Ulcerative Colitis: Turner D

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.

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 Experts were contacted for unpublished data.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.

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.

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.

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.