Current misunderstandings in the management of ulcerative colitis

Past and ongoing therapeutic concepts for ulcerative colitis have only been moderately successful. A significant proportion of patients with ulcerative colitis will still have to undergo colectomy and overall half of the patients do not achieve sustained remission, leading to impairment of physical and mental health, social life, employment issues and sexual activity. Reluctance to treat patients early on with sufficiently potent drug regimens is obvious. Several popular misconceptions might have led to this situation. First, ulcerative colitis is still considered a more 'benign' disease than Crohn's disease. Furthermore, the general assumption is often that colectomy can 'cure' the disease. Mucosal healing as a therapeutic target has not been widely accepted. Finally, the use of antitumour necrosis factor antibodies in ulcerative colitis has been low because this treatment is considered to be less effective than in Crohn's disease. In the current review we try to disprove these misunderstandings by discussing relevant studies showing how harmful this disease can be and explaining why future studies targeting sustained suppression of inflammation could have an enormous impact on the natural course of the disease. Until these studies are available, we encourage physicians to intensify and maintain treatment until sustained remission and mucosal healing has been reached

Characterization of Mucosal Lesions in Crohn's Disease Scored With Capsule Endoscopy: A Systematic Review

Background and Aims: There is little agreement on the nomenclature and description of Crohn’s disease (CD) lesions that can be found in the small and large bowel using capsule endoscopy (CE). We performed a systematic review to identify mucosal lesions that have been described using CE in CD, in both the small bowel and colon, with the aim to make propositions to homogenize such descriptions. Methods: A systematic literature search was conducted using Embase, Medline (OvidSP), and Cochrane Central on August 6, 2019. Clinical studies providing nomenclature and descriptions for small bowel and colonic inflammatory lesions using CE in CD were selected for data collection. Results: In total, 851 articles were included for abstract screening out of which 219 were analyzed for full-text review. Twenty-two articles were selected for data extraction. Seven items, accompanied by clear descriptions, were found for the small bowel: i.e., ulcer, erosion, aphthoid lesion, edema, fissure, cobblestone appearance, and villous atrophy. No studies were found describing inflammatory items using CE in colonic CD. Conclusions: The most frequently described CD lesions using CE were ulcers and erosions. Subjective interpretation of CE inflammatory findings plays an important role. Based on our findings, a range of suggestions regarding items and descriptions is made that might form the basis of a pan-enteric CE activity index

Prognostic Value of Colonic Tissue and Blood Eosinophils in Ulcerative Colitis.

BACKGROUND It has been suggested that eosinophils may be a prognostic marker of disease outcome in ulcerative colitis (UC), but conflicting data exist. The objective was to investigate the extent of mucosal eosinophils and peripheral blood eosinophil count in newly diagnosed UC patients and to investigate its predictive value in short- and long-term disease outcomes. METHODS The degree of eosinophilia in baseline colonic biopsies and blood of newly diagnosed UC patients was retrospectively analyzed. It was investigated if tissue and blood eosinophilia could be a marker of a severe phenotype of UC, defined as the need for corticosteroids or immunomodulators in the first year or treatment with therapeutic monoclonal antibodies or colectomy during follow-up. Time to therapeutic monoclonal antibodies and time to colectomy were also evaluated as outcomes. RESULTS There were 103 UC patients (median age 26 years) included. Median tissue peak eosinophil count (PEC) was 70.0 and median peripheral blood eosinophil count was 0.3 × 109/L at diagnosis. Tissue PEC (r = -0.161, P = .104) and blood eosinophil count (r = 0.022, P = .877) were not correlated with the severity of histologic inflammation. Logistic regression analyses did not identify PEC and blood eosinophil count as predictors of more severe disease outcomes. Tissue PEC and peripheral blood eosinophil count did not predict the time the initiation of therapeutic monoclonal antibodies or colectomy. CONCLUSION Baseline tissue or peripheral blood eosinophils are not markers of disease activity and cannot be used as a predictor of severe disease outcomes in both adults and children with UC

The risk of colectomy and colorectal cancer after appendectomy in patients with ulcerative colitis:a systematic review and meta-analysis

Background: Appendectomy decreases the risk of developing ulcerative colitis [UC], and is suggested to have a beneficial effect on the clinical course of established UC. However, recent studies showed no significantly decreased colectomy rate, and moreover an apparently increased risk of colorectal cancer [CRC]. We aimed to investigate the suggested correlation in a meta-analysis and to analyse possible confounding factors. Methods: A systematic review and meta-analysis were performed using MEDLINE, EMBASE, and the Cochrane Library. Data from studies describing the influence of appendectomy on colectomy and CRC were extracted from published reports. Exclusion criteria were patients aged <18 years, non-UC, and animal studies. Results: From 891 studies, 13 studies evaluating 73 323 UC patients [appendectomy n = 2859] were included. All studies, except one, were rated as poor quality. Overall, colectomy rate in appendectomised and non-appendectomised patients was not significantly different (odds ratio [OR] 1.25, 95% confidence interval [CI] 0.88-1.77, I2 = 53%). The proportion of colectomies undertaken for CRC or high-grade dysplasia [HGD] was significantly higher after appendectomy [OR 2.85, 95% CI 1.40-5.78, I2 = 32%], with 50% of the colectomies indicated for CRC/HGD compared with 9.4% in non-appendectomised patients. Possible additional confounding factors were a longer UC disease duration, less medication use, and a higher prevalence of primary sclerosing cholangitis [PSC] in appendectomised patients. Conclusions: Appendectomy in established UC is associated with apparently higher rates of subsequent CRC/HGD, but this appears to be due to inequalities in at-risk exposure between groups, presumably secondary to positive clinical effects of appendectomy on disease symptoms. This finding emphasises the importance of regular endoscopic surveillance in this patient group

The clinical relevance of an inflamed appendix in Crohn's disease.

BACKGROUND AND AIMS An appendectomy for appendiceal inflammation has been suggested to ameliorate the clinical course of patients with ulcerative colitis (UC). In contrast, for Crohn's disease (CD) an inverse association has been suggested with a higher incidence of CD and worse prognosis after appendectomy. The aim of this study was to analyse the clinical relevance of an inflamed appendix in CD patients undergoing ileocoecal resection (ICR). METHODS All consecutive patients undergoing primary ICR between 2007 and 2018 were considered for inclusion. Microscopic data of available appendiceal resection specimens (n=99) were revised by a dedicated IBD-pathologist and scored as inflamed or not inflamed. Eighteen patients had a previous appendectomy. Pathological findings were correlated with disease characteristics and recurrence rates (clinical, endoscopic and intervention-related). RESULTS In total, 117 patients were included: 77 (65.8%) females with a median age of 30 years [IQR 24 - 43] with a median follow up of 102 months [IQR 76-114]. Of patients without previous appendectomy (n=99), 39% had an inflamed appendix. No significant differences in disease characteristics (e.g. disease location, behaviour, time to surgery) or prognosis could be demonstrated between the two groups. In contrast, previous appendectomy (n=18) was associated with penetrating disease and numerically shorter disease duration at the time of resection. Furthermore, a trend was seen towards a stronger association with postoperative recurrence. CONCLUSION The current study could not confirm a different prognosis for CD patients with and without an inflamed appendix. In contrast, in patients with a previous appendectomy a trend was seen towards increased postoperative recurrence, which might be related to the higher incidence of penetrating disease

Lymphoma risk and overall safety profile of Adalimumab in patients with Crohn's disease with up to 6 years of follow-up in the pyramid

OBJECTIVES Real-world, prospective, long-term studies in Crohn’s disease (CD) characterizing adalimumab safety data and lymphoma risk were lacking. We present the final results from the PYRAMID registry, which was designed to rule out a doubling of lymphoma risk in adalimumab-treated patients with CD. Methods Patients with moderately to severely active CD newly prescribed or currently receiving adalimumab according to local product labels were followed for up to 6 years and analyzed for adverse events (AEs). The registry exposure-adjusted observed rate of lymphoma was compared with the estimated background lymphoma rate from a sex-matched general population in the Surveillance, Epidemiology, and End Results 17 Registry database adjusted for anticipated prior or concurrent thiopurine use in a CD population. Results A total of 5025 patients were evaluated (16680.4 PY of adalimumab registry exposure, ≈3 years/patient mean follow-up). Registry treatment-emergent AEs included 4129 serious AEs (n = 1853 [36.9%]; 24.8 E/100 PY), 792 serious infections (n = 556 [11.1%]; 4.7 E/100 PY), and 134 malignancies (n = 116 [2.3%]; 0.8 E/100 PY), including ten lymphomas. The observed lymphoma rate (0.060 E/100 PY) was lower than the estimated background rate (0.084 E/100 PY), and the upper bound of the one-sided 95% CI of the observed rate (0.102 E/100 PY) was lower than double the estimated rate (0.168 E/100 PY). Conclusions PYRAMID is the longest prospective adalimumab study in routine clinical practice, with up to 6 years of follow-up. No new safety signals were reported. The pre-specified registry objective of ruling out a doubling of lymphoma risk with adalimumab was met

Association of Biomarker Cutoffs and Endoscopic Outcomes in Crohn's Disease: A Post Hoc Analysis From the CALM Study

Abstract Background CALM was a randomized phase 3 trial in patients with Crohn's disease (CD) that demonstrated improved endoscopic outcomes when treatment was escalated based on cutoffs for inflammatory biomarkers, fecal calprotectin (FC), C-reactive protein (CRP), and CD Activity Index (CDAI) remission vs CDAI response alone. The purpose of this post hoc analysis of CALM was to identify drivers of treatment escalation and evaluate the association between biomarker cutoff concentrations and endoscopic end points. Methods The proportion of patients achieving CD Endoscopic Index of Severity (CDEIS) &lt;4 and no deep ulcers 48 weeks after randomization was evaluated according to CRP &lt;5 mg/L or ≥5 mg/L and FC &lt;250 μg/g or ≥250 μg/g. Subgroup analyses were performed according to disease location, and sensitivity analyses were conducted in patients with elevated CRP and/or FC at baseline. The association between endoscopic end points and biomarker cutoffs was performed using χ 2 test. Results The proportion of patients who achieved the primary end point CDEIS &lt;4 and no deep ulcers was significantly greater for those with FC &lt;250 µg/g (74%; P &lt; 0.001), with an additive effect for CRP &lt;5 mg/L. The association of FC &lt;250 µg/g with improved endoscopic outcomes was independent of disease location, although the greatest association was observed for ileocolonic disease. Fecal calprotectin &lt;250 µg/g, CRP &lt;5 mg/L, and CDAI &lt;150 gave a sensitivity/specificity of 72%/63% and positive/negative predictive values of 86%/42% for CDEIS &lt;4 and no deep ulcers 48 weeks after randomization. Conclusion This post hoc analysis of CALM demonstrated that a cutoff of FC &lt;250 µg/g is a useful surrogate marker for mucosal healing in CD

Fecal microbiota transplantation as novel therapy in gastroenterology : A systematic review

AIM: To study the clinical efficacy and safety of Fecal microbiota transplantation (FMT). We systematically reviewed FMT used as clinical therapy. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library and Conference proceedings from inception to July, 2013. Treatment effect of FMT was calculated as the percentage of patients who achieved clinical improvement per patient category, on an intention-to-treat basis. RESULTS: We included 45 studies; 34 on Clostridium difficile-infection (CDI), 7 on inflammatory bowel disease, 1 on metabolic syndrome, 1 on constipation, 1 on pouchitis and 1 on irritable bowel syndrome (IBS). In CDI 90% resolution of diarrhea in 33 case series (n = 867) was reported, and 94% resolution of diarrhea after repeated FMT in a randomized controlled trial (RCT) (n = 16). In ulcerative colitis (UC) remission rates of 0% to 68% were found (n = 106). In Crohn's disease (CD) (n = 6), no benefit was observed. In IBS, 70% improvement of symptoms was found (n = 13). 100% Reversal of symptoms was observed in constipation (n = 3). In pouchitis, none of the patients (n = 8) achieved remission. One RCT showed significant improvement of insulin sensitivity in metabolic syndrome (n = 10). Serious adverse events were rare. CONCLUSION: FMT is highly effective in CDI, and holds promise in UC. As for CD, chronic constipation, pouchitis and IBS data are too limited to draw conclusions. FMT increases insulin sensitivity in metabolic syndrome.Peer reviewe