Crohn Disease: Bernstein CN

Sadowski DC, Bernstein CN, Bitton A, Croitoru K, Fedorak RN, Griffiths A, Anonymous00036. · Royal Alexandra Hospital, Edmonton, Canada. · Can J Gastroenterol. · Pubmed #19319383 No free full text.

Abstract: BACKGROUND: Guidelines regarding the use of infliximab in Crohn's disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines. OBJECTIVE: To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn's disease. METHODS: A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement). OUTCOME: The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication. CONCLUSION: In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn's disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn's disease is substantial and strengthened by results from longterm clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated.

Panaccione R, Fedorak RN, Aumais G, Bernstein CN, Bitton A, Croitoru K, Enns R, Feagan B, Fishman M, Greenberg G, Griffiths A, Marshall JK, Rasul I, Sadowski D, Seidman E, Steinhart H, Sutherland L, Walli E, Wild G, Williams CN, Zachos M, Anonymous00234. · University of Calgary, Calgary, Canada. · Can J Gastroenterol. · Pubmed #15372114 links to  free full text

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Bernstein CN. · No affiliation provided · Clin Gastroenterol Hepatol. · Pubmed #15704044 No free full text.

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Mackalski BA, Bernstein CN. · University of Manitoba inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada. · Gut. · Pubmed #16609136 links to  free full text

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Shanahan F, Bernstein CN. · Alimentary Pharmabiotic Centre and Department of Medicine, National University of Ireland. Cork. · Inflamm Bowel Dis. · Pubmed #15290931 No free full text.

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Bernstein CN, Riddell RH. · University of Manitoba Inflammatory Bowel Diseases Clinical and Research Centre, Winnipeg, Canada. · Gastrointest Endosc Clin N Am. · Pubmed #11036542 No free full text.

Abstract: Colon biopsies are critical in helping to diagnose diarrhea, to distinguish different forms of colitis, to determine the extent of disease, and to determine if neoplasia has arisen in the setting of chronic colitis. Table 3 summarizes the recommended locations and numbers of biopsies for different scenarios. Some of the technical aspects pertaining to those are also discussed elsewhere in this issue. Colon biopsies in some instances can be definitive, but this usually requires the appropriate clinical scenario. For instance, to appreciate that segmental granulomatous colitis is Crohn's disease and not the much rarer colonic sarcoidosis requires ancillary clinical information. Often colon biopsies may definitively reveal an abnormality, but the findings may be nonspecific in regards to a definitive diagnosis. To use colon biopsies most appropriately in patient management and to get the most mileage from them usually requires frequent clinician-pathologist interaction, often repeat endoscopy with [table: see text] biopsies at a different time, and the assessment of the biopsies in the clinical context.

Bernstein CN. · GB-443 Health Sciences Centre, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada. · Curr Gastroenterol Rep. · Pubmed #10980993 No free full text.

Abstract: This article reviews the rationale and approach to dysplasia surveillance colonoscopy in inflammatory bowel disease. Recent developments in the field are also highlighted, including approaches to polyps that arise in patients with colitis and new diagnostic markers that may complement morphologic assessment for dysplasia.

Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, Bernstein CN, Staun M, Thomsen OØ, Innes A, Anonymous00002. · Hospital for General Internal Medicine, Christian-Albrechts University, Klinik für Allgemeine Innere Medizin, Kiel, Germany. · Gastroenterology. · Pubmed #16143120 No free full text.

Abstract: BACKGROUND & AIMS: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab' fragment of anti-tumor necrosis factor, CDP870) in Crohn's disease. METHODS: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of > or = 100 points or remission [Crohn's Disease Activity Index < or = 150 points]) in the intent-to-treat population. RESULTS: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. CONCLUSIONS: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.

Feagan BG, Sandborn WJ, Baker JP, Cominelli F, Sutherland LR, Elson CO, Salzberg BA, Archambault A, Bernstein CN, Lichtenstein GR, Heath PK, Cameron S, Hanauer SB. · The John P Robarts Research Institute, University of Western Ontario, London, ON, Canada. · Aliment Pharmacol Ther. · Pubmed #15709987 links to  free full text

Abstract: AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease. METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16. RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo. CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.

Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. · Gastrointestinal Unit, Massachusetts General Hospital, and Harvard Medical School, Boston 02114, USA. · N Engl J Med. · Pubmed #14985485 links to  free full text

Abstract: BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.

Sandborn WJ, Feagan BG, Hanauer SB, Present DH, Sutherland LR, Kamm MA, Wolf DC, Baker JP, Hawkey C, Archambault A, Bernstein CN, Novak C, Heath PK, Targan SR, Anonymous00273. · Mayo Clinic, Rochester, Minnesota 55905, USA. · Gastroenterology. · Pubmed #11313302 No free full text.

Abstract: BACKGROUND & AIMS: We evaluated CDP571, a humanized antibody to tumor necrosis factor, for the treatment of active Crohn's disease. METHODS: One hundred sixty-nine patients with moderate-to-severe Crohn's disease were enrolled in a 24-week placebo-controlled trial. Patients were initially randomized to a single dose of 10 or 20 mg/kg CDP571 or placebo to assess dose response. Patients were then retreated with 10 mg/kg CDP571 or placebo every 8 or 12 weeks to assess subsequent dosing intervals. The primary endpoint was clinical response at week 2, defined as a decrease in the Crohn's Disease Activity Index score > or = 70 points. RESULTS: At week 2, clinical response occurred in 45% of CDP571-treated patients compared with 27% of patients in the placebo group (P = 0.023). Patients appeared to benefit from retreatment with CDP571 over 24 weeks, but not all of the results for secondary endpoints were statistically significant. The frequency of severe or serious adverse events was similar among all groups. CONCLUSIONS: CDP571 at an initial dose of 10 or 20 mg/kg is safe and effective for treatment of patients with moderate-to-severe Crohn's disease. Preliminary evidence suggests that retreatment with 10 mg/kg CDP571 at dose intervals of 8 or 12 weeks may also be beneficial, but additional studies are needed.

Clara I, Lix LM, Walker JR, Graff LA, Miller N, Rogala L, Rawsthorne P, Bernstein CN. · University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada. · Am J Gastroenterol. · Pubmed #19455122 No free full text.

Abstract: OBJECTIVES: A single-item indicator of disease activity over an extended period of time, the Manitoba Inflammatory Bowel Disease Index (MIBDI), is introduced and compared against several standard measures for assessing activity in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Participants enrolled in the Manitoba IBD Cohort Study, a population-based longitudinal cohort study (N=353), were assessed semiannually by survey, clinical interview, and blood sample during a 2-year period. The MIBDI is based on patient self-reports of symptom persistence for the previous 6 months, using a 6-level response format. RESULTS: The MIBDI had good sensitivity compared with the Harvey-Bradshaw Index (HB; 0.88), Powell-Tuck Index (PT; 0.84), and Inflammatory Bowel Disease Questionnaire (IBDQ; 0.89), which was maintained at two subsequent annual measurements. Test-retest reliability was also strong (Spearman's r=0.81). Discriminant function analyses identified common discriminating variables of active disease for CD and UC that included HB, PT, and IBDQ subscales of bowel and systemic symptoms, prolonged symptom severity (e.g., abdominal and joint pain, tiredness, diarrhea), and recent persistent pain related to IBD. Unique discriminators included weight problems (CD) and blood in stool (UC). CONCLUSIONS: A single-item, patient-defined disease activity measure, the MIBDI, showed a high degree of sensitivity for classifying individuals with regard to disease status over time compared with the existing disease activity measures, and strong convergent validity with expected proxy measures of disease. These relationships remained consistent over time. Thus, the MIBDI shows promise as a valid, brief tool for measuring disease activity over an extended period.

Singh H, Demers AA, Nugent Z, Mahmud SM, Kliewer EV, Bernstein CN. · Internal Medicine, and the University of Manitoba IBD Clinical and Research Centre, Winnipeg, Manitoba, Canada. · Gastroenterology. · Pubmed #18996382 No free full text.

Abstract: BACKGROUND & AIMS: We evaluated the risk of cervical abnormalities in women with inflammatory bowel disease (IBD) in a population-based, nested, case-control study. METHODS: Cases with abnormal Papanicolaou (Pap) smears or cervical biopsies were matched with up to 3 controls (normal Pap smears) by year of birth, year of first health care coverage, and number of Pap smears in the preceding 5 years. A diagnosis of IBD before the index date was identified from the University of Manitoba IBD Epidemiology Database. Exposures to immunosuppressant drugs and corticosteroids were determined from the provincial drug prescription database. Analyses were adjusted for socioeconomic status and exposure to oral contraceptives and nonsteroidal anti-inflammatory drugs. RESULTS: 19,692 women with cervical cytologic and/or histologic abnormalities were matched with 57,898 controls with normal Pap smears. There was no association between cervical abnormalities and ulcerative colitis (odds ratio [OR], 1.03; 95% confidence interval [CI], 0.77-1.38). The increase in risk in women with Crohn's disease was limited to those exposed to 10 or more prescriptions of oral contraceptives (OR, 1.66; 95% CI, 1.08-2.54). The combined exposure to corticosteroids and immunosuppressants was associated with increased risk of cervical abnormalities (OR, 1.41; 95% CI, 1.09-1.81). There was no interaction between the effect of IBD and corticosteroids and/or immunosuppressants. CONCLUSIONS: These findings do not support an association between IBD itself and the risk of developing cervical abnormalities. An increased risk in patients given a combination of corticosteroids and immunosuppressants should be considered in managing women with IBD.

Thia KT, Mahadevan U, Feagan BG, Wong C, Cockeram A, Bitton A, Bernstein CN, Sandborn WJ. · Miles & Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA. · Inflamm Bowel Dis. · Pubmed #18668682 No free full text.

Abstract: BACKGROUND: Although metronidazole and ciprofloxacin are used to treat perianal Crohn's disease (CD), no placebo-controlled trials have been performed. METHODS: We performed a placebo-controlled pilot trial to evaluate the efficacy and safety of metronidazole and ciprofloxacin in patients with perianal CD. Twenty-five patients with CD and actively draining perianal fistulas were randomized to receive ciprofloxacin 500 mg, metronidazole 500 mg, or placebo twice daily for 10 weeks. Remission and response of perianal fistulas were defined as closure of all fistulas and closure of at least 50% of fistulas that were draining at baseline, respectively. The primary endpoint was remission at 10 weeks. RESULTS: Ten patients were randomized to ciprofloxacin, 7 to metronidazole, and 8 to placebo. Remission at week 10 occurred in 3 patients (30%) treated with ciprofloxacin, no patients (0%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.41). Response at week 10 occurred in 4 patients (40%) treated with ciprofloxacin, 1 patient (14.3%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P = 0.43). Termination of the trial prior to week 10 occurred in 1 patient (10%) treated with ciprofloxacin, 5 patients (71.4%) treated with metronidazole, and 1 patient (12.5%) treated with placebo (P < 0.02). No serious adverse events occurred. CONCLUSION: Remission and response occurred more frequently in patients treated with ciprofloxacin but the differences were not significant in this pilot study. Ciprofloxacin was well tolerated.

Leslie WD, Miller N, Rogala L, Bernstein CN. · Department of Medicine, University of Manitoba, Winnipeg, MB, Canada. · Inflamm Bowel Dis. · Pubmed #18623166 No free full text.

Abstract: BACKGROUND: This prospective study was undertaken to clarify the role of body mass and composition as a determinant of bone mineral density (BMD) in recently diagnosed inflammatory bowel disease (IBD). METHODS: A nested subgroup of 101 adult subjects of the population-based Manitoba IBD Cohort Study were enrolled. Baseline BMD and body composition were measured and repeated 2.3 +/- 0.3 years later. RESULTS: Greater weight, height, and body mass measurements were positively correlated with bone density at all sites (P < 0.01). Although both fat tissue and lean tissue showed positive relationships with BMD, lean tissue showed a much stronger correlation than fat tissue, especially for the total hip (r = 0.66, P < 0.001 versus r = 0.23, P < 0.05) and total body measurements (r = 0.59, P < 0.001 versus r = 0.04, P NS). Increase (or decrease) in hip bone density was strongly associated with an increase (or decrease) in all body mass variables (r = 0.49-0.54, P < 0.001). CONCLUSIONS: Measures of body mass are important determinants of baseline BMD in recently diagnosed IBD patients. Furthermore, change in body mass is correlated with change in BMD, especially at the total hip. Early optimization and maintenance of nutrition and body weight, particularly toward lean tissue mass, may play an important role in preventing IBD-related bone disease.

Okazaki T, Wang MH, Rawsthorne P, Sargent M, Datta LW, Shugart YY, Bernstein CN, Brant SR. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Inflamm Bowel Dis. · Pubmed #18521914 No free full text.

Abstract: BACKGROUND: IBD5, IL23R, and ATG16L1 genetic variations are established Crohn's disease (CD) risks alleles. We evaluated these in a population-based case-control study within a cohort to determine their penetrance, population attributable risk, independence, and relationship to other established CD risk factors, including NOD2. METHODS: DNA from 213 CD, 117 ulcerative colitis, and 310 healthy control subjects from the population-based University of Manitoba IBD Research Registry were genotyped for IBD5 and IL23R single-nucleotide polymorphisms (SNPs), and for the Thr300Ala ATG16L1 SNP. Univariate and multivariate analyses were performed for these and nongenetic risk factors. We introduce multidimensionality reduction (MDR) to explore gene-gene interactions. RESULTS: ATG16L1, IBD5, and IL23R SNPs were significantly associated with CD. Multivariate analysis showed independent CD association for carriers of ATG16L1 (odds ratio [OR] = 1.8, 95% confidence interval [CI] 1.09-3.24), IBD5-IGR2230 (OR = 2.16, 95% CI 1.30-3.59), and IL23R-rs10889677 (OR = 2.13, 95% CI 1.39-3.28) while retaining association for NOD2 mutation carriers (OR = 4.45, 95% CI 2.68-7.38), IBD family history (OR = 2.75, 95% CI 1.42-5.31), tobacco (OR = 2.06, 95% CI 1.35-3.14), and Jewish ethnicity (OR = 20.1, 95% CI 2.16-186.8). IL23R minor variants for Arg381Gln and Intron 6 rs7517848 showed independent, CD protection and 3' untranslated variant rs108896778 showed risk. MDR analysis suggested an interaction between IBD5, ATG16L1, and IL23R risk alleles. Penetrance values for ATG16L1 and IBD5 were 0.27% for heterozygotes, and 0.35% and 0.44%, respectively, for homozygotes. IL23R rs108896778 penetrance was 0.37%. CONCLUSIONS: A population-based analysis of CD risk factors is useful for characterizing the epidemiology of multiple CD genetic and nongenetic risk factors. Gene-gene interactions are likely, but require further evaluation in large population-based cohorts.

Bernstein CN. · University of Manitoba, Winnipeg, Manitoba, Canada. · Inflamm Bowel Dis. · Pubmed #18521909 No free full text.

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Lix LM, Graff LA, Walker JR, Clara I, Rawsthorne P, Rogala L, Miller N, Ediger J, Pretorius T, Bernstein CN. · Department of Community Health Sciences, University of Manitoba, Winnipeg, Canada. · Inflamm Bowel Dis. · Pubmed #18512245 No free full text.

Abstract: BACKGROUND: The aim was to assess quality of life (QOL) and psychological functioning in inflammatory bowel disease (IBD) as related to patterns of disease activity over time. METHODS: Study participants were 388 recently diagnosed individuals from the population-based Manitoba IBD Cohort Study. They completed mail-out surveys at 6-month intervals and clinical interviews annually. Based on their 2-year pattern of self-reported disease activity, participants were assigned to 1 of 3 groups: consistently active, fluctuating, or consistently inactive disease. Disease type (Crohn's disease [CD] or ulcerative colitis [UC]) was confirmed through chart review. Change over time was modeled for measures of QOL and positive and negative psychological functioning using mixed-effects regression analyses. RESULTS: Half of the participants had fluctuating disease activity, while almost one-third of participants reported consistent active disease. Participants with the fluctuating activity pattern showed significant improvement in disease-specific QOL compared to participants with consistent activity. Perceived stress, health anxiety, and pain anxiety decreased while pain catastrophizing and mastery increased over time, although the amount of change was not significantly different among disease activity patterns. However, when the data were averaged over time there were significant differences among disease activity patterns on most outcomes. Significant effects of CD versus UC were observed only for the pain measures. CONCLUSIONS: Change in IBD QOL is influenced by one's longitudinal profile of disease activity, but change in psychological functioning is not. Effects of disease activity on psychological functioning were modest, suggesting that disease has an impact even when patients are not experiencing active symptoms.

Leslie WD, Miller N, Rogala L, Bernstein CN. · Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. · Am J Gastroenterol. · Pubmed #18422819 No free full text.

Abstract: OBJECTIVES: Bone mineral density (BMD) is usually normal at the time of inflammatory bowel disease (IBD) diagnosis. The purpose of this study was to evaluate the role of vitamin D metabolism in recently diagnosed IBD. METHODS: Adult subjects with recently diagnosed IBD (median 4 yr) were recruited from the University of Manitoba IBD Research Registry into the Manitoba IBD Cohort Study. Baseline BMD and serum 25-hydroxy vitamin D (25OHD) were measured in a nested subgroup of 101 subjects of whom 94 had repeat BMD measurements 2.3 +/- 0.3 yr later. RESULTS: Only a minority (22 [21.8%]) of recently diagnosed IBD participants had optimal serum 25OHD levels (75 nmol/L or greater). Serum 25OHD was positively correlated with baseline BMD for the lumbar spine, total hip, and total body (all P < 0.05). MANOVA confirmed significant between-group differences in baseline T-scores when vitamin D status was categorized according to serum 25OHD quartile (P < 0.05). Gain in total body BMD between the baseline and follow-up DXA scans was positively correlated with 25OHD (r = 0.20, P < 0.05). CONCLUSIONS: Poorer vitamin D status correlates with lower baseline BMD at all measurement sites and better vitamin D status is correlated with a gain in total body BMD. Early optimization of vitamin D may play an important role in preventing IBD-related bone disease.

Kotlowski R, Bernstein CN, Silverberg MS, Krause DO. · Department of Animal Science, University of Manitoba, Winnipeg, Manitoba, Canada. · Inflamm Bowel Dis. · Pubmed #18340647 No free full text.

Abstract: BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory diseases of the digestive tract. Genetic factors and an abnormal immune response to infections are suspected to be involved in inflammatory bowel diseases. METHODS: In the present study 300 blood samples from CD patients (n = 100), UC patients (n = 100), and healthy controls (n = 100) were taken from a population-based case-control study. PCR assays and capillary electrophoresis were used to detect alpha 1 antitrypsin M, S, and Z alleles and the C-to-T transition at the -237 nucleotide position of the SLC11A1 promoter. Additionally, length polymorphism of (gt)n alleles in the promoter region and TGTG and CAAA insertion/deletion in the untranslated region (3' UTR) of the SLC11A1 gene were evaluated. RESULTS: The Z allele only for AAT was associated (P < 0.05) with CD. No other significant results were detected for AAT alleles. For SLC11A1, alleles 1 and 2 were significant (P < 0.05) for UC, but only allele 3 was significant (P < 0.05) for CD. There was a significant (P < 0.05) association of a CAAA insertion with CD but not for deletion in the 3' UTR. No differences (P < 0.05) were detected for TAAA. CONCLUSIONS: Because AAT and SLC11A1 proteins directly or indirectly function as inhibitors of human leukocyte elastase, mutations in the AAT and SLC11A1 genes may change the balance between elastase produced by leukocytes during phagocytosis.

Shugart YY, Silverberg MS, Duerr RH, Taylor KD, Wang MH, Zarfas K, Schumm LP, Bromfield G, Steinhart AH, Griffiths AM, Kane SV, Barmada MM, Rotter JI, Mei L, Bernstein CN, Bayless TM, Langelier D, Cohen A, Bitton A, Rioux JD, Cho JH, Brant SR. · Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21231, USA. · Genes Immun. · Pubmed #18246054 No free full text.

Abstract: Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Chami G, Raza M, Bernstein CN. · Department of Internal Medicine, University of Manitoba, Winnipeg, Canada. · Can J Gastroenterol. · Pubmed #17853952 links to  free full text

Abstract: OBJECTIVE: To determine the usefulness of positive and negative capsule endoscopies (CEs), and the impact of each on short- and long-term patient management. METHODS: Medical records were reviewed for 70 consecutive CE patients. Based on outcomes from referring physicians, it was determined whether CE was useful, partially useful or not useful at all in the overall patient management, and whether CE assisted in providing a diagnosis, and impacted on short-term long-term management. RESULTS: CE indications included overt bleeding (37%), occult bleeding (20%), iron deficiency (17%), abdominal pain and weight loss (13%), assessing the extent of or confirming a diagnosis of Crohn's disease (9%) and screening for familial adenomatous polyposis (4%). Positive studies were seen in 58% of overt bleeds, 50% of occult bleeds, 33% of iron deficiencies and 33% of Crohn's diseases. Overall, 28 studies (40%) were positive studies and 42 (60%) were negative studies. CE aided in diagnosis in 11 of 28 (39%) positive and 12 of 42 (29%) negative studies (P=0.35). Positive and negative CEs had an impact on short-term management in 12 of 28 (43%) versus 18 of 42 (43%) cases, respectively (P=1.0), and on long-term management in 14 of 28 (50%) versus 15 of 42 (36%) cases, respectively (P=0.23). For positive and negative studies, respectively, CE was considered useful in 12 of 28 (43%) versus 15 of 42 (36%) cases (39% overall), partially useful in 10 of 28 (36%) versus 10 of 42 (24%) cases (28% overall), and not useful at all in six of 28 (21%) versus 17 of 42 (40%) cases (33% overall). CONCLUSIONs: Although a negative CE may aid in making a definitive diagnosis in only 29% of patients, its effect on management and overall usefulness is similar to that of a positive CE. A physician's decision on whether to order CE should not be based solely on the pretest probability of a positive examination but also on the clinical utility of a negative study.

Longobardi T, Bernstein CN. · University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre and Department of Medicine, Winnipeg, Manitoba, Canada. · Am J Gastroenterol. · Pubmed #17459026 No free full text.

Abstract: OBJECTIVES: We tested the hypothesis of nonlinear longitudinal trends in health-care utilization by individuals with Crohn's disease (CD) and ulcerative colitis (UC) in Manitoba. METHODS: Administrative databases were used to report resource use in 2000/1. A total of 5,485 cases of CD and UC and 45,279 matched controls were separated into incident cases (0-2 yr of disease), cases with longstanding disease (3-10 yr), and cases with very longstanding disease (>10 yr). Relative risk ratios (RRR) indicating the likelihood of resource use, given disease duration, were computed using multinomial logistic regression analysis. Sensitivity analysis was conducted to test the robustness of results to altering the disease duration cutoffs. RESULTS: Independent of disease duration, in general, outpatient utilization was over twice as likely among IBD cases compared with controls whether or not the contact was made for IBD-specific reasons. The likelihood of utilization was greatest among incident cases for outpatient visits with an internist (RRR 6.16, 95% CI 5.11-7.43) and surgical visits (RRR 3.78, 95% CI 3.14-4.55). Inpatient stays for IBD-specific reasons in general were considered dependent on disease duration; in particular, there was a fourfold higher likelihood for the incident cases relative to their controls. For non-IBD-specific reasons, IBD cases were 1.5 times as likely to have inpatient stays, regardless of disease duration. CONCLUSIONS: Our results suggest that within the first 2 yr from disease diagnosis the most costly resources were employed. We can likely measure the greatest proportion of treatment effects on resource use within a relatively short period.

Bernstein CN, Wang MH, Sargent M, Brant SR, Collins MT. · Department of Internal Medicine, University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre, Winnipeg, Manitoba, Canada. · J Clin Microbiol. · Pubmed #17251406 links to  free full text

Abstract: In a population-based case-control study we have previously shown that 14% of healthy Manitobans carry one or two mutations in the NOD-2 locus, a gene highly associated with Crohn's disease (CD). The NOD-2 protein is the receptor responsible for recognition of bacterial peptidoglycans, and it is plausible that NOD-2 is involved in the recognition of mycobacteria. Thirty-seven percent of Manitobans with CD had >or=1 NOD-2 mutation, leading to a threefold increased risk of CD for single-mutant carriers and a 30-fold increased risk for double-mutant carriers. In the same population groups, we assessed the seroprevalence for Mycobacterium paratuberculosis and found it to be 35%, with no differences between CD, ulcerative colitis (UC), and controls. Because of high rates of CD and UC in Manitoba, we assessed whether there was an interaction between carrying a NOD-2 mutation and M. paratuberculosis seropositivity. An enzyme-linked immunosorbent assay for serum antibodies to M. paratuberculosis in cattle was adapted for human use. DNA was purified from whole blood. Subjects were genotyped for three NOD-2 variants, G908R, Cins1007fs, and R702W. Multivariate logistic regression analysis showed that NOD-2 gene mutations significantly associated with CD, but M. paratuberculosis serology did not. Furthermore, there was no interaction between NOD-2 mutation status and M. paratuberculosis serology status. For those with the NOD-2 mutation, the likelihood of CD subjects having positive M. paratuberculosis serology was similar to that of controls (odds ratio, 1.31; 95% confidence interval, 0.55-3.11). No interaction could be proven for UC or by combining CD and UC compared to controls. In conclusion, we could not find an interaction between the NOD-2 genotype and M. paratuberculosis serology in relationship to CD or UC.

Brant SR, Wang MH, Rawsthorne P, Sargent M, Datta LW, Nouvet F, Shugart YY, Bernstein CN. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. · Am J Gastroenterol. · Pubmed #17100976 No free full text.

Abstract: OBJECTIVES: Multiple established Crohn's disease (CD) and ulcerative colitis (UC) risk factors including family history, tobacco use, Jewish ethnicity, urban residency, and CARD15/NOD2 mutations have been evaluated singly and in hospital-based observational studies. The goal of this study was to assess the relative contributions of all these risk factors jointly in a nonreferral, population-based cohort derived from a population epidemiologic database. METHODS: CD (N = 232) and UC (N = 121) subjects were ascertained from our population-based IBD Registry derived from Manitoba Health, the single provincial insurer. Healthy controls (HC) (N = 336) were recruited via a 10:1 mailing matched for age, sex, and postal code. Ethnicity, tobacco use, family history, residency, and CARD15/NOD2 genotype status were determined. RESULTS: In both univariate analyses and analyses adjusted for all risk factors, CD was influenced independently by CARD15/NOD2 heterozygote and homozygote/compound-heterozygote status (adjusted odds ratios [OR] 3.7 and 40.0, respectively), Jewish ethnicity (OR 18.5), CD family history (OR 6.2), and smoking (OR 3.0 current and 1.7 ex-smoker, respectively). Penetrance for homozygote/compound-heterozygotes was 4.9%, heterozygotes 0.54%, and wild types 0.184%. Population attributable risk for CARD15 was 26.7% and current tobacco use was 46.8%. A tobacco-CARD15 interaction was not observed. UC was influenced by Jewish ethnicity (OR 37.1), and by family history (OR 2.6), ex-smoker status (OR 1.9), and CARD15/NOD2 heterozygote or homozygote/compound-heterozygote status (OR 1.9 and 6.4, respectively) in adjusted analyses only. CONCLUSIONS: CARD15/NOD2, family history, smoking, and Jewish ethnicity are independent risk factors for CD. Examination of these risk factors together in a single population-based cohort has provided initial data for population epidemiological characterization and genetic counseling uses.