Ulcerative Colitis: Steinhart AH

Seow CH, Benchimol EI, Griffiths AM, Steinhart AH. · Mount Sinai Hospital, Room 445, 600 University Ave, Toronto, Ontario, Canada, M5G 1X5. · Cochrane Database Syst Rev. · Pubmed #18646167 No free full text.

Abstract: BACKGROUND: Interferons (IFNs) are cytokines which possess immunoregulatory properties and have been used to successfully treat a number of chronic inflammatory disorders. It has been postulated that Type I IFNs may be able to re-establish the Th1/Th2 balance in Th2 predominant diseases like ulcerative colitis. OBJECTIVES: To systematically evaluate the efficacy and safety of type I IFN therapy for induction of remission in ulcerative colitis. SEARCH STRATEGY: The following electronic databases were searched: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders (IBD/FBD) Group Specialised Trial Register, and http://ClinicalTrials.gov. Reference lists of trials and review articles, as well as recent proceedings from major gastroenterology meetings were manually searched. Contact was made with pharmaceutical companies manufacturing type I IFNs. SELECTION CRITERIA: Randomised controlled trials of type I IFNs for induction of remission in UC were included. The study population included patients of any age with active ulcerative colitis. There were no exclusions based on type, dose or duration of IFN treatment. The primary outcome was induction of remission of ulcerative colitis. Secondary outcomes included: time to remission, mean change in disease activity index score, clinical, histological or endoscopic improvement, improvement in quality of life, and adverse events. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality using Jadad's criteria. A random or fixed effects model was chosen based on an assessment of heterogeneity, and studies were weighted using the DerSimonian & Laird or the Mantel-Haenszel method accordingly. Meta-analysis was performed using RevMan 4.2.10 software. MAIN RESULTS: Four studies were eligible for inclusion. Three studies compared type I IFNs to placebo and a single study compared IFNs to prednisolone enemas in patients with left-sided colitis. Meta-analysis was based on the three IFN-placebo studies. There was no significant benefit of type I IFNs over placebo for inducing remission in ulcerative colitis (RR 1.24; 95% CI 0.81 to 1.90). There were no statistically significant differences in any of the secondary outcome variables. AUTHORS' CONCLUSIONS: The existing literature does not support the efficacy of type I IFNs for induction of remission in patients with UC. Given concerns regarding the tolerability of IFN therapy, we suggest that the results of two ongoing trials are evaluated for efficacy and safety prior to development or commencement of further randomised controlled trials of type I IFNs in UC.

Panaccione R, Fedorak RN, Aumais G, Bernard EJ, Bernstein CN, Bitton A, Croitoru K, Dieleman LA, Enns R, Feagan BG, Franchimont D, Greenberg GR, Griffiths AM, Marshall JK, Pare P, Patel S, Penner R, Render C, Seidman E, Steinhart AH. · University of Calgary, Calgary, Canada. · Can J Gastroenterol. · Pubmed #18354755 links to  free full text

Abstract: Infliximab is a chimeric, monoclonal anti-tumour necrosis factor-alpha antibody. It has been previously demonstrated to be an effective treatment for patients with Crohn's disease who do not achieve the desired response with conventional treatments. Although the etiology of ulcerative colitis (UC) differs from that of Crohn's disease, randomized controlled trials have demonstrated that infliximab is also beneficial for the treatment of moderate to severe UC in patients who are either intolerant of or refractory to immunosuppressant agents or steroids, or those who are steroid-dependent. A review of the literature is followed by practical recommendations regarding infliximab that address the needs of clinicians and UC patients. Where there is a lack of evidence-based information, the expert panel provides its combined opinion derived from the members' clinical experiences.

Turner D, Steinhart AH, Griffiths AM. · Hospital for Sick Children, Division of Gastroenterology, Hepatology and Nutrition, 555 University Ave.,Toronto, Ontario, Canada, M5G 1X8. · Cochrane Database Syst Rev. · Pubmed #17636844 No free full text.

Abstract: BACKGROUND: Omega-3 fatty acids (n-3, fish oil) have been shown to have anti-inflammatory properties. Therefore, n-3 therapy may be beneficial in chronic inflammatory disorders such as ulcerative colitis. OBJECTIVES: To systematically review the efficacy and safety of n-3 for maintaining remission in ulcerative colitis (UC). SEARCH STRATEGY: The following databases were searched from their inception without language restriction: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Healthstar, PubMed, and ACP journal club. Experts were contacted for unpublished data. SELECTION CRITERIA: Randomized placebo-controlled trials (RCT) of fish oil for maintenance of remission in UC were included. Studies must have enrolled patients (of any age group) who were in remission at the time of recruitment, and were followed for at least six months. The intervention must have been fish oil given in pre-defined dosage. Co-interventions were allowed only if they were balanced between the study groups. The primary outcome was relapse rate and the secondary outcome was frequency of adverse events. Other outcomes to assess efficacy were change in disease activity scores and time to first relapse. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality. Meta-analysis weighted by the Mantel-Haenszel method was performed using RevMan 4.2.8 software. Random or fixed effect models were used according to degree of heterogeneity and subgroup analyses were performed to explore heterogeneity. A sensitivity analysis was performed excluding a study of questionable quality . MAIN RESULTS: The three studies that were included used different formulation and dosing of n-3 but none used enteric coated capsules. The pooled analysis showed a similar relapse rate in the n-3 treated patients and controls (RR 1.02; 95% CI 0.51 to 2.03; P = 0.96). Combining the studies resulted in virtually no statistical heterogeneity (P = 0.93, I(2) = 0%). Various subgroup and sensitivity analyses showed similar results. However, the total number of patients enrolled in these studies was small (n = 138). No significant adverse events were recorded in any of the studies and not enough data were available to pool the other secondary outcomes for meta-analysis. AUTHORS' CONCLUSIONS: No evidence was found that supports the use of omega 3 fatty acids for maintenance of remission in UC. Further studies using enteric coated capsules may be justified.

Turner D, Walsh CM, Steinhart AH, Griffiths AM. · Division of Gastroenterology, Hepatology and Nutrition, the Hospital for Sick Children, Toronto, Canada. · Clin Gastroenterol Hepatol. · Pubmed #17142106 No free full text.

Abstract: BACKGROUND & AIMS: Colectomy is a potentially life-saving procedure for patients with severe attacks of UC who fail medical therapy. We aimed to systematically review studies that reported the short-term colectomy rate in severe UC or reported variables that could predict treatment failure. METHODS: We conducted a systematic literature search for cohort studies and controlled trials published between 1974-2006. RESULTS: Thirty-two studies met the inclusion criteria; 16 reported short-term outcome and predictors of therapy failure, 13 only outcome, and 3 only predictors. In the pooled analysis, 581 of 1991 patients required colectomy (weighted mean 27; 95% confidence interval [CI], 26%-28%), and 22 died (1%; 95% CI, 0.7%-1.5%). In a heterogeneity-controlled meta-regression, colectomy rate did not change during the last 30 years (R(2) = 0.07, P = .8). Cyclosporine was used in only 100 patients, with a 51% (95% CI, 41%-60%) short-term success rate. A second meta-regression failed to demonstrate a dose-colectomy response of methylprednisolone therapy beyond 60 mg daily (R(2) < 0.01, P = .98). More than 20 variables were identified in 19 studies to predict medical therapy failure, but only a few were consistently reproduced: disease extent, stool frequency, temperature, heart rate, C-reactive protein, albumin, and radiologic assessment. CONCLUSIONS: The short-term colectomy rate in severe UC has remained stable during the last 30 years, despite the introduction of cyclosporine, which was not used frequently. We could not find any support for administering methylprednisolone at a higher dose than 60 mg/day. Variables that predict outcome of corticosteroid therapy could aid in the development of guidelines for introduction of rescue therapies in severe UC.

Bernstein CN, Eaden J, Steinhart AH, Munkholm P, Gordon PH. · Section of Gastroenterology, University of Manitoba Inflammatory Bowel Disease Clinical and Research Center, Winnipeg, Manitoba, Canada. · Inflamm Bowel Dis. · Pubmed #12479651 No free full text.

Abstract: The risk of colorectal cancer is increased in ulcerative colitis and Crohn's colitis. Regular dysplasia surveillance colonoscopy in chronic colitis generally has been adopted as a strategy to prevent colorectal cancer or at least to diagnose it in an earlier stage. This has not been proven to reduce mortality, but it does provide the clinician and the patient with some confidence that they are participating in an active strategy to deal with the problem of colorectal cancer in chronic colitis. Disease extent and duration have long been held to be risk factors for colorectal cancer in chronic colitis, and recently some special risk groups have been identified which may require either more intensive surveillance or alternative approaches to cancer prevention. These include patients with primary sclerosing cholangitis, patients with first-degree relatives with sporadic colon cancer, and possibly, patients with backwash ileitis. There is an emerging interest in potential chemopreventative strategies in both sporadic and colitis-associated colorectal cancer. There also have been suggestive data that chronic maintenance 5-aminosalicylate use might reduce the risk of developing colorectal cancer. Recent data have suggested some potential preventative benefit of using ursodeoxycholic acid in patients with ulcerative colitis and primary sclerosing cholangitis. The scientific rationale for using these agents is sound but clinical data are lacking to fully support these approaches as chemoprevention in chronic colitis at present.

Feagan BG, Greenberg GR, Wild G, Fedorak RN, Paré P, McDonald JW, Dubé R, Cohen A, Steinhart AH, Landau S, Aguzzi RA, Fox IH, Vandervoort MK. · Robarts Research Institute, London, ON N6A 5K8, Canada. · N Engl J Med. · Pubmed #15958805 links to  free full text

Abstract: BACKGROUND: Selective blockade of interactions between leukocytes and vascular endothelium in the gut is a promising strategy for the treatment of inflammatory bowel diseases. METHODS: We conducted a multicenter, double-blind, placebo-controlled trial of MLN02, a humanized antibody to the alpha4beta7 integrin, in patients with active ulcerative colitis. We randomly assigned 181 patients to receive 0.5 mg of MLN02 per kilogram of body weight, 2.0 mg per kilogram, or an identical-appearing placebo intravenously on day 1 and day 29. Eligible patients also received concomitant mesalamine or no other treatment for colitis. Ulcerative colitis clinical scores and sigmoidoscopic assessments were evaluated six weeks after randomization. RESULTS: Clinical remission rates at week 6 were 33 percent, 32 percent, and 14 percent for the group receiving 0.5 mg of MLN02 per kilogram, the group receiving 2.0 mg per kilogram, and the placebo group, respectively (P=0.03). The corresponding proportions of patients who improved by at least 3 points on the ulcerative colitis clinical score were 66 percent, 53 percent, and 33 percent (P=0.002). Twenty-eight percent of patients receiving 0.5 mg per kilogram and 12 percent of those receiving 2.0 mg per kilogram had endoscopically evident remission, as compared with 8 percent of those receiving placebo (P=0.007). For the minority of patients in whom an MLN02 antibody titer greater than 1:125 developed, incomplete saturation of the alpha4beta7 receptor on circulating lymphocytes was observed and no benefit of treatment was identifiable. CONCLUSIONS: In this short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active ulcerative colitis.

Nikolaus S, Rutgeerts P, Fedorak R, Steinhart AH, Wild GE, Theuer D, Möhrle J, Schreiber S. · Christian-Albrechts University, Kiel, Germany. · Gut. · Pubmed #12912859 links to  free full text

Abstract: BACKGROUND: and aims: Administration of interferon (IFN)-beta may represent a rational approach to the treatment of ulcerative colitis through its immunomodulatory and anti-inflammatory effects. The present study was performed to evaluate the efficacy and tolerability of IFN-beta-1a. METHODS: Patients (n=18) with moderately active ulcerative colitis were randomised to receive IFN-beta-1a or placebo. IFN-beta-1a was started at a dose of 22 micro g three times a week subcutaneously, and the dose was increased at two week intervals to 44 micro g and then to 88 micro g if no response was observed. The maximum duration of treatment was eight weeks. End points were clinical treatment response, defined as a decrease of at least 3 points from baseline in the ulcerative colitis scoring system (UCSS) symptoms score and induction of endoscopically confirmed remission. RESULTS: Baseline characteristics and disease severity were similar in both groups. Data from 17 patients are included in this report (10 patients in the IFN-beta-1a group and seven patients in the placebo group). Clinical response was achieved in five patients (50%) in the IFN-beta-1a group and in one (14%) in the placebo group (P=0.14). Remission was achieved in three patients in the IFN-beta-1a group and in none in the placebo group (p=0.02). Most adverse reactions associated with IFN-beta-1a were influenza-like symptoms or injection site reactions, and were mild or moderate in severity. CONCLUSIONS: IFN-beta-1a may represent a promising novel treatment approach in ulcerative colitis.

Seow CH, Stempak JM, Xu W, Lan H, Griffiths AM, Greenberg GR, Steinhart AH, Dotan N, Silverberg MS. · Division of Gastroenterology, Mount Sinai Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · Am J Gastroenterol. · Pubmed #19491856 No free full text.

Abstract: OBJECTIVES: We sought to evaluate whether two novel immunoglobulin A (IgA) cell wall polysaccharide antibodies, anti-laminarin (anti-L) and anti-chitin (anti-C), aid in the diagnosis and phenotype differentiation of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A cohort of 818 individuals with inflammatory bowel disease (IBD; 517 CD and 301 UC) from two IBD tertiary referral centers, with median ages of 33 and 39 years, respectively, and disease duration of 8.9 years, were phenotyped using the Montreal classification, and analyzed for seven anti-glycan antibodies (gASCA (anti-Saccharomyces cerevisiae) IgG, gASCA IgA, anti-chitobioside (GlcNAc(beta1,4)GlcNAc(beta)), anti-laminaribioside (Glc(beta1,3)Glb(beta)), anti-mannobioside (Man(alpha1,3)Man(alpha)), anti-L, and anti-C) and perinuclear atypical neutrophil cytoplasmic antibodies (pANCA). RESULTS: In the CD patient population, 73% were positive for >/=1 anti-glycan antibody. All glycan markers were specific for CD (85.4-97.7%) and more prevalent in CD vs. UC (P<0.0015). gASCA IgG and IgA best differentiated CD from UC followed by anti-L (area under the curve 0.818, 0.815, and 0.702, respectively). The addition of anti-L and anti-C to gASCA IgG and pANCA improved discrimination between CD and UC (P<0.001). Adding anti-L to gASCA and pANCA differentiated colonic CD and UC (P=0.02). An increasing number of positive antibodies was associated with early CD onset, penetrating phenotype, perianal disease, and the need for surgery (P<0.001). Anti-L was associated with ileocolonic CD (odds ratio (OR) 2.28, 95% confidence interval (CI) 1.40-3.69; P=0.001), and anti-C with penetrating (OR 2.75, 95% CI 1.50-5.04; P=0.001) and perianal disease (OR 1.95, 95% CI 1.06-3.59; P=0.03). CONCLUSIONS: Anti-L and anti-C improve differentiation between CD and UC. Anti-L may also differentiate between isolated colonic CD and UC. Both anti-L and anti-C are independently associated with a more aggressive CD phenotype.

Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. · No affiliation provided · Nat Genet. · Pubmed #19471306 No free full text.

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Turner D, Griffiths AM, Steinhart AH, Otley AR, Beaton DE. · Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Canada. · J Clin Epidemiol. · Pubmed #19124220 No free full text.

Abstract: BACKGROUND: We aimed to compare the judgmental and mathematical approaches in weighting the Pediatric Ulcerative Colitis Activity Index (PUCAI). METHODS: The PUCAI was previously weighted mathematically using multivariate regression modeling on 157 children with ulcerative colitis (UC). Independently, a Delphi group of 36 experts in pediatric UC judgmentally provided weights to the PUCAI's items. The agreement between the tools was evaluated using the 95% limits of agreement method. Validity was assessed on a prospective cohort of 48 UC children, using three constructs: colonoscopic appearance, physician's global assessment, and the Mayo score. Responsiveness was compared on a longitudinal cohort of 75 children. RESULTS: The weights of the resulting PUCAI tools were quite similar, but the Delphi group retained the laboratory items, excluded by the mathematical modeling. This difference was reflected by the Bland and Altman method. Both tools performed equally well in the validation and responsiveness cohorts. CONCLUSION: The judgmentally weighted PUCAI had good validity and responsiveness. The mathematical weighting, however, performed just as well without the laboratory items, resulting in a more feasible index. Therefore, the mathematical modeling has proven to be superior in weighting the PUCAI.

Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH. · Mount Sinai Hospital Inflammatory Bowel Disease Group, University of Toronto, 600 University Avenue, Toronto, ON M5G1X5, Canada. · Nat Genet. · Pubmed #19122664 links to  free full text

Abstract: Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Nguyen GC, Steinhart AH. · Mount Sinai Hospital IBD Centre, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada. · Inflamm Bowel Dis. · Pubmed #18623172 No free full text.

Abstract: BACKGROUND: We sought to determine patterns of hospitalizations for inflammatory bowel disease (IBD) to centers that regularly admit high volumes of IBD patients and whether they impacted health outcomes. METHODS: We queried US hospital discharges in the Nationwide Inpatient Sample to identify admissions with a primary diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) between 1998 and 2004. We determined patterns and predictors of hospitalization at high IBD volume admission centers (HIVACs) (>or=145 IBD admissions annually) and assessed their impact on mortality. RESULTS: Over 7 years the proportion of patients admitted to HIVACs increased from 2.3% to 14.8%. IBD patients were less likely to be admitted to an HIVAC if they were insured by Medicare (odds ratio [OR] 0.74; 95% confidence interval [CI]: 0.65-0.83) or Medicaid (OR 0.71; 95% CI: 0.60-0.84), or were uninsured (OR 0.42; 95% CI: 0.30-0.58) compared with those privately insured. Neighborhood income above the national median favored admission to an HIVAC (OR 1.99; 95% CI: 1.46-2.71). In-hospital mortality was lower among HIVACs compared to non-HIVACs (3.5/1000 versus 7.2/1000, P < 0.0001) and was persistent after adjustment for surgery status, age, comorbidity, and health insurance (OR 0.65; 95% CI: 0.49-0.87). When stratified by diagnosis, mortality was reduced at HIVACs among CD (OR 0.58; 95% CI: 0.37-0.90) but not UC admissions. CONCLUSIONS: There is a rising trend in hospitalizations for IBD at HIVACs, which confers mortality benefit for those with CD. Prospective studies are warranted to further explore the impact of these high-volume centers on IBD health outcomes.

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.

Maunder RG, Greenberg GR, Lancee WJ, Steinhart AH, Silverberg MS. · Mount Sinai Hospital and University of Toronto, Toronto, Canada. · Can J Gastroenterol. · Pubmed #18026574 links to  free full text

Abstract: GOALS: To determine whether the perceived impact of ulcerative colitis (UC) on activities of living (illness intrusiveness) is greater for people who are not living in a married or common-law relationship. BACKGROUND: In general, social and occupational achievement is not greatly impaired by UC, yet patients, especially young adults, often have interpersonal concerns. METHODS: One hundred fifty-five outpatients with UC were assessed for disease activity, and completed self-reports of marital status, income, social support and illness intrusiveness. RESULTS: Fifty-one patients (32.9%) were single, separated or divorced, and 104 patients (67.1%) were married or in common-law relationships. Compared with those who were married or in common-law relationships, single or separated patients were younger, had a lower household income, had lived with UC for fewer years and were less satisfied with social support. Among 135 patients in remission, marital status was significantly associated with illness intrusiveness, controlling for age, income and perceived social support (F=5.73; P=0.02). Low social support (F=4.94; P=0.03) and younger age (F=7.24; P=0.008) were independently associated with illness intrusiveness. Single patients in remission reported illness intrusiveness of similar severity to that reported by patients with active disease. CONCLUSIONS: The perceived impact of UC on the lives of patients is greater in those who are not married or living in common-law relationships. Youth, single status and lower social support commonly coexist, and exert additive effects on the functional impact of UC. Resources to improve social support should be directed toward this group of patients.

Turner D, Walsh CM, Benchimol EI, Mann EH, Thomas KE, Chow C, McLernon RA, Walters TD, Swales J, Steinhart AH, Griffiths AM. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Canada. · Gut. · Pubmed #17981888 No free full text.

Abstract: BACKGROUND: Despite the predominance of extensive disease in children with ulcerative colitis, data concerning severe paediatric ulcerative colitis are sparse. We reviewed rates and predictors of response to intravenous-corticosteroid therapy in a single-centre cohort with long-term follow-up. METHODS: 99 children (49% males; age 2-17 years) were hospitalised (1991-2000) for treatment of severe ulcerative colitis (90% extensive; 49% new onset ulcerative colitis). Clinical, laboratory and radiographic data were reviewed. A population-based subset was used to assess incidence. Predictors of corticosteroid response were analysed using univariate and multivariate analyses at days 3 and 5 of therapy. Colectomy rates were calculated using Kaplan-Meier survival analyses. RESULTS: 28% (95% CI, 23 to 34%) of children with ulcerative colitis resident in the Greater Toronto Area required admission for intravenous corticosteroid therapy, of whom 53 (53%; 95% CI, 44 to 63%) responded. Several predictors were associated with corticosteroid failure, but in multivariable modelling only C-reactive protein [OR = 3.5 (1.4 to 8.4)] and number of nocturnal stools [OR = 3.2 (1.6 to 6.6)] remained significant at both days 3 and 5. The Pediatric Ulcerative Colitis Activity Index (PUCAI), Travis and Lindgren's indices strongly predicted non-response. Radiographically, the upper range of colonic luminal width was 40 mm in children younger than 11 years versus 60 mm in older patients. Cumulative colectomy rates at discharge, 1 year and 6 years were 42%, 58% and 61%, respectively. CONCLUSIONS: Children with ulcerative colitis commonly experience at least one severe exacerbation. Response to intravenous corticosteroids is poor. The PUCAI, determined at day 3 (>45 points) should be used to screen for patients likely to fail corticosteroids and at day 5 (>70 points) to dictate the introduction of second-line therapies.

Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, Walters TD, Zachos M, Mamula P, Beaton DE, Steinhart AH, Griffiths AM. · Division of Gastroenterology, Hepatology and Nutrition, the Hospital for Sick Children, University of Toronto, Toronto, Canada. · Gastroenterology. · Pubmed #17681163 No free full text.

Abstract: BACKGROUND AND AIMS: Colonoscopic appearance, the primary measure of disease activity in adult ulcerative colitis, is less acceptable to children. Our aim was to develop a noninvasive activity index of pediatric ulcerative colitis. METHODS: Item selection was performed judgmentally using a Delphi group of 36 experts in pediatric inflammatory bowel disease. Item weighting was performed by regression modeling using a prospective cohort of 157 pediatric ulcerative colitis patients. Validation was assessed on a separate prospective cohort of 48 children with ulcerative colitis undergoing complete colonoscopy. Responsiveness was evaluated at a follow-up visit of 75 children using effect size statistics and diagnostic utility approaches. RESULTS: A list of 41 items was generated and reduced to 11 by rank order. Two physicians completed the Pediatric Ulcerative Colitis Activity Index (PUCAI) on each of the patients in the weighting cohort. Six clinical items were significant in the regression analysis; the laboratory items and an endoscopic appearance item did not improve the PUCAI performance. In the validation cohort, the PUCAI was highly correlated with the Physician's Global Assessment (r = 0.91, P < .001), Mayo score (r = 0.95, P < .001), and colonoscopic appearance (r = 0.77, P < .001). Correlations were higher than 2 noninvasive adult indices calculated concurrently. Interobserver and test-retest reliability were excellent (intraclass correlation coefficient = 0.95; 95% CI: 0.93-0.97). Cut-off points were established using receiver operator characteristic curves on the full cohort. Excellent responsiveness was found at repeated visits (effect size = 1.9, area under the receiver operator characteristic curve = 0.97). CONCLUSIONS: The rigorously developed PUCAI is a noninvasive, valid, highly reliable, and responsive index with which to assess disease activity in pediatric ulcerative colitis.

De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, Belaiche J, Vermeire S, Farwell L, Goris A, Libioulle C, Jani N, Dassopoulos T, Bromfield GP, Dubois B, Cho JH, Brant SR, Duerr RH, Yang H, Rotter JI, Silverberg MS, Steinhart AH, Daly MJ, Podolsky DK, Louis E, Hafler DA, Rioux JD, Anonymous00242, Anonymous00243. · Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Genes Immun. · Pubmed #17538633 No free full text.

Abstract: The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.

Dassopoulos T, Nguyen GC, Bitton A, Bromfield GP, Schumm LP, Wu Y, Elkadri A, Regueiro M, Siemanowski B, Torres EA, Gregory FJ, Kane SV, Harrell LE, Franchimont D, Achkar JP, Griffiths A, Brant SR, Rioux JD, Taylor KD, Duerr RH, Silverberg MS, Cho JH, Steinhart AH. · Johns Hopkins University Meyerhoff Inflammatory Bowel Disease Center, Baltimore MD, USA. · Inflamm Bowel Dis. · Pubmed #17427244 links to  free full text

Abstract: BACKGROUND: The NIDDK IBD Genetics Consortium (IBDGC) collects DNA and phenotypic data from inflammatory bowel disease (IBD) subjects to provide a resource for genetic studies. No previous studies have been performed on the reliability and validity of phenotypic determinations in either Crohn's disease (CD) or ulcerative colitis (UC) using primary records. Our aim was to determine the reliability and validity of these phenotypic assessments. METHODS: The de-identified records of 30 IBD patients were reviewed by 2 phenotypers per center using a standard protocol for phenotypic assessment. Each phenotyper evaluated 10 charts on 2 occasions 5 months apart. Reliability was expressed as the kappa (kappa) statistic. Performance characteristics were determined by comparison to a consensus-derived "gold standard" and by generation of receiver operating characteristic (ROC) curves. RESULTS: Agreement for diagnosis was excellent (kappa = 0.82; 95% confidence interval [CI]: 0.71-0.92). Agreement for CD location was good for jejunal, ileal, colorectal, and perianal disease with kappa between 0.60 and 0.74 but was fair for esophagogastroduodenal (kappa = 0.36). Agreement for UC extent (kappa = 0.67; 95% CI: 0.48-0.85), and CD behavior (kappa = 0.67; 95% CI: 0.49-0.83) were very good. Area under the ROC curves was greater than 0.84 for diagnosis, CD behavior, UC extent, and ileal and colonic CD location. CONCLUSIONS: IBD phenotype classification using a standard protocol exhibited very good to excellent inter- and intrarater agreement and validity. This study highlights the importance of standard protocols in generating reliable and valid phenotypic assessments. The data will facilitate estimates of phenotyping misclassification rates that should be considered when making inferences from IBD genotype-phenotype studies.

Lal S, Steinhart AH. · Department of Gastroenterology, University Hospitals, Aintree, Liverpool, UK. · Eur J Gastroenterol Hepatol. · Pubmed #17301656 No free full text.

Abstract: Primary sclerosing cholangitis is a chronic cholestatic disease with a progressive course, often culminating in hepatic transplantation. When associated with primary sclerosing cholangitis, ulcerative colitis commonly follows a mild course before, but a more progressive course following liver transplantation, with a significant proportion of patients becoming steroid dependent and/or requiring colectomy. We report the first case demonstrating the efficacy and safety of infliximab therapy for ulcerative colitis following hepatic transplantation.

van Bodegraven AA, Curley CR, Hunt KA, Monsuur AJ, Linskens RK, Onnie CM, Crusius JB, Annese V, Latiano A, Silverberg MS, Bitton A, Fisher SA, Steinhart AH, Forbes A, Sanderson J, Prescott NJ, Strachan DP, Playford RJ, Mathew CG, Wijmenga C, Daly MJ, Rioux JD, van Heel DA. · Department of Gastroenterology, VU University Medical Centre, Amsterdam, The Netherlands. · Gastroenterology. · Pubmed #17087940 No free full text.

Abstract: BACKGROUND & AIMS: Common germline genetic variation in the 3' region of myosin IXB (MYO9B) has been associated recently with susceptibility to celiac disease, with a hypothesis that MYO9B variants might influence intestinal permeability. These findings suggested the current study investigating a possible further role for MYO9B variation in inflammatory bowel disease. METHODS: Eight single-nucleotide polymorphisms (SNPs) were selected to tag common haplotypes from the 35-kb 3' region of MYO9B. These included the strongest celiac disease-associated variants reported in a Dutch cohort. These SNPs were studied in 3 independently collected and genotyped case-control cohorts of European descent (UK, Dutch, and Canadian/Italian), comprising in total 2717 inflammatory bowel disease patients (1197 with Crohn's disease, 1520 with ulcerative colitis) and 4440 controls. RESULTS: Common variation in MYO9B was associated with susceptibility to inflammatory bowel disease in all 3 cohorts examined (most associated SNP, rs1545620; meta-analysis P = 1.9 x 10(-6); odds ratio, 1.2), with the same alleles showing association as reported for celiac disease. CONCLUSIONS: MYO9B genetic variants predispose to inflammatory bowel disease. Interestingly, rs1545620 is a nonsynonymous variant leading to an amino acid change (Ala1011Ser) in the third calmodulin binding IQ domain of MYO9B. Unlike previous variants (in other genes) reported to predispose to inflammatory bowel disease, the association at MYO9B was considerably stronger with ulcerative colitis, although weaker association with Crohn's disease also was observed. These data imply shared causal mechanisms underlying intestinal inflammatory diseases.

Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian, Mezzanine Level, C-Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA. · Science. · Pubmed #17068223 links to  free full text

Abstract: The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Maunder RG, Greenberg GR, Hunter JJ, Lancee WJ, Steinhart AH, Silverberg MS. · Department of Psychiatry, Mount Sinai Hospital, Toronto, Canada. · Am J Gastroenterol. · Pubmed #17029612 No free full text.

Abstract: INTRODUCTION: Studies of psychological factors in ulcerative colitis (UC) have produced inconsistent findings. This study sought to determine whether perinuclear antineutrophil cytoplasmic antibody (pANCA) demarcates subtypes which differ with respect to psychobiological interactions. METHODS: In 148 outpatients with UC, the strength of the relationship between current UC disease activity and psychological distress was assessed. pANCA was determined by ELISA and immunofluorescence, disease activity was determined by symptoms, physical examination, and endoscopy using the St. Mark's index, and depressive symptoms and health anxiety were measured with self-report scales. Pearson correlations between disease activity and depressive symptoms and between disease activity and health anxiety were calculated. RESULTS: In 74 pANCA negative subjects, the relationship between disease activity and measures of psychological distress was significant for disease activity-depression (partial correlation = 0.48, p < 0.001) and for disease activity-health anxiety (partial correlation = 0.64, p < 0.001), whereas in 74 pANCA positive subjects, no relationships were found (disease activity-depression: partial correlation = 0.18, p= 0.14; disease activity-health anxiety: partial correlation = 0.20, p= 0.09). The differences in the strength of correlation between pANCA positive and pANCA negative subjects were statistically significant for both disease activity-depression (z = 2.0, p= 0.02) and activity-health anxiety (z = 3.3, p < 0.001). CONCLUSIONS: pANCA status demarcates psychobiologically distinct subtypes of UC, such that the absence of pANCA is associated with greater psychobiological interaction. These findings have implications for clinical care and understanding the pathophysiology of intestinal inflammation.

Regueiro M, Loftus EV, Steinhart AH, Cohen RD. · Inflammatory Bowel Disease Center and Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. · Inflamm Bowel Dis. · Pubmed #17012969 links to  free full text

Abstract: BACKGROUND: The goal of this work was to critically evaluate the published studies on the treatment of ulcerative proctitis (UP) and left-sided ulcerative colitis (L-UC). The results of this review provided the content for the accompanying treatment guidelines, Clinical Guidelines for the Medical Management of Left-sided Ulcerative Colitis and Ulcerative Proctitis: Summary Statement. METHODS: All English language articles published between 1995 and September 2005 were identified through a comprehensive literature search using OVID and PubMed. The quality of the data supporting or rejecting the use of specific therapies was categorized by a data quality grading scale. An "A+" grade was assigned to treatment supported by multiple high-quality randomized controlled trials with consistent results, whereas a "D" grade was given to therapy supported only by expert opinion. The therapeutic efficacy of a treatment was defined by its success in treating UP and L-UC compared with placebo. A medication was ranked as "excellent" if it was specifically studied for UP and L-UC and had consistently positive results compared with placebo or another agent. Quality and efficacy scores were agreed on by author consensus. RESULTS: For the acute treatment of UP or L-UC, the rectally administered corticosteroids and mesalazine (5-ASA), either alone or in combination with oral 5-ASAs, are the most effective therapy: evidence quality, A+; efficacy, excellent. Only rectally administered 5-ASA received an A+/excellent rating for maintenance of remission. Infliximab received an A+ grade for induction and maintenance of remission but only a "good" rating because the studies were performed in all UC, not specifically UP or L-UC. CONCLUSIONS: This critical evaluation of treatment provides a "report card" on medications available for the management of patients with UP and L-UC. The guidelines should provide a useful reference and supplement for physicians treating UC patients.

Regueiro M, Loftus EV, Steinhart AH, Cohen RD, Anonymous00130. · Inflammatory Bowel Disease Center and Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. · Inflamm Bowel Dis. · Pubmed #17012968 links to  free full text

Abstract: There are few published guidelines for the treatment of inflammatory bowel disease. Physicians choose therapy based on evidence-based data, peer and expert opinion, and personal experience. This article provides treatment guidelines for the induction and maintenance of ulcerative proctitis and left-sided colitis and the management of disease refractory to 5-aminosalicylic acid (5-ASA) compounds and corticosteroids The guidelines are derived from evidence-based data and, when lacking, expert opinion or the authors' experience. The comprehensive review of the literature is presented in the accompanying article, "The Medical Management of Left-Sided Ulcerative Colitis and Ulcerative Proctitis: Critical Evaluation of Therapeutic Trials". Rectally administered 5-ASA and corticosteroid suppositories are effective treatment for most ulcerative proctitis patients. Corticosteroid and 5-ASA enemas, which reach the splenic flexure of the colon, are recommended for patients with left-sided ulcerative colitis. The combination of rectally administered 5-ASA enemas and oral 5-ASA agents may afford better treatment of left-sided colitis and possibly prevent proximal extension of disease. Patients refractory to 5-ASAs and corticosteroids may require an immunomodulator or biological response modifier therapy. Those who have ongoing signs and symptoms of ulcerative proctitis and left-sided ulcerative colitis despite maximal medical therapy require a proctocolectomy.

Nguyen GC, Torres EA, Regueiro M, Bromfield G, Bitton A, Stempak J, Dassopoulos T, Schumm P, Gregory FJ, Griffiths AM, Hanauer SB, Hanson J, Harris ML, Kane SV, Orkwis HK, Lahaie R, Oliva-Hemker M, Pare P, Wild GE, Rioux JD, Yang H, Duerr RH, Cho JH, Steinhart AH, Brant SR, Silverberg MS. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Am J Gastroenterol. · Pubmed #16696785 No free full text.

Abstract: OBJECTIVES: Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. METHODS: Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. RESULTS: African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32-0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3-13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55-10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8-4.6) and erythema nodosum (3.3; 95% CI: 1.7-6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts. CONCLUSIONS: There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.