Ulcerative Colitis: Griffiths AM

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.

Turner D, Griffiths AM. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, 555 University Avenue, Toronto, M5G-1X8, Canada. · Curr Gastroenterol Rep. · Pubmed #18377798 No free full text.

Abstract: Upper gastrointestinal (GI) tract inflammation in inflammatory bowel disease has become increasingly recognized, even in the absence of specific localizing symptoms, as patients more frequently undergo upper endoscopy. Although the recent Montreal classification system allowed classification of upper GI involvement in Crohn's disease (CD), independent of other locations, a consensus regarding the definition of what qualifies as significant "involvement" is still lacking. Reported incidence data vary considerably depending on the definitions used and the selected target population. Pediatric data suggest that upper endoscopy is useful in differentiating CD from ulcerative colitis, when inflammation is otherwise predominantly confined to the colon; however, this question has yet to be studied in adults. Infliximab therapy for upper GI-CD seems as effective as that seen for more distal GI inflammation.

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.

Griffiths AM. · IBD Program, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, Ont. M5G 1X8, Canada. · Best Pract Res Clin Gastroenterol. · Pubmed #15157824 No free full text.

Abstract: In parallel with overall population trends, the incidence of paediatric ulcerative colitis (UC) has remained stable, whereas that of paediatric Crohn's disease (CD) has increased in recent decades. Still rare among preschool children, the incidence of both UC and CD rises steadily from middle childhood through adolescence. There is an unexplained preponderance of males with early-onset CD, and an equal gender distribution in paediatric UC. Observations on the familiality of paediatric inflammatory bowel disease (IBD) suggest that genetic susceptibility is particularly important to disease pathogenesis in young patients. In comparison to adult-onset disease, childhood UC is usually extensive but the anatomic localization of paediatric CD varies, as in adults. UC manifests uniformly as bloody diarrhea whereas the symptomatology of paediatric CD is much more diverse. Linear growth impairment frequently complicates chronic intestinal inflammation in paediatric CD. Key contributing factors have been defined; better immunomodulatory therapy and emerging biologic agents will potentially reduce its prevalence.

Bousvaros A, Kirschner BS, Werlin SL, Parker-Hartigan L, Daum F, Freeman KB, Balint JP, Day AS, Griffiths AM, Zurakowski D, Ferry GD, Leichtner AM. · Combined Program in Pediatric Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts 02115, USA. · J Pediatr. · Pubmed #11113835 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy of oral tacrolimus as an induction agent in steroid-refractory severe colitis. STUDY DESIGN: Open-label, multicenter trial of oral tacrolimus in patients with severe colitis. Patients not responding to conventional therapy received tacrolimus, 0.1 mg/kg/dose given twice a day, and the dosage was adjusted to achieve blood levels between 10 and 15 ng/mL. Response was defined as improvement in a number of clinical parameters (including abdominal pain, diarrhea, rectal bleeding, and cessation of transfusions). Patients who responded by 14 days continued to receive tacrolimus, and 6-mercaptopurine or azathioprine was added as a steroid-sparing agent 4 to 6 weeks after the tacrolimus was instituted. RESULTS: Fourteen patients were enrolled in the study. One patient elected to withdraw after 48 hours. Of the 13 remaining, 9 (69%) responded and were discharged. Tacrolimus was continued for 2 to 3 months in the responders, except for 1 patient who was given tacrolimus for 11 months. After 1 year of follow-up, only 5 (38%) patients were receiving maintenance therapy; the other 4 responders had undergone colectomy. CONCLUSION: Although tacrolimus is effective induction therapy for severe ulcerative or Crohn's colitis, fewer than 50% of patients treated will successfully achieve a long-term remission.

Ei-Matary W, Vandermeer B, Griffiths AM. · Dept. of Pediatrics, Faculty of Medicine, University of Alberta, Aberhart Centre 1, 11402 University Ave, Edmonton, Alberta, Canada, T6G 2J3. · Cochrane Database Syst Rev. · Pubmed #19588435 No free full text.

Abstract: BACKGROUND: Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. This review was performed to examine the efficacy of methotrexate for maintenance of remission in ulcerative colitis. OBJECTIVES: To systematically review randomized controlled trials examining the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane IBD/FBD Review Group Specialized Trials Register, MEDLINE (PUBMED), EMBASE (1984 to November 2008), Web of Science, Scopus, Database of Abstracts of Reviews of Effects (DARE), and Clinical trials database (ClinicalTrials.gov) were searched. In addition, references from selected papers and abstracts from Digestive Disease Week were also examined. SELECTION CRITERIA: Only randomized controlled trials (RCT) evaluating the efficacy of methotrexate for maintaining remission in patients with ulcerative colitis compared to placebo or any other intervention were considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author. The odds ratio of relapse, 95% confidence interval and P-value were calculated using the Mantel-Haenszel method. An intention to treat analysis was used. MAIN RESULTS: Only one trial fulfilled the inclusion criteria. This trial randomized 30 patients to methotrexate and 37 to placebo. Methotrexate was given orally in a dose of 12.5 mg/week. Fourteen patients in the methotrexate group and 18 patients in the placebo group who entered remission were followed for 9 months or to the time of first relapse. Sixty-four per cent of methotrexate patients relapsed compared to 44% of placebo patients (OR 2.25; 95% CI 0.54 to 9.45; P = 0.27). AUTHORS' CONCLUSIONS: The available evidence is not sufficient to recommend the use of methotrexate to maintain remission in patients with ulcerative colitis. A large scale methodologically rigorous randomized controlled trial is needed. Such a study should investigate higher doses of methotrexate and parenteral administration.

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.

This publication has no abstract.

Turner D, Griffiths AM. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, Toronto, Canada. · Curr Gastroenterol Rep. · Pubmed #19463224 No free full text.

Abstract: Upper gastrointestinal (GI) tract inflammation in inflammatory bowel disease has become increasingly recognized, even in the absence of specific localizing symptoms, as patients more frequently undergo upper endoscopy. Although the recent Montreal classification system allowed classification of upper GI involvement in Crohn's disease (CD), independent of other locations, a consensus regarding the definition of what qualifies as significant "involvement" is still lacking. Reported incidence data vary considerably depending on the definitions used and the selected target population. Pediatric data suggest that upper endoscopy is useful in differentiating CD from ulcerative colitis, when inflammation is otherwise predominantly confined to the colon; however, this question has yet to be studied in adults. Infliximab therapy for upper GI-CD seems as effective as that seen for more distal GI inflammation.

Turner D, Hyams J, Markowitz J, Lerer T, Mack DR, Evans J, Pfefferkorn M, Rosh J, Kay M, Crandall W, Keljo D, Otley AR, Kugathasan S, Carvalho R, Oliva-Hemker M, Langton C, Mamula P, Bousvaros A, LeLeiko N, Griffiths AM, Anonymous00063. · Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Jerusalem, Israel. · Inflamm Bowel Dis. · Pubmed #19161178 No free full text.

Abstract: BACKGROUND: We evaluated the psychometric performance of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in a real-life cohort from the Pediatric IBD Collaborative Research Group. METHODS: Two consecutive visits of 215 children with ulcerative colitis (UC) were included (mean age 11.2 +/- 3.6 years; 112 (52%) males; 63 (29%) newly diagnosed and the others after disease duration of 24 +/- 15.6 months). Validity was assessed using several constructs of disease activity. Distributional and anchor-based strategies were used to assess the responsiveness of the PUCAI to change over time following treatment. RESULTS: Reflecting feasibility, 97.6% of 770 eligible registry visits had a completed PUCAI score versus only 47.6% for a contemporaneously collected Pediatric Crohn's Disease Activity Index (odds ratio = 45.8, 95% confidence interval [CI] 28.6-73.5) obtained for children with Crohn's disease accessioned into the same database. The PUCAI score was significantly higher in patients requiring escalation of medical therapy (45 points [interquartile range, IQR, 30-60]) versus those who did not, (0 points [IQR 0-10]; P < 0.001), and was highly correlated with physician's global assessment of disease activity (r = 0.9, P < 0.001). The best cutoff to differentiate remission from active disease was 10 points (area under receiver operating characteristic curve [AUC] 0.94; 95% CI 0.90-0.97). Test-retest reliability was excellent (intraclass correlation coefficient = 0.89; 95% CI 0.84-0.92, P < 0.001) as well as responsiveness to change (AUC 0.96 [0.92-0.99]; standardized response mean 2.66). CONCLUSION: This study on real-life, prospectively obtained data confirms that the PUCAI is highly feasible by virtue of the noninvasiveness, valid, and responsive index. The PUCAI can be used as a primary outcome measure to reflect disease activity in pediatric UC.

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).

Turner D, Schünemann HJ, Griffith LE, Beaton DE, Griffiths AM, Critch JN, Guyatt GH. · Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Jerusalem, Israel. · J Clin Epidemiol. · Pubmed #19013766 No free full text.

Abstract: OBJECTIVE: We compared the minimal important difference (MID) values obtained by the receiver operating characteristics (ROC) curve approach using different strategies on four outcome measures to guide the optimal use of ROC curve. STUDY DESIGN AND SETTING: Studies of two psychometric scales (Rhinoconjunctivitis Quality-of-Life Questionnaire [RQLQ] and Chronic Respiratory Questionnaire [CRQ]) and two clinimetric indices (Pediatric Ulcerative Colitis Activity Index [PUCAI] and Pediatric Crohn's Disease Activity Index [PCDAI]) instruments provided prospective longitudinal data. The MID was calculated from 7- and 15-point global ratings of change dichotomized in multiple ways, using the ROC curve method. Analysis was performed twice: first, using only the two groups adjacent to the dichotomization point (e.g., including only patients who had a small vs. moderate change); and second, using the entire cohort split at the same cutoff (e.g., including both unchanged subjects with those with small change vs. those who experienced moderate or large change combined). RESULTS: Using the entire cohort, rather than just those with ratings adjacent to the dichotomization point, yielded more precise and sensible MID estimates. With one exception, high precision was obtained when using the ROC curve method for any cutoff on the rating scale. CONCLUSION: When calculating the MID using the ROC curve method, the use of the entire cohort maximizes precision.

Benchimol EI, Turner D, Mann EH, Thomas KE, Gomes T, McLernon RA, Griffiths AM. · Division of Gastroenterology, Hepatology & Nutrition, The Hospital of Sick Children, Toronto, Canada. · Am J Gastroenterol. · Pubmed #18510624 No free full text.

Abstract: BACKGROUND: Toxic megacolon (TMC) denotes a rare clinical syndrome accompanied by colonic dilatation, and is a serious complication of inflammatory bowel disease (IBD). This study assessed the clinical and radiologic characteristics of TMC in children with IBD. METHODS: A systematic search identified patients with IBD-associated TMC and matched them by age to controls with ulcerative colitis without evidence of TMC. Clinical characteristics and outcomes were compared with conditional logistic regression. Abdominal X-rays were interpreted by two blinded radiologists and findings were compared with controls. RESULTS: Ten children with TMC (median age 12.6 [7.3-15.5] yr) were matched with 20 controls (median age 12.8 [6.8-15.2] yr). Altered level of consciousness and hypotension were rare in children with TMC. Fever (P= 0.005), tachycardia (P= 0.0001), dehydration (P= 0.01), and electrolyte abnormalities (P= 0.0002) were more common in children with TMC than controls. Air-fluid levels (P= 0.005), intestinal thickening (P= 0.006), and abnormal colonic haustra (P= 0.012) were more commonly seen on X-rays of TMC cases. Transverse colon luminal diameter >or=56 mm was strongly suggestive of TMC (sensitivity 90%, specificity 90%, area under the ROC curve 0.91). No child with TMC died and 70% required colectomy during admission. Two of the three with intact colons at discharge required second-line therapy during the subsequent year. CONCLUSIONS: Colonic dilatation >or=56 mm in children with IBD strongly suggests TMC, if clinical signs are present. Mental alteration and hypotension may be less common in children than in adults. TMC in children with IBD is associated with poor outcome, with a high rate of corticosteroid failure.

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.

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.

Muise AM, Walters T, Wine E, Griffiths AM, Turner D, Duerr RH, Regueiro MD, Ngan BY, Xu W, Sherman PM, Silverberg MS, Rotin D. · Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, 555 University Ave, Toronto, Ontario, Canada. · Curr Biol. · Pubmed #17614280 No free full text.

Abstract: Inflammatory bowel disease (IBD), a relatively common chronic debilitating intestinal illness, is composed of two broadly defined groups, Crohn's disease (CD) and ulcerative colitis (UC). Although several susceptibility genes for CD have been recently described, susceptibility genes exclusive for UC have not been forthcoming. Here, we show that receptor protein-tyrosine phosphatase sigma (PTPRS-encoding PTPsigma) knockout mice spontaneously develop mild colitis that becomes severe when challenged with two known inducers of colitis. We also demonstrate that E-cadherin and beta-catenin, two important adherens junction proteins involved in maintenance of barrier defense in the colon, act as colonic substrates for PTPsigma. Furthermore, we show that three SNPs (rs886936, rs17130, and rs8100586) that flank exon 8 in the human PTPRS gene are associated with UC. The presence of these SNPs is associated with novel splicing that removes the third immunoglobulin-like domain (exon 9) from the extracellular portion of PTPsigma, possibly altering dimerization or ligand recognition. We propose that polymorphisms in the human PTPRS gene lead to ulcerative colitis.

Anonymous00166, Anonymous00167, Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, Higuchi LM, Hyams JS, Kirschner BS, Kugathasan S, Baldassano RN, Russo PA. · No affiliation provided · J Pediatr Gastroenterol Nutr. · Pubmed #17460505 No free full text.

Abstract: BACKGROUND: Studies of pediatric inflammatory bowel disease (IBD) have varied in the criteria used to classify patients as having Crohn disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Patients undergoing an initial evaluation for IBD will often undergo a series of diagnostic tests, including barium upper gastrointestinal series with small bowel follow-through, abdominal CT, upper endoscopy, and colonoscopy with biopsies. Other tests performed less frequently include magnetic resonance imaging scans, serological testing, and capsule endoscopy. The large amount of clinical information obtained may make a physician uncertain as to whether to label a patient as having CD or UC. Nevertheless, to facilitate the conduct of epidemiological studies in children, to allow the entry of children into clinical trials, and to allow physicians to more clearly discuss diagnosis with their patients, it is important that clinicians be able to differentiate between CD and UC. METHODS: A consensus conference regarding the diagnosis and classification of pediatric IBD was organized by the Crohn's and Colitis Foundation of America. The meeting included 10 pediatric gastroenterologists and 4 pediatric pathologists. The primary aim was to determine the utility of endoscopy and histology in establishing the diagnosis of CD and UC. Each member of the group was assigned a topic for review. Topics evaluated included differentiating inflammatory bowel disease from acute self-limited colitis, endoscopic and histological features that allow differentiation between CD and UC, upper endoscopic features seen in both CD and UC, ileal inflammation and "backwash ileitis" in UC, patchiness and rectal sparing in pediatric IBD, periappendiceal inflammation in CD and UC, and definitions of IC. RESULTS: Patients with UC may have histological features such as microscopic inflammation of the ileum, histological gastritis, periappendiceal inflammation, patchiness, and relative rectal sparing at the time of diagnosis. These findings should not prompt the clinician to change the diagnosis from UC to CD. Other endoscopic findings, such as macroscopic cobblestoning, segmental colitis, ileal stenosis and ulceration, perianal disease, and multiple granulomas in the small bowel or colon more strongly suggest a diagnosis of CD. An algorithm is provided to enable the clinician to differentiate more reliably between these 2 entities. CONCLUSIONS: The recommendations and algorithm presented here aim to assist the clinician in differentiating childhood UC from CD. We hope the recommendations in this report will reduce variability among practitioners in how they use the terms "ulcerative colitis," "Crohn disease," and "indeterminate colitis." The authors hope that progress being made in genetic, serological, and imaging studies leads to more reliable phenotyping.

Sylvester FA, Wyzga N, Hyams JS, Davis PM, Lerer T, Vance K, Hawker G, Griffiths AM. · Division of Gastroenterology and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut 06106, USA. · Inflamm Bowel Dis. · Pubmed #17206638 links to  free full text

Abstract: BACKGROUND: In children with inflammatory bowel disease (IBD) it is not known whether reductions in bone mineral density (BMD) are a consequence of bone turnover alterations and if BMD improves with treatment. METHODS: In a cohort of children with IBD, we prospectively measured indicators of bone remodeling, body mass index (BMI), disease activity, intact parathyroid hormone, serum IL-6, and insulin-like growth factor-I at diagnosis and then every 6 months for 2 years. BMD was determined annually using dual x-ray absorptiometry (DXA). BMD Z-scores were calculated using height/age. Baseline measurements and calcium intake were compared with a group of age- and sex-matched healthy children. RESULTS: We observed that at diagnosis total body BMD Z-score (mean +/- SD) was -0.78 +/- 1.02 for Crohn's disease (CD, n = 58), -0.46 +/- 1.14 for ulcerative colitis (UC, n = 18), and -0.17 +/- 0.95 for control (CL, n = 49) (P < 0.01, CD versus CL). In CD, a BMD Z-score <-1.0 was associated with lower BMI and higher serum IL-6. Patients with CD and UC had low bone turnover. Activation of bone formation paralleled clinical improvement, but BMC gain was less than expected over the 2-year study period, especially in CD. Prednisone use did not correlate with low BMD. CONCLUSIONS: Decreased bone turnover occurs in children newly diagnosed with IBD. Although indicators of osteoblast activity increase with clinical improvement, bone mineral accrual does not accelerate. Children with low BMI may be considered for BMD screening, since they are at risk for low bone mass.

Otley AR, Griffiths AM, Hale S, Kugathasan S, Pfefferkorn M, Mezoff A, Rosh J, Tolia V, Markowitz J, Mack D, Oliva-Hemker M, Wyllie R, Rothbaum R, Bousvaros A, Del Rosario JF, Evans J, Blanchard W, Hyams J, Anonymous00277. · FRCPC, Division of Gastroenterology & Nutrition, IWK Health Centre, Halifax, Nova Scotia, Canada. · Inflamm Bowel Dis. · Pubmed #16917222 No free full text.

Abstract: BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is of increasing importance in the evaluation of new therapies for inflammatory bowel disease (IBD). Available data concerning HRQOL in pediatric patients are sparse and uniformly cross-sectional. The aim of this study was to describe HRQOL and influential factors in newly diagnosed pediatric patients with Crohn's disease and ulcerative colitis during the first 12 months after diagnosis. MATERIALS AND METHODS: Participants were drawn from a large, prospectively derived observational IBD registry of pediatric patients studied through 18 U.S. and Canadian centers. Patients who had completed a baseline IMPACT questionnaire and for whom there were 12 months of follow-up data available were included. In addition to description of cohort, factors that were believed to influence HLQOL were assessed during the course of the year from diagnosis. RESULTS: Two hundred eighteen children met inclusion criteria (77% Crohn's disease, 23 % ulcerative colitis, mean age 12.7 +/- 1.9 years). Mean total IMPACT score at baseline was 154, 181 at 6 months, and 191 at 1 year (possible range 0-238, with increasing scores representing better quality of life). Repeated measures analysis showed that age and disease severity significantly negatively affected the IMPACT scores during the course of the year. CONCLUSIONS: In this large prospective pediatric IBD cohort, significant improvement in HRQOL is noted during the year from diagnosis. Mean IMPACT scores varied significantly depending on the disease severity and also decreased with increasing age.

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.

Achkar JP, Dassopoulos T, Silverberg MS, Tuvlin JA, Duerr RH, Brant SR, Siminovitch K, Reddy D, Datta LW, Bayless TM, Zhang L, Barmada MM, Rioux JD, Steinhart AH, McLeod RS, Griffiths AM, Cohen Z, Yang H, Bromfield GP, Schumm P, Hanauer SB, Cho JH, Nicolae DL. · Center for Inflammatory Bowel Disease, Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH, USA. · Am J Gastroenterol. · Pubmed #16542294 No free full text.

Abstract: OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.