Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer (CRC). Studies examining the magnitude of this association have yielded conflicting results. We performed ...a meta-analysis of population-based cohort studies to determine the risk of CRC in patients with UC.
We used MEDLINE, EMBASE, Cochrane, and CINAHL to perform a systematic literature search. We included 8 studies in the meta-analysis on the basis of strict inclusion and exclusion criteria. We calculated pooled standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) for risk of CRC in patients with UC and performed meta-regression analyses of the effect of cohort size, calendar period, observation time, percentage with proctitis, and rates of colectomy on the risk of CRC.
An average of 1.6% of patients with UC was diagnosed with CRC during 14 years of follow-up. SIRs ranged from 1.05 to 3.1, with a pooled SIR of 2.4 (95% CI, 2.1-2.7). Men with UC had a greater risk of CRC (SIR, 2.6; 95% CI, 2.2-3.0) than women (SIR, 1.9; 95% CI, 1.5-2.3). Young age was a risk factor for CRC (SIR, 8.6; 95% CI, 3.8-19.5; although this might have resulted from small numbers), as was extensive colitis (SIR, 4.8; 95% CI, 3.9-5.9). In meta-regression analyses, only cohort size was associated with risk of CRC.
In population-based cohorts, UC increases the risk of CRC 2.4-fold. Male sex, young age at diagnosis with UC, and extensive colitis increase the risk.
Summary
Background
Histologic healing is emerging as a new therapeutic goal in both routine practice and clinical trials in ulcerative colitis (UC). However, it requires repeated endoscopies and ...biopsies. Faecal calprotectin is a non‐invasive marker of mucosal healing (endoscopic and histologic healing).
Aim
To conduct a systematic review to clarify the correlation between faecal calprotectin levels and histologic activity in UC patients.
Methods
We searched PubMed/MEDLINE, EMBASE and Web of Science through September 2019 to identify studies in patients with confirmed diagnosis of UC, reporting the correlation between faecal calprotectin levels and histologic analysis.
Results
Twelve studies enrolling 1168 patients were included in the final review. Histologic remission was defined according to nonvalidated scores in five articles and using partially validated scores in seven articles. Faecal calprotectin values were measured in 6 of 12 studies (50%) with the same kit, while the remaining six studies adopted individually different kits. A clear correlation between faecal calprotectin levels and histology was showed in all included studies. Eleven different faecal calprotectin cut‐off points were identified to distinguish histological remission from histological activity, ranging from 40.5 to 250 μg/g.
Conclusions
Faecal calprotectin can be used to predict histologic remission in patients with UC, but the cut‐off level varies across studies, according to the test used to measure this biomarker and according to the definition of histologic remission. Larger prospective studies using validated histologic indexes are needed to identify a globally accepted faecal calprotectin cut‐off level to discriminate between histologic remission and histologically active disease.
Summary
Background
Inflammatory bowel disease (IBD) is a significant health problem in the industrialised world, currently increasing in developing countries. Understanding the global burden of IBD ...is important to tackle increasing disease occurrence.
Aim
To investigate the GBD (Global Burden of Disease) 2017 Study Database summarising and critically evaluating the global burden of IBD
Methods
We presented age‐standardised prevalence estimates, disability‐adjusted life years (DALYs) and its components: years lived with disability (YLDs) and years of life lost (YLLs) due to premature mortality. We reported these measures from 1990 to 2017 and stratified by region, socio‐demographic index (SDI), gender and age group.
Results
The latest IBD prevalence and burden estimates varied widely across regions, and were particularly elevated in high‐SDI countries. Despite an increasing prevalence from 1990 to 2017 (+6%), the IBD burden decreased (DALYs −12%). This decrease was driven by IBD‐associated premature mortality (YLLs −26%). This measure represented a high share of disease burden in low‐SDI countries (86% of DALYs), whereas disability constituted the predominant component in high‐SDI countries (71%) in 2017. Disease burden decreased particularly in children (DALYs −39% and YLLs −52%). In the last 10 years, however, prevalence plateaued in middle‐ to high‐SDI countries and steeply increased in low‐SDI countries.
Conclusions
These findings highlight significant improvements in IBD care in the last three decades, particularly in children. The global burden of IBD and premature mortality have progressively decreased. The increase in disease frequency observed in developing countries is worrying, especially considering the high associated premature mortality in these areas.
The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.
We evaluated ...ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg 320 patients or a weight-range-based dose that approximated 6 mg per kilogram of body weight 322) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks 172 patients or every 8 weeks 176) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale range, 0 to 12, with higher scores indicating more severe disease and no subscore >1 range, 0 to 3 on any of the four Mayo scale components).
The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.
Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).
Ulcerative colitis (UC) is a disease of the mucosal layer, and activity of the disease is assumed to be related to mucosal appearance. Mucosal healing has emerged as a major therapeutic goal in UC. ...Whether mucosal healing should be the ultimate therapeutic goal in these patients is unknown. Even when endoscopy suggests mucosal healing, evidence of histologic activity has been observed. Histologic healing requires complete recovery of the colonic mucosa, with absence of inflammation or structural changes. Histologic improvements have been linked with improved clinical outcomes, such as a reduced risk of relapse and need for surgery/hospitalization and a reduced risk of developing cancer. Hence, there is a rationale for aiming for histologic remission in UC. Numerous methods of classification of histologic activity in UC have been proposed, although only some of these are widely used. We review the current definitions of histologic remission, the range of scoring systems most commonly used, and the evidence of histologic improvement that is available from the latest therapies for UC. We also highlight questions that will require careful consideration if histologic remission is to become more widely used as an end point in clinical trials and a treatment goal in clinical practice.
Summary
Background
One of the greatest challenges in the current IBD clinical trial landscape is, perhaps, the recruitment and retention of eligible participants. Seamless testing of promising ...investigational compounds is paramount to address unmet needs, but this is hindered by a number of barriers, particularly patient concerns of placebo assignment.
Aims
To review the use of novel trial designs leveraging externally derived data to synthetically create control groups or augment existing ones, and to summarise the regulatory position on the use of external controls for market authorisation.
Methods
We conducted a PubMed literature search without restriction using search terms such as ‘external controls’ and ‘historical controls’ to identify relevant articles.
Results
External controls are increasingly being used outside the context of cancer and rare diseases, including IBD, and increasingly recognised by regulatory bodies. Such designs, particularly in earlier phase trials, can inform key nodes in drug development and permit evaluating efficacy of interventions without combating the ethical and numerical enrolment challenges described. However, the lack of randomisation and blinding subjects them to significant bias. Groups require robust statistical and computational approaches to ensure patient‐level data across groups are adequately balanced.
Conclusions
While this approach has several pitfalls, and is not robust enough to replace traditional randomised, placebo‐controlled trials, it may offer a compromise to address key research questions at a more rapid pace, with fewer patients, and lower cost.
Summary Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract, with increasing incidence worldwide. Crohn's disease might result from a complex interplay between genetic ...susceptibility, environmental factors, and altered gut microbiota, leading to dysregulated innate and adaptive immune responses. The typical clinical scenario is a young patient presenting with abdominal pain, chronic diarrhoea, weight loss, and fatigue. Assessment of disease extent and of prognostic factors for complications is paramount to guide therapeutic decisions. Current strategies aim for deep and long-lasting remission, with the goal of preventing complications, such as surgery, and blocking disease progression. Central to these strategies is the introduction of early immunosuppression or combination therapy with biologicals in high-risk patients, combined with a tight and frequent control of inflammation, and adjustment of therapy on the basis of that assessment (treat to target strategy). The therapeutic armamentarium for Crohn's disease is expanding, and therefore the need to develop biomarkers that can predict response to therapies will become increasingly important for personalised medicine decisions in the near future. In this Seminar, we provide a physician-oriented overview of Crohn's disease in adults, ranging from epidemiology and cause to clinical diagnosis, natural history, patient stratification and clinical management, and ending with an overview of emerging therapies and future directions for research.
The Food and Drug Administration (FDA) is moving from the Crohn's Disease Activity Index to patient-reported outcomes (PROs) and objective measures of disease, such as findings from endoscopy. PROs ...will become an important aspect of assessing activity of inflammatory bowel disease (IBD) and for labeling specific drugs for this disease. PROs always have been considered in the management of patients with rheumatoid arthritis or multiple sclerosis, and have included measurements of quality of life, disability, or fatigue. Several disease-specific scales have been developed to assess these PROs and commonly are used in clinical trials. Outcomes reported by patients in clinical trials of IBD initially focused on quality of life, measured by the Short-Form 36 questionnaire or disease-specific scales such as the Inflammatory Bowel Disease Questionnaire or its shorter version. Recently considered factors include fatigue, depression and anxiety, and work productivity, as measured by the Functional Assessment Chronic Illness Therapy-Fatigue, the Hospital Anxiety Depression, and the Work Productivity Activity Impairment Questionnaire, respectively. However, few data are available on how treatment affects these factors in patients with IBD. Although disability generally is recognized in patients with IBD, it is not measured. The international IBD disability index currently is being validated. None of the PROs currently used in IBD were developed according to FDA guidance for PRO development. PROs will be a major primary end point of future trials. FDA guidance is needed to develop additional PROs for IBD that can be incorporated into trials, to better compare patients' experience with different therapies.
Summary
Background
Uncertainty exists concerning the risk of infection and cancer associated with biologic therapies in elderly patients with inflammatory bowel disease (IBD).
Aims
To identify, ...synthesise and critically appraise the available evidence on the topic.
Methods
We systematically searched Medline/PubMed, Embase and Scopus, through October 2019, and recent conference proceedings, to identify studies investigating the risk of serious infections, opportunistic infections, any infection and cancer in elderly IBD patients (>60 years) exposed to biologics as compared to those unexposed to biologics. Two reviewers independently extracted study data and assessed each study’s risk of bias. We examined heterogeneity, and calculated summary effect estimates using fixed‐ and random effects models. Quality of evidence was determined with GRADE.
Results
We included 15 studies (one post hoc analysis of a randomised trial, nine cohort and five case‐control studies). Elderly IBD patients treated with biologics were at increased risk of developing serious infections (random effects summary relative risk: 2.70, 95% CI: 1.56‐4.66; seven studies; I2 = 57%) and opportunistic infections (3.16, 1.09‐9.20; four studies; I2 = 73%). The occurrence of any infection (1.67, 0.51‐5.43; five studies; I2 = 75%) and cancer (0.90, 0.64‐1.26; nine studies; I2 = 0%) was not significantly affected. Nevertheless, our confidence in the effect estimates is rather limited; the quality of evidence is low to very low.
Conclusions
Biologics are likely to increase the risk of serious and opportunistic infections in old IBD patients. Large prospective studies are needed to further assess the biologic treatments’ long‐term safety profile in this population.
LINKED CONTENT
This article is linked to Fumery et al papers. To view these articles, visit https://doi.org/10.1111/apt.17358 and https://doi.org/10.1111/apt.17401
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