Endpoints for extraintestinal manifestations in inflammatory bowel disease trials: the EXTRA consensus from the International Organization for the Study of Inflammatory Bowel Diseases.

Extraintestinal manifestations occur frequently in patients with inflammatory bowel disease (IBD) and remain a diagnostic and therapeutic challenge. The aim of the Endpoints for Extraintestinal Manifestations in Inflammatory Bowel Disease Trials (EXTRA) initiative was to achieve international expert consensus on how to assess these manifestations in IBD trials. A systematic literature review was done to identify methods to diagnose extraintestinal manifestations in patients with IBD and measure treatment outcomes. A consensus meeting involving a panel of 41 attendees, including gastroenterologists and referral specialists, was held on March 31, 2021, as part of an International Organization for the Study of Inflammatory Bowel Diseases initiative. The panel agreed that a specialist's expertise is needed to confirm the diagnosis of extraintestinal manifestations before the inclusion of a patient in IBD trials, except for axial spondyloarthritis, for which typical symptoms and MRI can be sufficient. Easy-to-measure endpoints were identified to assess the response of extraintestinal manifestations to treatment without needing specialist involvement. For uveitis, peripheral spondyloarthritis, and arthralgia, endpoint measurements need specialist expertise. The timing of endpoint measurements was discussed for individual extraintestinal manifestations. The EXTRA consensus proposes guidelines on how to thoroughly evaluate extraintestinal manifestations within IBD trials, and recommends that these guidelines are implemented in future trials to enable prospective assessment of these manifestations and comparison between studies.

Corticosteroid and Biologic Use Not Associated With Adverse Outcomes for Inflammatory Bowel Disease Patients Hospitalized With COVID-19.

BACKGROUND: To date, studies investigating the inflammatory bowel disease (IBD) patient experience with coronavirus disease 2019 (COVID-19) have consistently reported that the observed rate of COVID-19 within this population is similar to the general population. Limited research has suggested that corticosteroid use in the IBD population may be associated with worse COVID-19 outcomes, but it is still yet to be determined if specific IBD-related clinical factors are associated with worse outcomes. Our goal was to describe clinical COVID-19 outcomes for IBD patients and to identify the clinical factors that may be associated with worse outcomes. METHODS: In this retrospective study, we utilized the inpatient database within the largest hospital network in the New York City Metropolitan area to identify all IBD patients with confirmed COVID-19. RESULTS: Of 83 IBD/COVID-19 patients presenting to a hospital network emergency room, 56 were hospitalized. Overall, 19.6% of hospitalized IBD patients died, compared with 22.2% of all hospital system COVID-19 patients during the time period. There was no association between pre-admission corticosteroid use or biologic treatment with a severe course of COVID-19. CONCLUSIONS: In contrast to some prior reports, we did not observe an association of pre-admission corticosteroid use and adverse outcomes. While the mortality rate was high for IBD/COVID-19 patients, it was not greater than that for hospitalized COVID-19 patients generally. Though our results are encouraging, we continue to support the recommendations of the leading gastrointestinal and IBD societies to regard our patients as "at risk", and to observe caution in their care.

The Changing Prognosis of Ulcerative Colitis and Crohn Disease by Decades.

We present a bird's eye view of the prognosis for both ulcerative colitis and Crohn disease as contained in the database of an Inflammatory Bowel Disease gastroenterologist covering the period from 1950 until the present utilizing the variables of medical therapy, surgical intervention, complications, and deaths by decades.

Increasing Pediatricians' Awareness of the Association between Anal Skin Tags and Earlier Diagnosis of Crohn's Disease.

OBJECTIVE: To seek the habits of pediatricians by which anorectal skin tags (AST) of Crohn's disease might be overlooked. METHODS: Questionnaires were sent to pediatricians affiliated with the Northwell Health System. RESULTS: Based on the responses, the majority of pediatricians did feel the abdomen of children presenting with abdominal pain or diarrhea but did not spread the buttocks to seek the presence of AST unless there was rectal pain, rectal bleeding, or, in some cases, loose stools. CONCLUSIONS: The diagnosis of Crohn's disease could be made earlier when asymptomatic AST are searched for in children with gastrointestinal symptoms.

Management of iatrogenic perforation during colonoscopy in ulcerative colitis patients: a survey of gastroenterologists and colorectal surgeons.

PURPOSE: Patients with ulcerative colitis, a high-risk group for the development of colon cancer, undergo colonoscopy more frequently than the general population. This increase in endoscopic evaluation also exposes these patients to an increased risk of complications, including iatrogenic perforation. Our survey study aims to determine factors that affect the management choices for iatrogenic perforations for ulcerative colitis patients in remission and identify areas of consensus among general gastroenterologists, inflammatory bowel disease specialists, and colorectal surgeons. METHODS: An anonymous, cross-sectional survey was performed using an online platform. A matrix questionnaire posed five clinical scenarios with six management options for an iatrogenic perforation in ulcerative colitis patients with varying disease distribution, disease activity, and maintenance regimens. RESULTS: One hundred thirty-eight general gastroenterologists, 35 inflammatory bowel disease specialists, and 174 colorectal surgeons responded to the survey; 47, 41, and 23%, respectively, answered they did not feel comfortable managing perforations in ulcerative colitis patients in remission. We found the greatest concordance among gastroenterologists and colorectal surgeons in cases of perforation in ulcerative colitis with a history of dysplasia; the majority of respondents chose staged total proctocolectomy with ileal pouch anal anastomosis. We found discordance in decision making for ulcerative colitis in remission without dysplasia, with perforation occurring in colitis involved and uninvolved areas. CONCLUSION: Our survey revealed that a significant fraction of gastroenterologists and colorectal surgeons are uncomfortable managing iatrogenic colonic perforations in ulcerative colitis patients. We have identified knowledge and practice gaps in defining the optimal management of iatrogenic perforations in ulcerative colitis patients.

Effects of Vedolizumab Therapy on Extraintestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND: Approximately 15-20% of ulcerative colitis patients and 20-40% of those with Crohn's disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action. AIMS: This report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action. METHODS: We report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy. RESULTS: Vedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn's disease. CONCLUSIONS: These cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD.

Obesity/Bariatric Surgery and Crohn's Disease.

BACKGROUND: Crohn's disease (CD) following bariatric surgery has been previously described. It is not clear whether the clinical entity is due to rapid metabolism of fat, change in the bacterial milieu of the bowel, the loss of defense mechanisms of the stomach, or even a coincidence. OBJECTIVES: To present observations which might serve to sort out these various etiologies. DESIGN: We present 5 cases of colitis, ileocolitis or enteritis, some with fistula formation, with clinical onset following bariatric surgery and add these to the 7 cases previously identified as CD reported elsewhere. We provide the clinical features of these 12 cases to reconcile with causative mechanisms. LIMITATIONS: It remains possible that the onset of CD (or other inflammatory bowel disease) precedes the bariatric surgery which then accelerates the clinical manifestations described. Furthermore, without controls the association could remain a coincidence. CONCLUSIONS: We review the evidence for release of proinflammatory cells and cytokines contained in fat following the bariatric surgery, and also consider the roles that the surgical resection of stomach and shortening of the bowel may also bring about this syndrome. The earlier onset is more likely due to surgical loss of defenses of the stomach and the later onset to a metabolic alteration of the presurgical obesity, involving fat metabolism, and/or the microbiome. The role of characteristic creeping fat of CD is also addressed.

High Incidence of Recurrent Crohn's Disease Following Colectomy for Ulcerative Colitis Revealed with Long Follow-Up.

BACKGROUND AND AIMS: Ulcerative colitis (UC) patients with progression of their disease despite optimized medical therapy may warrant "curative" proctocolectomy with end ileostomy or ileo-anal pouch (IPAA) anastomosis. The aim of our study was to assess the incidence of later recurrent ileitis that lead to altering the initial diagnosis to Crohn's disease (CD). METHODS: A retrospective analysis was conducted on the inflammatory bowel disease database at Lenox Hill Hospital. The database consisted of patients that were diagnosed with UC or CD based on clinical assessment, endoscopic appearance, gross and histological examination, and imaging between 1960 and 2015. The post-colectomy follow-up period was at least 10 years. Recurrent disease was classified by evidence of transmural inflammation in the distal ileum, fistulizing disease, or stricturing disease. RESULTS: From our IBD database, we identified 128 patients who underwent elective or urgent colectomy with the preoperative diagnosis of UC. Thirty-two (25%) had either an IPAA or end ileostomy with documented recurrence of inflammation in the small bowel mucosa consistent with CD. There was no significant difference between the type of surgical approach and the chance of recurrent disease (p = .20). The average time to clinically significant recurrence was 5 years. CONCLUSION: The incidence of recurrent CD following colectomy for ulcerative colitis, when followed postoperatively for an average of 20 years, was 25%, considerably more than previously reported. Patients who come to colectomy for ulcerative colitis and are followed for at least 10 years show a high incidence of recurrent Crohn's disease in the ileostomy or ileo-anal pouch. Extended follow-up should be included in patients coming to colectomy for ulcerative colitis before they should be considered cured of their disease.

Sequential Crohn's Ileitis, Ileosigmoidal Fistula, Segmental Sigmoid Polyposis, and Sigmoid Stricture: The Natural History.

BACKGROUND: We have previously recognized segmental sigmoid polyps as an indicator of a fistula from Crohn's ileitis to the sigmoid or the proximal rectum. In the course of this study, we realized that many patients with this fistula had no sigmoid polyps, but the sigmoid was the site of marked inflammation and early or late stricture formation. Furthermore, in some patients with a stricture, the fistula was not recognized until the surgeon (or the pathologist) dissected an inflammatory peri-ileal and/or a perisigmoidal mass.In this study, we have sought to clarify the sequence of events by focusing on the segmental inflammation and the stricturing of the sigmoid so that its significance can be recognized as a local complication of the ileitis and the progression of its severity as opposed to arising sui generis. MATERIALS AND METHODS: From our database of >3000 patients with inflammatory bowel disease at Lenox Hill Hospital, we identified 45 patients with Crohn's ileitis and ileosigmoid fistula (ISF): 24 had segmental sigmoid polyps and 18 had segmental inflammatory sigmoid strictures. The fistula was first seen by imaging in 36 patients, but not until resection by the surgeon or dissection by the pathologist in 7 patients. RESULTS: The method of diagnosis for the initial recognition of the ISF and the sigmoid stricture is presented in Table 1. In 36 of the 45 cases, the ISF was recognized by radiologic imaging. In total, 31 of the 36 cases required surgical intervention, not because of the fistula, but because of small-bowel obstruction due to the ileitis. In 7 of the 31 (22%) cases, the fistula was recognized only by dissection of the inflammatory ileosigmoid mass by the surgeon or examination of the surgical specimen by the pathologist. The sequence of events from the originating ileitis to the ISF to the segmental sigmoid polyposis and stricture, with the resulting sigmoid obstruction, is shown in Figures 1A-E. CONCLUSIONS: We emphasize the natural history of the ISF so that its recognition will lead to earlier medical management of the originating ileitis. Furthermore, it adds evidence of the recognition that the causative agent of Crohn's disease is carried by the fecal stream.

Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective.

The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.

Risk of New or Recurrent Cancer in Patients With Inflammatory Bowel Disease and Previous Cancer Exposed to Immunosuppressive and Anti-Tumor Necrosis Factor Agents.

BACKGROUND & AIMS: Our understanding of malignancy associated with immunosuppression in patients with inflammatory bowel disease (IBD) comes from studies of individuals with no history of cancer. We investigated whether patients with IBD and a history of cancer who were subsequently immunosuppressed have an increased risk of developing incident cancer. METHODS: We performed a retrospective analysis of data from 333 patients with IBD treated at 8 academic medical centers who developed cancer and subsequently received treatment with anti-tumor necrosis factor (TNF), anti-TNF with an antimetabolite (thiopurines, methotrexate), antimetabolites, or no subsequent exposure to immunosuppressive agents (controls). We collected data on their primary outcomes of incident cancers (new or recurrent). Hazard ratios (HRs) were calculated by using Cox proportional hazards and Kaplan-Meier survival curves; study groups were compared by using the log-rank test. RESULTS: During the follow-up period, 90 patients (27%) developed an incident cancer. Patient characteristics between groups differed, but matching was not possible because of the relatively small sample sizes. There was no difference in time to incident cancer (P = .14) or type of incident cancer (P = .61) among the 4 groups. After adjusting for recurrence risk for type of prior cancer, there was no difference in risk of incident cancer (HR for anti-TNF, 0.32; 95% confidence interval [CI], 0.09-1.09; HR for anti-TNF with an antimetabolite, 0.64; 95% CI, 0.26-1.59; HR for an antimetabolite, 1.08; 95% CI, 0.54-2.15) or time to subsequent cancer between study arms (P = .22). CONCLUSION: On the basis of a retrospective study, in patients with IBD and a history of cancer, exposure to an anti-TNF agent or an antimetabolite after cancer was not associated with an increased risk of incident cancer, compared with patients who did not receive immunosuppression. Larger, matched, prospective studies are needed to confirm these findings.

Segmental sigmoid polyposis as a colonoscopic indicator of an ileosigmoid fistula in Crohn's ileitis.

BACKGROUND AND AIMS: Ileosigmoid fistulas (ISFs) are frequently undiagnosed prior to surgery. This study was designed to describe a polyp or cluster of polyps limited to the sigmoid colon as a marker of ISF in patients with ileitis. This novel finding will increase a gastroenterologist's opportunity to detect them preoperatively and their prognostic implication of worsening ileitis. METHODS: The medical records of patients with Crohn's disease and ISF were reviewed to determine whether colonoscopy had revealed polyposis limited to the sigmoid colon and its frequency. RESULTS: Thirty-seven patients with Crohn's ileitis complicated by ISF were identified from our database. Twenty had one or more sigmoid polyps without polyps elsewhere in the colon suggesting the site of fistula exit. Fifteen of the patients had ISF and five had ileorectal fistula (IRF). The fistula was detected by various means, including colonoscopy, sigmoidoscopy, small bowel X-ray series, barium enema, computed tomography, and magnetic resonance enterography. The ISF was generally diagnosed prior to the recognition and significance of the segmental polyps. These polyps were inflammatory or hyperplastic on pathologic review. CONCLUSION: Most ISFs and IRFs are now found preoperatively by imaging and some are incidental surgical findings. The segmental sigmoid polyps that we describe should help the gastroenterologist to be suspicious of ISF. The polyps are a surrogate marker for the progression of the fistula and the underlying ileitis as they tend to appear after the fistula has matured and lead to increased intensity of medical therapy well before surgical intervention is required.

Histological healing favors lower risk of colon carcinoma in extensive ulcerative colitis.

AIM: To search for the answer in extensive ulcerative colitis as to whether histological inflammation persisting despite endoscopic mucosal healing serves to increase the risk of colon cancer (CC) or high grade dysplasia (HGD). METHODS: This is a single center (Lenox Hill Hospital) retrospective cohort and descriptive study of extensive ulcerative colitis (UC) for 20 years or more with a minimum of 3 surveillance colonoscopies and biopsies performed after the first 10 years of UC diagnosis. Data analyzed included: duration of UC, date of diagnosis of (CC) or (HGD), number of surveillance colonoscopies, and biopsies showing histological inflammation and its severity in each of 6 segments when endoscopic appearance is normal. Two subgroups of patients were compared: group 1 patients who developed CC/HGD and group 2 patients who did not develop CC/HGD. RESULTS: Of 115 patients with longstanding UC reviewed, 68 patients met the inclusion criteria. Twenty patients were in group 1 and 48 in group 2. We identified the number of times for each patient when the endoscopic appearance was normal but biopsies nevertheless showed inflammation. Overall, histological disease activity in the absence of gross/endoscopic disease was found in 31.2% (95%CI: 28%-35%) of colonoscopies performed on the entire cohort of 68 patients. Histological disease activity when the colonoscopy showed an absence of gross disease activity was more common in group 1 than group 2 patients, 88% (95%CI: 72%-97%) vs 59% (95%CI: 53%-64%). Only 3/20 (15%) of patients in group 1 ever had a colonoscopy completely without demonstrated disease activity (i.e., no endoscopic or histological activity) as compared to 37/48 (77%) of patients in group 2, and only 3.3% (95%CI: 0.09%-8.3%) of colonoscopies in group 1 had no histological inflammation compared to 23% (95%CI: 20%-27%) in group 2. CONCLUSION: Progression to HGD or CC in extensive ulcerative colitis of long standing was more frequently encountered among those patients who demonstrate persistent histological inflammation in the absence of gross mucosal disease. Our findings support including the elimination of histological inflammation in the definition of mucosal healing, and support this endpoint as an appropriate goal of therapy because of its risk of increasing dysplasia and colon cancer.

6-Mercaptopurine/Azathioprine remains an important contributor in managing Crohn's disease.

Two large studies concluded that AZA started early after diagnosis of Crohn's disease have no late maintenance value. This is contrary to previous studies on 6MP for Crohn's disease and could lead to negating the value of two of the few drugs that have been proven successful. We here outline the many reasons why 6MP remains a valuable drug in the treatment of Crohn's disease.

Expert opinion: experience with 6-mercaptopurine in the treatment of inflammatory bowel disease.

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immunosuppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corticosteroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn's disease as well. Not much was ever made of the role of sulfasalazine for Crohn's disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-aminosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn's colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in patients with ulcerative colitis, but its placebo controlled trial for Crohn's disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless clinicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn's disease. What changes have taken place utilizing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960's and 1970's and its trial for Crohn's disease published in the New England Journal of Medicine in 1980?