Gilaad G. Kaplan

Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.

BACKGROUND & AIMS We conducted a systematic review to determine changes in the worldwide incidence and prevalence of ulcerative colitis (UC) and Crohns disease (CD) in different regions and with time. METHODS We performed a systematic literature search of MEDLINE (1950-2010; 8103 citations) and EMBASE (1980-2010; 4975 citations) to identify studies that were population based, included data that could be used to calculate incidence and prevalence, and reported separate data on UC and/or CD in full manuscripts (n = 260). We evaluated data from 167 studies from Europe (1930-2008), 52 studies from Asia and the Middle East (1950-2008), and 27 studies from North America (1920-2004). Maps were used to present worldwide differences in the incidence and prevalence of inflammatory bowel diseases (IBDs); time trends were determined using joinpoint regression. RESULTS The highest annual incidence of UC was 24.3 per 100,000 person-years in Europe, 6.3 per 100,000 person-years in Asia and the Middle East, and 19.2 per 100,000 person-years in North America. The highest annual incidence of CD was 12.7 per 100,000 person-years in Europe, 5.0 person-years in Asia and the Middle East, and 20.2 per 100,000 person-years in North America. The highest reported prevalence values for IBD were in Europe (UC, 505 per 100,000 persons; CD, 322 per 100,000 persons) and North America (UC, 249 per 100,000 persons; CD, 319 per 100,000 persons). In time-trend analyses, 75% of CD studies and 60% of UC studies had an increasing incidence of statistical significance (P < .05). CONCLUSIONS Although there are few epidemiologic data from developing countries, the incidence and prevalence of IBD are increasing with time and in different regions around the world, indicating its emergence as a global disease.

A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients.

BACKGROUND:We sought to determine nationwide, population-based trends in rates of Clostridium difficile (C. difficile) infection among hospitalized inflammatory bowel disease (IBD) patients in the United States, and to determine its mortality and economic impact.METHODS:We analyzed discharge records from the Nationwide Inpatient Sample, and used the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to identify Crohns disease (CD) and ulcerative colitis (UC) cases, and cases of C. difficile infection between 1998 and 2004. Temporal patterns of C. difficile incidence in IBD patients were compared to non-IBD gastroenterology patients and all-hospitalized patients. The impact of C. difficile on in-hospital mortality and resource utilization was quantified using multiple regression analysis.RESULTS:The prevalence of C. difficile among UC patients (37.3 per 1,000, 95% confidence interval [CI] 34.0–40.7 per 1,000) was higher than that among CD patients (10.9 per 1,000, 95% CI 9.9–12.0 per 1,000), non-IBD gastrointestinal (GI) patients (4.8 per 1,000, 95% CI 4.6–5.0 per 1,000), and general medical patients (4.5 per 1,000, 95% CI 4.2–4.7 per 1,000). C. difficile incidence nearly doubled among UC patients (26.6 per 1,000 to 51.2 per 1,000) over 7 yr. After adjustment for confounders, C. difficile infection was associated with greater mortality among patients with UC (odds ratio [OR] 3.79, 95% CI 2.84–5.06), but not CD (OR 1.66, 95% CI 0.75–3.66). C. difficile was also associated with 65% and 46% longer lengths of stay, which correlated with 63% and 46% higher average hospital charges, for CD and UC patients, respectively.CONCLUSIONS:C. difficile infection is a growing public health issue among hospitalized IBD patients, especially those with UC, and is associated with higher mortality and resource utilization, prompting the need for better preventative measures and early detection.

Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host.

Background: Fusobacterium nucleatum is a heterogeneous oral pathogen that is also a common resident of the human gut mucosa. Given that some strains of F. nucleatum are known to be invasive and proinflammatory in the oral mucosa, we compared strains isolated from patients with inflammatory bowel disease (IBD) with strains isolated from healthy controls to determine 1) whether this species was more commonly associated with IBD patients; and 2) whether gut‐derived F. nucleatum strains from IBD patients showed an increased capacity for invasion. Methods: Biopsy material was obtained from 56 adult patients undergoing colonoscopy for colon cancer screening purposes or assessment of irritable bowel syndrome status (34 patients), or to assess for presence of gastrointestinal disease (i.e., IBD or indeterminate colitis, 22 patients). We enumerated Fusobacterium spp. strains isolated from human gut biopsy material in a blinded fashion, and then compared the virulence potential of a subset of F. nucleatum strains using an invasion assay in a Caco‐2 model system. Results: Fusobacterium spp. were isolated from 63.6% of patients with gastrointestinal disease compared to 26.5% of healthy controls (P = 0.01). In total, 69% of all Fusobacterium spp. recovered from patients were identified as F. nucleatum. F. nucleatum strains originating from inflamed biopsy tissue from IBD patients were significantly more invasive in a Caco‐2 cell invasion assay than strains that were isolated from healthy tissue from either IBD patients or control patients (P < 0.05 to 0.001). Conclusions: This study indicates that colonization of the intestinal mucosa by highly invasive strains of F. nucleatum may be a useful biomarker for gastrointestinal disease. (Inflamm Bowel Dis 2011;)

Impact of Hospital Volume on Postoperative Morbidity and Mortality Following a Colectomy for Ulcerative Colitis

BACKGROUND & AIMS Postoperative morbidity and mortality following a colectomy for ulcerative colitis (UC) has been primarily reported from tertiary care referral centers that perform a high volume of operations; however, the postoperative outcomes among nonselected hospitals are not known. We set out to evaluate postoperative morbidity and mortality using a nationally representative database and to determine the factors that influenced outcomes. METHODS We analyzed the 1995-2005 Nationwide Inpatient Sample to identify 7108 discharges for UC patients who underwent a total abdominal colectomy. The effects of hospital volume on postoperative morbidity and mortality were evaluated in logistic regression models adjusting for demographic and clinical factors. RESULTS Postoperative mortality and morbidity rates were 2.3% and 30.8%, respectively. Most operations were performed in low-volume hospitals that had an increased risk of death (adjusted odds ratio [aOR], 2.42; 95% confidence interval [CI]: 1.26-4.63). In-hospital mortality was increased in patients who were admitted emergently (aOR, 5.40; 95% CI: 3.48-8.40), aged 60-80 years (aOR, 8.70; 95% CI: 3.30-22.92), and those with Medicaid (aOR, 4.29; 95% CI: 2.13-8.66). Emergently admitted UC patients whose surgery was performed 6 days after their admission had significantly increased likelihood of in-hospital death (aOR, 2.12; 95% CI: 1.13-3.97). CONCLUSIONS Postoperative mortality was lowest in hospitals that performed the highest volume of operations. Increasing the proportion of total colectomies performed in high-volume hospitals may improve clinical outcomes for patients with UC.

The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis.

OBJECTIVES:The epidemiology of primary sclerosing cholangitis (PSC) has been incompletely assessed by population-based studies. We therefore conducted a population-based study to determine: (a) incidence rates of large and small duct PSC in adults and children, (b) the risk of inflammatory bowel disease on developing PSC, and (c) patterns of clinical presentation with the advent of magnetic resonance cholangiopancreatography (MRCP).METHODS:All residents of the Calgary Health Region diagnosed with PSC between 2000 and 2005 were identified by medical records, endoscopic, diagnostic imaging, and pathology databases. Demographic and clinical information were obtained. Incidence rates were determined and risks associated with PSC were reported as rate ratios (RR) with 95% confidence intervals (CI).RESULTS:Forty-nine PSC patients were identified for an age- and gender-adjusted annual incidence rate of 0.92 cases per 100,000 person-years. The incidence of small duct PSC was 0.15/100,000. In children the incidence rate was 0.23/100,000 compared with 1.11/100,000 in adults. PSC risk was similar in Crohns disease (CD; RR 220.0, 95% CI 132.4–343.7) and ulcerative colitis (UC; RR 212.4, 95% CI 116.1–356.5). Autoimmune hepatitis overlap was noted in 10% of cases. MRCP diagnosed large duct PSC in one-third of cases. Delay in diagnosis was common (median 8.4 months). A minority had complications at diagnosis: cholangitis (6.1%), pancreatitis (4.1%), and cirrhosis (4.1%).CONCLUSIONS:Pediatric cases and small duct PSC are less common than adult large duct PSC. Surprisingly, the risk of developing PSC in UC and CD was similar. Autoimmune hepatitis overlap was noted in a significant minority of cases.

Incidence of primary sclerosing cholangitis: A systematic review and meta‐analysis

Incidence studies of primary sclerosing cholangitis (PSC) are important for describing the diseases burden and for shedding light on the diseases etiology. The purposes of this study were to conduct a systematic review of the incidence studies of PSC with a meta‐analysis and to investigate possible geographic variations and temporal trends in the incidence of the disease. A systematic literature search of MEDLINE (1950‐2010) and Embase (1980‐2010) was conducted to identify studies investigating the incidence of PSC. The incidence of PSC was summarized with an incidence rate (IR) and 95% confidence intervals. The test of heterogeneity was performed with the Q statistic. Secondary variables extracted from the articles included the following: the method of case ascertainment, the country, the time period, the age, the male/female incidence rate ratio (IRR), and the incidence of PSC subtypes (small‐duct or large‐duct PSC and inflammatory bowel disease). Stratified and sensitivity analyses were performed to explore heterogeneity between studies and to assess effects of study quality. Time trends were used to explore differences in the incidence across time. The search retrieved 1669 potentially eligible citations; 8 studies met the inclusion criteria. According to a random‐effects model, the pooled IR was 0.77 (0.45‐1.09) per 100,000 person‐years. However, significant heterogeneity was observed between studies (P < 0.001). Sensitivity analyses excluding non–population‐based studies increased the overall IR to 1.00 (0.82‐1.17) and eliminated the heterogeneity between studies (P = 0.08). The IRR for males versus females was 1.70 (1.34‐2.07), and the median age was 41 years (35‐47 years). All studies investigating time trends reported an overall increase in the incidence of PSC. Conclusion: The incidence of PSC is similar in North American and European countries and continues to increase over time. Incidence data from developing countries are lacking, and this limits our understanding of the global incidence of PSC. (HEPATOLOGY 2011;)

Comparative Effectiveness of Immunosuppressants and Biologics for Inducing and Maintaining Remission in Crohn's Disease: A Network Meta-analysis

BACKGROUND & AIMS There is controversy regarding the best treatment for patients with Crohns disease because of the lack of direct comparative trials. We compared therapies for induction and maintenance of remission in patients with Crohns disease, based on direct and indirect evidence. METHODS We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Central databases, through June 2014. We identified randomized controlled trials (N = 39) comparing methotrexate, azathioprine/6-mercaptopurine, infliximab, adalimumab, certolizumab, vedolizumab, or combined therapies with placebo or an active agent for induction and maintenance of remission in adult patients with Crohns disease. Pairwise treatment effects were estimated through a Bayesian random-effects network meta-analysis and reported as odds ratios (OR) with a 95% credible interval (CrI). RESULTS Infliximab, the combination of infliximab and azathioprine (infliximab + azathioprine), adalimumab, and vedolizumab were superior to placebo for induction of remission. In pair-wise comparisons of anti-tumor necrosis factor agents, infliximab + azathioprine (OR, 3.1; 95% CrI, 1.4-7.7) and adalimumab (OR, 2.1; 95% CrI, 1.0-4.6) were superior to certolizumab for induction of remission. All treatments were superior to placebo for maintaining remission, except for the combination of infliximab and methotrexate. Adalimumab, infliximab, and infliximab + azathioprine were superior to azathioprine/6-mercaptopurine: adalimumab (OR, 2.9; 95% CrI, 1.6-5.1), infliximab (OR, 1.6; 95% CrI, 1.0-2.5), infliximab + azathioprine (OR, 3.0; 95% CrI, 1.7-5.5) for maintenance of remission. Adalimumab and infliximab + azathioprine were superior to certolizumab: adalimumab (OR, 2.5; 95% CrI, 1.4-4.6) and infliximab + azathioprine (OR, 2.6; 95% CrI, 1.3-6.0). Adalimumab was superior to vedolizumab (OR, 2.4; 95% CrI, 1.2-4.6). CONCLUSIONS Based on a network meta-analysis, adalimumab and infliximab + azathioprine are the most effective therapies for induction and maintenance of remission of Crohns disease.

Quantitative Metabolomic Profiling of Serum, Plasma, and Urine by 1H NMR Spectroscopy Discriminates between Patients with Inflammatory Bowel Disease and Healthy Individuals

Serologic biomarkers for inflammatory bowel disease (IBD) have yielded variable differentiating ability. Quantitative analysis of a large number of metabolites is a promising method to detect IBD biomarkers. Human subjects with active Crohn’s disease (CD) and active ulcerative colitis (UC) were identified, and serum, plasma, and urine specimens were obtained. We characterized 44 serum, 37 plasma, and 71 urine metabolites by use of 1H NMR spectroscopy and “targeted analysis” to differentiate between diseased and non-diseased individuals, as well as between the CD and UC cohorts. We used multiblock principal component analysis and hierarchical OPLS-DA for comparing several blocks derived from the same “objects” (e.g., subject) to examine differences in metabolites. In serum and plasma of IBD patients, methanol, mannose, formate, 3-methyl-2-oxovalerate, and amino acids such as isoleucine were the metabolites most prominently increased, whereas in urine, maximal increases were observed for mannitol, allantoin, xylose, and carnitine. Both serum and plasma of UC and CD patients showed significant decreases in urea and citrate, whereas in urine, decreases were observed, among others, for betaine and hippurate. Quantitative metabolomic profiling of serum, plasma, and urine discriminates between healthy and IBD subjects. However, our results show that the metabolic differences between the CD and UC cohorts are less pronounced.

The Inflammatory Bowel Diseases and Ambient Air Pollution: A Novel Association

OBJECTIVES:The inflammatory bowel diseases (IBDs) emerged after industrialization. We studied whether ambient air pollution levels were associated with the incidence of IBD.METHODS:The health improvement network (THIN) database in the United Kingdom was used to identify incident cases of Crohns disease (n=367) or ulcerative colitis (n=591), and age- and sex-matched controls. Conditional logistic regression analyses assessed whether IBD patients were more likely to live in areas of higher ambient concentrations of nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matter <10μm (PM10), as determined by using quintiles of concentrations, after adjusting for smoking, socioeconomic status, non-steroidal anti-inflammatory drugs (NSAIDs), and appendectomy. Stratified analyses investigated effects by age.RESULTS:Overall, NO2, SO2, and PM10 were not associated with the risk of IBD. However, individuals ≤23 years were more likely to be diagnosed with Crohns disease if they lived in regions with NO2 concentrations within the upper three quintiles (odds ratio (OR)=2.31; 95% confidence interval (CI)=1.25–4.28), after adjusting for confounders. Among these Crohns disease patients, the adjusted OR increased linearly across quintile levels for NO2 (P=0.02). Crohns disease patients aged 44–57 years were less likely to live in regions of higher NO2 (OR=0.56; 95% CI=0.33–0.95) and PM10 (OR=0.48; 95% CI=0.29–0.80). Ulcerative colitis patients ≤25 years (OR=2.00; 95% CI=1.08–3.72) were more likely to live in regions of higher SO2; however, a dose–response effect was not observed.CONCLUSIONS:On the whole, air pollution exposure was not associated with the incidence of IBD. However, residential exposures to SO2 and NO2 may increase the risk of early-onset ulcerative colitis and Crohns disease, respectively. Future studies are needed to explore the age-specific effects of air pollution exposure on IBD risk.

Weekend Versus Weekday Admission and Mortality From Gastrointestinal Hemorrhage Caused by Peptic Ulcer Disease

BACKGROUND & AIMS Management of upper gastrointestinal bleeding (UGIB) often requires urgent endoscopic intervention; limitations in its availability on weekends might be associated with increased mortality, compared with patients admitted on weekdays. METHODS We used the 1993-2005 U.S. Nationwide Inpatient Sample to identify patients hospitalized for UGIB caused by peptic ulceration. Differences in in-hospital mortality between patients admitted on weekends and weekdays were evaluated by using logistic regression models, adjusting for patient and clinical factors including the timing of upper endoscopy. RESULTS Between 1993 and 2005, there were 237,412 admissions to 3,166 hospitals for peptic ulcer-related UGIB. Compared with patients admitted on a weekday, those admitted on the weekend had an increased risk of death (3.4% vs 3.0%; adjusted odds ratio [OR], 1.08; 95% confidence interval [CI], 1.02-1.15), higher rates of surgical intervention (3.4% vs 3.1%; OR, 1.09; 95% CI, 1.03-1.15), prolonged hospital stays, and increased hospital charges (P < .0001 for all comparisons). Patients admitted on the weekend had a longer mean time to endoscopy (2.21 +/- 0.01 vs 2.06 +/- 0.01 days; P < .0001) and were less likely to undergo endoscopy on the day of admission (30% vs 34%; P < .0001). After adjusting for the timing of endoscopy, weekend admission remained an independent predictor of increased mortality (OR, 1.12; 95% CI, 1.05-1.20). CONCLUSIONS Patients admitted to hospital on the weekend for peptic ulcer-related hemorrhage have higher mortality and more frequently undergo surgery. Although wait times for endoscopy are prolonged in patients hospitalized on the weekend, this delay does not appear to mediate the weekend effect for mortality.