The inflammatory bowel diseases (IBDs) are chronic immune-mediated inflammatory disorders, including ulcerative colitis (UC) and Crohn's disease (CD). IBD results from a complex interplay between ...environmental, microbial, and genetic factors to create an abnormal immunological response leading to intestinal inflammation. Many pathways driving inflammation have been described, and different pathways may predominate in an individual patient. The interleukin (IL)-23 pathway plays a key role in IBD pathogenesis through promoting a pathological Th17 response. Targeting IL-23 is effective in the treatment of IBD. Ustekinumab, a monoclonal antibody targeting the shared p40 subunit of IL-12/23, is approved for treatment of moderate-to-severe CD and UC. Specific IL-23p19 antagonists are in development and promising results from phase II trials of mirikizumab and risankizumab underscore the potential for this class of treatment. In this review, we summarize the mechanisms of action and the evidence from clinical trials supporting the efficacy and safety of different IL-23 antagonists for IBD.
Assessment of disease activity is essential for developing and determining appropriate therapy in patients with ulcerative colitis (UC). Validated clinical and endoscopic scoring systems have been ...established to accurately define disease activity. Clinical and endoscopic treatment targets have also been proposed, with gastroenterologists encouraged to optimize medical therapy to achieve these targets. Recently, histology has been recognized as an important prognostic factor and potential treatment target in patients with UC.
This review summarizes the recent literature regarding histologic scoring indices in UC and offers practical guidance to gastroenterologists on how to interpret histologic data.
Substantial evidence indicates that histology accurately predicts clinical relapse, hospitalization, corticosteroid use, and development of dysplasia. Furthermore, compared with endoscopy, findings suggest that histology may be more predictive of these outcomes. Because microscopic disease activity can persist in the absence of clinical or endoscopic disease activity, histology may be the ideal marker of inflammation. Standardized definitions of histologic response and remission and a biopsy procurement protocol are needed to guide clinical decision making. It is recommended that overall assessment of disease severity be determined according to the worst affected biopsy fragment. Crypt architectural distortion, basal plasmacytosis, and neutrophilic activity should be reported. A 5-category classification system based on disease chronicity/activity and basal plasmacytosis is proposed. It is not yet necessary to report on the degree of mucosal eosinophilia or use a validated scoring system, although the latter may aid in determining therapeutic response.
Although rarely used to measure inflammation and guide therapy, histologic disease activity is predictive of important clinical outcomes in UC. Randomized controlled trials are needed to determine whether histology should function as a treatment target.
Summary
Background
Stricturing Crohn's disease (CD) occurs most commonly in the terminal ileum and poses a clinical problem. Cross‐sectional imaging modalities such as intestinal ultrasound (IUS), ...computed tomography enterography (CTE), and magnetic resonance enterography (MRE) allow for assessment of the entire bowel wall and associated peri‐enteric findings. Radiologic definitions of strictures have been developed for CTE and MRE; their reliability and responsiveness are being evaluated in index development programs. A comprehensive assessment strategy for strictures using IUS is needed.
Aims
To provide a detailed summary of definitions, diagnosis and monitoring of strictures on IUS as well as technical aspects of image acquisition.
Methods
We searched four databases up to 6 January 2024. Two‐stage screening was done in duplicate. We assessed risk of bias using QUADAS‐2.
Results
There were 56 studies eligible for inclusion. Definitions for strictures on IUS are heterogeneous, but the overall accuracy for diagnosis of strictures is high. The capability of IUS for characterising inflammation versus fibrosis in strictures is not accurate enough to be used in clinical practice or trials. We summarise definitions for improvement of strictures on IUS, and discuss parameters for image acquisition and standardisation.
Conclusions
This systematic review is the first step for a structured program to develop a stricture IUS index for CD.
Standard definitions of Crohn's disease (CD) strictures on intestinal ultrasound (IUS) have yet to be described in a comprehensive systematic review. This systematic review identifies criteria for the definition, diagnosis and therapeutic assessment of small bowel CD strictures on IUS and summarises the technical parameters of image and video acquisition.
Background
Oral 5‐aminosalicylic (5‐ASA) preparations were intended to avoid the adverse effects of sulfasalazine (SASP) while maintaining its therapeutic benefits. Previously, it was found that ...5‐ASA drugs were more effective than placebo but had a statistically significant therapeutic inferiority relative to SASP. This updated review includes more recent studies and evaluates the effectiveness, dose‐responsiveness, and safety of 5‐ASA preparations used for maintenance of remission in quiescent ulcerative colitis.
Objectives
The primary objectives were to assess the efficacy, dose‐responsiveness and safety of oral 5‐ASA compared to placebo, SASP, or 5‐ASA comparators for maintenance of remission in quiescent ulcerative colitis. A secondary objective was to compare the efficacy and safety of once daily dosing of oral 5‐ASA with conventional (two or three times daily) dosing regimens.
Search methods
A literature search for relevant studies (inception to 9 July 2015) was performed using MEDLINE, EMBASE and the Cochrane Library. Review articles and conference proceedings were also searched to identify additional studies.
Selection criteria
Studies were accepted for analysis if they were randomized controlled trials with a minimum treatment duration of six months. Studies of oral 5‐ASA therapy for treatment of patients with quiescent ulcerative colitis compared with placebo, SASP or other 5‐ASA formulations were considered for inclusion. Studies that compared once daily 5‐ASA treatment with conventional dosing of 5‐ASA and 5‐ASA dose ranging studies were also considered for inclusion.
Data collection and analysis
The primary outcome was the failure to maintain clinical or endoscopic remission. Secondary outcomes included adherence, adverse events, withdrawals due to adverse events, and withdrawals or exclusions after entry. Trials were separated into five comparison groups: 5‐ASA versus placebo, 5‐ASA versus sulfasalazine, once daily dosing versus conventional dosing, 5‐ASA versus comparator 5‐ASA formulation, and 5‐ASA dose‐ranging. Placebo‐controlled trials were subgrouped by dosage. Once daily versus conventional dosing studies were subgrouped by formulation. 5‐ASA‐controlled trials were subgrouped by common 5‐ASA comparators (e.g. Asacol and Salofalk). Dose‐ranging studies were subgrouped by 5‐ASA formulation. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. Data were analyzed on an intention‐to‐treat basis.
Main results
Forty‐one studies (8928 patients) were included. The majority of included studies were rated as low risk of bias. Ten studies were rated at high risk of bias. Seven of these studies were single‐blind and three studies were open‐label. However, two open‐label studies and four of the single‐blind studies utilized investigator performed endoscopy as an endpoint, which may protect against bias. 5‐ASA was significantly superior to placebo for maintenance of clinical or endoscopic remission. Forty‐one per cent of 5‐ASA patients relapsed compared to 58% of placebo patients (7 studies, 1298 patients; RR 0.69, 95% CI 0.62 to 0.77). There was a trend towards greater efficacy with higher doses of 5‐ASA with a statistically significant benefit for the 1 to 1.9 g/day (RR 0.65; 95% CI 0.56 to 0.76) and the > 2 g/day subgroups (RR 0.73, 95% CI 0.60 to 0.89). SASP was significantly superior to 5‐ASA for maintenance of remission. Forty‐eight per cent of 5‐ASA patients relapsed compared to 43% of SASP patients (12 studies, 1655 patients; RR 1.14, 95% CI 1.03 to 1.27). A GRADE analysis indicated that the overall quality of the evidence for the primary outcome for the placebo and SASP‐controlled studies was high. No statistically significant differences in efficacy or adherence were found between once daily and conventionally dosed 5‐ASA. Twenty‐nine per cent of once daily patients relapsed over 12 months compared to 31% of conventionally dosed patients (8 studies, 3127 patients; RR 0.91, 95% CI 0.82 to 1.01). Eleven per cent of patients in the once daily group failed to adhere to their medication regimen compared to 9% of patients in the conventional dosing group (6 studies, 1462 patients; RR 1.22, 95% CI 0.91 to 1.64). There does not appear to be any difference in efficacy among the various 5‐ASA formulations. Forty‐four per cent of patients in the 5‐ASA group relapsed compared to 41% of patients in the 5‐ASA comparator group (6 studies, 707 patients; RR 1.08, 95% CI 0.91 to 1.28). A pooled analysis of two studies showed no statistically significant difference in efficacy between Balsalazide 6 g and 3 g/day. Twenty‐three per cent of patients in the 6 g/day group relapsed compared to 33% of patients in the 3 g/day group (216 patients; RR 0.76; 95% CI 0.45 to 2.79). One study found Balsalazide 4 g to be superior to 2 g/day. Thirty‐seven per cent of patients in the 4 g/day Balsalazide group relapsed compared to 55% of patients in the 2 g/day group (133 patients; RR 0.66; 95% CI 0.45 to 0.97). One study found a statistically significant difference between Salofalk granules 3 g and 1.5 g/day. Twenty‐five per cent of patients in the Salofalk 3 g/day group relapsed compared to 39% of patients in the 1.5 g/day group (429 patients; RR 0.65; 95% CI 0.49 to 0.86). Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia, and nasopharyngitis. There were no statistically significant differences in the incidence of adverse events between 5‐ASA and placebo, 5‐ASA and SASP, once daily and conventionally dosed 5‐ASA, 5‐ASA and comparator 5‐ASA formulations and 5‐ASA dose ranging studies. The trials that compared 5‐ASA and SASP may have been biased in favour of SASP because most trials enrolled patients known to be tolerant to SASP which may have minimized SASP‐related adverse events.
Authors' conclusions
5‐ASA was superior to placebo for maintenance therapy in ulcerative colitis. However, 5‐ASA had a statistically significant therapeutic inferiority relative to SASP. Oral 5‐ASA administered once daily is as effective and safe as conventional dosing for maintenance of remission in quiescent ulcerative colitis. There does not appear to be any difference in efficacy or safety between the various formulations of 5‐ASA. Patients with extensive ulcerative colitis or with frequent relapses may benefit from a higher dose of maintenance therapy. High dose therapy appears to be as safe as low dose and is not associated with a higher incidence of adverse events.
Patients with longstanding ulcerative colitis (UC) and colonic Crohn's disease (CD) have an increased risk of colorectal cancer (CRC). We assess the effectiveness of endoscopic surveillance in ...patients with inflammatory bowel disease (IBD) for diagnosing CRC and reducing CRC-related mortality.
MEDLINE, EMBASE, and CENTRAL were searched from inception to 19 September 2016. Randomized controlled trials (RCTs), observational cohorts, or case-control studies assessing any form of endoscopic surveillance for early CRC detection were eligible for inclusion; studies without a comparison non-surveillance group were excluded. The primary outcome was rate of CRC detection. Secondary outcomes were rate of early (Duke stage A and B) versus late (Duke stage C & D) CRC detection and rate of CRC-related death. Data were pooled using fixed or random effects models based on the degree of heterogeneity; pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method.
Five observational studies evaluating 7199 IBD patients were included; no RCTs met criteria for inclusion. There are limited new studies evaluating this clinical question (last included study published 2014). There was a significantly higher rate of cancer detection in the non-surveillance group (3.2%, 135/4256) compared to the surveillance group (1.8%, 53/2895) (OR 0.58 (95% CI: 0.42-0.80), p < 0.001). In four pooled studies, there was a significantly lower rate of CRC-associated death in the surveillance group (8.5%, 15/176) compared to the non-surveillance group (22.3%, 79/354) (OR 0.36 (95% CI: 0.19-0.69), p = 0.002). In two pooled studies, there was a significantly higher rate of early-stage CRC detection in the surveillance group (15.5%, 17/110) compared to the non-surveillance group (7.7%, 9/117) (OR 5.40 (95% CI: 1.51-19.30), p = 0.009).
Colonoscopic surveillance in IBD is associated with a reduction in CRC development and CRC-associated death, as well as increased detection of early-stage CRC.
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