The Phenotypic Spectrum of New-onset IBD in Canadian Children of South Asian Ethnicity: A Prospective Multi-Centre Comparative Study.

BACKGROUND: Canadian-born children of South Asian [SA] ethnicity develop inflammatory bowel disease [IBD] at similar rates to those among Caucasian children. We evaluated the variation in phenotypic spectrum of IBD in SA and Caucasian children in a national paediatric inception cohort of new-onset IBD. METHODS: Patients aged <17 years, enrolled in a Canadian nationwide inception cohort study, were included. Baseline demographic and IBD phenotypic features were compared between SA and Caucasian children. Longitudinal outcomes through 18 months of follow-up were compared matched by propensity scores. RESULTS: Of 1156 children enrolled over 2014 to 2019, 623 were Caucasian [98% and 88% parents Canadian born] and 114 SA [79% Canadian born, 87% parents SA born]. Fewer SAs have a first-degree relative with IBD, 6% vs 19% in Caucasians, p = 0.002. SAs present at a younger age, median age 11.4 years (interquartile range [IQR] 9.2-14.3) vs 13 years [IQR 10.9-15 years], p = 0.03 and more commonly with a UC/IBD-U [ulcerative colitis/IBD-unclassified] subtype [ratio of UC/IBD-U to CD 1.2:1 vs 1:1.8 for Caucasians, p <0.001]. Additionally, a greater proportion of SA CD patients present with colonic-only disease [colonic-only CD/UC/IBD-U in SAs 67% vs 57% for Caucasians, p = 0.001], and among those with CD, colonic CD in SAs 31% vs 23% in Caucasians, p = 0.20]. Perianal fistulising disease was also numerically more common in SAs (14 [27%] vs 64 [18%], p = 0.06]. Adjusting for differences in phenotypic presentation, anti-tumour necrosis factor [TNF] exposure, and time to initiation was similar, and two-thirds of children, whether anti-TNF exposed or naïve, were in corticosteroid-free clinical remission at 18 months irrespective of ethnicity. CONCLUSIONS: The phenotypic spectrum of new-onset IBD in SA children differs from that of Caucasian children, but treatment and clinical course are similar within phenotypic subgroups.

Phenotypic Variation in Paediatric Inflammatory Bowel Disease by Age: A Multicentre Prospective Inception Cohort Study of the Canadian Children IBD Network.

BACKGROUND AND AIMS: Incidence of paediatric inflammatory bowel disease [IBD] in Canada is among the highest worldwide, and age of onset may be decreasing. In a multicentre nationwide inception cohort study, we examined variation in phenotype of IBD throughout the paediatric age spectrum. METHODS: Children aged ≥2 years [y] and <17y [A1 age at diagnosis], with new onset IBD, were systematically evaluated at sites of the Canadian Children IBD Network. Prospectively recorded phenotypic data were compared between age groups. RESULTS: Among 1092 children (70% Caucasian; 64% Crohn's disease [CD], 36% ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U]; median age 13 y, interquartile range [IQR] 11-15 y), 210 [19%] were diagnosed before the age of age 10 y [Paris A1a] and 43 [4%] before age 6 y (very-early-onset [VEO-IBD]). CD was less common in younger children [42%, 56%, 66%, respectively, of VEO-IBD, A1a; A1b]. Colon-only IBD [UC/IBDU or CD-colon] was present in 81% of VEO-IBD and 65% of A1a; ileal disease increased progressively, reaching plateau at age 10 y. CD location was ileocolonic [L3] in 53% overall. Ileitis [L1] increased with age [6% of VEO-IBD; 13% of A1a; 21% of A1b], as did stricturing/penetrating CD [4% of A1a; 11% of A1b]. At all ages UC was extensive [E3/E4] in >85%, and disease activity moderate to severe according to Physician's Global Assessment [PGA] and weighted Paediatric Crohn's Disease Activity Index/Paediatric Ulcerative Colitis Activity Index [wPCDAI/PUCAI] in >70%. Heights were modestly reduced in CD [mean height z score -0.30 ± 1.23], but normal in UC/IBD-U. CONCLUSIONS: Paris classification of age at diagnosis is supported by age-related increases in ileal disease until age 10 years. Other phenotypic features, including severity, are similar across all ages. Linear growth is less impaired in CD than in historical cohorts, reflecting earlier diagnosis.

Systematic review with meta-analysis: magnetic resonance enterography signs for the detection of inflammation and intestinal damage in Crohn's disease.

BACKGROUND: In the treatment of Crohn's disease (CD), mucosal healing has become a major goal, with the hope of avoiding intestinal damage from chronic inflammation. Magnetic resonance enterography (MRE) has emerged as a non-invasive means of monitoring inflammation and damage. AIMS: As part of the development of MRE-based multi-item measures of inflammation and damage for paediatric studies, we carried out a systematic review and meta-analysis to identify MRE variables used to describe these two distinct concepts. METHODS: 2501 studies of MRI and CD were identified. Studies written in any language reporting individual MRE signs for patients diagnosed with CD were included. Two-hundred-and-forty-four studies were fully reviewed and 62 were included (inflammation, n = 51; damage, n = 24). Sensitivity, specificity and associated confidence intervals were calculated, and hierarchical summary ROC curves were constructed for each MRE sign. RESULTS: A total of 22 MRE signs were used to reflect inflammation, and 9 to reflect damage. Diagnostic accuracy of MRE signs of inflammation and damage was heterogeneous; however, wall enhancement, mucosal lesions and wall T2 hyperintensity were the most consistently useful for inflammation (most sensitivities >80% and specificities >90%), and detection of abscess and fistula were most consistently useful for damage (most sensitivities >90%, specificities >95%). CONCLUSIONS: Identifying the best MRE variables to reflect inflammation and damage will maximise the utility of this rapidly emerging technique and is the first stage of constructing MRE-based indices for evaluating inflammation and intestinal damage.

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

Validating Crohn's disease activity indices for use in assessing postoperative recurrence.

BACKGROUND: The Crohn's Disease Activity Index (CDAI) has been used in medical trials with scores <150 indicative of remission. Its value in assessing postoperative recurrence is unknown. The objective of this study was to explore the utility of the CDAI in determining the presence or absence of symptomatic disease recurrence in patients having previously undergone ileocolic resection for Crohn's disease. METHODS: Ninety-three patients underwent clinical and colonoscopic evaluation within 12 months of ileocolic resection. Endoscopic appearance was assessed using the Rutgeerts score (i0-i4). Symptomatic disease recurrence was defined by the composite of symptom severity warranting therapy and an endoscopic score ≥ i2. CDAI scores were calculated. Comparisons were made using the receiver operator curve (ROC). RESULTS: Thirty-nine (42%) patients had recurrent disease (22% symptomatic, 20% endoscopic only) at 12 months. Median CDAI for symptomatic recurrence was 198 (interquartile range [IQR]: 106-293), 80 for asymptomatic subjects (IQR 35-115). The area under the ROC curve for symptomatic disease and CDAI was 0.78 (95% confidence interval [CI] 0.64-0.91). Recurrence was best predicted by a CDAI of ≥ 148 (sensitivity 70%, specificity 81%). A strong linear relationship existed between the CDAI and Inflammatory Bowel Disease Questionnaire (r = 0.82). CONCLUSIONS: The CDAI performs reasonably well in the postoperative setting and 150 appears the best cutpoint for indicating symptomatic disease. However, it is likely not suitable for use as the primary outcome measure. These data suggest that a combination of symptom assessment plus endoscopic evidence of recurrence should remain the gold standard definition for assessing outcomes in postoperative CD trials.

Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response.

OBJECTIVE: To compare four faecal markers for their ability to predict steroid refractoriness in severe paediatric ulcerative colitis (UC). Construct validity and responsiveness to change were also assessed. METHODS: This was a prospective multicentre cohort study. Stool samples from 101 children (13.3 + or - 3.6 years; Pediatric UC Activity Index (PUCAI) at admission 72 + or - 12 points) were obtained at the third day of intravenous steroid therapy. Repeated samples at discharge were obtained from 24 children. Predictive validity was assessed using diagnostic utility statistics to predict steroid failure (ie, the need for salvage treatment). Concurrent validity was assessed using correlational analysis with the following constructs: PUCAI, Lindgren and Seo scores, physician's global assessment, albumin, erythrocyte sedimentation rate and C-reactive protein (CRP). Responsiveness was assessed using test utility and correlational strategies. RESULTS: Median values (IQR) were very high at baseline for all four markers (calprotectin 4215 microg/g (2297-8808); lactoferrin 212 microg/g (114-328); M2-pyruvate kinase (M2-PK) 363 U/g (119-3104); and S100A12 469 microg/g (193-1112)). M2-PK was numerically superior to the other three markers and CRP in predicting response to corticosteroid treatment (area under the receiver operating characteristic (ROC) curve 0.75 (95% CI 0.64 to 0.85; p<0.001) vs <0.65 for the others). However, it did not add to the predictive ability of the PUCAI (area under the ROC 0.81 (95% CI 0.73 to 0.89)). M2-PK also had the highest construct validity but with a modest mean correlation with all constructs (r=0.3; p<0.05). None of the markers was responsive to change (Spearman's rho correlation with change in the PUCAI <0.1; p>0.05, area under the ROC curve <0.65; p>0.05). CONCLUSIONS: The four markers were greatly elevated in severe paediatric UC. Only M2-PK had good construct and predictive validity, and none was responsive to change. The PUCAI, a simple clinical index, performed better than the faecal markers in predicting outcome following a course of intravenous corticosteroids in severe UC.

Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease.

BACKGROUND: Patients with Crohn's disease have defects in intestinal epithelial permeability that are inadequately explained by known inflammatory bowel disease (IBD) susceptibility genes. E-cadherin (CDH1) plays a vital role in maintaining the integrity of the intestinal barrier and its cellular localisation is disrupted in patients with Crohn's disease. AIM: To determine if polymorphisms in the CDH1 gene are associated with Crohn's disease and to determine the function associated with these polymorphisms. METHODS: The hypothesis was tested using a candidate gene approach using 20 Tag SNPs derived from the HapMap and Crohn's disease trios. Functional studies were carried out using HapMap cell lines and polarised epithelial cell lines (MDCK-1 and Caco2). RESULTS: Here we show that CDH1 is associated with Crohn's disease in 327 trios (rs10431923 excess transmission of "TT" genotype; p = 0.0020) and is replicated in the Wellcome Trust Case Control Consortium CD data set (TT risk allele; OR 1.2, p = 0.005). Patients with the Crohn's disease risk haplotype (rs12597188, rs10431923 and rs9935563; GTC allelic frequency 21%; p = 0.000016) exhibited increased E-cadherin cytoplasmic accumulation in their intestinal epithelium which may be explained by the presence of a novel truncated form of E-cadherin. Accordingly, expression of this truncated E-cadherin in cultured polarised epithelial cells resulted in abnormal intracellular accumulation and impaired plasma membrane localisation of both E-cadherin and beta-catenin. CONCLUSION: The mis-localisation of E-cadherin and beta-catenin may explain the increased permeability seen in some patients with Crohn's disease. Thus, the polymorphisms identified in CDH1 are important for understanding the pathogenesis of Crohn's disease and point to a defect in barrier defence.

Growth abnormalities persist in newly diagnosed children with crohn disease despite current treatment paradigms.

OBJECTIVES: We analyzed growth outcomes in children newly diagnosed with Crohn disease and determined whether growth abnormalities persist despite current therapies. PATIENTS AND METHODS: Clinical and growth data were prospectively obtained on an inception cohort younger than 16 years old at diagnosis and Tanner I to III during the study. RESULTS: In all, 176 children (mean age 10.1 years; 65% male) with mild (33%) or moderate/severe (67%) disease at diagnosis were studied. Disease activity at 1 year was inactive/mild (89%) or moderate/severe (11%). First-year treatments included immunomodulators (60%), corticosteroids (77%), 5-aminosalicylates (61%), infliximab (15%), and enteral nutrition (10%). By 2 years, 86% had received immunomodulators and 36% infliximab. Mean height z scores at diagnosis, 1 year, and 2 years were -0.49 +/- 1.2 standard deviations (SDs), -0.50 +/- 1.2, and -0.46 +/- 1.1, respectively. Of the subjects, 10%, 8%, and 6.5% had height z scores less than -2 SD at diagnosis, 1 year, and 2 years. A height velocity z score less than -1SD was seen in 45% of subjects at 1 year and 38% at 2 years. The mean height velocity z score, however, increased between 1 and 2 years from -0.71 to 0.26 (P < 0.03). Corticosteroid use greater than 6 months in the first year was associated with abnormal height velocity at 1 year (adjusted odds ratio = 4.5; 95% confidence interval [CI] = 2.2-9.6). No statistically significant effect on height velocity z scores was noted when comparing those receiving or not receiving infliximab. CONCLUSIONS: Growth delay persists in many children with CD following diagnosis, despite improved disease activity and the frequent use of immunomodulators and biologics. Additional strategies to improve growth outcomes require development.

Classification of carotid stenosis by millimeter CT angiography measures: effects of prevalence and gender.

BACKGROUND AND PURPOSE: Previous studies quantifying moderate and severe carotid stenosis by direct millimeter measures on CT angiography (CTA) did not consider how prevalence and gender may influence classification cutoff values. MATERIALS AND METHODS: Three hundred nineteen carotid arteries were evaluated in consecutive patients with known or suspected carotid artery disease. Millimeter measures were obtained of the stenotic carotid bulb lumen and distal internal carotid artery (ICA). Interclass correlation coefficients (ICC) defined interobserver and intraobserver agreement. North American Symptomatic Carotid Endarterectomy Trial (NASCET)-style percent stenosis ratios were calculated per carotid artery and used in linear regression and receiver operating characteristic (ROC) curve analysis to define equivalent millimeter quantification and classification values. Likelihood ratios and prevalence-specific positive/negative predictive values (PPV/NPV) were calculated to determine the most appropriate millimeter cutoff values to classify stenosis. RESULTS: Interobserver agreement was excellent for stenosis measures (0.90) and good for distal ICA measures (0.79). Gender-specific regression curves and ROC curves indicated that millimeter stenosis is an excellent tool to quantify and classify carotid stenosis. Assuming a 10% prevalence of severe stenosis, we found that the cutoff value maximizing NPV and PPV was 1.1 mm for both genders (female: PPV = 86.2, NPV = 97.7; male: PPV = 83.2, NPV = 95.9). Assuming a 40% prevalence of moderate stenosis, we found that the cutoff values differed between genders: female = 2.0 mm (PPV = 91.3, NPV = 91.5), male = 2.1 mm (PPV = 91.6, NPV = 92.4). Specific millimeter cutoffs will vary depending upon the clinical scenario, prevalence, and gender. CONCLUSIONS: Direct millimeter stenosis measures are an excellent tool to classify moderate and severe carotid artery stenosis. Millimeter classification cutoff values that best approximate NASCET classifications vary depending on prevalence and gender.

Severe paediatric ulcerative colitis: incidence, outcomes and optimal timing for second-line therapy.

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.

Diagnosing carotid stenosis near-occlusion by using CT angiography.

BACKGROUND/PURPOSE: Identification of carotid near-occlusion is essential before calculation of percent stenosis because stroke risk is lower than other severe stenosis and the treatment benefit is less. Calculations with reduced distal diameters are fallacious. CT angiography (CTA) is convenient and accurately quantifies internal carotid artery (ICA) stenosis. METHODS: In a blinded protocol, 268 carotid artery CTAs for known or suspected carotid disease were independently evaluated by 2 neuroradiologists. All carotid arteries were measured in millimeters at the narrowest diameter of the stenotic bulb, distal ICA well beyond the tapering bulb, and distal external carotid artery (ECA). Near-occlusions were independently identified, with disagreements settled by consensus meeting. Receiver operating characteristic (ROC) curve analysis defined the threshold values that best predicted near-occlusion according to (1) ICA stenosis, (2) distal ICA, (3) distal ICA: contralateral distal ICA, and (4) distal ICA: ECA. Paired permutations of variables were evaluated. RESULTS: Forty-two near-occlusion distal ICAs were identified. The ROC-derived threshold values determined near-occlusion carotid stenosis with a sensitivity range, 90.2-97.3; specificity, 84.1-89.9; positive predictive value (PPV), 61.3-66.7; and negative predictive value (NPV), 96.7-99.4. Ranges for paired permutations were also determined: sensitivity, 82.9-91.9; specificity, 95.4-96.8; PPV, 78.6-85.7; and NPV, 96.3-98.4. CONCLUSIONS: Threshold values provide guidelines for CTA interpretation when assessing carotid artery disease and the presence of near-occlusion. Ultimate identification of near-occlusion requires the interpreter's judgment, with attention to the following criteria: (1) notable stenosis of the ICA bulb and (2) distal ICA caliber reduction compared with (A) expected size, (B) contralateral ICA, and (C) ipsilateral ECA. Near-occlusion distal ICAs can be reliably identified on CTA.

Association between calcification of the cervical carotid artery bifurcation and white matter ischemia.

BACKGROUND AND PURPOSE: The association of cervical carotid artery bifurcation calcification to future stroke risk is unknown, though coronary artery calcification is a proven indicator of heart disease risk. Severity of white matter change has been correlated with future stroke risk. We sought to use white matter severity grade on CT as a surrogate predictor of relative future stroke risk and thus correlate white matter and future stroke risk with carotid calcification grade. METHODS: We retrospectively reviewed unenhanced neck and brain CTs in 209 patients. Carotid calcification degree was scored by the Agatston method, adapted from that commonly used to quantify coronary artery calcification. White matter change severity was scored by the European Task Force for Age-Related White Matter Change scale. Both scores were measured blinded to each other, and to age and sex covariables. Association was tested by univariate and multivariate analyses. RESULTS: Both carotid calcification and white matter scores were strongly, and independently, associated with increasing age (r = 0.61, P < .001; and r = 0.67, P < .001, respectively). Despite apparent association between carotid calcification and white matter scores on univariate analysis, there was no independent effect evident after adjusting for age as a covariant (r = 0.07, P = .14). Sex had no independent effect on white matter scores, though men had a marginally higher mean calcified carotid plaque load than women after controlling for age (P = .008). CONCLUSIONS: Carotid calcification scores do not independently predict severity of white matter ischemia. Future stroke risk, assessed by white matter severity scores, cannot be predicted from carotid calcium scores.

Quantification of carotid stenosis on CT angiography.

PURPOSE: Carotid artery stenosis quantification uses percent diameter ratios from conventional angiography. Multidetector high-speed CT angiography (CTA) allows direct millimeter measurement of carotid stenosis. We hypothesize a linear relationship between millimeter stenosis measurements and derived percent, alleviating cumbersome ratio calculations. METHODS: Two neuroradiologists separately reviewed CTAs of 268 carotid arteries, blinded to other information. The narrowest portion of each carotid stenosis was measured in millimeters from axial source images. Distal internal carotid arteries (ICAs) were measured beyond the bulb, where walls are parallel. North American Symptomatic Carotid Endarterectomy Trial (NASCET)-style ratios were calculated for each ICA, except for suspected near-occlusions. Interobserver agreement was calculated for all measurements. Correlation coefficients were calculated comparing millimeter and derived percent stenosis, followed by regression analysis. Sensitivity and specificity values tested validity. RESULTS: Interobserver agreement correlations were excellent, from 0.78 to 0.89 (2-tailed P