severely active disease. ER was attained by 3/6 [50.0%] participants with very mild or inactive disease, 5/26 [19.2%] with mild disease, 3/29 [10.3%] with moderate disease, and 1/38 [2.6%] with severe disease [p <0.001]. CR was achieved in 3/6 [50.0%] individuals who initially had disease in remission or very mild disease, 5/26 [19.2%] with mild disease, 6/29 [20.7%] with moderate disease, and 10/38 [26.3%] with severe disease [p = 0.422].

3.4. One-year endoscopic remission of isolated ileal disease stratified by baseline MM-SES-CD scores

Last, we analysed the prognostic capability of baseline MM-SES-CD in predicting ER in participants with isolated ileal disease. This analysis included 75 patients: nine had mild disease, 51 moderate disease, and 15 severe disease, as categorised by the MM-SES-CD. The maximum Youden index for mild and moderate disease was 0.140 [MM-SES-CD of 14] and 0.111 [MM-SES-CD of 33], respectively. At 1 year, ER was attained by 6/9 [66.7%] of individuals with mild disease, 17/51 [33.3%] with moderate disease, and 2/15 [13.3%] with severe disease [p = 0.027] [Table 6].

4. Discussion

This post-hoc analysis of several clinical trials has established several key findings regarding the novel MM-SES-CD and SES-CD scoring tools. First, we demonstrated that the MM-SES-CD scores can be stratified into categories that correspond to probability of ER at 1 year. We also found that patients with lower scores of the MM-SES-CD had numerically higher rates of 1-year CR, and time to CR over 52 weeks was significantly better in those with lower MM-SES-CD scores compared with higher scores. Additionally, this analysis is the first to establish a scoring system for isolated ileal CD which is predictive of ER remission at 1 year.

The SES-CD is a commonly used scoring system in clinical trials and practice as recommended by the IOIBD and some international guidelines to define CD endoscopic severity.^15,18,19 However, the SES-CD has only been validated in cross-sectional analyses, and does not perform as well as the SES-CD in prognostication of long-term clinical outcomes.⁸ Importantly, STRIDE-II outlines the gaps in knowledge surrounding the definition of endoscopic healing and the lack of validated tools to link disease thresholds with specific outcomes.²⁰ The MM-SES-CD is a novel endoscopic scoring system based on the SES-CD which may help to address this gap. It was developed to better account for the heterogeneity of CD endoscopic findings, as it assigns a weight to prognostically significant endoscopic lesions in its summative score, in comparison with the linear nature of the SES-CD.⁸ We previously demonstrated that the MM-SES-CD is a highly accurate scoring system that identifies patients with significantly lower probability of achieving ER as compared with the SES-CD.⁸ This current analysis expanded on prior findings by demonstrating that patients can be stratified into categories of severe, moderate, mild, or very mild/inactive MM-SES-CD scores based on their likelihood of 1-year ER [based on both strict and less strict definitions of ER] and time to 1-year CR.

Moreover, we have established prognostically significant cut-off categories of isolated ileal disease. Several cohort studies have observed isolated ileal disease to be a negative predictor of response to anti-TNFα therapy and response to biologic therapy. Additionally, compared with isolated colonic involvement, isolated ileal CD involvement is associated with an increased risk for change of disease behaviour and risk of developing intestinal complications such as need for surgery.^9,21,22 This analysis is the first to establish a predictive scoring tool for 1-year ER in those with isolated ileal CD which could be advantageous to both clinicians and trialists for measuring severity of endoscopic ileal CD.

The observations from this analysis provide a number of interesting applications to both clinical trials and clinical practice. With regards to clinical trials, it has already been demonstrated that an MM-SES-CD score of ≥45 could be considered as a stratification variable for patients randomisd into clinical trials. This cut-off could aid trialists to balance study arms and to differentiate individuals with severe endoscopic disease who have low probability of ER while on therapy. Furthermore, here we have established prognostically significant MM-SES-CD mild and moderately active CD categories. A score of 14-30 could be used to enrol those with mild disease, and a score of 31-44 could be used to enrol those with moderately active endoscopic disease. Last, the isolated ileal MM-SES-CD severity categories could be additionally used to further stratify study populations, with a score of <14 corresponding to mild disease, ≥14 to <33 moderate disease, and ≥33 severe ileal disease.

In clinical practice, the MM-SES-CD may have utility in identifying patients who have a low probability of ER and who might warrant more rigorous monitoring by their health care providers. International guidelines and consensus statements recommend treat-to-target monitoring in CD, and our current analysis establishes that both the SES-CD and the MM-SES-CD severity classifications are predictive of 1-year ER. In those identified as having a lower probability of achieving ER based on these scoring indices, time- and resource-intensive measures such as monitoring of biomarkers, monitoring of therapeutic drug concentrations, and repeated endoscopies may be considered to more closely monitor these patients. Knowing that a patient has a low probability of ER, a clinician may consider more intense pharmacotherapy such as combinations of anti-TNF with an immunomodulator, or may pursue non-medical treatment options such as surgery earlier. Contrary to this, for those identified with high probability of achieving ER based on the SES-CD and MM-SES-CD, more lenient monitoring and/or less intense treatment regimens might be considered.

This analysis has a number of strengths, most notably that it is the first study to demonstrate that CD endoscopic severity strata have prognostic value, and to establish score cut-offs for isolated ileal CD. Furthermore, high-quality data from three phase 3/4 clinical trials [UNITI, EXTEND, and the CT-P13 study] were used with central, blinded, endoscopic reading. This analysis is not without its limitations. First, further validation of the MM-SES-CD is required in both clinical trials and clinical practice. Second, our analysis combined individuals with very mild and inactive disease; thus additional investigation is required to define ER within these strata using the MM-SES-CD. To define ER according to the MM-SES-CD would require additional studies to establish MM-SES-CD-related remission definitions and long-term outcomes associated with lack of progression of disease. Moreover, future studies that analyse the relationship between less invasive measures of CD activity, such as biomarkers [CRP, faecal calprotectin] and the MM-SES-CD would be beneficial.

In summary, we have identified MM-SES-CD categories which are predictive of 1-year ER and time to CR. We have also demonstrated that the existing SES-CD categories have prognostic value. We previously have shown that in comparison with the MM-SES-CD, the SES-CD is unable to comprehensively capture CD endoscopic heterogeneity, and the MM-SES-CD is more accurate in identifying those with low probability of ER.⁸ The MM-SES-CD provides additional value over other CD scoring indices as it is simple to use, assigns greater weights to prognostically significant endoscopic lesions, and has established severity categories that are predictive of ER. Our novel scoring tool additionally delineates isolated ileal disease severity cut-offs that predict ER. Future research should continue to move away from arbitrary classifications of disease severity, and towards the use of tools that have been demonstrated to predict prognosis of long-term outcomes.

Acknowledgements

This study, carried out under YODA Project # 2021-4684, used data obtained from the Yale University Open Data Access Project, which has an agreement with Janssen Research & Development, L.L.C. The interpretation and reporting of research using these data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research & Development, L.L.C. This publication [Vivli protocol #00007077] is based on research using data from AbbVie whcih has been made available through Vivli, Inc. Vivli has not contributed to or approved, and is not in any way responsible for, the contents of this publication. Data were obtained by permission from Celltrion Inc.

Funding

No authors have received support for the submitted manuscript. None of this work was supported by funding from any source.

Conflict of Interest

NN has received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, Sandoz, Novartis, and Ferring. J-FC reports: receiving research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, 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 holding stock options in Intestinal Biotech Development. JKM has received honoraria from Janssen, AbbVie, Allergan, Bristol-Meyer-Squibb, Ferring, Janssen, Lilly, Lupin, Merck, Pfizer, Pharmascience, Roche, Shire, Takeda and Teva. WR has received support for the following: speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult; consultant for Abbott Laboratories, Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC. PSD is supported by an American Gastroenterology Association Research Scholar Award. He has received research support and/or consulting from Takeda, Janssen, Pfizer, Abbvie, Gilead, Lily, BMS, Novartis; stock options and board member for DigbiHealth; Licensing royalties from Precidiag.

Author Contributions

NN: study concept and design; acquisition and compilation of data; statistical analysis; data interpretation; drafting of the manuscript. CP: study design; drafting of the manuscript. ECLW: acquisition and compilation of data; statistical analysis; drafting of the manuscript. J-FC: study design; drafting of the manuscript. JKM: study design; drafting of the manuscript; MD: study design; drafting of the manuscript. WR: study concept and design; acquisition and compilation of data; data interpretation; drafting of the manuscript. PSD: study concept and design; statistical analysis; data interpretation; drafting of the manuscript.

References

Author notes