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.

Black/African American Patients with Pediatric Crohn's Disease Report Less Anxiety and Fatigue than White Patients.

OBJECTIVES: To compare patient-reported outcomes in black/African American patients with white patients participating in IBD Partners Kids & Teens, in order to identify possible racial healthcare disparities in pediatric inflammatory bowel disease (IBD) as future targets for improvement. STUDY DESIGN: This was a cross-sectional analysis comparing patient-reported outcomes in black/African American patients with white patients, aged 9-18 years, with IBD participating in the IBD Partners Kids & Teens cohort from August 2013 to April 2018. Secondary outcomes included number of IBD-related hospitalizations and surgeries, current medication use, and disease activity. RESULTS: We included 401 patients with Crohn's disease (white = 378 [94%]; black/African American = 23 [6%]). For children with Crohn's disease, black/African American patients compared with white patients reported less anxiety (40.7 vs 47.5, P = .001) and fatigue (44.3 vs 48.4, P = .047) despite more frequently reported treatment with biologics (91% vs 61%, P = .006) and antibiotics (17% vs 5%, P = .03) and history of hospitalizations (81% vs 52%, P = .02). CONCLUSIONS: Black/African American children with Crohn's disease were less likely to report anxiety or fatigue than white patients, despite an apparent more severe disease course reflected by greater reported frequency of treatment with biologics and antibiotics and history of hospitalizations.

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.

Continued Statural Growth in Older Adolescents and Young Adults With Crohn's Disease and Ulcerative Colitis Beyond the Time of Expected Growth Plate Closure.

BACKGROUND: Cessation of statural growth occurs with radiographic closure of the growth plates, radiographically defined as bone age (BA) 15 years in females and 17 in males. METHODS: We determined the frequency of continued growth and compared the total height gain beyond the time of expected growth plate closure and the chronological age at achievement of final adult height in Crohn's disease (CD) vs ulcerative colitis (UC) and described height velocity curves in inflammatory bowel disease (IBD) compared with children in the National Health and Nutrition Examination Survey (NHANES). We identified all females older than chronological age (CA) 15 years and males older than CA 17 years with CD or UC in the ImproveCareNow registry who had height documented at ≥3 visits ≥6 months apart. RESULTS: Three thousand seven patients (48% female; 76% CD) qualified. Of these patients, 80% manifested continued growth, more commonly in CD (81%) than UC (75%; P = 0.0002) and in females with CD (83%) than males with CD (79%; P = 0.012). Median height gain was greater in males with CD (1.6 cm) than in males with UC (1.3 cm; P = 0.0004), and in females with CD (1.8 cm) than in females with UC (1.5 cm; P = 0.025). Height velocity curves were shifted to the right in patients with IBD vs NHANES. CONCLUSIONS: Pediatric patients with IBD frequently continue to grow beyond the time of expected growth plate closure. Unexpectedly, a high proportion of patients with UC exhibited continued growth, indicating delayed BA is also common in UC. Growth, a dynamic marker of disease status, requires continued monitoring even after patients transition from pediatric to adult care.

Thiopurines are negatively associated with anthropometric parameters in pediatric Crohn's disease.

AIM: To determine the distribution of anthropometric parameter (AP)-z-scores and characterize associations between medications/serum biomarkers and AP-z-scores in pediatric Crohn's disease (CD). METHODS: CD patients [< chronological age (CA) 21 years] were enrolled in a cross-sectional study. Descriptive statistics were generated for participants' demographic characteristics and key variables of interest. Paired t-tests were used to compare AP-z-scores calculated based on CA (CA z-scores) and bone age (BA) (BA z-scores) for interpretation of AP's. Linear regression was utilized to examine associations between medications and serum biomarkers with AP-z-scores calculated based on CA (n = 82) and BA (n = 49). We reported regression coefficients as well as their corresponding p-values and 95% confidence intervals. RESULTS: Mean CA at the time of the study visit was 15.3 ± 3.5 (SD; range = 4.8-20.7) years. Mean triceps skinfold (P = 0.039), subscapular skinfold (P = 0.002) and mid-arm circumference (MAC) (P = 0.001) BA z-scores were higher than corresponding CA z-scores. Medications were positively associated with subscapular skinfold [adalimumab (P = 0.018) and methotrexate (P = 0.027)] and BMI CA z-scores [adalimumab (P = 0.029)]. Azathioprine/6-mercaptopurine were negatively associated with MAC (P = 0.045), subscapular skinfold (P = 0.014), weight (P = 0.002) and BMI (P = 0.013) CA z-scores. ESR, CRP, and WBC count were negatively associated, while albumin and IGF-1 BA z-scores were positively associated, with specific AP z-scores (P < 0.05). Mean height CA z-scores were higher in females, not males, treated with infliximab (P = 0.038). Hemoglobin (P = 0.018) was positively associated, while platelets (P = 0.005), ESR (P = 0.003) and CRP (P = 0.039) were negatively associated with height CA z-scores in males, not females. CONCLUSION: Our results suggest poor efficacy of thiopurines and a possible sex difference in statural growth response to infliximab in pediatric CD. Prospective longitudinal studies are required.

Probing the Association of Pancreatitis in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) has been increasingly diagnosed in children and adults. Similarly, acute and chronic pancreatitis are increasingly prevalent conditions with potentially devastating consequences. There is a growing body of literature linking these 2 conditions. The purpose of this review is to provide a comprehensive outline of the association between IBD and pancreatitis and to explore their putative pathophysiology. Based on the collective reports, 2 outstanding reasons for pancreatitis in patients with IBD are medications and IBD complications.

Report of the CCFA pediatric bone, growth and muscle health workshop, New York City, November 11-12, 2011, with updates.

Growth retardation, delayed puberty, decreased bone mass, altered bone architecture, hypovitaminosis D and skeletal muscle mass deficits are common in children with inflammatory bowel diseases. The Crohn's and Colitis Foundation of America sponsored a multidisciplinary workshop on the subject of Bone and Skeletal Growth in Pediatric IBD, held in New York City in November 2011. The topic of the workshop was a key recommendation of the Foundation's Pediatric Challenges meeting in 2005. The Litwin Foundation provided a generous grant to support this crucial research and workshop through the CCFA. The workshop featured 15 presentations by researchers from the United States, Canada, Switzerland, Germany, and the United Kingdom and a number of posters elucidating diverse aspects of the problem of growth retardation and compromised bone health in pediatric Crohn's disease and ulcerative colitis. The workshop comprised original, basic, and clinical research and relevant reviews of underlying genetics, molecular biology, endocrinology, immunology, and bone physiology research. Investigators funded by CCFA and the Litwin Family Foundation are marked by an asterisk after their name in the text. Workshop presentations fell under 3 broad categories: "Mechanisms of Suppression and Growth of Bone Cell Function by Inflammation," "Impact of IBD on Growth and Bone Health," and "Approaches to Address Growth Failure and Low Bone Mass in Children with IBD," summarized herein. We have cited the publications that resulted from this granting mechanism in the appropriate section and references for pertinent updates on each topic.

Comparison of the presentation and course of pediatric inflammatory bowel disease in South Asians with Whites: a single center study in the United States.

We compared the severity of pediatric inflammatory bowel disease in South Asians with Whites in the US. South Asians more commonly presented with poor weight gain, developed fistulas, and received treatment with antibiotics, methotrexate, adalimumab, and steroids. South Asians appear to have a more complicated presentation and course of pediatric inflammatory bowel disease.

Cuff inflation-supplemented laryngoscope-guided nasal intubation: a comparison of three endotracheal tubes.

BACKGROUND: Softer endotracheal (ET) tubes are more difficult to navigate in the oropharynx than the stiffer polyvinyl chloride (PVC) tubes during nasotracheal intubation (NTI). Cuff inflation has been used to guide PVC tubes into the laryngeal inlet during blind NTI, but it has not been tested when performing NTI under direct laryngoscopic guidance. We assessed the role of cuff inflation in improving oropharyngeal navigation of 3 ET tubes of varying stiffness during direct laryngoscope-guided NTI. Simultaneously, we also assessed and compared the nasotracheal navigability and incidence of nasal injury with these ET tubes during cuff inflation-supplemented, laryngoscope-guided NTI. METHODS: One hundred sixty-two adults were randomized to undergo NTI with either a conventional PVC (n = 54), wire reinforced (WR; n = 54) or a silicone-tipped WR (SWR; n = 54) ET tube. Ease of insertion of these tubes was assessed during passage from nose into oropharynx, from oropharynx into laryngeal inlet aided by cuff inflation if needed, and from laryngeal inlet into trachea. Nasal morbidity was assessed by a blinded observer. RESULTS: All ET tubes could be inserted into the trachea. Seventy-one of 162 ET tubes could be inserted from the oropharynx into the laryngeal inlet without cuff inflation. Eighty-six of the remaining 91 tubes that did not enter the laryngeal inlet without cuff inflation could be inserted when using the cuff inflation technique. Thus, a total of 157 ET tubes could be inserted into the laryngeal inlet with cuff inflation (95% confidence interval of difference of proportions between total number of tubes passed [157] and those without cuff inflation [71]: 53% [45%-61%]). The remaining 5 tubes had to be inserted with the help of Magill forceps. The incidence of epistaxis was lowest with the SWR tube (difference of proportions [95% confidence interval] SWR versus PVC 27% [8%-45%]; SWR versus WR 20% [1%-38%]; WR versus PVC 7% [-12% to 26%]). CONCLUSIONS: The cuff inflation technique consistently improved the oropharyngeal insertion of the 3 ET tubes of varying stiffness during direct laryngoscope-guided NTI. Supplemented with the cuff inflation technique, the SWR ET tube seems to be better than the PVC and WR ET tubes in terms of complete nasotracheal navigability and less perioperative nasal injury.

Determination of bone age in pediatric patients with Crohn's disease should become part of routine care.

BACKGROUND: Impaired growth and delayed puberty are common in pediatric Crohn's disease (CD). Bone age (BA) is important for interpretation of statural growth. Our aims were to 1) determine the distribution of BA-Z scores; 2) identify clinical factors associated with BA-Z scores; and 3) compare anthropometric Z scores based on chronological age (CA) (CA-Z) versus BA-Z in pediatric CD. METHODS: CD patients ≤ CA 15 in females and 17 years in males were enrolled in a cross-sectional study. BA was determined with left hand/ wrist x-ray. In all, 49 patients (65% male; 84% Caucasian; mean CA 13 years) examined between January 2007 and July 2009 qualified for the study. RESULTS: Mean BA-Z score was -1.40 ± 1.50 (standard deviation). 41% had BA-Z score < -2.0. Mean BA-Z scores were lower in females (P = 0.02), Caucasians (P = 0.006), Tanner stage 1-3 children (P = 0.004), and patients with colonic disease (P = 0.0006), past corticosteroid exposure (P = 0.01), current azathioprine/6-mercaptopurine treatment (P = 0.003), or lower height (P = 0.006), weight (P < 0.001), or body mass index (BMI) (P = 0.01) CA-Z scores. Mean height, weight, and BMI BA-Z scores were 0.73 units (P < 0.0001), 0.51 units (P < 0.0001), and 0.23 units (P < 0.0001) greater than mean height, weight, and BMI CA-Z scores. CONCLUSIONS: Low BA occurs frequently in CD. Determination of BA should become the standard of care in pediatric CD patients, allowing clinically meaningful interpretation of growth in the context of skeletal maturation, leading to improved treatment recommendations, as growth is a dynamic marker of disease status. Prospective longitudinal studies are required to clarify determinants of BA and patterns of BA advancement in CD.

Predictors of proctocolectomy in children with ulcerative colitis.

OBJECTIVES: Few clinical predictors are associated with definitive proctocolectomy in children with ulcerative colitis (UC). The purpose of the present study was to identify clinical predictors associated with surgery in children with UC using a disease-specific database. METHODS: Children diagnosed with UC at age <18 years were identified using the Pediatric Inflammatory Bowel Disease Consortium (PediIBDC) database. Demographic and clinical variables from January 1999 to November 2003 were extracted alongside incidence and surgical staging. RESULTS: Review of the PediIBDC database identified 406 children with UC. Approximately half were girls (51%) with an average age at diagnosis of 10.6 ±â€Š4.4 years in both boys and girls. Average follow-up was 6.8 (±4.0) years. Of the 57 (14%) who underwent surgery, median time to surgery was 3.8 (interquartile range 4.9) years after initial diagnosis. Children presenting with weight loss (hazard ratio [HR] 2.55, 99% confidence interval [CI] 1.21-5.35) or serum albumin <3.5 g/dL (HR 6.05, 99% CI 2.15-17.04) at time of diagnosis and children with a first-degree relative with UC (HR 1.81, 99% CI 1.25-2.61) required earlier surgical intervention. Furthermore, children treated with cyclosporine (HR 6.11, 99% CI 3.90-9.57) or tacrolimus (HR 3.66, 99% CI 1.60-8.39) also required earlier surgical management. Other symptoms, laboratory tests, and medical therapies were not predictive for need of surgery. CONCLUSION: Children with UC presenting with hypoalbuminemia, weight loss, a family history of UC, and those treated with calcineurin inhibitors frequently require restorative proctocolectomy for definitive treatment. Early identification and recognition of these factors should be used to shape treatment goals and initiate multidisciplinary care at the time of diagnosis.

Menarche in pediatric patients with Crohn's disease.

BACKGROUND AND AIMS: The timing of menarche in Crohn's disease (CD) is poorly described. Our objectives were to study age at menarche onset in CD, and factors associated with this. METHODS: We compared the age at menarche of 34 CD patients with that for 545 controls, using data in the National Health and Nutrition Examination Survey (NHANES). RESULTS: Mean chronological age (CA) of CD patients (15.6 years) did not differ from that of the NHANES cohort (15.7 years; P = 0.91). The median CA at menarche (13.9 years) in CD was older than in the NHANES sample (12.0 years) (P < 0.00005). In CD patients, the cumulative incidence of menarche was 10 % at CA 12 years, 51 % at CA 14 years, and 100 % at CA 16 years. Sixty-eight percent reached menarche by bone age (BA) 13.5 years and 100 % by BA greater than 14.0 years. Menarche occurred earliest in South Asians, followed by East Asians, and then Caucasians (P = 0.02). CONCLUSIONS: CA at menarche is delayed in CD compared with the NHANES cohort. BA at menarche in CD is similar to BA at menarche reported for healthy children. CA at menarche in CD differs by race. If menarche has not occurred by BA greater than 14.0 years, endocrinology referral should be considered.

High-dose infliximab for treatment of pediatric ulcerative colitis: a survey of clinical practice.

AIM: To assess attitudes and trends regarding the use of high-dose infliximab among pediatric gastroenterologists for treatment of pediatric ulcerative colitis (UC). METHODS: A 19-item survey was distributed to subscribers of the pediatric gastroenterology (PEDSGI) listserv. Responses were submitted anonymously and results compiled in a secure website. RESULTS: A total of 113 subscribers (88% based in the United States) responded (101 pediatric gastroenterology attendings and 12 pediatric gastroenterology fellows). There were 46% in academic medical institutions and 39% in hospital-based practices. The majority (91%) were treating >10 patients with UC; 13% were treating >100 patients with UC; 91% had prescribed infliximab (IFX) 5 mg/kg for UC; 72% had prescribed IFX 10 mg/kg for UC. Using a 5-point Likert scale, factors that influenced the decision not to increase IFX dosing in patients with UC included: "improvement on initial dose of IFX" (mean: 3.88) and "decision to move to colectomy" (3.69). Lowest mean Likert scores were: "lack of guidelines or literature regarding increased IFX dosing" (1.96) and "insurance authorization or other insurance issues" (2.34). "Insurance authorization or other insurance issues" was identified by 39% as at least somewhat of a factor (Likert score ≥ 3) in their decision not to increase the IFX dose. IFX 10 mg/kg was more commonly used for the treatment of pediatric UC among responders based in the United States (75/100) compared to non-United States responders (6/13, P = 0.047). Induction of remission was reported by 78% of all responders and 81% reported maintenance of remission with IFX 10 mg/kg. One responder reported one death with IFX 10 mg/kg. CONCLUSION: IFX 10 mg/kg is more commonly used in the United States to treat pediatric UC. Efficacy and safety data are required to avoid insurance barriers for its use.

Sex differences in statural growth impairment in Crohn's disease: role of IGF-1.

BACKGROUND: Growth impairment in Crohn's disease (CD) is more common in males than females for unknown reasons. Since insulin-like growth factor-1 (IGF-1) is important for statural growth, we hypothesized that IGF-1 levels are lower in males with CD. METHODS: Sex differences in hormone Z-scores based on chronological age (CA-Z) and bone age (BA-Z) were examined in a cross-sectional study of 82 CD patients <21 years of age (43% female). RESULTS: IGF-1 CA-Z and BA-Z-scores were 0.50 units (P = 0.04) and 1.24 units (P = 0.003) lower in males. Mean bone age (12.2 years) was lower than chronological age (13.1 years) (P < 0.0001). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and albumin did not differ by sex (P ≥ 0.08), but were associated with IGF-1 CA-Z and BA-Z-scores (P ≤ 0.02). Insulin-like growth factor binding protein-3 (IGFBP-3) CA-Z and BA-Z-scores were 0.71 units (P = 0.004) and 1.26 units (P < 0.001) lower in males. Inflammatory markers were correlated with sex hormone CA-Z and BA-Z and pituitary hormone BA-Z-scores in males (P ≤ 0.03), but not females (P ≥ 0.25). IGF-1 BA-Z-scores were positively associated with height BA-Z-scores (P = 0.03). Mean height BA-Z-scores were lower in males (P = 0.03). CONCLUSIONS: Lower IGF-1 levels in males may explain sex differences in growth impairment in CD. Inflammation appears to more adversely affect hormone levels and statural growth in males. Prospective longitudinal studies are needed to further clarify the role of IGF-1 in sex differences in statural growth impairment in pediatric CD.

Role of small bowel follow-through in diagnosing inflammation of the terminal ileum in pediatric patients.

BACKGROUND: The small bowel follow-through (SBFT) is a noninvasive imaging modality for evaluating terminal ileum (TI) inflammation. The accuracy of this modality in pediatric patients is not well established. PATIENTS AND METHODS: We retrospectively determined the sensitivity and specificity of SBFT for detecting TI inflammation diagnosed on histology in 93 pediatric patients studied in a single institution. RESULTS: The mean age at the first study was 12.9 years (range 1.1-20.9 years). Forty-five percent were girls. Twenty-five patients (27%) had abnormal TIs on SBFT. Seventeen patients (18%) had TI inflammation diagnosed by biopsy. The sensitivity of SBFT was 59% and the specificity was 80% for detecting TI inflammation diagnosed on histology. Sensitivity and specificity did not change by demographic factors, final diagnoses, presenting symptoms, or laboratory parameters, reflecting the presence of intestinal inflammation. CONCLUSIONS: The sensitivity and specificity of SBFT in pediatric patients were poor and did not vary with demographic factors, final diagnoses, presenting symptoms, or laboratory parameters. Prospective longitudinal studies comparing various imaging modalities (SBFT, magnetic resonance enterography, and capsule endoscopy) are required to determine which is the most effective tool for evaluating pediatric patients for TI inflammation.