James F. Blanchard

Cancer risk in patients with inflammatory bowel disease

The objective of the current study was to determine the incidence of cancer among persons with inflammatory bowel disease (IBD) and to compare these incidence rates with those of the non‐IBD population using population‐based data from the administrative claims data of Manitobas universal provincial insurance plan (Manitoba Health).

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.

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

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.

A population-based case control study of potential risk factors for IBD.

BACKGROUND:We aimed to pursue potential etiological clues to Crohns disease (CD) and ulcerative colitis (UC) through a population-based case control survey study.METHODS:Cases with CD (n = 364) and UC (n = 217), ages 18–50 yr were drawn from the population-based University of Manitoba IBD Research Registry. Potential control subjects were drawn from the population-based Manitoba Health Registry by age, gender, and geographic residence matching to the cases (n = 433). Subjects were administered a multiitem questionnaire.RESULTS:By univariate analysis, some of the variables predictive of CD included lower likelihood of living on a farm, of having drunk unpasteurized milk or having eaten pork, and UC patients were less likely to have drunk unpasteurized milk and to have eaten pork. On multivariate analysis, variables significantly associated with CD were being Jewish (OR = 4.32, 95% CI 1.10–16.9), having a first degree relative with IBD (OR = 3.07, 95% CI 1.73–5.46), ever having smoked (OR = 1.54, 95% CI, 1.06–2.25), living longer with a smoker (OR = 1.03, 95% CI, 1.01–1.04). Being a first generation Canadian (OR = 0.33, 95% CI, 0.17–0.62), having pet cats before age 5 (OR = 0.66, 95% CI, 0.46–0.96) and having larger families (OR = 0.87, 95% CI, 0.79–0.96) were protective against CD. For UC being Jewish (OR = 7.46, 95% CI, 2.33–23.89), having a relative with IBD (OR = 2.23, 95% CI, 1.27–3.9), and ever smoking (OR = 1.62, 95% CI, 1.14–2.32) were predictive.CONCLUSION:This study reinforced the increased risk associated with family history, being Jewish, and smoking history, however, a number of significant associations with CD and UC on univariate and multivariate analysis may support the “hygiene hypothesis” and warrant further exploration in prospective studies.

Mucosal Transmission and Induction of Simian AIDS by CCR5-Specific Simian/Human Immunodeficiency Virus SHIV SF162P3

ABSTRACT Nonhuman primate models are increasingly used in the screening of candidate AIDS vaccine and immunization strategies for advancement to large-scale human trials. The predictive value of such macaque studies is largely dependent upon the fidelity of the model system in mimicking human immunodeficiency virus (HIV) type 1 infection in terms of viral transmission, replication, and pathogenesis. Herein, we describe the efficient mucosal transmission of a CCR5-specific chimeric simian/human immunodeficiency virus, SHIVSF162P3. Female rhesus macaques were infected with SHIVSF162P3 after a single atraumatic application to the cervicovaginal mucosa. The disease course of SHIVSF162P3-infected monkeys is similar and as varied as natural HIV infection in terms of viral replication, gradual loss of CD4+ peripheral blood mononuclear cells, and the development of simian AIDS-defining opportunistic infections. The SHIVSF162P3/macaque model should facilitate direct preclinical assessment of HIV vaccine strategies in addition to antiviral compounds directed towards envelope target cell interactions. Furthermore, this controlled model provides the setting to investigate immunologic responses and putative host-specific susceptibility factors that alter viral transmission and subsequent disease progression.

Declines in risk behaviour and sexually transmitted infection prevalence following a community-led HIV preventive intervention among female sex workers in Mysore India.

Objective:To investigate the impact on sexual behaviour and sexually transmitted infections (STI) of a comprehensive community-led intervention programme for reducing sexual risk among female sex workers (FSW) in Mysore, India. The key programme components were: community mobilization and peer-mediated outreach; increasing access to and utilization of sexual health services; and enhancing the enabling environment to support programme activities. Methods:Two cross-sectional surveys among random samples of FSW were conducted 30 months apart, in 2004 and 2006. Results:Of over 1000 women who sell sex in Mysore city, 429 participated in the survey at baseline and 425 at follow-up. The median age was 30 years, median duration in sex work 4 years, and the majority were street based (88%). Striking increases in condom use were seen between baseline and follow-up surveys: condom use at last sex with occasional clients was 65% versus 90%, P < 0001; with repeat clients 53% versus 66%, P < 0.001; and with regular partners 7% versus 30%, P < 0.001. STI prevalence declined from baseline to follow-up: syphilis 25% versus 12%, P < 0.001; trichomonas infection 33% versus 14%, P < 0.001; chlamydial infection 11% versus 5%, P = 0.001; gonorrhoea 5% versus 2%, P = 0.03. HIV prevalence remained stable (26% versus 24%), and detuned assay testing suggested a decline in recent HIV infections. Conclusion:This comprehensive HIV preventive intervention empowering FSW has resulted in striking increases in reported condom use and a concomitant reduction in the prevalence of curable STI. This model should be replicated in similar urban settings across India.

Modelling HIV/AIDS epidemics in Botswana and India: impact of interventions to prevent transmission

OBJECTIVE To describe a dynamic compartmental simulation model for Botswana and India, developed to identify the best strategies for preventing spread of HIV/AIDS. METHODS The following interventions were considered: a behavioural intervention focused on female sex workers; a conventional programme for the treatment of sexually transmitted infections; a programme for the prevention of mother-to-child transmission; an antiretroviral treatment programme for the entire population, based on a single regimen; and an antiretroviral treatment programme for sex workers only, also based on a single regimen. FINDINGS The interventions directed at sex workers as well as those dealing with sexually transmitted infections showed promise for long-term prevention of human immunodeficiency virus (HIV) infection, although their relative ranking was uncertain. In India, a sex worker intervention would drive the epidemic to extinction. In Botswana none of the interventions alone would achieve this, although the prevalence of HIV would be reduced by almost 50%. Mother-to-child transmission programmes could reduce HIV transmission to infants, but would have no impact on the epidemic itself. In the long run, interventions targeting sexual transmission would be even more effective in reducing the number of HIV-infected children than mother-to-child transmission programmes. Antiretroviral therapy would prevent transmission in the short term, but eventually its effects would wane because of the development of drug resistance. CONCLUSION Depending on the country and how the antiretroviral therapy was targeted, 25-100% of HIV cases would be drug- resistant after 30 years of use.

Violence against female sex workers in Karnataka state, south India: impact on health, and reductions in violence following an intervention program.

BackgroundViolence against female sex workers (FSWs) can impede HIV prevention efforts and contravenes their human rights. We developed a multi-layered violence intervention targeting policy makers, secondary stakeholders (police, lawyers, media), and primary stakeholders (FSWs), as part of wider HIV prevention programming involving >60,000 FSWs in Karnataka state. This study examined if violence against FSWs is associated with reduced condom use and increased STI/HIV risk, and if addressing violence against FSWs within a large-scale HIV prevention program can reduce levels of violence against them.MethodsFSWs were randomly selected to participate in polling booth surveys (PBS 2006-2008; short behavioural questionnaires administered anonymously) and integrated behavioural-biological assessments (IBBAs 2005-2009; administered face-to-face).Results3,852 FSWs participated in the IBBAs and 7,638 FSWs participated in the PBS. Overall, 11.0% of FSWs in the IBBAs and 26.4% of FSWs in the PBS reported being beaten or raped in the past year. FSWs who reported violence in the past year were significantly less likely to report condom use with clients (zero unprotected sex acts in previous month, 55.4% vs. 75.5%, adjusted odds ratio (AOR) 0.4, 95% confidence interval (CI) 0.3 to 0.5, p < 0.001); to have accessed the HIV intervention program (ever contacted by peer educator, 84.9% vs. 89.6%, AOR 0.7, 95% CI 0.4 to 1.0, p = 0.04); or to have ever visited the project sexual health clinic (59.0% vs. 68.1%, AOR 0.7, 95% CI 0.6 to 1.0, p = 0.02); and were significantly more likely to be infected with gonorrhea (5.0% vs. 2.6%, AOR 1.9, 95% CI 1.1 to 3.3, p = 0.02). By the follow-up surveys, significant reductions were seen in the proportions of FSWs reporting violence compared with baseline (IBBA 13.0% vs. 9.0%, AOR 0.7, 95% CI 0.5 to 0.9 p = 0.01; PBS 27.3% vs. 18.9%, crude OR 0.5, 95% CI 0.4 to 0.5, p < 0.001).ConclusionsThis program demonstrates that a structural approach to addressing violence can be effectively delivered at scale. Addressing violence against FSWs is important for the success of HIV prevention programs, and for protecting their basic human rights.