Peter Church

Infliximab Maintains Durable Response and Facilitates Catch-up Growth in Luminal Pediatric Crohn's Disease

Background:Infliximab induces and maintains clinical remission in children with Crohns disease (CD), but specifically pediatric long-term data remain sparse. Methods:Patients (N = 195) who received infliximab ± immunomodulator for luminal CD were retrospectively reviewed. Outcomes included clinical response, linear growth, and mucosal healing. Durability of response was assessed using Cox proportional hazards models. Levels of infliximab and antibodies (antibodies to infliximab) were measured when response was lost. Results:Among 195 patients (median age, 13.9 yr; median CD duration, 1.6 yr), 81% experienced complete response (judged by physician global assessment and pediatric Crohns disease activity index ⩽10). Longer duration of diagnosed CD and female gender were associated with lower response. During first year of follow-up, 35% of subjects had regimen individualized through dose escalation/interval shortening. Despite regimen optimization, 16/157 complete responders experienced loss of response at a rate of 2% to 6% per year over 5 years, associated with development of antibodies to infliximab. Concurrent immunomodulation for ≥30 weeks significantly decreased loss of response (hazard ratio = 0.25, 95% confidence interval, 0.08–0.76; P = 0.014). Follow-up endoscopic examination was performed in 40 responders, of whom 22 (73%) demonstrated complete resolution of mucosal ulceration. Patients with growth potential (Tanner 1/2 at induction) demonstrated significant improvements in mean height z-score from induction to years 1 and 2 of follow-up (P < 0.001). With infliximab initiation within the first 18 months after diagnosis, mean height z-score normalized to 0 after 3 years. Conclusions:These data demonstrate sustained effectiveness of infliximab in children and adolescents with luminal CD. Durability of response is increased by concomitant immunomodulation. Clinical response is associated with enhanced linear growth, particularly when therapy is initiated early.

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

In the treatment of Crohns 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.

Hepatotoxicity caused by methotrexate therapy in children with inflammatory bowel disease: a systematic review and meta-analysis.

Background:Methotrexate (MTX) is an immunomodulator used in pediatric inflammatory bowel disease (IBD) maintenance regimens. However, MTX use is associated with liver toxicity. We aimed to systematically review and meta-analyze the incidence of hepatotoxicity with MTX use among children with IBD. Methods:We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from 1946 to April 2013 for cohort studies and collected information about the study design, IBD treatment results, and hepatotoxicity. Pooled proportions of toxicity with 95% confidence interval (CI) were estimated using a random-effects model. Results:Twelve high-quality studies were included in this review. Fifty-seven of 457 patients treated with MTX developed varied degrees of abnormal liver biochemistry. The pooled proportion of patients with abnormal liver biochemistry was 10.2% (95% CI 5.4%–18.5%) across all studies included in the meta-analysis. Due to hepatotoxicity, dose reductions were required in 6.4% (95% CI 4.3%–9.5%), whereas 4.5% (95% CI 2.8%–7.2%) of patients required discontinuation. Conclusions:Hepatotoxicity after the use of MTX among IBD patients was a relatively common event. Monitoring for hepatotoxicity is strongly recommended, as discontinuation of MTX may be necessary in a significant proportion of children.

Subclinical cardiovascular changes in pediatric solid organ transplant recipients: A systematic review and meta-analysis

CV disease is a major cause of morbidity and mortality following solid organ transplantation in adults. While the prevalence of multiple cardiometabolic risk factors is increased in pediatric solid organ transplant recipients, it is not clear whether they have subclinical CV changes. cIMT, central pWV, and CAC are indicative of subclinical CV disease, and, in adults, predict future CV events. The objective of this systematic review and meta‐analysis was to investigate the prevalence of subclinical CV changes, as measured by cIMT, pWV, and CAC among pediatric solid organ transplant recipients. We searched MEDLINE® and EMBASE and conducted meta‐analysis for studies that evaluated cIMT, central pWV, and CAC among pediatric solid organ transplant recipients (kidney, lung, intestine and liver). The search identified nine eligible studies that included a total of 259 patients and 685 healthy controls. Eight studies reported on kidney transplant recipients and one study on a combined cohort of kidney and liver transplant recipients. The mean cIMT of transplant recipients was significantly higher than that of healthy controls (mean difference = 0.05 mm, 95% CI 0.02–0.07; p < 0.0001) with an estimated pooled prevalence of elevated cIMT of 56.0% (95% CI 17.0–95.0). The one study that assessed pWV showed increased vascular stiffness in transplant recipients compared to healthy controls. No studies assessing for CAC were found. There were limited data regarding subclinical CV disease following pediatric solid organ transplantation. In conclusion, kidney transplantation in childhood is associated with a higher prevalence of subclinical CV changes compared to healthy children. Longitudinal studies are needed to determine whether children have increased CV morbidity and mortality after transplantation.

Accuracy and interobserver agreement of diffusion-weighted imaging in pediatric inflammatory bowel disease

PURPOSE To determine interobserver agreement (IOA) and accuracy of conventional MR enterography (MRE), qualitative diffusion, and apparent diffusion coefficient (ADC) values for detecting clinically active inflammation. METHODS MREs in 57 consecutive children with suspected inflammatory bowel disease were retrospectively reviewed. RESULTS Substantial IOA for conventional MRE (kappa=0.65) and qualitative diffusion (kappa=0.64), but fair to good IOA for ADC, (intra-class coefficient=0.63) were seen. Conventional MRE detected active clinical inflammation well (area under curve [AUC] 0.725), while qualitative diffusion and ADC did not perform well (AUC=0.572 and 0.461, respectively). CONCLUSION DWI can be helpful in diagnosing inflammatory bowel disease but does not perform well in identifying those with active inflammation.

Can MR enterography screen for perianal disease in pediatric inflammatory bowel disease?: Can MRE Screen for Perianal Disease in P-IBD?

Pediatric Crohns disease is associated with perianal disease (PAD). Magnetic resonance enterography (MRE) assesses small bowel involvement in pediatric inflammatory bowel disease (PIBD). Pelvic MRI (P‐MRI) is the gold standard for assessing PAD.

Associations Among Mucosal and Transmural Healing and Fecal Level of Calprotectin in Children With Crohn’s Disease

Background & Aims: Bowel healing is an important goal of therapy for patients with Crohns disease (CD). Although there have been many studies of mucosal healing, transmural healing (ie, in the bowel wall) has not been investigated in children. We analyzed data from the ImageKids study to determine associations among mucosal, transmural healing and levels of calprotectin and C‐reactive protein in children with CD. Methods: We collected data from a multi‐center study designed to develop 2 magnetic resonance enterography (MRE)‐based measures for children with CD (6–18 years old). In our analysis of 151 children (mean age, 14.2 ± 2.4 years), all patients underwent MRE and a complete ileocolonoscopic evaluation; fecal levels of calprotectin and blood levels of C‐reactive protein were measured. Mucosal healing was defined as simple endoscopic severity index in CD score below 3, transmural healing as an MRE visual analogue score below 20 mm, and deep healing as a combination of transmural and mucosal healing. Results: We identified mucosal healing with transmural inflammation in 9 children (6%), transmural healing with mucosal inflammation in 38 children (25%), deep healing in 21 children (14%), and mucosal and transmural inflammation in 83 children (55%). The median level of calprotectin was lowest in children with deep healing (mean level, 10 &mgr;g/g; interquartile range, 10–190 &mgr;g/g), followed by children with either transmural or mucosal inflammation, and highest in children with mucosal and transmural inflammation (810 &mgr;g/g; interquartile range, 539–1737 &mgr;g/g) (P < .001). Fecal level of calprotectin identified children with deep healing with an area under the receiver operating characteristic curve value of 0.93 (95% CI, 0.89–0.98); level of C‐reactive protein identified children with deep healing with an area under the receiver operating characteristic curve value of 0.81 (95% CI, 0.71–0.9). A calprotectin cutoff value of 100 &mgr;g/g identified children with deep healing with 71% sensitivity and 92% specificity; a cutoff value of 300 &mgr;g/g identified children with mucosal healing with 80% sensitivity and 81% specificity. Conclusions: In a prospective study of children with CD, we found that one‐third have healing in only the mucosa or the bowel wall (not both). Levels of fecal calprotectin below 300 &mgr;g/identify children with mucosal healing, but a lower cutoff value (below 100 &mgr;g/g) is needed to identify children with deep healing. Clinicaltrials.gov no: NCT01881490.

Symptoms Do not Correlate With Findings From Colonoscopy in Children With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

Background & Aims: Approximately 75% of children with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD). IBD in patients with PSC (PSC‐IBD) often has a unique phenotype, including a mild clinical course, yet it is associated with an increased risk of colorectal cancer compared with colonic IBD without PSC. We investigated whether subclinical endoscopic and histologic inflammation could account for the increased risk of colorectal cancer in patients with PSC‐IBD, and whether these patients have increased fecal levels of calprotectin, a marker of inflammation. Methods: We performed a prospective study of children (age, <18 y) with colonic IBD with and without PSC who underwent colonoscopy from February 1, 2016, through March 31, 2017, at the Hospital for Sick Children in Toronto, Canada. We collected pediatric ulcerative colitis activity index (PUCAI) scores (to measure symptoms) and fecal levels of calprotectin from 37 children with PSC‐IBD and 50 children with only IBD (controls; UC or IBD‐unclassified). Colonoscopies were scored using the Mayo endoscopic subscore and the UC Endoscopic Index of Severity (UCEIS) scores, and histologic activity was graded. Among patients in clinical remission, endoscopic scores and the odds of active endoscopic disease (based on a UCEIS score ≥1) were compared between patients with and without PSC in univariate and multivariable analyses. Correlations between activity markers were compared between groups. The ability of fecal calprotectin to identify mucosal healing in patients with PSC‐IBD was assessed using receiver operating characteristic curve analyses. Analogous analyses were performed for histologic activity. Results: Patients with PSC‐IBD in clinical remission had higher endoscopic scores and greater odds of active endoscopic disease than controls (odds ratio, 5.9; 95% CI, 1.6–21.5). There was a higher degree of correlation between PUCAI and UCEIS scores in controls (r = 0.82) than in patients with PSC‐IBD (r = 0.51; P = .01). Fecal levels of calprotectin correlated with UCEIS in patients with PSC‐IBD (r = 0.84) and controls (r = 0.82; P = .80). Fecal levels of calprotectin identified mucosal healing in patients with PSC‐IBD with an area under the receiver operating characteristic curve of 0.94 (optimal cut‐point, 93 &mgr;g/g; 100% sensitivity and 92% specificity). Histologic activity scores and the odds of active histologic disease were also greater in patients in clinical remission with PSC‐IBD than controls. Conclusions: Children with PSC‐IBD in clinical remission, based on PUCAI scores, have a significantly higher risk of active endoscopic and histologic disease than children with colitis without PSC. Fecal levels of calprotectin correlate with endoscopic findings in pediatric patients with PSC‐IBD; levels below 93 &mgr;g/g are associated with mucosal healing.

A Simple Endoscopic Score Modified for the Upper Gastrointestinal Tract in Crohn’s Disease [UGI-SES-CD]: A Report From the ImageKids Study

Objective There is no standardized endoscopic description of upper gastrointestinal (UGI) disease in Crohns disease (CD). We prospectively applied the Simple Endoscopic Score for CD (SES-CD) to the UGI tract as a planned sub-study of the multicenter prospective ImageKids study. We aimed to assess the utility of the UGI-SES-CD and its clinical significance in pediatric CD. Design Patients underwent an esophagogastroduodenoscopy (EGD), ileocolonoscopy and magnetic resonance enterography (MRE) with explicit clinical data recorded. SES-CD was scored at each region (esophagus, stomach body, antrum and duodenum). Half of the patients were followed for 18 months when a repeat MRE was performed. Results Two hundred and two children were included (56% males, mean age 11.5 ± 3.2 years, median wPCDAI 25. UGI-SES-CD score ranged from 0-17, with 95 (47%) having a UGI-SES-CD ≥1; no narrowing was detected. UGI-SES-CD ≥1 was associated with higher wPCDAI (32.5 vs 20; p=0.03), PGA of inflammation (45mmVAS vs 30mmVAS; p=0.04), ileocolonoscopic SES-CD (10 vs 7; p=0.004), fecal calprotectin (717mcg/g vs 654mcg/g; p=0.046) and radiologic global assessment of damage by MRE (7mmVAS vs 0; p=0.04). 93 patients were followed for 18 months and no association was identified between initial UGI SES-CD and markers of disease course such as surgery, MRE assessment, or treatment escalation. Conclusion UGI-SES-CD is an easily reported objective scoring system and is associated with a more severe disease phenotype but not with disease course.

Clinical Outcomes With Therapeutic Drug Monitoring in Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis

Background and Aims We undertook a systematic review and meta-analysis examining the effectiveness of therapeutic drug monitoring [TDM] to improve clinical outcomes in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha [anti-TNF] drugs. Methods We searched MEDLINE, Epub Ahead of Print, EMBASE and Cochrane up to October 2017 for randomized trials [RCTs] and cohort studies comparing proactive or reactive TDM to each other or empiric care. Outcomes included clinical remission [primary], clinical relapse, endoscopic remission, anti-TNF response durability, cost and adverse events [secondary]. Pooled odds ratios and mean differences were calculated. Results The search identified nine studies [three RCTs, six observational], focused on infliximab maintenance therapy in adults. Neither proactive nor reactive TDM was associated with superior clinical remission rates compared to empiric dose optimization. However, evidence of a cost benefit, particularly for reactive TDM vs empiric care, was identified. In several studies, TDM, particularly proactive TDM, was associated with favourable outcomes related to durability of anti-TNF response, such as lower drug discontinuation rates compared to empiric care and reactive TDM, and lower relapse rates compared to empiric care. No consistent benefit was found for endoscopic or surgical outcomes. Conclusions The existing limited evidence does not support an association between any TDM strategy and superior clinical remission rates but does support a cost savings benefit [particularly for reactive TDM] and suggests a potential benefit for anti-TNF durability [particularly proactive TDM]. Additional, longer-term studies are needed, particularly to further investigate proactive TDM, and to generate data on other anti-TNF agents, the induction period and paediatric populations.