Charles N. Bernstein

Toward an Integrated Clinical, Molecular and Serological Classification of Inflammatory Bowel Disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohns disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study

OBJECTIVE:The aim of this study was to determine the prevalence of the major extraintestinal manifestations of inflammatory bowel disease (IBD) and their relation to disease diagnosis and gender.METHODS:We used the population-based University of Manitoba IBD Database, which includes longitudinal files on all subjects of all health system contacts identified by International Classification of Diseases, 9th Revision, Clinical Modification codes for visit diagnosis. We extracted a cohort from our database, which included subjects with a known diagnosis of IBD for at least 10 yr. We then determined how many contacts each subject had for each of the following extraintestinal IBD-associated immune diseases: primary sclerosing cholangitis, ankylosing spondylitis, iritis/uveitis, pyoderma gangrenosum, and erythema nodosum. We calculated the prevalence of the extraintestinal diseases using an administrative definition of having at least five health system contacts for the diagnosis in question. This administrative definition has previously been validated in Crohns disease and ulcerative colitis (UC).RESULTS:A total of 6.2% of patients with IBD had one of six major extraintestinal diseases studied in this report. Only 0.3% of patients had multiple extraintestinal diseases. Iritis/uveitis was the most common extraintestinal disease of all assessed (2.2% of women and 1.1% of men). Iritis/uveitis was more common among women, particularly those with UC (3.8%). Primary sclerosing cholangitis was most common among men with UC (3%). Ankylosing spondylitis was more common among men, and the highest rate was seen among men with Crohns disease (2.7%). Pyoderma gangrenosum was more common in Crohns (1.2%) with no gender predilection. Erythema nodosum was similarly present in Crohns and UC but was more common among women (1.9%).Conclusions:The associations of immune mediated diseases in extraintestinal sites may help us to further our understanding of IBD pathogenesis, and it may help us in developing a paradigm of disease subsets.

Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis

The recommended approach to the increased risk of colorectal carcinoma in ulcerative colitis has been colonoscopic surveillance rather than prophylactic colectomy. This strategy is based on the assumption that dysplastic lesions can be detected before invasive cancer has developed. We have analysed published reports on dysplasia surveillance to find out whether this assumption is valid. Ten prospective studies (1225 patients) satisfied our criteria. Of 40 patients with dysplasia-associated mass or lesion (DALM) detected, 17 (43%) already had cancer at immediate colectomy. The risks of cancer at immediate colectomy were 42% (10 of 24 patients) for high-grade and 19% (3 of 16) for low-grade dysplasia. Of 47 patients found to have high-grade dysplasia after the initial colonoscopy, 15 (32%) had cancer. 16-29% of patients with untreated low-grade dysplasia progressed to DALM, high-grade dysplasia, or cancer. Of patients with indefinite results, 28% progressed to high-grade dysplasia and 9% to cancer, so continued surveillance is essential. The risk of progression to dysplasia was only 2.4% for patients whose initial result was negative, so surveillance could perhaps be less frequent for these patients. Immediate colectomy is essential for all patients diagnosed with high-grade or low-grade dysplasia. A diagnosis of dysplasia does not preclude the presence of invasive cancer. We believe that patients should be informed about the limitations of colonoscopic surveillance so that they can take part rationally in decision-making about their management.

The Epidemiology of Inflammatory Bowel Disease in Canada: A Population-Based Study

BACKGROUND:Previously, we have demonstrated a high incidence and prevalence of Crohns disease (CD) and ulcerative colitis (UC) in the Canadian province of Manitoba. However, the epidemiology of inflammatory bowel disease (IBD) in other regions of Canada has not been defined. The aim of this study was to estimate the incidence and prevalence of CD and UC in diverse regions of Canada and the overall burden of IBD in Canada.METHODS:We applied a common case identification algorithm, previously validated in Manitoba to the provincial health databases in British Columbia (BC), Alberta (AB), Saskatchewan (SK), Manitoba (MB), and Nova Scotia (NS) to determine the age-adjusted incidence rates per 100,000 person-years for 1998–2000 and prevalence per 100,000 for mid 2000 and to estimate the IBD burden in Canada. Poisson regression was used to assess differences in incidence rates and prevalence by gender, age, and province.RESULTS:The incidence rate for CD ranged from 8.8 (BC) to 20.2 (NS), and for UC ranged from 9.9 (BC) to 19.5 (NS). The prevalence of CD was approximately 15- to 20-fold higher than the incidence rate, ranging from 161 (BC) to 319 (NS). This was similar for the prevalence of UC, which ranged from 162 (BC) to 249 (MB). Adjusting for age and province, the female:male ratio for incidence ratio was 1.31 (p < 0.0001) for CD and 1.02 (n.s.) for UC and was mostly stable across the five provinces.CONCLUSIONS:Approximately 0.5% of the Canadian population has IBD. Canada has the highest incidence and prevalence of CD yet reported.

The Incidence of Fracture among Patients with Inflammatory Bowel Disease: A Population-Based Cohort Study

The prevalence of osteopenia among patients with inflammatory bowel disease ranges from 40% to 50%, and frank osteoporosis is seen in 2% to 30% of patients (1-5). These estimates are based on measurement of bone mineral density, in which osteoporosis is defined as a bone mass T-score less than 2.5 (6). Much has been written about the prevalence and causes of osteopenia, and a few reports have been published on the treatment of osteopenia in inflammatory bowel disease (7-9). However, the clinical importance of osteopenia among persons with inflammatory bowel disease is unclear because no data have been published on the actual risk for fracture in persons with inflammatory bowel disease. The most common fractures associated with osteoporosis are those of the hip, spine, and distal radius (10). Rib fractures are also of interest since they are common among persons with low bone mass (11). We sought to determine whether persons with inflammatory bowel disease had an increased risk for these fractures compared with persons without inflammatory bowel disease. Methods The incidence of fracture in a cohort of persons with inflammatory bowel disease was compared with that in a cohort of persons without inflammatory bowel disease, matched 1 to 10 to the inflammatory bowel disease cohort by age, sex, and geographic location of residence. The inflammatory bowel disease cohort (n =6027) consisted of persons in the population-based University of Manitoba IBD Database, which has been described elsewhere (12). In brief, the database was developed by using Manitoba Health administrative databases. Manitoba Health (Government of Manitoba) provides comprehensive health care coverage for residents of Manitoba, Canada (population, 1.14 million). Since Manitoba residents are not obliged to pay premiums for health care coverage, nonparticipation in the plan is rare. Manitoba Health maintains computerized databases of physician services and hospitalizations for all persons registered with the system. Each physician service record includes information on the identity of the patient, the date of service, services provided, and diagnosis, which is subsequently coded as a three-digit International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) code. After each hospitalization, a detailed abstract is created that includes up to 16 diagnoses coded as five-digit ICD-9-CM codes. By extracting physician service records and hospitalizations for all Manitoba residents from 1984 to 1997, we created a population-based database of all persons who had received a diagnosis of Crohn disease (ICD-9-CM code 555.xx) or ulcerative colitis (ulcerative colitis) (ICD-9-CM code 556.xx). The cohort of persons without inflammatory bowel disease was created by randomly selecting 10 persons without inflammatory bowel disease from the Manitoba Health population registry. These 60 270 controls were matched to persons with inflammatory bowel disease by year of birth, sex, and postal area of residence at the date of diagnosis of the index case of inflammatory bowel disease. The incidence of hospitalization for hip fracture was calculated by using the Manitoba Health administrative database for hospital discharge abstracts (using ICD-9-CM code 820.xx). Outpatient health system contacts and hospitalization contacts for spine fractures (ICD-9-CM code 806.xx), rib fractures (ICD-9-CM 807.0x to 807.1x) and wrist/forearm fractures (ICD-9-CM 813.xx) were analyzed in a similar fashion. Incidence rates were calculated on the basis of person-years of follow-up for 1984 to 1997. Incidence rate ratios (IRRs) and 95% CIs were calculated by comparing the incidence of fracture in persons with inflammatory bowel disease with that in controls, using Poisson regression. To determine whether enhanced physician contact and an increased frequency of radiography in persons with inflammatory bowel disease influenced the estimated incidence of rib, forearm, and spine fractures, we performed supplementary analyses in which we excluded all persons who had undergone radiography of the chest, ribs, abdomen, or spine in the 2 years before the date of fracture. The construction of the University of Manitoba IBD Database and its use in clinical studies were approved by the University of Manitoba Research Ethics Board and by the Access and Confidentiality Committee of Manitoba Health and was funded by the National Health and Research Development Program of Canada. Comparison of persons with inflammatory bowel disease with matched controls was performed without external funding. Results Person-years of follow-up were 21 340 for Crohn disease and 19 665 for ulcerative colitis. The mean age at the start of follow-up was 36.3 16.7 years for persons with Crohn disease and 42.0 18.0 years for persons with ulcerative colitis. Forty-one percent of persons with Crohn disease and 50% of those with ulcerative colitis were male. Overall, 405 incident fractures occurred among persons with inflammatory bowel disease, for an incidence of 98.8 per 10 000 persons (Table 1). The incidence of fractures among persons with inflammatory bowel disease increased with advancing age for all fracture sites (Table 1). This was particularly true for hip fractures, which occurred mostly among persons older than 60 years of age and were rare among persons younger than 40 years of age. The overall crude incidence rate of fractures was higher in persons with ulcerative colitis than those with Crohn disease. This finding reflects the older age distribution of persons with ulcerative colitis, since fracture rates were similar in each age stratum (Table 1). Table 1. Crude Incidence of Fracture among Persons with Inflammatory Bowel Disease in Manitoba, Canada, 19841997 Compared with controls, persons with inflammatory bowel disease had a significantly elevated incidence of fracture at the hip (IRR, 1.59 [95% CI, 1.27 to 2.00]; P<0.001), spine (IRR, 1.74 [CI, 1.34 to 2.24]; P<0.001), wrist/forearm (IRR, 1.33 [CI, 1.11 to 1.58]; P=0.001), and rib (IRR, 1.25 [CI, 1.02 to 1.52]; P=0.03) (Table 2). For these fractures combined, persons with inflammatory bowel disease had an increased incidence of approximately 40% (IRR, 1.41 [CI, 1.27 to 1.56]; P<0.001). The patterns of increased fracture incidence were similar in persons with Crohn disease and those with ulcerative colitis (Table 2) and in men and women with inflammatory bowel disease (data not shown). When fractures in persons who had had radiography in the previous 2 years were excluded from analysis, the results changed little for fractures of the spine (IRR, 1.81 [CI, 1.39 to 2.37]), forearm (IRR, 1.37 [CI, 1.16 to 1.63]), and rib (IRR, 1.27 [CI, 1.03 to 1.56]). Table 2. Age-Specific Incidence Rate Ratios for Fracture in Persons with Inflammatory Bowel Disease, Manitoba, Canada, 19841997 Discussion We found significantly increased rates of hip, spine, and forearm fractures among persons with inflammatory bowel disease compared with persons without this disease in the general population. Because our rates of fracture were calculated from administrative health data, it is important to discuss the accuracy of this data source. Inaccuracies in hospital discharge coding have been reported (13, 14). The accuracy of hospital discharge coding was recently reported for hip fracture admissions in Baltimore, Maryland, in which variations in comorbid diagnoses or complications on hospital face sheets ranged from 12% to 17% (15). However, the rate of miscoding hip fracture in the Baltimore hospitals studied is rare (Hawkes WG. Personal communication) and was found to be rare in studies using hospital discharge abstracts data in Pittsburgh, Pennsylvania; Portland, Oregon; and Minneapolis, Minnesota (Fox KM. Personal communication). Data from Manitoba have shown excellent correlation (>95%) for hip fracture on linkage between hospital separation diagnosis and physician billing data (16). Since fractures at the spine, rib, and forearm may not necessitate hospitalization and the accuracy of physician outpatient billing records is less certain, we are less confident in our estimates of the actual incidence of these fractures. Furthermore, spine or rib fracture may sometimes go undetected. This may introduce a detection bias, since patients with inflammatory bowel disease may have more frequent physician visits and radiography for other indications and therefore may be more likely to have these fractures diagnosed. To determine whether such bias accounted for increased rates of rib, spine, and forearm fracture, we conducted supplementary analyses excluding persons who had had radiography of the chest, ribs, spine, or abdomen in the 2 years before the fracture date. Results of this analysis did not change the overall results appreciably, suggesting that enhanced radiologic screening does not fully explain the higher rates of these fractures among persons with inflammatory bowel disease. Our finding of increased rates of fracture in persons with inflammatory bowel disease indicates that lower bone mineral density in this population is clinically relevant. It will now be important to delineate risk factors for low bone density and fracture in inflammatory bowel disease. Although use of corticosteroids in inflammatory bowel disease may be a factor (17), diminished bone mass in inflammatory bowel disease in the absence of corticosteroid use has been reported (18). Since treatment with bisphosphonates has been shown to ameliorate corticosteroid-induced osteoporosis (19), it will be particularly important to clarify the relative contribution of corticosteroid use to development of osteoporosis in inflammatory bowel disease. Other factors may also play a role. Studies have shown that patients with Crohn disease are more likely to smoke and patients with inflammatory bowel disease may have lower levels of sex hormones and ingest less than the recommended daily amount of calcium and

Depression and anxiety in inflammatory bowel disease: A review of comorbidity and management

Abstract While there has been a great deal of speculation over the years on the importance of emotional factors in inflammatory bowel disease (IBD), it is only in the last decade or so that studies with stronger designs have been available to clarify the nature of this relationship. This review considers recent evidence on the prevalence of anxiety and depressive disorders in IBD, the role of these disorders as a risk factor for IBD onset, the degree to which they affect the course of the IBD, and the contribution of corticosteroid treatment to psychiatric symptom onset. There is evidence that anxiety and depression are more common in patients with IBD and that the symptoms of these conditions are more severe during periods of active disease. The few studies that address the issue of anxiety and depression as risk factors for IBD do not yet provide enough information to support definite conclusions. There is evidence, however, that the course of the disease is worse in depressed patients. Treatment with corticosteroids can induce mood disorders or other psychiatric symptoms. The second part of the review focuses on patient management issues for those with comorbid anxiety or depression. Practical approaches to screening are discussed, and are recommended for routine use in the IBD clinic, especially during periods of active disease. We review evidence‐based pharmacological and psychological treatments for anxiety and depression and discuss practical considerations in treating these conditions in the context of IBD to facilitate overall management of the IBD patient.

High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease.

Background: It is not clear which species of bacteria may be involved in inflammatory bowel disease (IBD). One way of determining which bacteria might be likely candidates is to use culture-independent methods to identify microorganisms that are present in diseased tissues but not in controls. Aims: (1) To assess the diversity of microbial communities of biopsy tissue using culture-independent methods; (2) to culture the bacteria found in the tissues of patients with IBD but not in the controls; (3) to identify potential virulence factors associated with cultured bacteria. Methods: 84 biopsy specimens were collected from 15 controls, 13 patients with Crohn’s disease (CD) and 19 patients with ulcerative colitis (UC) from a population-based case–control study. Ribosomal intergenic spacer analysis (RISA) was conducted to identify unique DNA bands in tissues from patients with CD and UC that did not appear in controls. Results: RISA followed by DNA sequencing identified unique bands in biopsy specimens from patients with IBD that were classified as Escherichia coli. Targeted culture showed a significantly (p<0.05) higher number of Enterobacteriaceae in specimens from patients with IBD. The B2+D phylogenetic group, serine protease autotransporters (SPATE) and adherence factors were more likely to be associated with tissues from patients with UC and CD than with controls. Conclusions: The abundance of Enterobacteriaceae is 3–4 logs higher in tissues of patients with IBD and the B2+D phylogenetic groups are more prevalent in patients with UC and CD. The B2+D phylogenetic groups are associated with SPATE and adherence factors and may have a significant role in disease aetiology.

World Gastroenterology Organization Practice Guidelines for the Diagnosis and Management of IBD in 2010

Inflammatory bowel disease (IBD) represents a group of idiopathic, chronic, inflammatory intestinal conditions. Its two main disease categories are: Crohns disease (CD) and ulcerative colitis (UC), which feature both overlapping and distinct clinical and pathological features. While these diseases have, in the past, been most evident in the developed world, their prevalence in the developing world has been gradually increasing in recent decades. This poses unique issues in diagnosis and management which have been scarcely addressed in the literature or in extant guidelines. Depending on the nature of the complaints, investigations to diagnose either form of IBD or to assess disease activity will vary and will also be influenced by geographic variations in other conditions that might mimic IBD. Similarly, therapy varies depending on the phenotype of the disease being treated and available resources. The World Gastroenterology Organization has, accordingly, developed guidelines for diagnosing and treating IBD using a cascade approach to account for variability in resources in countries around the world.

Association Between the Use of Antibiotics in the First Year of Life and Pediatric Inflammatory Bowel Disease

OBJECTIVES:The development of commensal flora in infants has been shown to be sensitive to antibiotic use. Altered intestinal flora is thought to contribute to the etiology of inflammatory bowel disease (IBD), an idiopathic chronic condition. We aimed to determine if early use of antibiotics was associated with the development of IBD in childhood.METHODS:Nested case–control analysis of the population-based University of Manitoba Inflammatory Bowel Disease Epidemiologic Database was carried out. IBD status was determined from a validated administrative database definition. A total of 36 subjects diagnosed between 1996 and 2008 were matched to 360 controls, on the basis of age, sex, and geographic region. Antibiotic data were drawn from the Manitoba Drug Program Information Network, a comprehensive population-based database of all prescription drugs for all Manitobans dating back to 1995. Antibiotic use in the first year of life was compared between IBD cases and controls.RESULTS:The mean age at IBD diagnosis was 8.4 years. Twenty-one cases (58%) had one or more antibiotic dispensations in their first year of life compared with 39% of controls. Crohns disease was diagnosed in 75% of IBD cases. Those receiving one or more dispensations of antibiotics were at 2.9 times the odds (95% confidence interval: 1.2, 7.0) of being an IBD case.CONCLUSIONS:Subjects diagnosed with IBD in childhood are more likely to have used antibiotics in their first year of life.

Brain-gut interactions in inflammatory bowel disease.

Psycho-neuro-endocrine-immune modulation through the brain-gut axis likely has a key role in the pathogenesis of inflammatory bowel disease (IBD). The brain-gut axis involves interactions among the neural components, including (1) the autonomic nervous system, (2) the central nervous system, (3) the stress system (hypothalamic-pituitary-adrenal axis), (4) the (gastrointestinal) corticotropin-releasing factor system, and (5) the intestinal response (including the intestinal barrier, the luminal microbiota, and the intestinal immune response). Animal models suggest that the cholinergic anti-inflammatory pathway through an anti-tumor necrosis factor effect of the efferent vagus nerve could be a therapeutic target in IBD through a pharmacologic, nutritional, or neurostimulation approach. In addition, the psychophysiological vulnerability of patients with IBD, secondary to the potential presence of any mood disorders, distress, increased perceived stress, or maladaptive coping strategies, underscores the psychological needs of patients with IBD. Clinicians need to address these issues with patients because there is emerging evidence that stress or other negative psychological attributes may have an effect on the disease course. Future research may include exploration of markers of brain-gut interactions, including serum/salivary cortisol (as a marker of the hypothalamic-pituitary-adrenal axis), heart rate variability (as a marker of the sympathovagal balance), or brain imaging studies. The widespread use and potential impact of complementary and alternative medicine and the positive response to placebo (in clinical trials) is further evidence that exploring other psycho-interventions may be important therapeutic adjuncts to the conventional therapeutic approach in IBD.