International Organization For The Study Of Inflammatory Bowel Disease Research Articles

Outcomes and endpoints of postoperative recurrence in Crohn's Disease: systematic review and consensus conference.

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 standardize 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. 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 2 rounds of voting, the statement was excluded. In the systematic review, 3,071 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 randomized 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 reflected by the presence of complications. Agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognize primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy- and/or imaging-based endpoints.

Disease Clearance as a New Outcome in Ulcerative Colitis: a Systematic Review and Expert Consensus.

The concept of disease clearance has been proposed as a potential target in ulcerative colitis (UC). We conducted a systematic review to investigate the role of disease clearance, defined as a composite outcome including simultaneous clinical, endoscopic, and histologic remission of disease in the management of patients with UC. Based on the literature data, statements regarding disease clearance were developed and voted on by the members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) according to a Delphi methodology. A definition of disease clearance was proposed to standardize its use in clinical practice and clinical trials and to provide practical recommendations for its implementation as a therapeutic target in UC.

A238 BILE ACID COMPOSITION AND DIETARY FAT: IMPLICATIONS FOR CROHN’S DISEASE IN A COHORT OF HEALTHY FIRST-DEGREE RELATIVES

Abstract Background Crohn’s disease (CD) is a chronic relapsing inflammatory disease of the gastrointestinal tract. The etiology of CD may arise from complex interactions including host genetics, diet, and the intestinal microbiome. Increased consumption of saturated fats, characteristic of the Western diet, is a known risk factor for CD. Dietary fat (DF) is absorbed by the host through the release of primary bile acids (PBAs) and bio-transformed by the microbiome into secondary bile acids (SBAs). Altogether, bile acids (BAs) can act as signaling molecules involved in host immune regulation and potentially in CD onset. Purpose To investigate the relationship between CD risk, BAs, and DF, and evaluate the predictive performance of CD onset of these factors by developing machine learning models. Method We used samples healthy first-degree relatives (FDRs) recruited as part of the Crohn’s Colitis Canada- Genes, Environment, Microbial (GEM) project. Those who developed CD (n=87) were matched 1:4 by age, sex, follow-up time, and geographic location with control FDRs remaining healthy (n=347). Serum, urine, and stool BA were measured using ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. DF types were derived from food frequency questionnaire data. We used conditional logistic regressions to identify associations between CD onset, BAs (n=93), and DFs (n=9). We further explored the relationships of significant CD-related BAs and DF via Generalized Estimation Equations. Finally, we used a tree-based machine-learning algorithm (XGBoost) with 5-fold cross-validation to assess the prediction performance of CD onset using BA from all sources as well as DF. Two-sided p<0.05 was considered significant. Result(s) In total, 10 of 93 BAs, and two of nine DFs were significantly associated with increased odds of CD onset (p<0.05). Additionally, five BAs were significantly associated with DF (p<0.05). Serum-derived BAs had the best predictive performance for CD, with a mean AUC of 0.70 [95% CI: 0.63;0.76], followed by stool derived BAs with a mean AUC= 0.65 [0.55;0.75], and followed by urine derived Bas with a mean AUC= 0.57 [0.48;0.66]. Lastly DF was not a predictive marker of CD onset with a mean AUC= 0.50 [0.41;0.60]. Conclusion(s) This study suggests that BAs are associated with the pathogenesis of CD and the effects may be influenced by DF. Serum-derived BAs may be able to better predict the risk of CD than other stool or urine derived BA, while DF is not directly implicated in CD risk. Submitted on behalf of the CCC-GEM consortium. Funding Crohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) III The Leona M. and Harry B. Helmsley Charitable Trust Kenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel Diseases The International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) Jingcheng Shao is the recipient of a Data Science Institute Summer Undergraduate Data Science award Disclosure of Interest None Declared

Dietary Interventions in Inflammatory Bowel Disease.

Inflammatory bowel disease, which primarily includes ulcerative colitis and Crohn’s disease, is a group of chronic diseases of the gastrointestinal tract. Mainly affecting young people, it is characterized by periods of exacerbation and remission. In recent years, there has been an increase in the prevalence of inflammatory bowel disease worldwide, including Poland. The potential impact of nutrition and selected dietary components that are directly or indirectly involved in the pathogenesis of intestinal lesions in IBD is not fully clear. Evaluating the impact of diet on the course of IBD is very complex due to the fact that regardless of a dietary model adopted, each one is based on consumption of many different food groups which affect one another. However, the growing need to produce dietary recommendations for these patients has prompted the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) to develop nutrition guidelines for the patients. The present paper characterizes the dietary models most commonly discussed in research studies and their potential impact on IBD activity.

COVID-19 pandemic: is it time for shared surgical guidelines? A systematic review of the literature.

The recent COrona Virus Disease 2019 (COVID-19) pandemic caused a massive disruption of surgical activity and after a year from its first outbreak surgeons still struggle to keep their regular activity coexisting with the virus exhausting requests of healthcare resources. The aim of this paper is to offer a comprehensive overview of the most important recommendations by the International Guidelines about general surgery, and possibly to invite building common shared guidelines to preserve the potential to provide surgical assistance despite the pandemic. This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. PubMed, Embase, Cochrane and Web of Science databases were searched. The searches revealed a total of 18579 articles published up to the end of February 2021. Five articles published between March and May 2020, were included in the present study: Guidelines from The European Society of Trauma and Emergency Surgery (ESTES), The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and The European Association for Endoscopic Surgeons (EAES), The Endoscopic and Laparoscopic Surgeons of Asia (ELSA), The European Hernia Society (EHS) and The International Organization for the Study of Inflammatory Bowel Disease (IOS-IBD). In the likely scenario that the SARS-CoV-2 pandemic will become an endemic chronic problem, we should not be forced to choose between COVID-19 or surgery in the future and find a way to make both coexisting.

Precision Medicine in Inflammatory Bowel Diseases: Challenges and Considerations for the Path Forward

Precision medicine strives to optimize health by delivering care tailored to each person’s unique biology. The striking heterogeneity of inflammatory bowel disease (IBD) in phenotypic presentation, disease course, and treatment response renders it ideally suited to benefit from precision medicine approaches. Despite recent innovative research, implementations of truly tangible precision medicine applications in IBD are few. Although the past 20 years have ushered in a slew of novel therapies, our ability to use them in a rational, biology-driven fashion remains fairly crude. Although the limitations of a one-size-fits-all approach in IBD are widely acknowledged, clinical practice has struggled to move meaningfully beyond them. In this regard, the IBD community must cover substantial ground to catch up with other fields, such as oncology. Despite the important differences between cancer and IBD, including the clonal nature of malignancy, the IBD community can still glean important lessons from the successes of precision oncology. Here, we review some of the major barriers to progress in precision IBD and propose calls to action while drawing on precision oncology for insights. We have omitted certain generic challenges, such as the need for harmonization, global data sharing, and ethical/privacy considerations, which are reviewed elsewhere,1Denson L.A. Curran M. McGovern D.P.B. et al.Challenges in IBD research: precision medicine.Inflamm Bowel Dis. 2019; 25: S31-S39Crossref PubMed Scopus (39) Google Scholar,2Liu X. Luo X. Jiang C. et al.Difficulties and challenges in the development of precision medicine.Clin Genet. 2019; 95: 569-574Crossref PubMed Scopus (20) Google Scholar focusing on challenges specific to precision IBD (Figure 1). A fundamental first challenge is that current IBD diagnostic and classification schemes, such as the Lennard-Jones criteria and Montreal classification,3Silverberg M.S. Satsangi J. Ahmad T. et al.Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a working party of the 2005 Montreal World Congress of Gastroenterology.Can J Gastroenterol. 2005; 19: 5A-36ACrossref PubMed Scopus (2350) Google Scholar do not capture the significant heterogeneity of IBD. Even the segregation of IBD into Crohn’s disease (CD), ulcerative colitis (UC), and the ill-defined entity IBD-unclassified is a vast oversimplification of complex pathophysiologic processes. More than 240 genetic risk variants interact with epigenetic, immunologic, and microbial factors, under the influence of dynamic environmental exposures, to elicit the rich array of clinical manifestations of IBD.4Chang J.T. Pathophysiology of inflammatory bowel diseases.N Engl J Med. 2020; 383: 2652-2664Crossref PubMed Scopus (138) Google Scholar The narrow focus of existing diagnostic/classification systems on phenotypic features, such as disease location and behavior, and their constraint by categorical definitions of CD as discontinuous and transmural and of UC as continuous and mucosal prevent them from encompassing and meaningfully describing the full breadth of IBD. One potential approach is to reorganize the clinical criteria that make up existing classification systems. For example, a novel index including a subset of the Lennard-Jones criteria was shown to better distinguish CD from UC than the original criteria.5Reinisch S. Schweiger K. Pablik E. et al.An index with improved diagnostic accuracy for the diagnosis of Crohn’s disease derived from the Lennard-Jones criteria.Aliment Pharmacol Ther. 2016; 44: 601-611Crossref PubMed Scopus (2) Google Scholar However, a solution that leverages molecular characterization will almost certainly be better equipped to capture and delineate the numerous distinct IBD subtypes. Work from the International IBD Genetics Consortium, which examined associations between genetic risk scores and IBD subphenotypes, supported a continuum of disorders better explained by three IBD subgroups (ileal CD, colonic CD, and UC) compared with the traditional 2 subgroups (CD and UC).6Cleynen I. Boucher G. Jostins L. et al.Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study.Lancet. 2016; 387: 156-167Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar Here, there are lessons to take from oncology’s playbook. At comprehensive cancer centers, systematic molecular tumor characterization, especially for genetic aberrations using next-generation sequencing, is the standard of care. Malignancies are not solely defined by qualitative descriptors but also by their genetic architecture. In many cases, these molecular signatures can be used to risk-stratify patients and to select biology-specific treatment regimens.7Malone E.R. Oliva M. Sabatini P.J.B. et al.Molecular profiling for precision cancer therapies.Genome Med. 2020; 12: 8Crossref PubMed Scopus (187) Google Scholar The success of this approach in oncology has hinged on the availability of large numbers of novel targeted drugs; in 2020 alone, 21 therapeutic compounds were approved by the US Food and Drug Administration.8New oncology drug approvals in 2020.Clinical Oncology News. December 15, 2020; (Available at:) (Accessed December 11, 2021)https://www.clinicaloncology.com/FDA-Watch/Article/12-20/New-Oncology-Drug-Approvals-in-2020/61464Google Scholar It is time to move beyond our current phenotypically driven IBD classification to outline the molecular blueprint of IBD and to reveal all its subtypes, each likely with a distinct disease trajectory and treatment response profile. Thus, molecularly defined subphenotypes can be explored for their ability to predict prognosis and likelihood of treatment response, which are central goals in precision IBD. Although past studies have largely sought to identify biomarkers that align with conventional IBD types/phenotypes (eg, CD vs UC, ileal vs colonic CD), we must instead define novel IBD subtypes that align with molecular biomarkers. Important tools to accomplish this will include unsupervised clustering methods9Shen R. Mo Q. Schultz N. et al.Integrative subtype discovery in glioblastoma using iCluster.PLoS One. 2012; 7e35236Crossref Scopus (162) Google Scholar and systems biology methods that conceptualize IBD pathogenesis as a network rather than linear interactions, thus emphasizing nodes amenable to therapeutic interventions. Broad racial/ethnic representation and longitudinal assessment will be vital to capture the heterogeneity of IBD. Any novel biomarkers or precision medicine tools, whether for classification or other purposes (eg, prognosis, treatment response), will need to be the product of processes that ensure reproducibility. Industry collaborations can facilitate standardized access to samples under monitored conditions. Classic endoscopic, histologic, and radiographic assessment will continue to play an important, but perhaps complementary, role in IBD classification. Emerging approaches, such as artificial intelligence (AI) methods, including computer vision and deep learning/neural networks, can help to automate, standardize, and enhance the reproducibility of these traditional assessments and aid in identifying novel subgroups by detecting patterns not previously discernible.10Chahal D. Byrne M.F. A primer on artificial intelligence and its application to endoscopy.Gastrointest Endosc. 2020; 92: 813-820Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar,11van der Laak J. Litjens G. Ciompi F. Deep learning in histopathology: the path to the clinic.Nat Med. 2021; 27: 775-784Crossref PubMed Scopus (64) Google Scholar The big data multiomics approach advocated here is not without its own inherent challenges, including the small effect sizes of many analytic measures, such as the majority of genetic variants,12McGovern D.P.B. Kugathasan S. Cho J.H. Genetics of inflammatory bowel diseases.Gastroenterology. 2015; 149: 1163-1176Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar relative to intersubject heterogeneity. This mandates processes to reconcile statistical and clinical significance (one should not be equated with the other) and to integrate numerous—at times, seemingly disparate—effects into a cohesive model that explains biological phenomena. In addition, although current technologies allow us to probe many multiomics facets of IBD, modalities to quantify the exposome remain limited—a real challenge given the very significant effect of the environment on IBD pathophysiology and likely on treatment response. A second challenge is the lack of criterion standard, precision medicine–appropriate endpoints. Such endpoints must be objective, clearly defined, reproducible, attainable within a sensible timeframe, and deeply rooted in disease biology and, thus, causally associated with clinically meaningful long-term outcomes. Clinical activity indices, despite being highly relevant for patients and regulatory agencies, are not suitable, given their subjective nature and imperfect correlation with inflammatory activity. Even seemingly “hard” outcomes, such as surgery, hospitalization, and treatment escalation, are suboptimal because they lack standardized definitions and may reflect physician practices and/or patient preferences. Regulatory agencies are increasingly embracing objective outcomes, such as endoscopy and histology in trial design, but have simultaneously mandated patient-reported outcomes (PROs) as coprimary endpoints.13Williet N. Sandborn W.J. Peyrin-Biroulet L. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease.Clin Gastroenterol Hepatol. 2014; 12: 1246-1256Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Although the importance of the patient experience cannot be undermined, PROs capture a construct driven not only by inflammation but by myriad other influences (eg, anatomy, diet, microbiome, functional processes). As such, the juxtaposition of PROs and endpoints like mucosal healing dilutes the objectivity of the latter. The differential biological determinants of clinical activity and endoscopic healing are illustrated by the PROgECT trial, in which a colonic gene expression signature predicted mucosal healing in patients with UC treated with golimumab while showing no association with clinical response or remission.14Telesco S.E. Brodmerkel C. Zhang H. et al.Gene expression signature for prediction of golimumab response in a phase 2a open-label trial of patients with ulcerative colitis.Gastroenterology. 2018; 155: 1008-1011Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar An additional unknown is the optimal timepoint at which to assess outcomes for each therapy, reflecting our incomplete understanding of pharmacodynamics. We must also account for variability in drug exposure because this can obscure the interpretation of changes in molecular and cellular pharmacodynamic markers of treatment response. A fundamental first step is for the IBD community to achieve consensus on a core set of precision medicine–appropriate endpoints to be systematically applied across studies. Although overlap is to be expected with endpoints identified through initiatives such as Selecting Therapeutic Targets in IBD (STRIDE),15Turner D. Ricciuto A. Lewis A. et al.STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.Gastroenterology. 2021; 160: 1570-1583Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar discrepancies are anticipated (regarding PROs, for example), which must be reconciled moving forward. Although endoscopic, histologic, and radiographic endpoints are likely the most objective and appropriate of currently available outcome measures, they are far from perfect. None encapsulates the totality of the concepts of inflammatory burden, disease severity, and prognosis, and all have operational challenges, such as optimal indices/cutoffs and training standards.16Gottlieb K. Daperno M. Usiskin K. et al.Endoscopy and central reading in inflammatory bowel disease clinical trials: achievements, challenges and future developments.Gut. 2021; 70: 418-426PubMed Google Scholar As previously alluded to, AI may facilitate the reproducible interpretation of image-based outcomes and assist with the development of novel instruments. Ultimately, the IBD community must develop novel endpoints more tailored to the needs of precision medicine. Molecular biomarkers (eg, a molecular inflammatory score based on intestinal gene expression)17Argmann C. Tokuyama M. Ungaro R.C. et al.Molecular characterization of limited ulcerative colitis reveals novel biology and predictors of disease extension.Gastroenterology. 2021; 161: 1953-1968Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar warrant exploration because they have a more direct relationship to disease biology. Peripheral biomarkers from blood, stool, urine, etc represent the holy grail because their easy collection allows more frequent monitoring and treatment adjustment. In oncology, bioengineering advances in micro- and nanofluidics have enabled peripheral blood-based biomarkers, such as liquid biopsies, from which circulating tumor cells can be isolated. Biosensors and wearables offer the advantage of continuous monitoring with instantaneous feedback. Such emerging technologies hold great promise to revolutionize the way in which we measure treatment success in IBD.18Ho D. Quake S.R. McCabe E.R.B. et al.Enabling technologies for personalized and precision medicine.Trends Biotechnol. 2020; 38: 497-518Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar A major limitation of studies to date is the lack of longitudinal assessment. Prospective, longitudinal studies are needed to validate prognostic, predictive, and outcome biomarkers. In addition, longitudinal serial assessment is necessary to elucidate the temporal evolution of biomarkers in relation to disease stage and severity, as well as treatment response. A common shortcoming of studies has been a failure to account for patient differences in disease duration/severity and treatment, all of which are likely to affect disease biology and molecular profiles. Prospective longitudinal follow-up of inception cohorts, with initial sampling of treatment-naive patients and subsequent repeated sampling as the disease evolves and is treated, is likely the design best suited to address this. Serial sampling is vital because short-term changes in biomarkers may better predict long-term outcomes than single baseline parameters.19Waljee A.K. Liu B. Sauder K. et al.Predicting corticosteroid-free endoscopic remission with vedolizumab in ulcerative colitis.Aliment Pharmacol Ther. 2018; 47: 763-772Crossref PubMed Scopus (49) Google Scholar,20Waljee A.K. Liu B. Sauder K. et al.Predicting corticosteroid-free biologic remission with vedolizumab in Crohn’s disease.Inflamm Bowel Dis. 2018; 24: 1185-1192Crossref PubMed Scopus (33) Google Scholar Although inception cohort studies are the criterion standard, they are hugely resource intensive. Accordingly, we must strive to develop infrastructure and protocols to accomplish similar objectives by leveraging clinical care processes. The widespread implementation of electronic health records (EHRs) can greatly facilitate the use of routinely collected health data to ascertain longitudinal phenotypes, exposures, and outcomes, variables for which we must establish standardized definitions to optimize efficiency and accuracy. Coupling this approach to standardized biospecimen collection at key timepoints during routine follow-up presents an opportunity to democratize precision medicine studies to include more community-based centers. This recruitment strategy increases the potential “audience,” enhancing study power, and, importantly, helps include a more representative spectrum of IBD severity. Powerful tools result from the union of EHRs and machine learning, particularly deep learning. Deep learning is well suited for medical data because it can identify patterns in sparse, noisy data and requires little input-feature engineering.21Norgeot B. Glicksberg B.S. Butte A.J. A call for deep-learning healthcare.Nat Med. 2019; 25: 14-15Crossref PubMed Scopus (98) Google Scholar Nelson et al22Nelson C.A. Butte A.J. Baranzini S.E. Integrating biomedical research and electronic health records to create knowledge-based biologically meaningful machine-readable embeddings.Nat Commun. 2019; 10: 3045Crossref PubMed Scopus (17) Google Scholar have developed a method to embed clinical features from EHRs into a heterogeneous knowledge network, termed the Scalable Precision Medicine Oriented Knowledge Engine (SPOKE), which integrates data from 29 publicly available databases, effectively creating medically relevant “barcodes” for individual medical variables in EHRs that map onto SPOKE. These high-dimensional, knowledge-guided patient health signatures have been used as features in random forest modeling to recognize prodromal features of disease, such as multiple sclerosis, several years before diagnosis.23Nelson C.A. Bove R. Butte A.J. et al.Embedding electronic health records onto a knowledge network recognizes prodromal features of multiple sclerosis and predicts diagnosis.J Am Med Inform Assoc. 2022; 29: 424-434Crossref PubMed Scopus (3) Google Scholar Norgeot et al24Norgeot B. Glicksberg B.S. Trupin L. et al.Assessment of a deep learning model based on electronic health record data to forecast clinical outcomes in patients with rheumatoid arthritis.JAMA Network Open. 2019; 2e190606Crossref PubMed Scopus (76) Google Scholar have also leveraged machine learning and structured EHR data to predict future outcomes in patients with rheumatoid arthritis. The concept of repeated biological sampling, recognizing spatiotemporal disease evolution, is well established in precision oncology. When a patient’s cancer relapses, its molecular underpinnings are assumed to have shifted; the tumor is resampled and reanalyzed for molecular alterations, and therapies are adjusted accordingly. This is possible because drugs have been developed that directly target specific aberrations. Similarly, molecular characterization at a single timepoint for the purpose of treating IBD is potentially insufficient and may need to be repeated at the time of relapse. For example, such repeated sampling can help elucidate the molecular shift in patients previously responsive to an antitumor necrosis factor who have lost the response to this mechanism of action despite adequate drug exposure and the absence of immunogenicity. A significant translational gap separates precision medicine discovery and implementation in IBD. A leading contributing factor is the current model of discovery by siloed academic groups. Although this has led to numerous novel and groundbreaking discoveries, it is not a pathway that typically culminates in biomarkers that are robustly validated, reproducible according to technical standards, approved by regulatory bodies, and widely available and reimbursed, all prerequisites for global acceptance and implementation. Oncology again leads by example, having developed a model that incorporates biomarkers into drug development programs, including companion diagnostics. As an example, pembrolizumab was shown to be efficacious for non–small-cell lung cancer tumors that express the marker programmed death ligand 1 (PD-L1) in ≥50% of cells.25Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (5718) Google Scholar In this randomized controlled trial, PD-L1 was measured using a commercially available companion diagnostic.25Reck M. Rodríguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (5718) Google Scholar As a result, both pembrolizumab and its companion diagnostic have received regulatory approval for this indication. To accommodate the inclusion of biomarkers, oncology trials have undergone a major shift in design. Several novel biomarker-focused trial designs have been developed and are reviewed elsewhere.26Hu C. Dignam J.J. Biomarker-driven oncology clinical trials: key design elements, types, features, and practical considerations.JCO Precis Oncol. 2019; 3 (PO.19.00086)Google Scholar By comparison, biomarker-driven trials remain rare in IBD. Although industry-partnered research programs that intertwine drug and biomarker development, with a focus on biomarker-driven trials, represent one arm of the solution, much work remains on the clinical implementation side. Decision support tools are needed to guide clinicians on which tests to perform and how to apply results. One example of this is the decision tool incorporating clinical, genetic, and serologic markers for predicting disease progression in CD.27Siegel C.A. Horton H. Siegel L.S. et al.A validated web-based tool to display individualised Crohn’s disease predicted outcomes based on clinical, serologic and genetic variables.Aliment Pharmacol Ther. 2016; 43: 262-271Crossref PubMed Scopus (66) Google Scholar Molecular tumor boards, interdisciplinary meetings during which experts achieve consensus on how to translate complex biological data into concrete clinical recommendations, have been widely adopted in oncology. An analogous approach may be of great utility in IBD, and virtual communication platforms can facilitate access to necessary experts. Mechanisms must also be put in place to migrate these data to EHRs so that they are available for health care providers and patients to make informed decisions on biomarker-aided clinical strategies. Feasibility and cost-effectiveness are not challenges to be diminished. Cost-effectiveness studies are, in fact, entirely lacking in the precision IBD space and represent an important area in need of future research. The costs of bringing precision medicine applications to the clinic can be colossal and prohibitive in some cases. This is especially true because large randomized controlled trials are the criterion standard to establish effectiveness before implementation. Nevertheless, a whole blood gene expression profile that has been associated with more severe CD is being used to stratify patients to a more aggressive treatment approach vs the standard of care in a randomized controlled trial in the first study of its kind28Biasci D. Lee J.C. Noor N.M. et al.A blood-based prognostic biomarker in IBD.Gut. 2019; 68: 1386-1395Crossref PubMed Scopus (78) Google Scholar,29Lee J.C. Lyons P.A. McKinney E.F. et al.Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis.J Clin Invest. 2011; 121: 4170-4179Crossref PubMed Scopus (201) Google Scholar (discussed later). That said, certain interventions where the balance is highly weighted toward benefit over risk and cost may be suitable for implementation even without costly randomized controlled trials. Examples that may be ready for prime time include screening for NUDT15 variants, which are associated with thiopurine-induced myelosuppression, before medication initiation, particularly in patients of East Asian ancestry as well as the use of HLA-DQA1∗05–based assays to determine people at high risk of developing immunogenicity to anti–tumor necrosis factor (TNF) therapies.30Walker G.J. Harrison J.W. Heap G.A. et al.Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease.JAMA. 2019; 321: 773-785Crossref PubMed Scopus (73) Google Scholar,31Sazonovs A. Kennedy N.A. Moutsianas L. et al.HLA-DQA1∗05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn’s disease.Gastroenterology. 2020; 158: 189-199Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar The success of precision oncology would not have been possible without access to drugs with multiple mechanisms of action. This will likely be true in IBD as well. Fortunately, numerous novel biologics and small molecules are in the IBD pipeline. However, with increasing therapeutic options comes the threat of careless cycling through medications without attempts to optimize drug performance. Even with the handful of currently available agents, it is likely that we can substantially improve outcomes by optimizing their use. To maximize drug optimization, we must deepen our limited understanding of drug mechanisms of action, including counterregulatory processes. In a study published more than 20 years ago, almost all 24 patients with CD treated with a single infliximab infusion achieved clinical remission at 1 week, and TNF secretion was undetectable within a day, suggesting almost universal efficacy of the anti-TNF mechanism.32Nikolaus S. Raedler A. Kühbacker T. et al.Mechanisms in failure of infliximab for Crohn’s disease.Lancet. 2000; 356: 1475-1479Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar However, all patients subsequently experienced a recurrence of symptoms at variable timepoints, preceded by a rise in TNF. Greater insight into the processes that prompt a loss of response in specific patients at specific timepoints, potentially even very early after treatment initiation, could enable individualized drug regimens that prevent such loss of response. Between 2008 and 2013, 26% of oncology trials investigated combination therapy to maximize efficacy, compared to <7% of nononcology trials.33Wu M. Sirota M. Butte A.J. Chen B. Characteristics of drug combination therapy in oncology by analyzing clinical trial data on ClinicalTrials.gov.Pac Symp Biocomput. 2015; : 68-79PubMed Google Scholar We have repeatedly witnessed a ceiling effect in IBD clinical trials; therapeutic regimens that combine multiple biologics and/or small molecules may represent one way to break through. Such combination therapy appears intuitive when considering the multifactorial nature of IBD and the intricacies and redundancies of the immune system. Illustrating the concept of redundancy, using single-cell RNA sequencing, Smillie et al34Smillie C.S. Biton M. Ordovas-Montanes J. et al.Intra- and inter-cellular rewiring of the human colon during ulcerative colitis.Cell. 2019; 178: 714-730Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar found that oncostatin M phenocopies TNF in UC and that this might be one of the mechanisms of anti-TNF resistance, a finding that might inform subsequent treatment strategies. The rising number of drugs greatly complicates the task of treatment selection, especially when considering combination regimens. AI-based methods could assist. One example is personalized phenotypic medicine, which can be used to predict optimal drug dosing for efficacy and safety using relatively few data points from the treated patient only.18Ho D. Quake S.R. McCabe E.R.B. et al.Enabling technologies for personalized and precision medicine.Trends Biotechnol. 2020; 38: 497-518Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Throughout this commentary, we have turned to precision oncology as a paradigm to inform steps forward in IBD. Although we acknowledge that cancer may be uniquely suited to precision medicine applications given its clonal nature and the chance to identify and to therapeutically address molecular drivers, we remain convinced that there are important lessons to learn from our oncology colleagues and that it is precisely the differences between cancer and IBD that allow these lessons to stand out. Other chronic immune-mediated diseases may appear to be more intuitive comparators, but they suffer from many of the same challenges as IBD. That said, conditions such as the inflammatory arthritides have witnessed important successes on the precision medicine front, some of which may have direct applications to IBD, such as markers of treatment response or prognostic markers. As an example, PreductSURE IBD,35PredictImmune. PredictSURE IBD.https://www.predictimmune.com/predictsureibd/Google Scholar a commercially available 17-gene quantitative polymerase chain reaction–based blood assay intended to identify IBD patients at high risk of early and frequent relapse, is based on a T-cell exhaustion signature that was first linked to prognosis in autoimmune conditions such as systemic lupus erythematosus and anti-neutrophilic cytoplasmic autoantibody–positive vasculitis.36McKinney E.F. Lee J.C. Jayne D.R.W. et al.T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.Nature. 2015; 523: 612-616Crossref PubMed Scopus (0) Google Scholar The availability of multiomics data and computational proficiency will continue to grow exponentially over the coming years, extending the boundaries of what is achievable for IBD precision medicine. A concerted effort by the IBD community to overcome the obstacles discussed here is necessary to achieve the full potential of precision medicine for patients with IBD as it concerns disease classification/prediction, endpoints, longitudinal assessment, translational commitment, and therapeutic insights. These efforts must engage all parts of the IBD family, including patients, clinicians, and scientists, and should embrace advances from other disciplines even beyond inflammation/immunity to substantiate and ensure wide reach of the benefits of precision IBD.

BNT162b2 Messenger RNA COVID-19 Vaccine Effectiveness in Patients With Inflammatory Bowel Disease: Preliminary Real-World Data During Mass Vaccination Campaign

A 2-dose regimen of the BNT162b2 messenger (m)RNA COVID-19 vaccine (Pfizer-BioNTech; Pfizer, New York, NY) has demonstrated 95% efficacy in preventing COVID-19 in a phase III placebo-controlled randomized clinical trial1Polack F.P. et al.N Engl J Med. 2020; 383: 2603-2615Google Scholar and in real-world data analyses.2Dagan N. et al.N Engl J Med. 2021; 384: 1412-1423Google Scholar,3Chodick G. et al.Clin Infect Dis. Published online May. 2021; 17https://doi.org/10.1093/cid/ciab438Google Scholar Patients with inflammatory bowel disease (IBD) treated with immune-modifying agents are considered partially immunosuppressed, and thus, the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) recommends that patients with IBD should be vaccinated against COVID-19 and that vaccination should not be deferred in patients receiving immune-modifying therapies.4Siegel C.A. et al.Gut. 2021; 70: 635-640Google Scholar Because patients with immune conditions (including IBD) were excluded from the COVID-19 vaccine clinical trials, it is important to describe accumulating real-world data.5Kim JH, et al. Nat Med 27:205–211.Google Scholar In Israel, patients with IBD were given priority for early vaccination in the campaign, which is, as of June 23, 2021, the most extensive worldwide (63.6% of the total population received at least 2 doses, and 59.5% of the population was fully vaccinated).6Our World in Data. Coronavirus (COVID-19) Vaccinations-Statistics and Research.https://ourworldindata.org/covid-vaccinationsDate accessed: June 24, 2021Google Scholar This study is a preliminary report of the effect of mass vaccination in patients with IBD. This retrospective cohort study was conducted using data from the Maccabi Healthcare Services (MHS) central computerized database. MHS is the second largest state-mandated health care provider in Israel, covering >2.5 million members (25% of the population) and is a representative sample of the Israeli population. To evaluate vaccine effectiveness, this study included individuals from the MHS IBD registry aged ≥16 years who received the BNT162b2 mRNA COVID-19 vaccine and matched patients (1:3) who were vaccinated between December 19, 2020 and March 10, 2021. Individual matching was performed based on sex, birth year, coexisting comorbidities, and month of the first vaccination dose. IBD status was defined according to the MHS IBD registry based on physician diagnosis and dispensed medications.7Kariv R. et al.Harefuah. 2018; 157: 655-659Google Scholar The analysis excluded patients with a history of a positive polymerase chain reaction (PCR) result or a diagnosis of COVID-19 any time before the first BNT162b2 vaccination. All eligible patients were required to have a minimum of 30 days of follow-up after the second vaccine dose date, referred to as the “index date,” to observe study outcomes. Retrospective follow-up lasted from the index date until April 11, 2021 (details are provided in the Supplementary Text). The MHS Ethics Committee approved the study protocol. The study included 12,231 patients with IBD and 36,254 matched patients. Overall, 50.0% were women, and the mean age was 47 ± 17 years in both groups. Follow-up was a median of 71 days (interquartile range, 52–80 days), and the interval between vaccines was a median of 21 days (interquartile range, 20–21 days). Baseline characteristics and positive PCR result by disease type and treatment are presented in Supplementary Table 1. Breakthrough infection rates >7 days after the second dose were 0.19 % in patients with IBD and 0.15% in matched patients and after >14 days after the second dose were 0.14% and 0.10%, respectively. The calculated relative risk (RR) for IBD was 1.21 (95% confidence interval [CI], 0.74–1.97) >7 days after the second dose and 1.26 (95% CI, 0.71–2.23) >14 days after the second dose. The Mantel-Cox log-rank test from the Kaplan-Meier survival analysis (Figure 1A) was not statistically significant (P = .430). Of 23 patients with IBD who had a positive PCR result >7 days after the second dose, 9 had symptoms, 2 were hospitalized, and 1 died (details in Supplementary Table 2a). Compared with their matched patients, patients with Crohn’s disease (CD) were at a greater risk for breakthrough infection (P = .055), while no significant difference (P = .310) was shown among patients with ulcerative colitis (UC) (Figure 1B and C). The RR for CD and matched patients was 1.52 (95% CI, 0.69–3.28) >7 days after the second dose and 1.82 (95% CI, 0.69–4.79) >14 days after the second dose, whereas for UC and matched patients, the RR was 0.53 (95% CI, 0.18–1.58) >7 days after the second dose and 0.95 (95% CI, 0.28–3.81) >14 days after the second dose. In multivariable Cox proportional hazard models, patients with CD had an elevated risk for breakthrough infection compared with patients with UC >7 days and >14 days after the second dose, with hazard ratios of 3.56 (95% CI, 1.29–9.83) and 3.38 (95% CI, 1.07–10.64), respectively. No increased risk was demonstrated for patients treated with immune-modifying therapies (Supplementary Table 2a and b). In this study, we describe the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in patients with IBD. As demonstrated in the general population, the vaccine is highly efficient, with a very low absolute breakthrough infection rate (0.1%) for fully vaccinate patients. Our large cohort allowed us to explore the effect of immune-modifying treatments in patients with IBD on the risk for COVID-19 infection after vaccination. A publication by the IOIBD recommended that patients with IBD vaccinated against COVID-19 be counseled that vaccine efficacy may be decreased when receiving systemic corticosteroids.4Siegel C.A. et al.Gut. 2021; 70: 635-640Google Scholar Despite the wide use of immune-modifying medications, vaccine effectiveness in our study cohort was high. A recent publication by Wong et al8Wong SY, et al. Gastroenterology. Published online April 20, 2021, https://doi.org/10.1053/j.gastro.2021.04.025.Google Scholar demonstrated that a protective serologic response after mRNA vaccine administration developed in all patients with IBD in their cohort, where most patients were treated with immune-modifying treatments. Their findings support our results. A trend toward an increased risk for breakthrough infection compared with matched patients was observed among patients with CD but not among patients with UC. If validated by other and larger cohorts, these findings suggest that patients with CD may have an increased risk for breakthrough infection. In conclusion, to the best of our knowledge, this is the one of the first reports of real-world COVID-19 vaccine effectiveness in patients with IBD. Overall vaccine effectiveness was excellent and comparable to the reference population. The authors thank the following members of the Maccabi Institute for Research & Innovation COVID-19 Task Force: Tal Patalon, Lilac Tene, Shay Ben Moshe, Vered Rosenberg, Inbal Goldshtein, and Asaf Peretz. Amir Ben-Tov, MD (Conceptualization: Lead; Methodology: Equal; Writing – original draft: Lead). Tamar Banon, MSc (Formal Analysis: Lead; Methodology: Equal; Writing – original draft: Lead). Gabriel Chodick, PhD (Methodology: Equal; Writing – review & editing: Supporting). Revital Kariv, (Methodology: Equal; Writing – review & editing: Supporting). Amit Assa, MD (Conceptualization: Equal; Writing – review & editing: Supporting). Sivan Gazit, MD (Conceptualization: Lead; Methodology: Equal; Writing – review & editing: Lead). Patient characteristics such as age, sex, vaccine month, and incident COVID-19 infections are described in Supplementary Table S1. Study outcomes were measured by the first positive reverse-transcription polymerase chain reaction SARS-CoV-2 test result or incident diagnosis of COVID-19 (from community care or hospitalization) occurring >7 days and >14 days after the index date. Outcomes were evaluated with Kaplan-Meier curves and relative risk (RR) to analyze patients with inflammatory bowel disease and their matched patients and then evaluated separately for patients with Crohn’s disease and those with ulcerative colitis with their matched patients. In a secondary analysis, internal comparisons were made among patients with inflammatory bowel disease. Cox’s regression analyses were performed and evaluated positive polymerase chain reaction outcomes >7 days and >14 days after the second vaccine dose. Covariates in the models included age, sex, type of inflammatory bowel disease, and whether patients were on immunosuppressive treatment (binary variable) 3 months before the index date. Download .pdf (.12 MB) Help with pdf files Supplementary Table

Diet and Inflammatory Bowel Disease: What Quality Standards Should Be Applied in Clinical and Laboratory Studies?

Many patients suffering from inflammatory bowel disease (IBD) follow restrictive diets, as many respective recommendations circulate. Efforts are made to evaluate and summarize the published information, for example, in a recent consensus manuscript by the International Organization for the Study of IBD (IOIBD). However, the standards that should be applied to make claims about dietary effects are poorly defined. In this manuscript, the scientific basis of recommendations for nutritional interventions in IBD is analyzed. Epidemiological evidence on diet in IBD is always biased by numerous factors, and the number of robust dietary intervention studies is limited due to methodological difficulties. Therefore, animal models are used to test hypotheses with respect to dietary factors and intestinal inflammation. Naturally, animal models have limitations, and knowledge of key characteristics of colitis animal models is crucial to understand their advantages and disadvantages. In recent years the important role of the microbiota for IBD and dietary factors has been discovered. Microbiota data are added to many publications on IBD and nutrition. The quality of those data varies largely. Subsequently, quality standards for microbiota analyses also are discussed. Finally, quality requirements to be applied on recommendations for dietary changes in patients with IBD are suggested.

STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD

The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD. Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale. In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn's disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth. STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.

Selecting End Points for Disease-Modification Trials in Inflammatory Bowel Disease: the SPIRIT Consensus From the IOIBD

Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are chronic and disabling disorders. Prospective disease-modification trials to prevent disease progression are eagerly awaited. However, disease progression is not clearly defined. The objective of the Selecting End PoInts foR Disease-ModIfication Trials (SPIRIT) initiative was to achieve international expert consensus on the endpoints to be used in future IBD-disease modification trials. This initiative under the auspices of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) began with a systematic literature search to evaluate the current evidence on the definition of disease progression in IBD. On October 22, 2019, a consensus meeting took place during the United European Gastroenterology Week (UEGW) Congress in Barcelona, during which predefined proposed statements were discussed in a plenary session and voted on anonymously. Agreement was defined as at least 75% of participants voting for any one statement. The group agreed that the ultimate therapeutic goal in both CD and UC is to prevent disease impact on patient's life (health-related quality of life, disability, fecal incontinence), midterm complications (encompass bowel damage in CD, IBD-related surgery and hospitalizations, disease extension in UC, extraintestinal manifestations, permanent stoma, short bowel syndrome), and long-term complications (gastrointestinal and extraintestinal dysplasia or cancer, mortality). Recommendations on which goals to achieve in disease-modification trials for preventing disease progression in patients with IBD are proposed by the SPIRIT consensus. However, these recommendations will require validation in actual clinical studies before implementation in disease-modification trials.

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Discovery and development of new drugs for the treatment of inflammatory bowel disease (IBD) has intensified significantly within the past decade. However, numerous hurdles affect the pace and efficiency with which new drugs are developed. On March 20, 2019 the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) held a meeting entitled “Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design” in Miami, Florida. In addition to IOIBD members and IBD specialists, representatives from both industry and regulatory agencies were invited to speak and provide expert opinions and perspectives on the current landscape, factors influencing the evolution of IBD clinical trial design and endpoints, and potential novel approaches that may advance the field. The goal of this article is to provide a top-line summary of both materials presented by the invited speakers and the discussion that ensued after each of their talks. This article is not intended as a systematic or exhaustive review of the literature and should not be considered a guideline for clinical trials or practice. Rather, it should be viewed with the intent to provoke thought, stimulate research, and provide an impetus for continued discussion on more efficient and novel approaches to IBD clinical trial design. Select slides (developed by the speakers) presented during the meeting are included as supporting material. These slides are presented with minimal modification, except where additional context was required when viewed independently from the speaker’s original presentation. The meeting opened with an overview of some of the existing challenges and gaps associated with clinical trial design and drug development. Current rates of patient recruitment for participation in IBD clinical trials are low. This observation reflects both “competition” for patients that has occurred as a result of the myriad of clinical trials of potential new therapies as well as a reluctance to expose patients to placebo treatment considering the availability of multiple approved therapies. This situation is particularly problematic for enrollment of phase Ia and IIb proof-of-concept studies. Long timelines, invasive procedures, and changing regulatory recommendations have led to increased burdens for patients, investigators, and industry sponsors. Furthermore, contemporary clinical trial populations frequently include refractory patients who may have failed multiple medical therapies or who present late in their disease course. This observation is particularly relevant when considering Crohn’s disease (CD) trials, where patients may additionally enter studies with established bowel damage. These factors may affect trial outcomes in terms of both drug safety and efficacy. The proclivity toward enrollment of these patients is accompanied by a dearth of trials for rarely studied patient populations, such as those with early disease, external fistulas, strictures, stomas, postoperative disease, acute severe ulcerative colitis (UC), isolated proctitis, (solely) upper gastrointestinal disease, a history of (cured) cancer, and pouchitis. Historically, the lack of validated indices for measuring disease activity has contributed to the problem of studying these specific populations. Current approaches to measurement of disease activity, the most pressing limitations and pitfalls associated with these methods, and evolving approaches and regulatory recommendations for assessment of disease activity and its impact on patients (as discussed at the meeting) are summarized below. A number of modalities are available for objective measurement of disease activity (endoscopy, histopathology, imaging, biomarkers), some of which are particularly well suited to the disease process and have roles in patient management (eg, magnetic resonance imaging for CD). The goals of therapy, however, must also include improvements in disease characteristics important to patients—those that improve their function and well-being. This fundamental concept is reflected in regulatory guidance that recommends the inclusion of both objective measures of disease activity (currently endoscopy) and patient-reported outcomes (PROs) in registration trials of potential therapies for UC.1US Department of Health and Human Services Center for Drug Evaluation and ResearchUlcerative colitis: Clinical trial endpoints guidance for Industry. Food and Drug Administration, Silver Spring, MD2016Google Scholar,2European Medicines AgencyGuideline on the development of new medicinal products for the treatment of ulcerative colitis. CHMP/EWP/18463/2006 Rev 1.https://www.ema.europa.eu/en/development-new-medicinal-products-treatment-ulcerative-colitisDate accessed: November 1, 2019Google Scholar The US Food and Drug Administration (FDA) defines a PRO as “any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else.”3Food and Drug AdministrationGuidance for Industry. Patient-reported outcome measures: Use in medical product development to support labeling claims.https://www.fda.gov/media/77832/downloadDate accessed: November 23, 2020Google Scholar However, the current absence of well-defined, reliable, IBD-specific PROs and/or clinical outcome assessments that reflect the inflammatory burden of IBD and that also meet regulatory standards has led to challenges for design of pivotal trials. Interim solutions (eg, PRO2)4Khanna R. Zou G. D'Haens G. et al.A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity.Aliment Pharmacol Ther. 2015; 41: 77-86Crossref PubMed Scopus (99) Google Scholar have been developed that integrate patient-reported items (abdominal pain, stool frequency, rectal bleeding) present in the composite Crohn’s Disease Activity Index (CDAI)5Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's Disease Activity Index. National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2938) Google Scholar for CD and the Mayo Clinic Score6Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Scopus (1976) Google Scholar for UC. Although outcomes based on the CDAI have historically been used as the basis for drug approval, the CDAI has also faced criticism for its subjective nature and lack of correlation with more objective measures of disease activity. High placebo response rates when used as the sole criterion for patient selection and the inability to capture disease activity in certain patient subgroups (eg, fistulizing CD) are additional factors that initially led to regulatory recommendations to exclude the use of the CDAI in contemporary registration trials. Although the CDAI is currently considered an acceptable outcome measure for clinical trials, the FDA has consistently recommended the inclusion of endoscopic evaluation as a co-primary endpoint to ensure that a clinical improvement is accompanied by a benefit in the underlying disease process. Although some regulatory guidance exists for trial endpoints and definitions,1US Department of Health and Human Services Center for Drug Evaluation and ResearchUlcerative colitis: Clinical trial endpoints guidance for Industry. Food and Drug Administration, Silver Spring, MD2016Google Scholar there are some differences (Supplementary Table 1) between the FDA and the European Medicines Agency guidance for UC.7Reinisch W. Gottlieb K. Colombel J.F. et al.Comparison of the EMA and FDA guidelines on ulcerative colitis drug development.Clin Gastroenterol Hepatol. 2019; 17: 1673-1679Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Guidance for CD from the FDA is lacking. Furthermore, many questions remain regarding specific instruments and their validity, specificity, sensitivity, and clinical relevance. The implications for the use of combined outcomes in IBD clinical trials are also unclear. For example, (1) the appropriate ranges and scores for enrollment and endpoint assessment, (2) the effect of new endpoints on placebo responses and effect sizes and consequently on trial sample size and power, (3) the interaction between PROs and endoscopy when used as co-primary or composite scores (population- vs patient-level analyses), and (4) the generalizability of trial outcomes to the real world are as yet unknown. Importantly, these questions will need to be revisited once validated PROs (currently in development) are available and acceptable to regulatory agencies. Endoscopy has been the gold standard for objective assessment of UC disease activity in clinical trials since Truelove reported on the efficacy of cortisone in 1956.8Truelove S.C. Treatment of ulcerative colitis with local hydrocortisone.Br Med J. 1956; 2: 1267-1272Crossref PubMed Scopus (39) Google Scholar Numerous indices for measuring endoscopic disease activity in UC have since been developed9Samaan M.A. Mosli M.H. Sandborn W.J. et al.A systematic review of the measurement of endoscopic healing in ulcerative colitis clinical trials: recommendations and implications for future research.Inflamm Bowel Dis. 2014; 20: 1465-1471Crossref PubMed Scopus (52) Google Scholar; however, the endoscopic component of the composite Mayo Clinic Score is used most commonly in clinical trials. There is some evidence that the Mayo endoscopic subscore (MES) is a reliable measure,10Feagan B.G. Sandborn W.J. D'Haens G. et al.The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis.Gastroenterology. 2013; 145: 149-157Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar although knowledge regarding the responsiveness or sensitivity of the MES to change with effective therapy is currently limited. Definitions for endpoints incorporating the MES are also changing (Supplementary Table 2), such that the FDA currently recommends that a MES equal to 1 should not include friability. Mucosal healing, which was previously assessed as a MES ≤ 1 (an outcome associated with high placebo response rates), is also evolving. Additional endpoints of interest include combined assessments of both endoscopic and histopathologic outcomes. Histopathologic disease activity persists in many patients despite a normal-appearing mucosa.11Riley S.A. Mani V. Goodman M.J. et al.Microscopic activity in ulcerative colitis: what does it mean?.Gut. 1991; 32: 174-178Crossref PubMed Scopus (414) Google Scholar The inclusion of histopathologic outcomes and evidence for the discordance between histopathologic and endoscopic appearance in UC can be found in studies dating back to the 1950s, and the association between persistent histopathologic disease activity and risk of disease relapse was first demonstrated over 50 years ago. Indeed, multiple lines of evidence support an association between improved outcomes in UC and histopathologic remission (ie, symptomatic remission and reduced risks for relapse, surgery/hospitalization, and development of colorectal cancer).12Peyrin-Biroulet L. Bressenot A. Kampman W. Histologic remission: the ultimate therapeutic goal in ulcerative colitis?.Clin Gastroenterol Hepatol. 2014; 12: 929-934Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar Although guidelines support the value of histopathology as a sensitive measure of inflammation, they do not currently support treating patients to this target because of a lack of data demonstrating clinical utility.13Peyrin-Biroulet L. Sandborn W. Sands B.E. et al.Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target.Am J Gastroenterol. 2015; 110: 1324-1338Crossref PubMed Scopus (1065) Google Scholar Histopathologic outcomes are nevertheless being included in contemporary clinical trials to assess the anti-inflammatory properties of potential therapies. Numerous indices have also been developed to measure histopathologic disease activity14Mosli M.H. Parker C.E. Nelson S.A. et al.Histologic scoring indices for evaluation of disease activity in ulcerative colitis.Cochrane Database Syst Rev. 2017; 5: CD011256PubMed Google Scholar and have been used in clinical trials (including the commonly used Geboes score,15Geboes K. Riddell R. Ost A. et al.A reproducible grading scale for histological assessment of inflammation in ulcerative colitis.Gut. 2000; 47: 404-409Crossref PubMed Scopus (578) Google Scholar Nancy Histological Index,16Marchal-Bressenot A. Salleron J. Boulagnon-Rombi C. et al.Development and validation of the Nancy histological index for UC.Gut. 2017; 66: 43-49Crossref PubMed Scopus (194) Google Scholar and the Robarts Histopathology Index17Mosli M.H. Feagan B.G. Zou G. et al.Development and validation of a histological index for UC.Gut. 2017; 66: 50-58Crossref PubMed Scopus (166) Google Scholar). Several indices were shown to be reliable and similarly responsive to change.18Jairath V. Peyrin-Biroulet L. Zou G. et al.Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial.Gut. 2019; 68: 1162-1168Crossref PubMed Scopus (32) Google Scholar Although histopathologic appearance is clearly an important determinant of disease behavior, critical questions remain regarding the use of this disease measure in clinical trials, including whether there are surrogate markers for histopathologic healing that would reduce the need for invasive procedures, the predictive value of histopathology, optimal disease cutoffs for available validated indices, and most appropriate contexts for use of the Geboes score, Nancy Histological Index, and Robarts Histopathology Index. Further study is also needed to determine the stability and reliability of a specific index in the same segment. Although central reading of histopathology slides has also been implemented in contemporary clinical trials to improve the reliability of assessment, there are multiple practical issues that require consideration before reading including biopsy location (prespecified, most severe, multiple segments), size, number and method for processing (both of which may vary according to planned assessments; ie, immunohistochemistry, RNA), and orientation and quality of section. Finally, central reader training and familiarity with the endoscopic and histopathologic indices used in clinical trials are critical to reduce variability and increase trial efficiency. As alluded to earlier, the path forward for assessment of CD activity is less well-defined and is complicated by the heterogeneous nature of the disease. Signs and symptoms may also vary based on disease location (ie, abdominal pain predominates in ileal disease, whereas increased stool frequency is more likely observed in patients with colonic disease), and endoscopic outcomes are currently favored in CD clinical trials. The move away from using solely nonspecific sign and symptom-based measures such as the CDAI toward the inclusion of more objective disease activity measures (ie, endoscopy, magnetic resonance imaging, biomarker) has been motivated by the deficiencies described above and, importantly, high placebo response rates, which are a particularly confounding factor for clinical trial design that results in reduced sensitivity to detect true differences between active drug and placebo, and the need for increased sample sizes to demonstrate treatment effects. High placebo response rates may also occur as a result of the inherent subjectivity of assessment of endoscopic appearance. In clinical trials, this variability is mitigated by blinded central reading of endoscopy videos,10Feagan B.G. Sandborn W.J. D'Haens G. et al.The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis.Gastroenterology. 2013; 145: 149-157Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar a process that is recommended by both the FDA and European Medicines Agency when image interpretation is a critical component of trial eligibility or safety or efficacy endpoints. Both agencies also recommend adjudication for scoring discrepancies, although the most appropriate methodology for this process is a matter of debate,19Gottlieb K. Hussain F. Voting for image scoring and assessment (VISA)—theory and application of a 2 + 1 reader algorithm to improve accuracy of imaging endpoints in clinical trials.BMC Med Imaging. 2015; 15: 6Crossref PubMed Scopus (17) Google Scholar,20Reinisch W. Mishkin D.S. Oh Y.S. et al.Analysis of various central endoscopy reading methodologies in the BERGAMOT exploratory induction cohort evaluating etrolizumab in Crohn’s disease.J Crohns Colitis. 2018; 12: S161Crossref Google Scholar and empirical evidence is needed to support various approaches and reading paradigms. The most commonly used indices for endoscopic assessment of CD are the Crohn’s Disease Endoscopic Index of Severity (CDEIS)21Mary J.Y. Modigliani R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).Gut. 1989; 30: 983-989Crossref PubMed Scopus (318) Google Scholar and the Simple Endoscopic Score for Crohn’s Disease (SES-CD).22Daperno M. D'Haens G. Van Assche G. et al.Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD.Gastrointest Endosc. 2004; 60: 505-512Abstract Full Text Full Text PDF PubMed Scopus (975) Google Scholar The CDEIS and the SES-CD are similarly reliable and responsive instruments,23Khanna R. Zou G. D'Haens G. et al.Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease.Gut. 2016; 65: 1119-1125Crossref PubMed Scopus (52) Google Scholar,24Khanna R. Zou G. Stitt L. et al.Responsiveness of endoscopic indices of disease activity for Crohn's disease.Am J Gastroenterol. 2017; 112: 1584-1592Crossref PubMed Scopus (28) Google Scholar and both instruments are poorly correlated with symptoms. The SES-CD is currently favored over the CDEIS in clinical trials primarily because of ease of use, although variability in the assessment of lesions between segments/anastomosis, anal lesions, superficial ulcers, and stenosis can be problematic (Supplementary Figure 1). Standardized scoring conventions (Supplementary Table 3) have been proposed that improve the reliability of the SES-CD25Dubcenco E. Zou G. Stitt L. et al.Effect of standardised scoring conventions on inter-rater reliability in the endoscopic evaluation of Crohn's disease.J Crohns Colitis. 2016; 10: 1006-1014Crossref PubMed Scopus (19) Google Scholar and should be adopted and implemented across clinical development programs. Historically, considerable variability has existed for the SES-CD and the CDEIS in terms of cutoffs used for defining disease activity both for trial eligibility and outcome assessment. The current regulatory recommendation for trial eligibility is an SES-CD score ≥ 6 (or ≥4 isolated ileal disease) to define baseline endoscopic disease severity. The recommended endpoint definitions for endoscopic remission is defined by an SES-CD score of 0 to 2, and endoscopic response is defined by a 50% reduction in the SES-CD score from baseline. Additional empirical data are needed to understand the operating properties of these indices when used as either dichotomous or continuous measures. Magnetic resonance imaging plays a critical role in both diagnosis and management of CD and is the only modality capable of detecting and monitoring all manifestations of disease activity as well as transmural complications (eg, perianal fistula, fibrosis). The 2 potential contexts for the use of magnetic resonance imaging in clinical trials are patient selection26Coimbra A.J. Rimola J. O'Byrne S. et al.Magnetic resonance enterography is feasible and reliable in multicenter clinical trials in patients with Crohn's disease, and may help select subjects with active inflammation.Aliment Pharmacol Ther. 2016; 43: 61-72Crossref PubMed Scopus (51) Google Scholar (confirmation of eligibility based on disease activity and exclusion for complications) and as a pharmacodynamic outcome measure.27Samaan M.A. Puylaert C.A.J. Levesque B.G. et al.The development of a magnetic resonance imaging index for fistulising Crohn's disease.Aliment Pharmacol Ther. 2017; 46: 516-528Crossref PubMed Scopus (35) Google Scholar Magnetic resonance imaging could potentially reduce the rate at which patients are excluded from clinical trials for failure to meet disease activity criteria because of its ability to identify disease in all segments; ileocolonoscopy may fail to identify up to 54% of active small bowel or upper gut CD.28Samuel S. Bruining D.H. Loftus Jr., E.V. et al.Endoscopic skipping of the distal terminal ileum in Crohn's disease can lead to negative results from ileocolonoscopy.Clin Gastroenterol Hepatol. 2012; 10: 1253-1259Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar,29Leighton J.A. Gralnek I.M. Cohen S.A. et al.Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn's disease.Clin Gastroenterol Hepatol. 2014; 12: 609-615Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar The Magnetic Resonance Index of Activity30Rimola J. Rodriguez S. Garcia-Bosch O. et al.Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn's disease.Gut. 2009; 58: 1113-1120Crossref PubMed Scopus (497) Google Scholar (MaRIA) score is evolving as a phamacodynamic outcome measure in clinical trials. The MaRIA score measures 4 disease components: wall thickening, hyperenhancement, edema, and presence of ulcers. For clinical use, active disease is determined by the presence of thickening and enhancement (segmental MaRIA score > 7), whereas severe disease is assessed as the presence of edema and ulcers (MaRIA score ≥ 11 at the segment level). The MaRIA score is well correlated to the CDEIS,30Rimola J. Rodriguez S. Garcia-Bosch O. et al.Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn's disease.Gut. 2009; 58: 1113-1120Crossref PubMed Scopus (497) Google Scholar,31Rimola J. Ordas I. Rodriguez S. et al.Magnetic resonance imaging for evaluation of Crohn's disease: validation of parameters of severity and quantitative index of activity.Inflamm Bowel Dis. 2011; 17: 1759-1768Crossref PubMed Scopus (358) Google Scholar has substantial inter-rater reliability,32Jairath V. Ordas I. Zou G. et al.Reliability of measuring ileo-colonic disease activity in crohn's disease by magnetic resonance enterography.Inflamm Bowel Dis. 2018; 24: 440-449Crossref PubMed Scopus (33) Google Scholar and is responsive to changes in endoscopic disease activity.33Ordas I. Rimola J. Rodriguez S. et al.Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn's disease.Gastroenterology. 2014; 146: 374-382Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar A simplified version of the MaRIA score, based on thickening, edema, fat stranding, and ulcers, that does not require the use of contrast has also been developed and shown to accurately detect changes in endoscopic disease activity in response to therapeutic intervention (Supplementary Figure 2).34Ordas I. Rimola J. Alfaro I. et al.Development and validation of a simplified magnetic resonance index of activity for Crohn's disease.Gastroenterology. 2019; 157: 432-439Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Streamlined and validated endpoints are critical to the success of contemporary clinical trial design. However, the IOIBD meeting also highlighted the need for development and implementation of novel methods and designs for future clinical trials to improve the efficiency of drug development and address some of the current critical challenges. A general summary of potential novel approaches discussed at the meeting (without specific prioritization) follows. Surrogate biomarkers, for example, may eventually replace the need for invasive procedures currently required for endpoint evaluation. Predictive biomarkers may both enhance the power of studies (Supplementary Figure 3) and address current recruitment challenges by enrolling and stratifying patients based on risk of disease progression and/or likelihood for response, which may eventually involve the inclusion of patients based on genetic, genomic, proteome, or microbiome signatures. Further opportunities also exist to define and shape regulatory policy in this latter area, where the rapidly expanding knowledge of microbiome science and its role in the fundamental processes of human health and disease is leading to the development of novel microbiome-based therapies (Supplementary Figure 4). There is consistent evidence for microbiome dysbiosis in IBD (eg, reduced microbiome diversity, compositional instability, expansion of potential pathobiomes),35Imhann F. Vich Vila A. Bonder M.J. et al.Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease.Gut. 2018; 67: 108-119Crossref PubMed Scopus (356) Google Scholar and modulation of the microbiome represents a promising area for the treatment of IBD. Many questions remain, however, for drug development and regulatory bodies including (but not limited to) those relating to a more exact definition of dysbiosis, appropriate therapeutic targets (eg, those that are deficient vs those that are pathogenic), the goal(s) of therapy, and monitoring of microbiome restoration and/or efficacy of treatment. Innovative methods for data collection and sharing were also highlighted as having the potential to help drive research and drug development. Continuous data collection with prediction analysis could be beneficial to clinical management of IBD to minimize periods of disease progression (eg, before the onset of overt signs and symptoms) and to better predict disease relapse as well as for clinical trials to avoid the challenges associated with retrospective recall of subjective disease characteristics. The use of wearable sensors (eg, Fitbit) to continuously capture patient data (eg, sleep, physical activity, heart rate) that might reliably detect IBD relapse before the onset of symptoms is 1 example where currently available and widely adopted technology could be used to improve clinical trial data collection and disease management. Technologic advances in general have allowed for the collection of vast amounts of data from the general population that could potentially be shared and used for healthcare coaching, for trial recruitment, to inform epidemiologic studies, and for postmarketing analyses of drug safety and efficacy (Supplementary Figure 5). Sharing of data across clinical trials and standardized (boilerplate) informed consent would additionally advance the field and enable efficient trial design by allowing the use of trial data for multiple research initiatives, including assessment of the operating characteristics of evaluative instruments and a more accurate estimate of placebo response rates. Finally, innovation in trial design beyond the traditional placebo-controlled induction and maintenance paradigms currently used (particularly for proof-of-concept studies, which suffer from extended timelines) and advances in regulatory harmonization were also identified during the meeting as future goals necessary for the advancement of IBD research. Innovative trial design concepts discussed were the use of active comparators, shorter maintenance studies, greater use of adaptive designs (eg, those that allow for prospectively planned modifications to 1 or more aspects of the design based on data that accumulates during the trial), integrated (seamless) phase II and III trials, Bayesian approaches (eg, those that consider information from prior studies and new trial results as part of a continual data stream, in which inferences are being updated each time new data become available), and platform studies, the latter of which may allow the assessment of multiple interventions (potentially from multiple sponsors) in a single trial, guided by a master protocol, and intervention-specific indices.36Woodcock J. LaVange L.M. Master protocols to study multiple therapies, multiple diseases, or both.N Engl J Med. 2017; 377: 62-70Crossref PubMed Scopus (433) Google Scholar Although operationally complex, the advantages of such an approach have been demonstrated in the I-SPY2 breast cancer study,37Quantum Leap Healthcare CollaborativeThe I-SPY 2 trial.https://www.ispytrials.org/i-spy-platform/i-spy2Date accessed: November 1, 2020Google Scholar where timeframes for proof-of-concept studies were reduced from 40 to 18 months. These concepts and the perspective gained from the significant advances of the past decade will help shape the future of clinical research and drug development. A summary of potential opportunities for a path forward in IBD research is shown in Supplementary Table 4. The IOIBD Defining Endpoints and Biomarkers in Inflammatory Bowel Disease Writing Group represents expert speakers and panelists who participated in the meeting and who also served as authors in the development of the Meeting Summary. Members are as follows: Fabio Cataldi, AbbVie Inc; Geert D'Haens, Amsterdam UMC/AMC; Brian G. Feagan, University of Western Ontario, Robarts Clinical Trials, Inc; Stephen Hanauer, Northwestern University; Vipul Jairath, University of Western Ontario, Robarts Clinical Trials, Inc; Peter Lakatos, McGill University Health Center; Christopher Leptak, US Food and Drug Administration; Dermot McGovern, Cedars-Sinai Medical Center; Andrew Mulberg, Amicus Therapeutics, Inc; Julian Panes, Hospital Clinic Barcelona, IDIBAPS, CIBERehd; Asit Parikh, Takeda Pharmaceuticals; Laurent Peyrin-Biroulet, CHU de Nancy; Walter Reinisch, Medical University of Vienna; Robert Riddell, Mount Sinai Hospital; David Rubin, University of Chicago; Bruce Sands, Icahn School of Medicine at Mount Sinai; Johannes Spleiss, Tillotts Pharma AG; Richard Strauss, Janssen Research Development; Swati Tole, Genentech Inc; Juli Tomaino, US Food and Drug Administration. Maria T. Abreu and William J. Sandborn drafted the manuscript, and all authors critically reviewed, contributed important intellectual content, and approved the final draft for submission. Supplementary Table 1Concordance of FDA and EMA GuidelinesPoint of Agreement Between the EMA and FDAPoint of Divergence Between the FDA and EMAPoint Addressed Only by the FDAPoint Addressed Only by the EMAFDAEMAPrimary endpointAssessment of disease activity by modified version of the Mayo Score/Ulcerative Colitis Disease Activity IndexRejection of Physician’s Global Assessment for primary endpointClinical remission based on stool frequency, rectal bleeding, and endoscopy scores (composite endpoint)Significant effect on symptoms and mucosal healing is required (co-primary endpoints)Composite endpoint possibleRecommends standardizing the Mayo ScoreAdvocates corticosteroid-free induction endpointRecommends validation of patient-reported outcome instruments for use as a primary outcome parameter to gauge symptomatic reliefEndoscopyCentral reading of endoscopyHistologyHistologic confirmation of diseaseHistologic grading scales and scoring techniques should be discussed with the agencyStudy designNeeds to reflect clinical treatment goals, moderated by the capabilities of the drug, and the particular needs of the patient populationProvides detailed advice for study design based on the induction-maintenance paradigmOthersNeed for pharmacokinetic and pediatric studiesAcute severe colitis, extraintestinal manifestations, and pouchitis are coveredUse of the Montreal classification is advocatedCorticosteroid-free dependency is defined according to European Crohn’s and Colitis Organization guidelinesNOTE. EMA, European Medicines Agency.Adapted from Reinsich et al. Comparison of the EMA and FDA guidelines on ulcerative colitis drug development. Clin Gastroenterol Hepatol 2019;17:1673–1679. Open table in a new tab Supplementary Table 2Endoscopic Endpoints in UCEndpointDefinitionClinical remissionComposite term that includes both symptomatic remission AND endoscopic improvement (Mayo endoscopic subscore of 0 or 1)Endoscopic improvementMES equal to 0 or 1 (when starting at a score of 2 or 3)Endoscopic remissionMES equal to 0Mucosal healingHistorically defined as a MES equal to 0, NOW defined as a composite term of endoscopic improvement and histologic remission Open table in a new tab Supplementary Table 3Standardized Scoring Conventions for SES-CD Assessments Associated With Poor ReliabilityArea of Poor ReliabilityScoring ConventionImpassable stricture with a view to the next segmentScoring ulceration or affected surface beyond an impassable stricture is not performed unless the bowel mucosa is properly visualizedImpassable strictureIf screening endoscopy for trial eligibility requires dilation is to be completed, the patient should not be considered eligible. If not for screening, after balloon dilation of the stenosis upstream, segments may be scored provided that a sufficient proportion of the mucosa is observed (ie, enough to reliably score “ulcerated” or “affected” surface).Contiguous ulceration involving 2 segmentsContiguous ulceration at the junction of 2 colonic segments, with minimal extension into either segment, is scored once on the side that appears most affected. If contiguous ulceration extends clearly over a long distance over the 2 segments, then ulceration can be scored for 2 segments.Ulceration at the ileocecal valve or ileocolic anastomosisUlceration at the ileocecal valve or ileocolic junction (regardless of whether there is suspicion that these are ischemic) is scored in the ileal segment. Ulceration on the colonic surface of the ileocecal valve but not in the ileum itself is scored as right colon.Aphthoid ulcerationAphthous ulceration is scored as superficial ulceration and contributes to the estimate of the ulcerated surface area.Anal canal ulcers and stricturesAnal canal ulcers and strictures as well as other anal lesions are included in the score and scored as part of the rectum.Stenosis between 2 segments or ileocecal valve or ileocolic anastomosisStenosis is scored only once in the distal segment when it is located at the junction between 2 segments, including anal stenosis that is scored at the rectum. Stenosis of the ileocecal valve or ileocolic junction is scored as ileal. Open table in a new tab Supplementary Table 4Opportunities for a Path Forward in IBD Research•Streamlined, validated endpoints•Aligning and incorporating clinical research with clinical practice to bridge research and health care•Development of novel methods of endpoint collection (wearable devices and digital medicine)•Development of predictive biomarkers to enhance study power•Validation of inflammatory biomarkers as surrogate endpoints•Microbiome-based and other novel therapeutics•Sharing of data across sponsors•Innovative study and program design○Active comparator studies○Shorter maintenance studies○Adaptive study designs○Seamless phase II→III studies○Bayesian studies○Platform studies•Regulatory harmonization, innovation, and reform Open table in a new tab Supplementary Figure 2Correlation between (A) changes in the simplified MaRIA score and changes in endoscopic disease activity and (B) accuracy of the simplified MaRIA score to predict changes in endoscopic disease activity in response to treatment. Data are based on 37 patients with active CD who underwent magnetic resonance imaging and endoscopy at baseline and after 12 weeks of treatment with corticosteroids (n = 12) or tumor necrosis factor inhibitors (n = 25). Adapted from Ordas I, Rimola J, Alfaro I, et al. Development and validation of a simplified magnetic resonance index of activity for Crohn's disease. Gastroenterology 2019;157:432–439. AUC, area under the curve.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 3Theoretical benefit of patient stratification to improve clinical trial efficiency. The ability to stratify and accurately predict the proportion of patients who will respond to therapy based on a particular biomarker- or gene-based signature (ie, based on the biology of the patient’s underlying disease) will reduce the number needed to treat and improve the efficiency of clinical trials. Sequential stratification of patients based on biologic signatures may eventually reduce populations to levels consistent with orphan disease status. CR, clinical response; NNT, number needed to treat; SNP, single nucleotide polymorphism.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 4Microbiome-based therapeutic approaches. A wide range of microbiome-based approaches (above and below line) are being considered to transform the treatment of IBD.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 5Potential utility of shared data sources. Vast amounts of patient- and population-level data exist in multiple sources that could be used for a multitude of purposes, including trial recruitment and postmarketing analyses of drug safety and efficacy.View Large Image Figure ViewerDownload Hi-res image Download (PPT) NOTE. EMA, European Medicines Agency. Adapted from Reinsich et al. Comparison of the EMA and FDA guidelines on ulcerative colitis drug development. Clin Gastroenterol Hepatol 2019;17:1673–1679.

2019 Harry Shwachman Award

The Shwachman Award is presented annually by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) to an individual who has made major, lifelong scientific or educational contributions to the field of pediatric gastroenterology, hepatology, or nutrition in North America. The 2019 Shwachman Award recipient is Anne Marie Griffiths, MD, FRCPC, Professor, in the Department of Paediatrics at the University of Toronto and former Chief and Fellowship Training Program Director in the Division of Gastroenterology, Hepatology and Nutristion at the Hospital for Sick Children (SickKids) in Toronto. Dr Griffiths is also co-lead for the SickKids IBD Centre, and holds the Northbridge Chair in Pediatric IBD. Anne is a shining star as a scientist, clinician, educator, and mentor in the field of pediatric inflammatory bowel diseases (IBD), and a guiding star to her many trainees and mentees. Anne was born in Montreal, Québec and moved to Toronto, Ontario as a child. She remembers Montreal fondly, citing Dr Wilder Penfield, a neuroscientist and surgeon (and namesake for Penfield Avenue, which runs through McGill University's downtown campus) as one of her favorite scientists. She gained her sense of scholarship, leadership, and commitment from her parents, themselves spiritual leaders in their community. Anne completed undergraduate and medical studies at the University of Toronto, and her residency in pediatrics and pediatric gastroenterology training at SickKids. A lifelong learner, she returned to University of Toronto while junior faculty to complete graduate training in Clinical Epidemiology to ensure that her ongoing clinical research remained of the highest standards. At SickKids, Anne built her legacy—impactful scientific research, the empathetic care of children, and mentorship of a generation of pediatric gastroenterologists who have themselves become international leaders in the field. Anne states that she was influenced later in her medical career to pursue scientific research by her colleagues and mentors at SickKids. In particular, Peter Durie and Phil Sherman (both former Shwachman recipients) played a profound role in her growth as a scientist through inspiration and career facilitation. This inspiration has resulted in more than 300 peer-reviewed publications to date. Observations in the SickKids IBD clinic of the familiality of Crohn disease and ulcerative colitis in young patients prompted her with Innovation funding from the SickKids Foundation to begin collecting DNA from multiplex families, when the study of genetic susceptibility in complex disorders was just beginning. Becoming a leader in the genetics of pediatric IBD, Anne went on to collaborate and co-author multiple publications with the North American and International IBD Genetics consortia. More recently, her knowledge about the genetics of IBD and foresight in banking DNA from affected children and their parents has contributed to the discovery of multiple monogenic forms of Very Early Onset IBD. In addition, Anne developed multiple measurement tools, which have become essential to clinical trials in pediatric IBD, including the Pediatric Crohn's Disease Activity Index (with Jeffrey Hyams), the Pediatric Ulcerative Colitis Activity Index (with Dan Turner), and the IMPACT questionnaire for quality of life (with Anthony Otley). More recently, her leadership skills and scientific acumen were recognized by being nominated as the Principal Investigator of the Canadian Children IBD Network: A Joint Partnership of CIHR and the CH.I.L.D. Foundation. Her quietly effective leadership and strong sense for the needs of the IBD community continue to be recognized both nationally and internationally. Anne's impact is felt most strongly by her mentees. She has directly trained or mentored a large cadre of gastroenterologists and scientists who currently hold leadership positions in more than 20 countries around the world. In addition, her leadership in making SickKids an IBD clinical and research center of excellence and her work as Fellowship Director and Division Head allowed Anne to attract trainees to SickKids who are now international leaders in IBD, liver disease, nutrition, pancreatic illnesses, and other specialties. Anne has always had the uncanny ability to “skate where the puck is going, not where it has been” (a quote from Wayne Gretzky's father, Walter Gretzky) when it comes to IBD research. However, she only occasionally skated there by herself, instead choosing to point her trainees in the direction of the most important IBD research questions and allowing them to build their own careers with their guidance. Anne has raised her 4 lovely and successful children, Gerald, Joanna, Malcolm, and Christopher, together with her lifelong partner Jonathan. The children have careers in law, business, and medicine. In addition to her ongoing professional career, Anne cherishes time with her 3 young grandchildren, as well as experiencing other cultures through international travels with Jonathan and her family. The honor of the Shwachman Award comes after Anne received numerous international awards for her contribution to gastroenterology in recent years. These include: induction into the International Organization for the Study of IBD (IOIBD) (2015), The Dr. August von Hauner Medal from the University of Munich (2017), the Physician Research Award for Career Excellence from SickKids (2018), the R.D. McKenna Memorial Lecturer Award from the Canadian Association of Gastroenterology (2019), and the American Association of Gastroenterology Institute Research Mentor Award (2019). The latter was particularly memorable because it was awarded through nomination by many of her current and former trainees. The NASPGHAN Shwachman Award encapsulates a lifetime of contributions Dr Griffiths has made to the fields of clinical care and research in pediatric IBD, and her work to expand pediatric gastroenterology overall through training and mentorship of the next generation of leaders in our field. Congratulations Anne!

Guideline for Nutrition and Diet in Inflammatory Bowel Disease

Sponsoring Organization: The International Organization for the Study of Inflammatory Bowel Disease (IOIBD)Background and ObjectiveWhich foods to eat

Association Between Inflammatory Bowel Disease and Pruritus.

Inflammatory bowel disease (IBD) is often complicated by extraintestinal manifestations. We frequently encounter IBD patients with pruritus; however, clinical evidence for the association of these conditions is lacking. Therefore, the present study investigated the incidence of pruritus in IBD patients. Seventy-one IBD outpatients, including 55 with ulcerative colitis (UC) and 16 with Crohn disease, and 39 healthy volunteers (HVs) were surveyed about their pruritus symptoms using a visual analogue scale (VAS). Disease activities in UC and Crohn disease patients were classified according to partial Mayo and IOIBD (International Organization for the Study of inflammatory Bowel Disease) scores, respectively. Skin barrier condition was examined by measuring transepidermal water loss and stratum corneum hydration. The distribution of intraepidermal nerve fibers in skin samples from 9 UC patients was examined immunohistochemically using an antiprotein gene product (PGP) 9.5 antibody. Visual analogue scale scores were higher in IBD patients than in HV (P < 0.001). Active stage IBD patients had more severe pruritus VAS scores than those in the remission stage (P = 0.036). Transepidermal water loss was higher in IBD patients (P < 0.001) and active stage IBD patients (P = 0.004), while stratum corneum hydration was lower in IBD patients (P = 0.019) and active stage IBD patients than in HV (P = 0.019). A relationship was observed between the degree of pruritus and number of PGP9.5-immunoreactive intraepidermal nerve fibers in UC patients. Inflammatory bowel disease patients, particularly active stage patients, frequently exhibit symptoms of pruritus and dry skin. This result may have predictive and therapeutic implications for the treatment of IBD symptoms.

Editorial introductions

Current Opinion in Gastroenterology was launched in 1985. It is one of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of gastroenterology is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Maria T. AbreuMaria T. AbreuDr Maria T. Abreu is a gastroenterologist who specializes in inflammatory bowel disease (IBD). She completed her medical degree at the University of Miami, Miller School of Medicine, USA. Her postdoctoral training included an internship and residency in medicine at the Brigham and Women's Hospital in Boston, Massachusetts and a clinical and research fellowship in gastroenterology at the University of California, Los Angeles (UCLA), USA. She was an Associate Professor of Medicine with Mount Sinai School of Medicine, NYC and head of the IBD Center. She is currently the Director of the Crohn's and Colitis Center, Professor of Medicine and Professor of Microbiology and Immunology at the University of Miami, Miller School of Medicine. Dr Abreu was honored in April 2018, with the Provost's Award for Scholarly Activity. She was appointed in June 2018 to serve as the Vice Chair of Research for the Department of Medicine. Dr Abreu has more than 20 years of leadership experience in basic, translational and clinical research and mentoring. She is a nationally and internationally renowned physician-scientist in IBD. Dr Abreu was elected to the American Society for Clinical Investigation in 2010 and to the Association of American Physicians (AAP) in 2018. She holds key positions with several professional societies. She is the immediate past Council Chair of the American Gastroenterological Association (AGA) Institute Council. Her most recent appointment is as the Deputy Chair of the International Organization for the Study of Inflammatory Bowel Disease (IOIBD), where she will serve as Chairperson starting in 2019. In March 2018, Dr Abreu was recognized by the CCF (Crohn's & Colitis Foundation) by presentation of the Honorary Book of Hope Award presented at the 28th annual Book of Hope CCF Luncheon. She has received the 2016 Minority Digestive Health Care Award for her commitment to helping minority trainees and researching GI health issues in minority populations. Dr Abreu is frequently invited as a speaker (in English and Spanish) at CME-accredited seminars and symposia on basic science and clinical topics all over the world. As an educator, she regularly speaks at national and international symposia. She has authored more than 100 peer-reviewed articles, books, chapters and reviews. Additionally, she has served as an editorial board member for Inflammatory Bowel Diseases and Gastroenterology & Hepatology News, a former editor for the Journal of Immunology and former associate editor of Journal of Crohn's & Colitis. She is currently a reviewer for several other prestigious journals. Mitchell L. SchubertMitchell L. SchubertDr Mitchell L. Schubert is currently Professor of Internal Medicine and Physiology at Virginia Commonwealth University Health Science Center, USA, as well as Chief of the Section of Gastroenterology and Director of Endoscopy at the McGuire Veterans Affairs Medical Center in Richmond, Virginia, USA. Dr Schubert graduated from New York University, USA, in 1973 and Baylor College of Medicine, USA, in 1977. He completed an internal medicine residency and National Institutes of Health gastroenterology fellowship at Virginia Commonwealth University, USA. He joined the medical faculty at Virginia Commonwealth University in 1982. Dr Schubert has served on NIH and VA Study Sections as well as numerous American Gastroenterological Association, American College of Gastroenterology, and Veterans Administration committees. He is President of the Richmond Gastroenterological Society, Section Editor for Current Opinion in Gastroenterology, and Associate Editor for Digestive Diseases and Sciences. Dr Schubert's research interests involve the study of acid-related disorders. His laboratory studies the regulation of gastric acid secretion in health and disease. Dr Schubert has been the recipient of the Veterans Administration Career Development Award, American Gastroenterological Association (AGA) Research Scholar Award, and has authored over 100 original papers and reviews including the chapters “Gastric Secretion” for Sleisenger and Fordtran's textbook, Gastrointestinal and Liver Disease and “Regulation of Gastric Acid Secretion” for Johnson's textbook, Physiology of the Gastrointestinal Tract.

Identification of Endpoints for Development of Antifibrosis Drugs for Treatment of Crohn’s Disease

Intestinal fibrosis is a challenge to management of patients with Crohn's disease (CD); there is an urgent need to expedite development of antifibrosis drugs for this disease. The International Organization for the Study of Inflammatory Bowel Disease (IOIBD) aimed to identify a set of endpoints that can be used to determine efficacy of antifibrosis agents tested in clinical trials of patients with CD. We conducted a systematic review to identify clinical, radiologic, biochemical, endoscopic, and composite endpoints used in assessing activity of fibrostenosing CD and response to treatment, and determined their operational properties. A panel of IOIBD experts performed a consensus process to identify the best endpoints for inclusion in clinical trials, through a 2-round, Delphi-style online survey. A total of 36 potentially relevant endpoints for intestinal fibrosis were selected and assessed. Forty-eight physicians with expertise in inflammatory bowel disease, from 5 regions (North America, Europe, Middle East, Asia/Pacific, and Latin America), participated in the Delphi consensus process. A core set of 13 endpoints (complete clinical response, long-term efficacy, sustained clinical benefit, treatment failure, radiological remission, normal quality of life, clinical remission without steroids, therapeutic failure, deep remission, complete absence of occlusive symptoms, symptom-free survival, bowel damage progression, and no disability) were rated as critical. Agreement was high among the experts. Members of the IOIBD reached expert consensus on a set of endpoints that can be used to assess antifibrosis agents in trials of patients with CD. Studies are needed to clarify methods for measuring these outcomes and validate measurement instruments.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice.

The Efficacy of the Consumption of n-3 Polyunsaturated Fatty Acids for the Maintenance of Remission in Patients with Inflammatory Bowel Disease

The aim of the present study was to investigate the efficacy of the actual consuming n-3 PUFA for remission-maintenance in IBD patients. A questionnaire on the dietary habits of patients one month before hospitalization (Q1) was completed by 24 patients with IBD (10 ulcerative colitis (UC) subjects and 14 Crohn’s disease (CD) subjects) treated at our hospital. We educated the study subjects about an n-3 PUFA diet, and a follow-up survey (Q2) was conducted 6 to 12 months after discharge. Disease activity was evaluated using the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score and/or the Crohn’s Disease Activity Index (CDAI) score for CD and the partial UCDAI score without endoscopic evaluation for UC. Q1 showed that the average n-3 and n-6 PUFA intakes were 1673 ± 1651 mg and 9146 ± 5217 mg, respectively, and the average n-3/n-6 ratio was 0.27 ± 0.31. In Q2, the intake of n-3 PUFA was significantly higher (3671 ± 1684 mg, p < 0.001), whereas the n-6 PUFA intake decreased significantly (5217 ± 1973 mg, p < 0.001) compared to those in Q1. As a consequence, the dietary n-3/ n-6 ratio was significantly increased (0.87 ± 0.60, p < 0.001). Maintenance of the remission rate was significantly higher in IBD patients who complied with the n-3 diet, and these patients maintained a dietary n-3/n-6 ratio of 0.432 or higher (17 of 23 cases; 70.8%, p < 0.03) compared to that observed for IBD patients who did not comply with the diet. These results emphasize the importance of adjusting dietary PUFA and suggest that the n-3 diet may be effective in maintaining the remission of IBD.

Defining endoscopic response and remission in ulcerative colitis clinical trials: an international consensus.

Recently, endpoints for clinical trials have been changing from measuring clinical response to mucosal healing in ulcerative colitis. Endoscopic evaluation is the current gold standard to assess mucosal lesions and has become a major measure of therapeutic efficacy in addition to patients reported outcomes. To achieve consensus on endoscopic definitions of remission and response for clinical trials in patients with ulcerative colitis. In reaching the current international recommendations on an International Organization For the Study of Inflammatory Bowel Disease (IOIBD) initiative, we first performed a systematic review of technical aspects of endoscopic scoring systems. Then, to achieve consensus on endoscopic definitions of remission and response for clinical trials, we conducted a two-round vote using a Delphi-style process among fifteen specialists in the field of inflammatory bowel diseases. The literature review showed that many endoscopic indices have been proposed to evaluate disease activity in ulcerative colitis; most are unvalidated and arbitrary definitions have been used in clinical trials for defining endoscopic response or remission. At the end of the voting process, the investigators ranked initially the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) 0 for the definition of endoscopic remission, and a decrease in Mayo endoscopic score ≥1 grade or a decrease in UCEIS ≥2 points for the definition of endoscopic response in ulcerative colitis. These international recommendations represent the first consensus on measurement indices for endoscopic outcomes in ulcerative colitis. They should be subject to prospective testing in clinical trials of ulcerative colitis.

Development of an index to define overall disease severity in IBD

Background and aimDisease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims...