Hyperadiponectinemia During Infliximab Induction Therapy in Pediatric Crohn Disease.

OBJECTIVES: The inflammatory process in Crohn disease (CD) involves the visceral fat, characterized by adipocyte hyperplasia and altered adipose tissue and serum concentrations of tumor necrosis factor (TNF), leptin, adiponectin and resistin. We investigated the effect of anti-TNF therapy with infliximab (IFX) on serum adipokine levels in pediatric CD. METHODS: Serum concentrations of resistin (ng/mL), leptin (ng/mL), and total adiponectin (µg/mL) were assessed by enzyme-linked immunosorbent assays (ELISA) in 18 pediatric CD patients (mean age 15.0 ±â€Š1.5 years) before first, second, and fourth IFX infusion (weeks 0, 2, and 14) and compared with baseline values from sex- and BMI-matched healthy controls (HC, mean age 13.4 ±â€Š1.6 years). RESULTS: At baseline, CD patients (mean age 15.0 ±â€Š1.5 years, 10 of 18 boys) compared with HC (13.4 ±â€Š1.6 years, 7 of 15 boys) had higher resistin levels (median 14.7 ng/mL, range 5.1-50.5 vs 7.3 ng/mL, 0.5-14.5); P = 0.0002). At weeks 2 and 14, resistin decreased to 6.9 ng/mL (2.9-16.8) (P < 0.0001) and 9.2 ng/mL (4.1-20.6; P = 0.0011), respectively. Leptin and adiponectin were comparable between patients and HC at baseline. Leptin increased in girls from 9.5 ng/mL (4.0-30.1) to 16.0 ng/mL (7.9-35.2; P = 0.0156) and 17.2 ng/mL (10.8- 26.8; P = 0.1953) at weeks 0, 2, and 14 respectively; with a trend in boys from 2 (0.6-12.9) to 2.8 (1.7-8.6; P = 0.0840) and 3.3 (1.3-4.6; P = 0.1309). Adiponectin peaked initially from 7.8 µg/mL (4.6-11.9) at week 0 to 9.2 µg/mL (4.1-20.7; P = 0.0005) at week 2 and thereafter fell to 6.5 µg/mL (3.0-12.7; P = 0.0182) at week 14. CONCLUSIONS: TNF blockade is associated with changes in circulating adipokines. The marked early increase of the potent anti-inflammatory adiponectin may contribute to the rapid response to IFX in CD.

Incidence and Risk Factors for Perianal Disease in Pediatric Crohn Disease Patients Followed in CEDATA-GPGE Registry.

OBJECTIVES: Perianal disease (PD) with fistula and/or abscess formation is a severe complication in Crohn disease (CD). We examined prevalence, incidence, and risk factors for PD development in a pediatric CD cohort. METHODS: Patients with CD from the prospective, multicenter registry for inflammatory bowel disease from Germany and Austria (CEDATA-GPGE) were included if diagnosed at the age of 18 years or younger, registered within 3 months after diagnosis, and having at least 2 follow-up visits within the first year of registration. We examined potential risk factors for PD with Kaplan-Meier analysis and a final Cox model considering sex, family history of inflammatory bowel disease, extraintestinal manifestations, disease location, and induction therapy (corticosteroids or nutritional therapy). RESULTS: Of 2406 patients with CD, 742 fulfilled inclusion criteria (59% boys, mean age at diagnosis 12.4 ±â€Š3.4 years). PD was present at diagnosis in 41 patients (5.5%; 80.9% boys), whereas 32 patients (4.3%, 81.3% male) developed PD during follow-up (mean 2.0 ±â€Š1.6 years). The cumulative incidence of PD at 12 and 36 months after diagnosis was 3.5% and 7.5%, respectively. Potential risk factors for PD development during follow-up were male sex (hazard ratio = 3.2, [95%; confidence interval 1.2-7.8]) and induction therapy with corticosteroids (hazard ratio = 2.5 [1.1-5.5]). Diagnostic evaluation at PD diagnosis was incomplete in 40% of affected subjects. PD resolved within 1 year in 50% of cases. CONCLUSIONS: Approximately 10% of CD patients in our cohort suffered from PD within the first 3 years of their disease. Male sex and initial corticosteroid therapy were associated with an increased risk to develop PD after diagnosis.

Investigating the early metabolic fingerprint of celiac disease - a prospective approach.

OBJECTIVES AND STUDY: In the development of Celiac Disease (CD) both genetic and environmental factors play a crucial role. The Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 loci are strongly related to the disease and are necessary but not sufficient for the development of CD. Therefore, increasing interest lies in examining the mechanisms of CD onset from the early beginning. Differences in serum and urine metabolic profiles between healthy individuals and CD patients have been reported previously. We aimed to investigate if the metabolic pathways were already altered in young, 4 month old infants, preceding the CD diagnosis. METHODS: Serum samples were available for 230 four month old infants of the PreventCD project, a multicenter, randomized, double-blind, dietary intervention study. All children were positive for HLA-DQ2 and/or HLA-DQ8 and had at least one first-degree relative diagnosed with CD. Amino acids were quantified after derivatization with liquid chromatography - tandem mass spectrometry (MS/MS) and polar lipid concentrations (acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins) were determined with direct infusion MS/MS. We investigated the association of the metabolic profile with (1) the development of CD up to the age of 8 years (yes/no), (2) with HLA-risk groups, (3) with the age at CD diagnosis, using linear mixed models and cox proportional hazards models. Gender, intervention group, and age at blood withdrawal were included as potential confounder. RESULTS: By the end of 2014, thirty-three out of the 230 children (14%) were diagnosed with CD according to the ESPGHAN criteria. Median age at diagnosis was 3.4 years (IQR, 2.4-5.2). Testing each metabolite for a difference in the mean between healthy and CD children, we (1) could not identify a discriminant analyte or a pattern pointing towards an altered metabolism (Bonferroni corrected P > 0.05 for all). Metabolite concentrations (2) did not differ across the HLA-risk groups. When investigating the age at diagnosis using (3) survival models, we found no evidence for an association between the metabolic profile and the risk of a later CD diagnosis. CONCLUSION: The metabolic profile at 4 months of age was not predictive for the development of CD up to the age of 8 years. Our results suggest that metabolic pathways reflected in serum are affected only later in life and that the HLA-genotype does not influence the serum metabolic profile in young infants before introduction of solid food.

Long-term development of bone geometry and muscle in pediatric inflammatory bowel disease.

OBJECTIVES: The muscle-bone unit is crucial for normal bone development. As muscle mass is frequently reduced in pediatric patients with inflammatory bowel disease (pIBD), we investigated the impact of muscles on the bone development over time. METHODS: Bone and muscle parameters were measured repeatedly in 102 pIBD patients (67 boys; 82 Crohn's disease; 30 newly diagnosed) by peripheral quantitative computed tomography (pQCT) at the forearm. The first and last measurements were included in the evaluation. Results were expressed as sex- and age-specific and partly height-corrected Z-scores for a healthy reference population. RESULTS: At baseline, patients showed reduced Z-scores for height (median -0.7; range -3.7 to 1.6), trabecular bone mineral density (TrbBMD; -0.6; 3.0-2.8), and for height-corrected cortical cross-sectional area (CSA(height); -0.4; -3.0 to 2.2), cortical thickness (CrtTh(height); -0.7; -3.0 to 1.2), and MuscleCSA(height) (-1.0; -4.9 to 2.0; all P<0.01). Cortical bone mineral density (CrtBMD) and height-corrected TotalCSA(height) Z-scores were elevated (0.57; -4.55 to 2.8, both P<0.01). Over time, TotalCSA(height) (+0.36; -1.5 to 4.5) further increased, CorticalCSA(height) (+0.21; -2.1 to 3.0) and MuscleCSA(height) (+0.64; -2.0 to 3.9, all P<0.01) improved, whereas CrtBMD decreased toward normalization (-0.36; -5.1 to 3.6, P<0.05). The change in MuscleCSA(height) significantly correlated with the changes in TrbBMD (r=0.42), TotalCSA(height) (r=0.35), CorticalCSA(height) (r=0.38), and CrtTh(height) (r=0.24; all P<0.02). The relations became even stronger after adjustment for several confounders. CONCLUSIONS: Bone metabolism and geometry are altered in pIBD patients expressed by low trabecular mineral density, low cortical thickness, and high cortical mineral density. The increased height-corrected cortical CSA might reflect a compensatory effect. In our cohort, treatment increased height-corrected muscle CSA and its changes were closely associated with bone parameters. Therefore, physical activity to enhance muscle mass and bone health should be promoted in pIBD patients.

The impact of human breast milk components on the infant metabolism.

BACKGROUND & AIMS: Breastfeeding is beneficial for mothers and infants. Underlying mechanisms and biochemical mediators thus need to be investigated to develop and support improved infant nutrition practices promoting the child health. We analysed the relation between maternal breast milk composition and infant metabolism. METHODS: 196 pairs of mothers and infants from a European research project (PreventCD) were studied. Maternal milk samples collected at month 1 and month 4 after birth were analysed for macronutrient classes, hormone, and fatty acid (FA) content. Phospholipids, acylcarnitines, and amino acids were measured in serum samples of 4-month old infants. Associations between milk components and infant metabolites were analysed with spearman correlation and linear mixed effect models (LME). P-values were corrected for multiple testing (PLME). RESULTS: Month 1 milk protein content was strongly associated with infant serum lyso-phosphatidylcholine (LPC) 14:0 (PLME = 0.009). Month 1 milk insulin was associated to infant acetylcarnitine (PLME = 0.01). There were no associations between milk protein content and serum amino acids and milk total fat content and serum polar lipids. Middle- and odd-chain FA% in breast milk at both ages were significantly related to serum LPC and sphingomyelins (SM) species in infant serum (all PLME<0.05), while FA% 20:5n-3 and 22:6n-3 percentages were significantly associated to serum LPC 22:6 (PLME = 1.91×10-4/7.93×10-5) in milk only at month 4. Other polyunsaturated fatty acids and hormones in milk showed only weak associations with infant serum metabolites. CONCLUSIONS: Infant serum LPC are influenced by breast milk FA composition and, intriguingly, milk protein content in early but not late lactation. LPC 14:0, previously found positively associated with obesity risk, was the serum metabolite which was the most strongly associated to milk protein content. Thus, LPC 14:0 might be a key metabolite not only reflecting milk protein intake in infants, but also relating high protein content in milk or infant formula to childhood obesity risk.

Lean body mass, physical activity and quality of life in paediatric patients with inflammatory bowel disease and in healthy controls.

BACKGROUND AND AIMS: Physical activity is important for muscle and bone strength in the growing child and may be impaired in paediatric patients with inflammatory bowel disease (IBD) even during quiescent disease. The SenseWearPro(2) armband allows to measure physical activity under everyday life conditions. METHODS: Thirty-nine IBD patients (27 Crohn's disease, 12 ulcerative colitis, 24 boys) in remission (n=26) or with only mild disease activity (n=13) were compared to 39 healthy age and sex-matched controls. Body weight, height, body mass index (BMI), lean body mass as phase angle α (determined by bioelectrical impedance analysis), and dynamometric grip force were expressed as age- and sex-related Z-scores. SenseWearPro(2) armbands were applied for three consecutive days to record number of steps, duration of physical activity and sleeping time. Quality of life was assessed with the German KINDL and IMPACT III questionnaires, energy intake with prospective food protocols. Differences between patients and pair-matched controls were analysed by paired t-test. RESULTS: Patients showed lower Z-scores for phase angle α (difference -0.72; 95% CI [-1.10; -0.34]) and lower grip strength (-1.02 [-1.58; -0.47]) than controls. They tended towards lesser number of steps per day (-1339 [-2760; 83]) and shorter duration of physical activity (-0.44 h [-0.94; 0.06]), particularly in females and patients with mild disease. Quality of life and energy intake did not differ between patients and controls. CONCLUSION: In spite of quiescent disease lean body mass and physical activity were reduced. Interventions to encourage physical activity may be beneficial in this lifelong disease.