Safety of Immunosuppression in A Prospective Cohort of Inflammatory Bowel Disease Patients with a HIstoRy of CancEr: SAPPHIRE Registry.

BACKGROUND AND AIMS: In patients with inflammatory bowel disease (IBD) and a history of cancer, retrospective studies suggest that exposure to immunosuppressive agents does not increase the risk of incident (recurrent or new) cancer compared to unexposed patients. SAPPHIRE is a prospective registry aimed at addressing this issue. METHODS: Since 2016, patients with IBD and confirmed index cancer prior to enrollment were followed annually. Patients receiving chemotherapy or radiation at enrollment, or recurrent cancer within five years were excluded. Primary outcome was development of incident cancer related to exposure to immunosuppressive medications. RESULTS: Among 305 patients (47% male, 88% white), median age at IBD diagnosis and cancer were 32 and 52 years, respectively. Index cancers were solid organ (46%), dermatologic (32%), gastrointestinal (13%), and hematologic (9%). During median follow-up of 4.8 years, 210 (69%) were exposed to immunosuppressive therapy and 46 (15%) developed incident cancers (25 new, 21 recurrent). In unadjusted analysis, the crude rate of incident cancer in unexposed patients was 2.58/100 person-years versus 4.78/100 PY (relative risk 1.85, 95% CI 0.92-3.73) for immunosuppression exposed patients. In a proportional hazards model adjusting for sex, smoking history, age and stage at index malignancy, and non-melanoma skin cancer, no significant association was found between receipt of immunosuppression and incident cancer (adjusted hazard ratio, aHR, 1.41, 95% CI: 0.69-2.90), or with any major drug class. CONCLUSION: In this interim analysis of patients with IBD and a history of cancer, despite numerically elevated aHRs, we did not find a statistically significant association between subsequent exposure to immunosuppressive therapies and development of incident cancers.

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

BACKGROUND: Outcomes after ileocolonic resection in Crohn's disease [CD] are heterogeneous, and a clear definition of postoperative recurrence remains to be determined. Our Endpoints Working Group of the International Organization for the study of Inflammatory Bowel Disease [IOIBD] aimed to standardise postoperative outcomes, to discuss which endpoints should be used for postoperative clinical trials, and to define those which could be used in trials or registries. METHODS: Based on a systematic review of the literature, recommendations and statements were drafted and sent to all IOIBD members for a first round of voting. Recommendations and statements were revised based on the voters' comments during a consensus hybrid conference open to all IOIBD members. If no agreement was reached after two rounds of voting, the statement was excluded. RESULTS: In the systematic review, 3071 manuscripts were screened of which 434 were included. Sixteen recommendations were identified, of which 11 were endorsed. Recommendations and statements include that endoscopy remains the gold standard and should be used as a short-term primary endpoint in both observational cohorts and randomised controlled trials. Clinical symptoms classically used in clinical trials for luminal CD are not reliable in this specific situation. For that reason, longer-term endpoints should be based on the evidence of macroscopic inflammation assessed by imaging techniques, endoscopy, or as reflected by the presence of complications. CONCLUSIONS: Agencies recommend the use of clinical evaluations, as in the case of luminal CD, and do not recognise primary endpoints based solely on endoscopy. This consensus has led to agreement on the need to define postoperative endoscopy-based and/or imaging-based endpoints.

Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting.

Many patients with inflammatory bowel disease (IBD) have persistent symptoms and disease activity despite the best available medical or surgical treatments. These patients are commonly referred to as having difficult-to-treat IBD and need additional therapeutic strategies. However, the absence of standard definitions has impeded clinical research efforts and comparisons of data. Under the guidance of the endpoints cluster of the International Organization for the Study of Inflammatory Bowel Disease, we held a consensus meeting to propose a common operative definition for difficult-to-treat IBD. 16 participants from 12 countries voted on 20 statements covering various elements of difficult-to-treat IBD, such as failure of medical and surgical treatments, disease phenotypes, and specific complaints from patients. "Agreement" was defined as at least 75% consensus. The group agreed that difficult-to-treat IBD is defined by the failure of biologics and advanced small molecules with at least two different mechanisms of action, or postoperative recurrence of Crohn's disease after two surgical resections in adults, or one in children. In addition, chronic antibiotic-refractory pouchitis, complex perianal disease, and comorbid psychosocial complications that impair disease management also qualified as difficult-to-treat IBD. Adoption of these criteria could serve to standardise reporting, guide enrolment in clinical trials, and help identify candidates for enhanced treatment strategies.

Long-Term Outcomes of the Excluded Rectum in Crohn's Disease: A Multicenter International Study.

BACKGROUND: Many patients with Crohn's disease (CD) require fecal diversion. To understand the long-term outcomes, we performed a multicenter review of the experience with retained excluded rectums. METHODS: We reviewed the medical records of all CD patients between 1990 and 2014 who had undergone diversionary surgery with retention of the excluded rectum for at least 6 months and who had at least 2 years of postoperative follow-up. RESULTS: From all the CD patients in the institutions' databases, there were 197 who met all our inclusion criteria. A total of 92 (46.7%) of 197 patients ultimately underwent subsequent proctectomy, while 105 (53.3%) still had retained rectums at time of last follow-up. Among these 105 patients with retained rectums, 50 (47.6%) underwent reanastomosis, while the other 55 (52.4%) retained excluded rectums. Of these 55 patients whose rectums remained excluded, 20 (36.4%) were symptom-free, but the other 35 (63.6%) were symptomatic. Among the 50 patients who had been reconnected, 28 (56%) were symptom-free, while 22(44%) were symptomatic. From our entire cohort of 197 cases, 149 (75.6%) either ultimately lost their rectums or remained symptomatic with retained rectums, while only 28 (14.2%) of 197, and only 4 (5.9%) of 66 with initial perianal disease, were able to achieve reanastomosis without further problems. Four patients developed anorectal dysplasia or cancer. CONCLUSIONS: In this multicenter cohort of patients with CD who had fecal diversion, fewer than 15%, and only 6% with perianal disease, achieved reanastomosis without experiencing disease persistence.

Patients with distal Crohn's disease often undergo colon resection with a stoma to divert the intestinal stream from the rectum in hopes of achieving sufficient healing to allow ultimate re-establishment of intestinal continuity. Patients and practitioners alike should be aware of the long-term success rates of this procedure. Our retrospective study of 197 patients found that half required later proctectomy and an additional one-quarter remained symptomatic with excluded rectums. Only 14% remained symptom-free after reanastomosis, and only 6% if perianal disease was the initial surgical indication. These data provide estimation of long-term surgical outcomes.

IOIBD Recommendations for Clinical Trials in Ulcerative Proctitis: The PROCTRIAL Consensus.

BACKGROUND & AIMS: Clinical trials evaluating biologics and small molecules in patients with ulcerative colitis are predominantly excluding ulcerative proctitis. The objective of the Definition and endpoints for ulcerative PROCtitis in clinical TRIALs initiative was to develop consensus statements for definitions, inclusion criteria, and endpoints for the evaluation of ulcerative proctitis in adults. METHODS: Thirty-five international experts held a consensus meeting to define ulcerative proctitis, and the endpoints to use in clinical trials. Based on a systematic review of the literature, statements were generated, discussed, and approved by the working group participants using a modified Delphi method. Consensus was defined as at least 75% agreement among voters. RESULTS: The group agreed that the diagnosis of ulcerative proctitis should be made by ileocolonoscopy and confirmed by histopathology, with the exclusion of infections, drug-induced causes, radiation, trauma, and Crohn's disease. Ulcerative proctitis was defined as macroscopic extent of lesions limited to 15 cm distance from the anal verge in adults. Primary and secondary endpoints were identified to capture response of ulcerative proctitis to therapy. A combined clinical and endoscopic primary endpoint for the evaluation of ulcerative proctitis disease activity was proposed. Secondary endpoints that should be evaluated include endoscopic remission, histologic remission, mucosal healing, histologic endoscopic mucosal improvement, disability, fecal incontinence, urgency, constipation, and health-related quality of life. CONCLUSIONS: In response to the need for guidance on the design of clinical trials in patients with ulcerative proctitis, the Definition and end points for ulcerative PROCtitis in clinical TRIALs consensus provides recommendations on the definition and endpoints for ulcerative proctitis clinical trials.

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.

Diversion proctocolitis and the problem of the forgotten rectum in inflammatory bowel diseases: A systematic review.

BACKGROUND AND AIMS: Diversion proctocolitis (DP) is a non-specific mucosal inflammation arising in the defunctionalized colon and/or rectum following faecal diversion (colostomy, ileostomy). Differential diagnosis of DP from the underlying disease in patients with inflammatory bowel diseases (IBD) is often unclear. As a result, it might be difficult to undertake any specific treatment. We aimed to systematically review the literature evidence on DP in IBD patients. METHODS: For this qualitative systematic review, we searched PubMed, EMBASE and Scopus to identify all studies published until July 2021 including IBD patients affected by DP. RESULTS: Overall, 37 papers published between 1982 and 2021 were included. A total of 1.211 IBD patients were included: 613 UC (50.6%), 524 CD (43.3%), 66 IBD-unclassified (IBD-U) (5.4%), 8 unspecified patients (0.7%). Most patients with DP are asymptomatic, although inflammation is detectable in almost all patients with a rectal stump. Reduced short-chain fatty acids and an altered microbiome, may trigger mucosal inflammation and have been proposed as causing factors. An increased risk of developing cancer on DP has been reported in patients with a history of previous dysplasia/cancer. CONCLUSIONS: The etiopathogenesis of DP is still unknown. The efficacy of mesalamine, corticosteroids or short-chain fatty acids has not been proven by randomized trials yet. Since the incidence of cancer of the rectal stump can reach 4.5 per 1.000 diverted patients-year, IBD patients undergoing subtotal colectomy with end-ileostomy should undergo close endoscopic surveillance, being eventually counseled for surgery with or without the restoration of the intestinal continuity.

Earlier Anti-Tumor Necrosis Factor Therapy of Crohn's Disease Correlates with Slower Progression of Bowel Damage.

INTRODUCTION: Crohn's disease (CD) follows a relapsing and remitting course incurring cumulative bowel damage over time. The question of whether or not the timing of the initiating biologic therapy affects long-term disease progression remains unanswered. Herein, we calculated rates of change in the Lémann index-which quantifies accumulated bowel damage-as a function of the time between the disease onset and initiation of biologic therapy. We aimed to explore the impact of the earlier introduction of biologics on the rate of progression of long-term cumulative bowel damage. METHODS: Medical records of CD patients treated during 2009-2014 at The Mount Sinai Hospital were queried. Inclusion criteria were two comprehensive assessments allowing calculation of the index at t1 and t2: two time-points ≥ 1 year apart. Patients with biologics introduced before or within 3 months at inclusion (t1) were defined as Bio-pre-t1 and those who did not as Bio-post-t1. The rate of disease progression was calculated as the change in the index per year during t1-t2. RESULTS: A total of 88 patients were studied: 58 Bio-pre-t1 and 30 Bio-post-t1. Among the 58 Bio-pre-t1 cases, damage progressed in 29 (50%), regressed in 20 (34.5%), and stabilized in 9 (15.5%). Median time to initiation of biologics among patients whose index improved was nominally shorter compared to that in patients whose index progressed (8 vs. 15 years). Earlier introduction of biologics tended to correlate with the slower rate of progression (ρ = 0.241; p = 0.069). CONCLUSIONS: Earlier introduction of biologics tended to correlate with the slower progression of bowel damage in CD, reflected by the reduced rate of Lémann index progression.

Small Bowel Lesions Mimicking Crohn's Disease.

PURPOSE OF REVIEW: Not all injuries of the terminal ileum are Crohn's disease. It is the purpose of this review to consider the differential diagnosis of other acute and chronic ileal lesions. RECENT FINDINGS: The recognition of a granulomatous disease of the terminal ileum, distinct from tuberculosis, dates back over 85 years and perhaps much farther, but over the past decades, many other clinical pathologic entities have been described that are neither tuberculosis nor Crohn's eponymous regional enteritis. In recent years, the catalog of lesions mimicking Crohn's disease of the small bowel and proposals for differential diagnosis and treatment have expanded to include newly reported appendiceal pathology, primary cancers and lymphomas of the intestine, unexpected metastases from distant organs, unusual infections, vasculitides and other ischemic conditions, Behçet's disease, endometriosis, and drug reactions. A diagnosis of Crohn's disease should not be a reflex action in the face of small bowel structural or inflammatory lesions without consideration of pathology in adjacent organs, primary and metastatic lesions of the small intestine, infections, vascular diseases, infiltrative diseases, drug injury, or other "idiopathic" conditions.

The Management of Intestinal Penetrating Crohn's Disease.

Crohn's disease (CD) leads to the development of complications through progressive uncontrolled inflammation and the transmural involvement of the bowel wall. Most of the available literature on penetrating CD focuses on the perianal phenotype. The management of nonperianal penetrating complications poses its own set of challenges and can result in significant morbidity and an increased risk of mortality. Few controlled trials have been published evaluating this subgroup of patients for clinicians to use for guidance. Utilizing the available evidence, we review the epidemiology, presentation, and modalities used to diagnosis and assess intestinal fistulas, phlegmons, and abscesses. The literature regarding the medical, endoscopic, and surgical management options are reviewed providing physicians with a therapeutic framework to comprehensively treat these nonperianal penetrating complications. Through a multidisciplinary evidence-based approach to the complex sequela of CD outcomes can be improved and patient's quality of life enhanced.10.1093/ibd/izx108_video1izx108_Video5754037501001.

Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease.

The treatment of inflammatory bowel disease (IBD)-ulcerative colitis (UC) and Crohn's disease (CD)-has evolved beyond surgery with the introduction of biologic agents, primarily antibodies against mediators of inflammation and cell attraction. Anti-tumor necrosis factor (TNF) agents have been the first line treatment for moderate to severe ulcerative colitis and Crohn's disease for more than 15 years. During that time much has been learnt about how best to use these agents. This review will assess the evidence on how to optimize the use of anti-TNF agents; when and how to start treatment; how to monitor treatment and when to de-escalate it; and the potential adverse effects of these drugs. New and emerging treatments such as anti-attractants, anti-interleukins, and Janus kinase (JAK) inhibitors will also be discussed.

Autoimmune pancreatitis and inflammatory bowel disease: Case series and review of the literature.

BACKGROUND: An association between autoimmune pancreatitis (AIP) and inflammatory bowel disease (IBD) has been documented, but its clinical significance remains unclear. AIMS: Characterize the particular phenotypes of IBD and AIP in patients with both diseases (IBD-AIP). METHODS: Retrospective study of patients with IBD-AIP followed at our IBD referral centre and literature search to identify previous reports of IBD-AIP patients. RESULTS: We found 5 cases of IBD-AIP in our records and 5 prior studies reporting 47 additional IBD-AIP patients. A combined analysis showed that most IBD-AIP patients were young males with ulcerative colitis, usually extensive, and that in all Crohn's disease cases, the colon was involved. IBD severity was heterogeneous across studies, ranging from mild disease to severe disease requiring colectomy. The most frequent type of AIP was idiopathic duct-centric pancreatitis (type 2) and it most often occurred after the diagnosis of IBD. AIP presentation and treatment were similar to those in the general population. CONCLUSIONS: AIP occurs rarely with IBD; in the other way around, up to 1/3 of AIP patients, especially type 2, may have concomitant IBD. IBD-AIP patients are usually males presenting extensive colitis. More data are needed on the impact of AIP, if any, in IBD course.

Inflammatory Bowel Disease and Pancreatitis: A Review.

BACKGROUND AND AIMS: Pancreatic abnormalities are common in inflammatory bowel disease (IBD) patients and represent a heterogeneous group of conditions that include acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis and asymptomatic abnormalities. We sought to review the available evidence concerning the aetiology, clinical presentation, diagnosis and treatment of pancreatic conditions in IBD patients. METHODS: A PubMed/Medline query was conducted addressing pancreatic disorders in IBD. Reference lists from studies selected were manually searched to identify further relevant reports. Relevant manuscripts about pancreatic disorders in patients with IBD were selected and reviewed. RESULTS: Thiopurines and gallstones are the most frequent causes of acute pancreatitis in IBD patients. Thiopurine-induced acute pancreatitis is usually uncomplicated and self-limited. Some evidence suggests that chronic pancreatitis may be more common in IBD. Most cases are idiopathic, affecting young males and patients with ulcerative colitis. Autoimmune pancreatitis is a relatively newly recognized disease and is increasingly diagnosed in IBD, particularly for type 2 autoimmune pancreatitis in ulcerative colitis patients. Asymptomatic exocrine insufficiency, pancreatic duct abnormalities and hyperamylasaemia have been identified in up to 18% of IBD patients, although their clinical significance and relationship with IBD remain undefined. CONCLUSIONS: The wide spectrum of pancreatic manifestations in IBD is growing and may represent a challenge to the clinician. A collaborative approach with a pancreas specialist may be the most productive route to determine aetiology, guide additional diagnostic workup, illuminate the aetiology and define the treatment and follow-up of these patients.

Race and fistulizing perianal Crohn's disease.

BACKGROUND: There is increasing recognition of Crohn's disease (CD) in non-white populations. However, reports of racial disparities in the phenotype of CD are still inconsistent. AIM: : The aim of this study was to test the hypothesis that African American (AA) patients have higher incidence of severe fistulizing perianal Crohn's disease (FPD) compared with white patients. METHODS: Cross-sectional analysis of 333 adult CD patients treated at The Mount Sinai Hospital with infliximab between May 2011 and December 2011 was conducted. Self-reported race/ethnicity was recorded and proportions of each group with FPD were compared across the population. RESULTS: Among all 333 evaluable CD patients on infliximab, 73.6% were white, 11.4% AA, 13.2% Hispanic, and 1.8% Asian. Of these 333 patients, 88 had FPD: only 48 of these (54.5%) were white, whereas fully 18 (20.5%) were AA, 20 (22.7%) were Hispanic, and 2 (2.3%) were Asian. Thus, patients receiving infliximab for FPD were significantly more likely to be AA or Hispanic than white (AA vs. whites: risk ratio=2.63; 95% confidence interval, 1.74-3.96; P=<0.0001; Hispanics vs. whites: risk ratio=2.32; 95% confidence interval, 1.54-3.50; P=0.0001). There was no statistically significant difference between AA and Hispanics. CONCLUSION: CD patients at our medical center with FPD requiring infliximab therapy were significantly more likely to be AA or Hispanic.

High rates of metachronous colon cancer or dysplasia after segmental resection or subtotal colectomy in Crohn's colitis.

BACKGROUND: In ulcerative colitis, total proctocolectomy is the treatment of choice for patients with colonic dysplasia or cancer because of the high risk for metachronous neoplasia. It is unknown whether patients with Crohn's disease and colon cancer or dysplasia have a similar risk. METHODS: We retrospectively reviewed the charts of 75 patients treated at our center from 2001 to 2011 with Crohn's disease and colon cancer who underwent segmental resection or subtotal colectomy (STC). We then identified the presence or absence of subsequent colon cancer or dysplasia in these patients during the follow-up (0-19 years). RESULTS: Of the 64 patients with colon cancer, 25 had at least 1 metachronous cancer (39%). The mean time to a new cancer was 6.8 years. Eighty-five percent of patients (21/25) were undergoing annual screening colonoscopy. Of the 11 patients with dysplasia, 5 (46%) had a new dysplasia. Mean time to a new dysplastic lesion was 5.0 years. Nineteen of the 47 patients (40%) who had a segmental resection for colon cancer developed metachronous cancer and 6/17 patients (35%) with a STC had metachronous cancer. Two of the 4 patients (50%) with STC for dysplasia (50%) had a new dysplasia and 3/7 patients (43%) with segmental resection had a new dysplasia. There was no significant difference (P = 0.61) between recurrence rates in patients with segmental resection versus STC. CONCLUSIONS: The high rate of metachronous colon cancer after surgical resection suggests that total proctocolectomy should be considered. Larger studies are required to determine if the same is true for dysplasia.

Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia.

BACKGROUND: The expression and distribution of farnesoid X receptor (FXR) in colitis and colitis-associated neoplasia (CAN) is unknown. We investigated FXR expression in neoplastic and nonneoplastic tissue from ulcerative colitis (UC) patients, with or without primary sclerosing cholangitis (PSC), as well as the role of DNA methylation in FXR expression in colorectal cancer (CRC) cell lines. METHODS: Samples from the right (RC) and left (LC) colon of patients with UC, with and without PSC, and with or without CAN, were stained by immunohistochemistry and scored semiquantitatively for nuclear FXR expression. FXR expression was analyzed by western blot and polymerase chain reaction (PCR) in nine different CRC cell lines before and after demethylation with 5-azacytidine. RESULTS: In nondysplastic samples, FXR expression demonstrated a diminishing expression from proximal to distal colon (strong FXR expression: 39% RC samples vs. 14% LC samples; P = 0.007). With moderate-to-severe inflammation, FXR expression was almost always absent or weak in both UC and PSC-UC, regardless of location. With quiescent/mild inflammation, 56% of UC samples in the RC retained strong FXR expression versus 24% of PSC-UC samples (P= 0.017). FXR was absent in 72% of the neoplastic samples, with an inverse association with the grade of dysplasia. FXR expression was absent in all CRC cell lines, in some cases due to DNA methylation. CONCLUSIONS: FXR expression is inversely correlated with neoplastic progression and severity of inflammation in UC. Patients with PSC-UC have diminished FXR expression in the proximal colon compared to UC patients. This finding could contribute to the higher risk of proximal neoplasia in PSC patients.