Growth After Menarche in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Growth impairment in pediatric patients with pediatric onset inflammatory bowel disease (IBD) is multifactorial. Reports on the effect of age at menarche on adult stature in this population are limited. This study investigated the impact of age at menarche, disease-associated factors, and mid-parental height on growth from menarche to final height (FHt) in pediatric patients with Crohn disease (CD) and ulcerative colitis (UC) and IBD unclassified (IBD-U). METHODS: Subjects were enrolled from a prospectively maintained pediatric IBD database when IBD preceded menarche and dates of menarche and FHt measurements were recorded. RESULTS: One hundred forty-six patients: CD 112 and UC 30/IBD-U 4. Mean age (years) at diagnosis (10.9 vs 10.1), menarche (14.4 vs 14.0), and FHt (19.6 vs 19.7). CD and UC/IBD-U patients showed significant association between Chronological age (CA) at menarche and FHt (cm, P < 0.001) but not FHt z score (FHt-Z) < -1.0 (P = 0.42). FHt-Z < -2.0 occurred in only 5 patients. Growth impairment (FHt-Z < -1.0) was associated with surgery before menarche (P = 0.03), jejunal disease (P = 0.003), low mid-parental height z score (MPH-Z) (P < 0.001), hospitalization for CD (P = 0.03) but not UC, recurrent corticosteroid, or anti-tumor necrosis factor alpha (anti-TNFα) therapy. CONCLUSIONS: Early age of menarche was associated with greater potential for linear growth to FHt but not FHt-Z (P < 0.05). Surgery before menarche, jejunal disease, hospitalization for CD, low MPH, and weight z score were associated with FHt-Z < -1.0.

Sex-Specific Pathways Lead to Statural Growth Impairment in Children with Crohn's Disease.

OBJECTIVES: To examine the underlying mechanisms that lead growth impairment to occur more commonly in males than females with Crohn's disease (CD). STUDY DESIGN: Children and adolescents with CD were enrolled in a prospective multicenter longitudinal cohort study. Height Z-score difference was computed as height Z-score based on chronological age (height chronological age-Z-score) minus height Z-score based on bone age (height bone age-Z-score) using longitudinal data. Specific serum cytokines were measured, hormone Z-scores were calculated based on bone age (bone age-Z), and their longitudinal associations were examined. RESULTS: There were 122 children with CD (63% male) who completed 594 visits. The mean ± SD chronological age was 11.70 ± 1.79 years. The mean ± SD height chronological age-Z-score was -0.03 ± 0.99 in males and -0.49 ± 0.87 in females. The mean ± SD height bone age-Z-score was 0.23 ± 0.93 in males and 0.37 ± 0.96 in females. The magnitude of the mean height Z-score difference was greater in females (-0.87 ± 0.94) than males (-0.27 ± 0.90; P = .005), indicating growth was better in females than males. The following negative associations were identified: in females, interleukin (IL)-8 (P < .001) and IL-12p70 (P = .035) with gonadotropin-bone age-Z-scores; IL-8 (P = .010), IL-12p70 (P = .020), and interferon-γ (P = .004) with sex hormone-bone age-Z-scores, and IL-8 (P = .044) and interferon-γ (P < .001) with insulin-like growth factor 1-bone age-Z-scores; in males, IL-1 beta (P = .019) and IL-6 (P = .025) with insulin-like growth factor 1-bone age-Z-scores. CONCLUSIONS: Our data suggest that sex-specific molecular pathways lead to growth impairment in children with CD (primarily growth hormone/insulin-like growth factor-1 axis in males and primarily hypothalamic-pituitary-gonadal axis in females). Mapping these sex-specific molecular pathways may help in the development of sex-specific treatment approaches targeting the underlying inflammation characteristic of CD.

Clinical Variables Associated With Statural Growth in Pediatric Crohn's Disease Differ by Sex (The Growth Study).

BACKGROUND: Statural growth impairment is more common in male patients with Crohn's disease (CD). We identified clinical variables associated with height z score differences by sex in children participating in the Growth Study, a prospective multicenter longitudinal study examining sex differences in growth impairment in pediatric CD. METHODS: Patients with CD (female patients with bone age [BA] ≥4 years 2 months and ≤12 years; male patients with BA ≥5 years and ≤14 years at screening) who had completed study visit 1 qualified. The height z score difference was computed as height z score based on chronological age minus height z score based on BA. RESULTS: One hundred thirteen patients with CD (36% female) qualified. The mean chronological age was 12.0 ± 1.8 (SD) years. The magnitude of the mean height z score difference was significantly greater in female patients (-0.9 ± 0.8) than in male patients (-0.5 ± 0.9; P = 0.021). An initial classification of inflammatory bowel disease as CD (P = 0.038) and perianal disease behavior at diagnosis (P = 0.009) were associated with higher standardized height gain with BA progression, and arthralgia at symptom onset (P = 0.016), azathioprine/6-merpcaptopurine (P = 0.041), and probiotics (P ≤ 0.021) were associated with lower standardized height gain with BA progression in female patients. Patient-reported poor growth at symptom onset (P = 0.001), infliximab (P ≤ 0.025), biologics (P ≤ 0.015), methotrexate (P = 0.042), and vitamin D (P ≤ 0.010) were associated with higher standardized height gain with BA progression, and initial classification as CD (P = 0.025) and anorexia (P = 0.005) or mouth sores (P = 0.004) at symptom onset were associated with lower standardized height gain with BA progression in male patients. CONCLUSIONS: Different clinical variables were associated with statural growth in male patients vs female patients, suggesting that sex-specific molecular pathways lead to statural growth impairment in CD.

Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease.

BACKGROUND AND AIMS: Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. METHODS: Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. RESULTS: 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). CONCLUSION: An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.

Introduction to and Screening Visit Results of the Multicenter Pediatric Crohn's Disease Growth Study.

BACKGROUND: Statural growth impairment is more common in males with Crohn's disease (CD). We assessed sex differences in height Z score differences and bone age (BA) Z scores and characterized age of menarche in a novel contemporary cohort of pediatric CD patients undergoing screening for enrollment in the multicenter longitudinal Growth Study. METHODS: Crohn's disease patients (females with chronological age [CA] 5 years and older and younger than 14 years; males with CA 6 years and older and younger than 16 years) participated in a screening visit for the Growth Study. Height BA-Z scores are height Z scores calculated based on BA. Height CA-Z scores are height Z scores calculated based on CA. The height Z score difference equals height CA-Z score minus height BA-Z score. RESULTS: One hundred seventy-one patients (60% male) qualified for this analysis. Mean CA was 12.2 years. Mean height CA-Z score was -0.4, and mean height BA-Z score was 0.4 in females. Mean height CA-Z score was -0.1, and mean height BA-Z score was 0.2 in males. The absolute value of the mean height Z score difference was significantly greater in females (0.8) than males (0.3; P = 0.005). The mean BA-Z score in females (-1.0) was significantly lower than in males (-0.2; P = 0.002). The median CA at menarche was 13.6 (95% CI, 12.6-14.6) years. CONCLUSIONS: Our screening visit data suggest that standardized height gain is lower in males with skeletal maturation and delayed puberty is common in females in CD. We are investigating these findings in the ongoing Growth Study.

Variation in Care in the Management of Children With Crohn's Disease: Data From a Multicenter Inception Cohort Study.

BACKGROUND: Variation in care is common in medical practice. Reducing variation in care is shown to improve quality and increase favorable outcomes in chronic diseases. We sought to identify factors associated with variation in care in children with newly diagnosed Crohn's disease (CD). METHODS: Prospectively collected data from a 28-site multicenter inception CD cohort were analyzed for variations in diagnostic modalities, treatment, and follow-up monitoring practices, along with complicated disease outcomes over 3 years in 1046 children. Generalized linear mixed effects models were used to investigate the intercenter variations in each outcome variable. RESULTS: The mean age at diagnosis was 12 years, and 25.9% were nonwhite. The number of participants ranged from 5 to 112 per site. No variation existed in the initial diagnostic approach. When medication exposure was analyzed, steroid exposure varied from 28.6% to 96.9% (P < 0.01) within 90 days, but variation was not significant over a 3-year period (P = 0.13). Early anti-tumor necrosis factor (anti-TNF) exposure (within 90 days) varied from 2.1% to 65.7% (P < 0.01), but variation was not significant over a 3-year period (P > 0.99). Use of immunomodulators (IMs) varied among centers both within 90 days (P < 0.01) and during 3 years of follow-up (P < 0.01). A significant variation was seen at the geographic level with follow-up small bowel imaging and colonoscopy surveillance after initial therapy. CONCLUSIONS: Intercenter variation in care was seen with the initial use of steroids and anti-TNF, but there was no difference in total 3-year exposure to these drugs. Variation in the initiation and long-term use of IMs was significant among sites, but further research with objective measures is needed to explain this variation of care. Small bowel imaging or repeat colonoscopy in CD patients was not uniformly performed across sites. As our data show the widespread existence of variation in care and disease monitoring at geographic levels among pediatric CD patients, future implementation of various practice strategies may help reduce the variation in care.

Thalidomide use and outcomes in pediatric patients with Crohn disease refractory to infliximab and adalimumab.

OBJECTIVE: The aim of the study was to evaluate thalidomide as rescue therapy for pediatric patients with severe refractory Crohn disease (CD) who failed to respond to antitumor necrosis factor (TNF) biologic agents. PATIENTS AND METHODS: A computerized database was used to identify children with CD who had failed conventional immunosuppression therapy and received thalidomide rescue therapy. Twelve patients, mean age at diagnosis 10 years, were identified. Eight children had disease localized to the ileum and colon and 4 to the gastroduodenal area and colon. Five cases were complicated by strictures and 7 by fistulae. Previous drug therapy included azathioprine/6-mercaptopurine (11/12), methotrexate (7/12), and anti-TNF biologics (12/12). Outcome measures were Harvey-Bradshaw Index, change in prednisone dose, hospitalizations, bowel resections, and incision and drainage procedures. Laboratory evaluations were calculated before and after 1 to 6 months of thalidomide. RESULTS: Mean Harvey-Bradshaw Index score improved from 11.8 to 3.9 (P = 0.0004), mean prednisone dose decreased from 13.9 to 2.3  mg/day (P = 0.001), mean number of hospitalizations decreased from 6.3 to 1.3 (P = 0.002), and erythrocyte sedimentation rate decreased from 35 to 14  mm/h (P = 0.02). The surgery rate pre-thalidomide was 0.031 and on thalidomide was 0.004. Of the 7 patients with fistulae, 5 had complete fistula closure, 1 had partial closure, and 1 showed no improvement. Adverse reactions that resulted in discontinuation of thalidomide are as follows: 42% peripheral neuropathy, 17% worsening of the CD, 8% dizziness, and 8% allergic reaction. All 5 patients who developed peripheral neuropathy had clinical resolution of the neurologic symptoms within 2 to 3 months after stopping thalidomide. CONCLUSIONS: Thalidomide is a potentially effective rescue therapy for severe refractory CD in children who fail to respond to anti-TNF medications.

Clinical aspects and pathophysiology of inflammatory bowel disease.

The chronic inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are recognized as important causes of gastrointestinal disease in children and adults. In this review we delineate the clinical manifestations and diagnostic features of IBD. In addition, we summarize important recent advances in our understanding of the immune mediators of intestinal inflammation. This information has led to new therapeutic approaches in IBD. Further, we discuss the considerable data that point to the significance of genetic factors in the development of IBD and the genetic loci which have been implicated through genome-wide searches. The commensal bacterial flora also appears to be a critical element, particularly in regards to Crohn's disease, although the precise role of the bacteria in the disease manifestations remains unclear. Current investigations promise to yield fresh insights in these areas.