Meena Thayu

Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn disease.

INTRODUCTIONThe risk of malignancy as a complication of Crohn disease has been well described (1-3). In addition to the established risk of colorectal cancer associated with inflammatory bowel disease, extraintestinal malignancies such as lymphoma have been reported. Areas of intestine with chronic

Longitudinal Assessment of Bone Density and Structure in an Incident Cohort of Children With Crohn's Disease

BACKGROUND & AIMS The impact of childhood Crohns disease (CD) on volumetric bone mineral density (vBMD), bone structure, and muscle mass have not been established. The objective of this longitudinal study was to assess musculoskeletal outcomes in an incident cohort of children with CD using peripheral quantitative computed tomography (pQCT). METHODS Tibia pQCT was performed in 78 CD subjects (ages, 5-18 years) at diagnosis and in 67 over the subsequent year. pQCT outcomes were converted to sex- and race-specific z scores based on reference data in over 650 controls. Multivariable linear regression models identified factors associated with changes in bone outcomes. RESULTS At diagnosis, CD subjects had significant deficits in trabecular vBMD (z score, -1.32+/-1.32; P< .001), cortical section modulus (a measure of bone geometry and strength) (z score, -0.44+/-1.11; P< .01), and muscle (z score, -0.96+/-1.02; P< .001) compared with controls. Over the first 6 months, trabecular vBMD and muscle z scores improved significantly (both, P< .001); however, section modulus worsened (P= .0001), and all 3 parameters remained low after 1 year. Increases in muscle z scores were associated with less severe declines in cortical section modulus z scores. Improvements in trabecular vBMD z scores were greater in prepubertal subjects. Glucocorticoids were associated with increases in cortical vBMD. CONCLUSIONS Substantial deficits in trabecular vBMD, cortical bone geometry, and muscle were observed at CD diagnosis. Trabecular vBMD improved incompletely; however, cortical deficits progressed despite improvements in muscle. Glucocorticoids were not associated with bone loss. Therapies to improve bone accrual in childhood CD are needed.

Circulating microRNA is a biomarker of pediatric Crohn disease.

Objective: The gold standard for the diagnosis and evaluation of Crohn disease (CD) is endoscopy/colonoscopy, although this is invasive, costly, and associated with risks to the patient. Recently, circulating microRNAs (miRNAs) have emerged as promising noninvasive biomarkers. Here, we examined the utility of serum miRNAs as biomarkers of CD in children. Patients and Methods: Studies were conducted using sera samples from patients with pediatric CD, healthy controls, and a comparison group of patients with pediatric celiac disease. Serum miRNA levels were explored initially using a microfluidic quantitative reverse transcription-polymerase chain reaction array platform. Findings were subsequently validated using quantitative reverse transcription-polymerase chain reaction in larger validation sample sets. The diagnostic utility of CD-associated serum miRNA was examined using receiver operating characteristic analysis. Results: A survey of miRNA levels in the sera of control and patients with CD detected significant elevation of 24 miRNAs, 11 of which were chosen for further validation. All of the candidate biomarker miRNAs were confirmed in an independent CD sample set (n = 46). To explore the specificity of the CD-associated miRNAs, they were measured in the sera of patients with celiac disease (n = 12); none were changed compared with healthy controls. Receiver operating characteristic analyses revealed that serum miRNAs have promising diagnostic utility, with sensitivities for CD above 80%. Significant decreases in serum miRNAs were observed in 24 incident patients with pediatric CD after 6 months of treatment. Conclusions: The present study identifies 11 CD-associated serum miRNA with encouraging diagnostic potential. Our findings suggest serum miRNAs may prove useful as noninvasive biomarkers in CD.

Effects of Sex, Race, and Puberty on Cortical Bone and the Functional Muscle Bone Unit in Children, Adolescents, and Young Adults

CONTEXT Sex and race differences in bone development are associated with differences in growth, maturation, and body composition. OBJECTIVE The aim of the study was to determine the independent effects of sex, race, and puberty on cortical bone development and muscle-bone relations in children and young adults. DESIGN AND PARTICIPANTS We conducted a cross-sectional study of 665 healthy participants (310 male, 306 black) ages 5-35 yr. OUTCOMES Tibia peripheral quantitative computed tomography measures were made of cortical bone mineral content (BMC) and bone mineral density (BMD), periosteal (Peri) and endosteal circumferences, section modulus (Zp), and muscle area. Regression models were adjusted for tibia length, age, race, sex, and Tanner stage. RESULTS All cortical measures were greater in blacks than whites (all P < or = 0.001) in Tanner stages 1-4; however, differences in BMC, Peri, and Zp were negligible in Tanner stage 5 (all interactions, P < 0.01). Cortical BMC, Peri, and Zp were lower in females than males in all Tanner stages (all P < 0.001), and the sex differences in Peri and Zp were greater in Tanner stage 5 (interaction, P < 0.02). Cortical BMD was greater (P < 0.0001) and endosteal circumference was lower (P < 0.01) in Tanner 3-5 females, compared with males. Adjustment for muscle area attenuated but did not eliminate sex and race differences in cortical dimensions. Associations between muscle and bone outcomes did not differ according to sex or race. CONCLUSION Sex and race were associated with maturation-specific differences in cortical BMD and dimensions that were not fully explained by differences in bone length or muscle. No race or sex differences in the functional muscle bone unit were identified.

Determinants of changes in linear growth and body composition in incident pediatric Crohn's disease.

BACKGROUND & AIMS Pediatric Crohns disease (CD) is associated with growth, lean mass (LM), and fat mass (FM) deficits. This study assessed and identified determinants of changes in height and body composition in children with CD following. METHODS Whole-body LM and FM were assessed using dual-energy x-ray absorptiometry in 78 CD subjects at diagnosis, 6, 12, and a median of 43 months (range, 24-63) later. Race- and sex-specific Z scores for lean mass (LM-ht-Z) and fat mass (FM-ht-Z) relative to height were derived using reference data in >900 controls. Serum cytokines and growth factors were measured, and quasi-least squares regression was used to identify determinants of changes in height and body composition. RESULTS LM-ht-Z and FM-ht-Z (both P<.005) improved significantly after diagnosis; however, female patients had persistent LM deficits vs controls (-0.50+/-1.02, P<.05). Serum interleukin-6, tumor necrosis factor-alpha, and lipopolysaccharide binding protein decreased significantly (all P<.001). Greater increases in LM-ht-Z were associated with infliximab therapy (P<.05), increases in albumin (P<.001) and decreases in erythrocyte sedimentation rate (P<.05), interleukin-6 (P<.005), and lipopolysaccharide binding protein (P<.05). Greater increases in FM-ht-Z were associated with glucocorticoid, methotrexate, and infliximab therapy, and increases in albumin (P<.05) and growth hormone binding protein (P<.05). Overall, height-Z did not improve; however, greater increases in insulin-like growth factor-1 (P<.05) and decreases in tumor necrosis factor-alpha (P<.05), interleukin-6 (P<.05), and lipopolysaccharide binding protein (P<.05) levels were associated with increases in height-Z. CONCLUSIONS Immune-mediated mechanisms contribute to growth and body composition deficits in CD. Therapies should target these deficits.

Improvement in biomarkers of bone formation during infliximab therapy in pediatric Crohn's disease: results of the REACH study.

BACKGROUND & AIMS Crohns disease (CD) is associated with altered bone metabolism. This study examined changes in bone formation and resorption after infliximab induction and associations between bone biomarkers, linear growth, and disease activity (Pediatric Crohns Disease Activity Index [PCDAI]) after 54 weeks of infliximab therapy. METHODS One hundred twelve subjects ages 6-17 years with moderate to severe CD received infliximab induction (5 mg/kg/dose) at weeks 0, 2, and 6; week-10 responders were randomized to infliximab every 8 or every 12 weeks maintenance therapy. Serum bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), urine C-telopeptide of collagen cross-links (CTX-1), and deoxypyrodinoline (DPD) were collected at baseline and 10 weeks. PCDAI and height z-scores were assessed at baseline and at 10 and 54 weeks. RESULTS Models were adjusted for bone age, gender, height, and steroid use. Baseline BSAP and P1NP levels were negatively associated with PCDAI (both P = .01). BSAP and P1NP increased during induction (both P < .001) and were associated with 54-week increases in height z-score (P < .05 and P < .001, respectively). Improvements in P1NP were associated with 54-week decreases in PCDAI (P = .01). CTX-1 and DPD also increased during induction (P < .001 and P = .01, respectively) but were not associated with changes in PCDAI. Changes in CTX-1 were associated with improvements in height z-score (P < .002). CONCLUSIONS Infliximab therapy is associated with dramatic increases in BSAP and P1NP, consistent with inhibition of tumor necrosis factor-alpha effects on osteoblasts. The increases in CTX-1 and DPD likely reflect coupling of bone formation and resorption and increases in linear growth.

Interpretation of Biomarkers of Bone Metabolism in Children: Impact of Growth Velocity and Body Size in Healthy Children and Chronic Disease

OBJECTIVES To determine the effects of growth, maturation, and whole body bone mineral content (WB-BMC) accrual on biomarkers of bone formation (bone-specific alkaline phosphatase [BSAP]) and resorption (urine deoxypyridinoline/creatinine [DPD]) in healthy children and children with Crohns disease. STUDY DESIGN BSAP and DPD were measured at baseline, with growth and dual energy x-ray absorptiometry (DXA) WB-BMC measured at baseline and 6 months in 202 control subjects and 110 subjects with Crohns disease, ages 5 to 21 years. Multivariable linear regression identified determinants of biomarkers in control subjects and subjects with Crohns disease. RESULTS In control subjects, BSAP and DPD were significantly and independently associated with sex, Tanner stage, WB-BMC, height velocity, and WB-BMC accrual rates; these covariates explained 77% to 80% of the variability in the bone biomarkers, respectively. Subjects with Crohns disease had lower height-for-age (P < .001) and WB-BMC-for-height (P <.05) than control subjects. Crohns disease was associated with lower BSAP (P < .001) and greater DPD (P < .001), independent of growth, maturation, baseline WB-BMC, and WB-BMC accrual, compared with control subjects. CONCLUSIONS These data illustrate the potential confounding effects of growth and WB-BMC on bone metabolism biomarkers in children. After adjustment for these effects, Crohns disease was associated with lower biomarkers of bone formation and greater bone resorption.

Gender differences in body composition deficits at diagnosis in children and adolescents with Crohn's disease.

Background: Childhood Crohns disease (CD) is associated with poor growth and decreased body mass index (BMI); however, lean mass (LM) and fat mass (FM) deficits prior to therapy have not been characterized. Objectives: To quantify LM and FM in incident pediatric CD subjects and controls, and to identify determinants of LM and FM deficits. Methods: Whole body LM and FM were assessed using DXA in 78 CD subjects and 669 healthy controls, ages 5‐21 yr. Gender specific z‐scores for LM (LM‐Ht) and FM (FM‐Ht) relative to height were derived using log linear regression models in the controls. Multivariate linear regression models adjusted for potential confounders. Results: CD was associated with significantly lower height and BMI for age. Within CD subjects, FM‐Ht and LM‐Ht were significantly lower in females compared with males (FM‐Ht z: −0.66 ± 0.83 vs. −0.08 ± 0.95, p < 0.01; LM‐Ht z: −1.12 ± 1.12 vs. −0.57 ± 0.99, p < 0.05). In females, CD was associated with significantly lower LM‐Ht (p < 0.001) and FM‐Ht (p = 0.001), adjusted for age, race and Tanner stage, compared with controls. LM and FM deficits were significantly greater in older females with CD; 47% of adolescent females had LM‐Ht ≤ 5th percentile. In non‐black males, CD was also associated with lower LM‐Ht (p < 0.02); FM‐Ht deficits were not significant. Conclusions: Incident CD was associated with significant LM deficits in males and females, and FM deficits in females. Future studies are needed to identify etiologies for the age and gender differences and to evaluate therapies for these deficits.

Skeletal health of children and adolescents with inflammatory bowel disease.

Current evidence points to suboptimal bone health in children and adolescents with inflammatory bowel disease (IBD) when compared with their healthy peers. This compromise is evident from diagnosis. The clinical consequences and long-term outcome of this finding are still unknown. The mechanism of suboptimal bone health in children and adolescents with IBD lays mainly in reduced bone formation, but also reduced bone resorption, processes necessary for bone growth. Factors contributing to this derangement are inflammation, delayed growth and puberty, lean mass deficits, and use of glucocorticoids. We recognize that evidence is sparse on the topic of bone health in children and adolescents with IBD. In this clinical guideline, based on current evidence, we provide recommendations on screening and monitoring bone health in children and adolescents with IBD, including modalities to achieve this and their limitations; monitoring of parameters of growth, pubertal development, and reasons for concern; evaluation of vitamin D status and vitamin D and calcium intake; exercise; and nutritional support. We also report on the current evidence of the effect of biologics on bone health in children and adolescents with IBD, as well as the role of bone active medications such as bisphosphonates. Finally, we summarize the existing numerous gaps in knowledge and potential subjects for future research endeavors.

Association of Chronic Kidney Disease with Muscle Deficits in Children

The effect of chronic kidney disease (CKD) on muscle mass in children, independent of poor growth and delayed maturation, is not well understood. We sought to characterize whole body and regional lean mass (LM) and fat mass (FM) in children and adolescents with CKD and to identify correlates of LM deficits in CKD. We estimated LM and FM from dual energy x-ray absorptiometry scans in 143 children with CKD and 958 controls at two pediatric centers. We expressed whole body, trunk, and leg values of LM and FM as Z-scores relative to height, sitting height, and leg length, respectively, using the controls as the reference. We used multivariable regression models to compare Z-scores in CKD and controls, adjusted for age and maturation, and to identify correlates of LM Z-scores in CKD. Greater CKD severity associated with greater leg LM deficits. Compared with controls, leg LM Z-scores were similar in CKD stages 2 to 3 (difference: 0.02 [95% CI: -0.20, 0.24]; P = 0.8), but were lower in CKD stages 4 to 5 (-0.41 [-0.66, -0.15]; P = 0.002) and dialysis (-1.03 [-1.33, -0.74]; P < 0.0001). Among CKD participants, growth hormone therapy associated with greater leg LM Z-score (0.58 [0.03, 1.13]; P = 0.04), adjusted for CKD severity. Serum albumin, bicarbonate, and markers of inflammation did not associate with LM Z-scores. CKD associated with greater trunk LM and FM, variable whole body LM, and normal leg FM, compared with controls. In conclusion, advanced CKD associates with significant deficits in leg lean mass, indicating skeletal muscle wasting. These data call for prospective studies of interventions to improve muscle mass among children with CKD.