Long-term Extent Change of Pediatric-Onset Ulcerative Colitis.

BACKGROUND: Data describing extent change (progression or regression) in pediatric-onset ulcerative colitis (UC) are scarce. GOAL: We aimed to describe extent change in pediatric-onset UC during long-term follow-up and to assess predictors of extent change. STUDY: Medical charts of pediatric-onset UC patients with at least 5-year follow-up were analyzed retrospectively. Disease extent was determined using the Paris classification. It was examined at diagnosis and during follow-up at different time points. The impact of possible predictors on extent change including age at diagnosis, gender, clinical manifestations, disease, severity indices, and different therapeutic regimens during disease course was assessed. RESULTS: Patients (n=134, 55% males) were followed for a median duration of 13.1 (range, 5 to 28) years. Median age at diagnosis was 13.1 (range, 2 to 17.8) years. Of 134 patients, 40.5% had extensive or pancolitis, 33.5% left-sided colitis, and 26% had proctitis at diagnosis. On follow-up (n=117), 45% had unchanged disease extent, 35% experienced extent progression, whereas 20% experienced regression of disease extent. The multivariate Cox models demonstrated that among children with left-sided disease at diagnosis, presence of extraintestinal manifestations (hazard ratio, 5.19; P=0.022), and higher pediatric UC activity index (hazard ratio, 8.77; P=0.008) were associated with extent progression to extensive disease. Predictors of extent regression have not been identified. CONCLUSIONS: Disease extent changes significantly over time in pediatric-onset UC. In our cohort, presence of extraintestinal manifestation and higher pediatric UC activity index score at diagnosis were associated with progression from limited to extensive disease during follow-up.

Predictors of pouchitis after ileal pouch-anal anastomosis in pediatric-onset ulcerative colitis.

OBJECTIVES: Few studies have reported on the incidence and risk factors for pouchitis following colectomy and ileal pouch-anal anastomosis (IPAA) in patients with pediatric-onset ulcerative colitis (UC). We aimed to determine clinical predictors for the development of pouchitis following IPAA in this population. PATIENTS AND METHODS: We performed a retrospective chart review of all pediatric UC cases that were diagnosed at the Schneider Children's Medical Center of Israel between 1981 and 2013 and who underwent colectomy during disease course. Potential predictors for pouchitis and chronic pouchitis including various demographic, clinical, endoscopic, and histological variables at diagnosis and at the time of surgery were assessed. RESULTS: Of 188 patients with pediatric-onset UC, 33 (18%) underwent colectomy and IPAA surgery. During a median postsurgical follow-up of 7.6 (range: 1-21.5) years following IPAA, 20/33 (60%) patients developed pouchitis including 11/33 (33%) patients who developed chronic pouchitis. Kaplan-Meier survival estimates of the cumulative probability for pouchitis were 9% at 1 year and 36 and 55% at 5 and 10 years, respectively. Multivariate Cox models showed that older age at colectomy (hazard ratio: 0.86, P=0.024) was a protective factor, whereas preoperative vitamin-D deficiency (≤20 ng/ml) (hazard ratio: 4.4, P=0.021) increased the risk for pouchitis. Age at diagnosis, sex, disease extent, and preoperative therapeutic regimens did not affect the risk of pouchitis. CONCLUSION: Long-term risk for pouchitis is significantly high in pediatric-onset UC after IPAA. Vitamin-D deficiency and younger age at colectomy may increase the risk for pouchitis.

Risk of Colectomy in Patients With Pediatric-onset Ulcerative Colitis.

OBJECTIVES: Data describing the incidence and risk factors for colectomy in pediatric ulcerative colitis (UC) is inconsistent. Our aim was to describe the colectomy rate and to identify risk factors associated with colectomy in a large cohort of children with UC with long-term follow-up. MATERIALS AND METHODS: We performed a retrospective chart review of pediatric UC cases that were diagnosed at Schneider Children's Medical Center of Israel between 1981 and 2013. Potential predictors for colectomy including age at diagnosis, sex, disease extent, severity indices, and different therapeutic regimens during disease course were assessed. RESULTS: Of 188 patients with pediatric onset UC, 34 (18%) underwent colectomy. Median follow-up was 6.9 years (range, 1-30). Kaplan-Meier survival estimates of the cumulative probability for colectomy were 4% at 1 year and 17% at 10 years from diagnosis. Multivariate Cox models showed that male sex (hazard ratio 4.2, P = 0.001) and severe disease at diagnosis reflected by Pediatric Ulcerative Colitis Activity Index score ≥65 (hazard ratio 8.9, P < 0.001) were associated with increased risk for colectomy. Age, disease extent, ethnicity, family history of inflammatory bowel disease, early introduction of immunomodulators, or treatment with antitumor necrosis factor α agent did not affect the risk of colectomy. CONCLUSIONS: Male sex and higher Pediatric Ulcerative Colitis Activity Index score at diagnosis are independent risk factors for colectomy.

The natural history of pediatric-onset IBD-unclassified and prediction of Crohn's disease reclassification: a 27-year study.

OBJECTIVES: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) in patients who were initially diagnosed as inflammatory bowel disease-unclassified (IBDU) remains challenging. Our aims were to describe the natural history of pediatric-onset IBDU patients during prolonged period of follow up and to identify associated predictors for CD reclassification among them. MATERIALS AND METHODS: In this retrospective single center study, out of 723 patients with pediatric onset IBD, we identified 53 patients (7.3%) diagnosed with IBDU at the Schneider Children's Medical Center of Israel between 1986 and 2013. Potential predictors for CD reclassification including age at diagnosis, gender, clinical manifestations, disease extent and laboratory findings were assessed. RESULTS: The median follow-up was 6.8 (± 6.7) years. Reclassification to CD was observed in 24/53 (45%) of patients. The median interval from diagnosis to CD reclassification was 9.4 years. In 58% of these patients, CD reclassification occurred within 5 years from diagnosis. Multivariate Cox models showed that familial history of CD and hypoalbuminemia at diagnosis were significantly associated with CD reclassification (HR 11.3, p = .02 and HR 5.3, p = .03, respectively). All other assessed clinical, laboratory and endoscopic parameters did not serve as predictors for CD reclassification later on. CONCLUSIONS: In our cohort, a substantial high proportion of pediatric onset IBDU patients were later re-diagnosed as CD. Only a family history of CD and hypoalbuminemia could predict reclassification among IBDU patients.

Incidence of Bowel Surgery and Associated Risk Factors in Pediatric-Onset Crohn's Disease.

BACKGROUND: Data describing the incidence and the risk factors for surgical interventions in pediatric Crohn's disease (CD) is inconsistent. Our aim was to describe the rates of intestinal surgery and to identify associated risk factors in a large cohort of children with CD. METHODS: Medical charts of 482 children with CD from the Schneider Pediatric Inflammatory Bowel Disease cohort who were diagnosed between 1981 and 2013 were carefully reviewed retrospectively. RESULTS: Of 482 patients, 143 (29.7%) underwent intestinal surgery with a median follow-up time of 8.6 years (range, 1-30.5). Kaplan-Meier survival estimates of the cumulative probability of CD-related intestinal surgery were 14.2% at 5 years and 24.5% at 10 years from diagnosis. Of these, 14% needed more than one operation. Multivariate Cox models showed that isolated ileal disease (hazard ratio [HR] 2.39, P = 0.008), complicated behavior (penetrating or stricturing) (HR 2.44, P < 0.001) and higher severity indices, at diagnosis, including Harvey-Bradshaw (HR 1.06, P = 0.009) and short Pediatric Crohn's Disease Activity Index (HR 1.02, P = 0.001) were associated with increased risk for intestinal surgery. Age, gender, family history of CD, early introduction of immunomodulators, treatment with anti-tumor necrosis factor α, or diagnosis before the year 2000 did not affect the risk of bowel surgery. CONCLUSIONS: Ileal location, complicated behavior, and higher disease activity indices at diagnosis are independent risk factors for bowel surgery, whereas anti-tumor necrosis factor α treatment and diagnosis during the "biological era" are not associated with diminished long-term surgical risk.

Evolution of disease phenotype in pediatric-onset Crohn's disease after more than 10 years follow up-Cohort study.

BACKGROUND: Pediatric-onset Crohn's disease (CD) is a heterogeneous disorder which is subjected to progression and complications in a substantial proportion of patients. AIMS: We aimed to assess the progression in pediatric-onset CD phenotype on long term follow up. METHODS: Medical charts of pediatric onset CD patients with at least 10 years follow-up were analyzed retrospectively. Disease phenotype was determined at diagnosis and during follow up at different time points. Phenotype was determined according to the Paris classification. The impact of possible predictors on phenotype progression was assessed as well as the association between different therapeutic regimens during disease course and phenotype progression. RESULTS: Progression of disease location, behavior, and perianal involvement was observed in 20%, 38% and 20% of patients, respectively, after a median follow-up of 16.4 (±4.4) years. Microscopic ileocolonic disease at diagnosis was significant predictors for progression of disease extent. Treatment with anti tumor necrosis factor-ɑ agents and number of flares per years of follow-up were associated with progression of disease extent, behavior and perianal involvement. CONCLUSION: Disease extent, behavior and prevalence of perianal disease change significantly over time in pediatric-onset CD. In our cohort, most clinical, laboratory and endoscopic parameters do not serve as predictors for long-term disease progression.

Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab.

BACKGROUND & AIMS: There is controversy about whether levels of anti-tumor necrosis factor (TNF) and antidrug antibodies (ADAs) are accurate determinants of loss of response to therapy. We analyzed the association between trough levels of anti-TNF agents or ADAs and outcomes of interventions for patients with loss of response to infliximab or adalimumab. METHODS: We performed a retrospective study of pediatric and adult patients with inflammatory bowel disease and suspected loss of response to anti-TNF agents treated at medical centers throughout Israel from October 2009 through February 2013. We examined the correlation between outcomes of different interventions and trough levels of drug or ADAs during loss of response. An additional subanalysis was performed including only patients with a definite inflammatory loss of response (clinical worsening associated with increased levels of C-reactive protein or fecal calprotectin, or detection of inflammation by endoscopy, fistula discharge, or imaging studies). RESULTS: Among 247 patients (42 with ulcerative colitis), there were 330 loss-of-response events (188 to infliximab and 142 to adalimumab). Trough levels of adalimumab greater than 4.5 mcg/mL and infliximab greater than 3.8 mcg/mL identified patients who failed to respond to an increase in drug dosage or a switch to another anti-TNF agent with 90% specificity; these were set as adequate trough levels. Adequate trough levels identified patients who responded to expectant management or out-of-class interventions with more than 75% specificity. Levels of antibodies against adalimumab >4 microgram per mL equivalent (mcg/mL-eq) or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity. Patients with high titers of ADAs had longer durations of response when anti-TNF agents were switched than when dosage was increased (P = .03; log-rank test), although dosage increases were more effective for patients with no or low titers of ADAs (P = .02). An analysis of definite inflammatory loss-of-response events (n = 244) produced similar results; patients with adequate trough levels had a longer duration of response when they switched to a different class of agent than when anti-TNF was optimized by either a dosage increase or by a switch within the anti-TNF class (P = .002; log-rank test). CONCLUSIONS: The results of this retrospective analysis suggest that trough levels of drug or ADAs may guide therapeutic decisions for more than two-thirds of inflammatory bowel disease patients with either clinically suspected or definite inflammatory loss of response to therapy.

Concomitant autoantibodies in newly diagnosed diabetic children with transient celiac serology or proven celiac disease.

BACKGROUND: We previously demonstrated that children with Type 1 Diabetes Mellitus (T1DM) may have transiently elevated tissue transglutaminase antibodies (TTG) on a gluten-containing diet. This study aimed to examine if the presence of autoantibodies in newly diagnosed T1DM differs between patients with celiac disease and those with transient celiac serology. METHODS: Forty children were identified who had been diagnosed with T1DM between 2003 and 2009 and who had elevated serum IgA-TTG antibody levels at diagnosis. Blood samples were collected for measurement of insulin (IA-2A) antibodies, islet cell antigen (ICA) antibodies, glutamic acid decarboxylase (GAD) antibodies, thyroglobulin (TgAb) antibodies, and thyroid peroxidase (TPO) antibodies. Children diagnosed with celiac disease (CD; group 1, n=23) and children in whom TTG antibody levels spontaneously normalized over time (group 2, n=17) were compared. RESULTS: No significant differences in positivity rates between groups 1 and 2 were found for any of the autoantibodies tested. The respective findings were as follows: IA-2A 50% and 47.1% (p=0.855); ICA 77.3% and 76.5% (p=0.953); GAD 27.3% and 52.9% (p=0.102). Thyroid antibodies were found positive in a limited number of patients: TgAb 4.5% and 11.8%; TPO 4.5% and 11.8%. In addition, antibody titer levels did not differ significantly for all autoantibodies. Difference in occurrence of clinical or subclinical thyroid disease did not reach significance (4.3% vs. 29.4%; p=0.07). Age was positively correlated with the presence of thyroglobulin and thyroid peroxidase antibodies, and negatively correlated with the presence of insulin antibody. CONCLUSION: Neither the number of concomitant autoantibodies nor their titers in newly diagnosed T1DM differed between patients with proven CD and those with transient TTG serology.

Long-term outcome of tumor necrosis factor alpha antagonist's treatment in pediatric Crohn's disease.

BACKGROUND: Anti tumor necrosis factor alpha (TNFα) agents have become widely used in pediatric inflammatory bowel disease (IBD). So far, only few studies examined the long-term results of anti-TNFα treatment in children with IBD. METHODS: The long-term outcome of pediatric patients with IBD was assessed retrospectively in a multicenter cohort of children treated with anti-TNFα beyond induction treatment. Short- and long-term response rates, predictors for loss of response, data on growth and laboratory parameters were assessed. RESULTS: 120 patients [101 crohn's disease (CD), 19 ulcerative colitis (UC) or indeterminate colitis (IC)] received either infliximab or adalimumab. The mean age at initiation of anti-TNFα was 13.4 ± 3.9 years and the median duration of anti-TNFα treatment was 15 months (range: 2-90). Overall, 89% of the cohort experienced short-term response following induction. Response was associated with improvement in weight and BMI Z-scores (p<0.001) but not with linear growth. Responders experienced a significant decrease in erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) during treatment (p<0.001). Albumin and hemoglobin both improved but only albumin increased significantly (p<0.001). The cumulative probability of losing response to anti-TNFα treatment was 17%, 38%, and 49% after 1, 3, and 5 years, respectively. Responders had a significantly lower weight and BMI Z-scores at initiation of anti-TNFα treatment in compared to non-responders (p=0.04 and 0.02 respectively). CONCLUSIONS: Our long term cohort supports the current evidence on the effectiveness and safety of anti-TNFα treatment in children with IBD. Response to treatment was interestingly associated with lower weight and BMI.

From blood smear to lipid disorder: a case report.

Neutral lipid storage disease (Chanarin-Dorfman syndrome) is a rare autosomal recessive disorder of lipid metabolism, characterized by systemic accumulation of neutral lipids in multiple tissues. We report a case of a 14-year-old girl with generalized ichthyosis, liver cirrhosis, and a hearing impairment. A peripheral blood smear demonstrated marked cytoplasmatic vacuoles in most polymorphonuclear cells (Jordan's anomaly). Bone marrow examination revealed vacuoles in myeloid precursors. Genetic analysis showed that the patient was homozygous for the p.Arg312Ter mutation in the CGI-58 gene, a key enzyme in lipid metabolism. The peripheral blood smear is diagnostic, and should be performed in any patient with ichthyosis.

Spontaneous normalization of anti-tissue transglutaminase antibody levels is common in children with type 1 diabetes mellitus.

BACKGROUND: The prevalence of celiac disease among type 1 diabetes mellitus (T1DM) patients is 5-10 times higher than in the general population. Thus, evaluation of celiac serology is indicated at diagnosis of T1DM and on follow up. AIM: This study was prompted by the observation that elevated anti-TTG antibody levels in diabetic children may spontaneously normalize despite continued consumption of gluten. The objective of the study was to investigate the prevalence of this phenomenon and associated factors. MATERIALS AND METHODS: The files of all children diagnosed with type 1 diabetes mellitus from 2003-2009 at a tertiary pediatric medical center were reviewed for those with elevated serum levels of anti-TTG antibody. Clinical, medical, laboratory, and treatment data were collected. Findings were compared between patients diagnosed with celiac disease and patients with initially elevated anti-TTG antibody levels that spontaneously normalized. RESULTS: Forty-eight of the 738 patients with type 1 diabetes attending our center (6.5%) had elevated anti-TTG antibody blood levels. Celiac disease was diagnosed in 23, and anti-TTG antibody levels normalized in 17 (35.4%), all of whom consumed gluten. At one-year follow-up, there was no significant difference between the groups in HbA1c level or change in anthropometric measurements. CONCLUSION: Physicians treating children with type 1 diabetes and mildly elevated anti-TTG antibody levels might consider 12-month serologic follow-up on a gluten-containing diet rather than immediate duodenal biopsy.

[Eosinophilic esophagitis--the experience in a tertiary pediatric center].

BACKGROUND: Eosinophilic esophagitis (EoE) is an inflammatory disorder with increasing prevalence. It typically presents with swallowing difficulties, heartburn or dyspepsia, and in toddlers, failure to thrive. EoE is characterized by eosinophilic infiltrates of the esophageal mucosa, and endoscopies with tissue diagnosis are mandatory. Hypersensitivity has been implicated in the pathogenesis, therefore, most treatment options include steroids and allergen avoidance. AIMS: To summarize a tertiary pediatric clinic's experience with EoE in children and adolescents, describe the spectrum of clinical presentations and treatment options, and raise awareness of this disorder among medical personnel. METHODS: A retrospective, descriptive study of patients diagnosed with EoE at our institute over the past 5 years. Demographic details, presenting symptoms, laboratory studies, endoscopic and pathologic findings were analyzed. Information regarding medical and nutritional therapies and response to treatment were summarized. RESULTS: Fifteen cases of EoE in children and adolescents are described. Average age at diagnosis was 9 years (range 0.7-161. The most common complaint was dysphagia (60%e. The majority demonstrated food allergies 19/121. Most of the patients were treated with topical ingested steroids, while others had either elemental formula or allergen elimination. Favorable responses were seen in most patients treated with steroids (8/11). Long-term results of nutritional therapy are insufficient to draw conclusions on its efficacy. CONCLUSIONS: EoE causes major eating difficulties and affects quality of life in children, sometimes accompanied by failure to thrive. There is a clear association with food allergies, and positive responses to steroids are common. A high index of suspicion and referral to a gastroenterologist for definite diagnosis are required. Combining medical with nutritional treatment seems promising but further studies regarding the long-term outcome are needed.

Follow-up of children with celiac disease - lost in translation?

BACKGROUND: Celiac disease (CD) is a prevalent condition with a broad spectrum of presentations requiring a lifelong gluten-free diet (GFD). Our aims were to examine the presentation and adherence to a GFD as well as the adequacy of follow-up of children diagnosed with CD at a tertiary referral center. METHODS: A retrospective electronic chart review of pediatric patients suspected of CD (n = 581) who were seen at our institute between January 1999 and December 2008 was performed. RESULTS: 387 children were diagnosed with CD (F/M ratio of 1.54, median age: 6.25 years). Presenting symptoms were iron deficiency anemia (n = 82, 34%), short stature (n = 59, 24.5%) and abdominal pain (n = 59, 24.5%). In 63 patients (16.3%) an associated autoimmune disease was recorded. Only 42.7% of the patients (165/387) had regular out-patient gastroenterologist visits; 22% (86/387) were followed by their primary care physician. Over 35% (136/387) were completely lost to follow-up. Negative serology on follow-up was present in 91% of the CD patients(150/165) followed at our center in comparison to 70% (60/86) in those followed up by their primary physician (p = 0.0002). CONCLUSIONS: At least in our referral center, follow-up of children diagnosed with CD is far from satisfactory. Initiatives aimed at improving adherence to regular follow-up are needed as this intervention is associated with a significant increase in patient compliance with a long-term GFD.

The role of duodenal bulb biopsy in the diagnosis of celiac disease in children.

BACKGROUND AND STUDY AIMS: It is suggested that for celiac disease (CD) diagnosis, biopsies should also be taken from the duodenal bulb. Whether bulb biopsies suggestive of CD can be found on upper gastrointestinal endoscopy (EGD) done for reasons other than CD diagnosis is not clear. The aim of our study was to evaluate the contribution of routine bulb biopsies to the diagnosis of CD, when taken regardless of prior suspicion of CD. METHODS: The study included 96 children who underwent EGD for suspected CD and a control group of 69 children who underwent EGD for reasons other than CD. The mucosal changes were evaluated using the Marsh-Oberhuber classification. RESULTS: Among the 87 children diagnosed with CD, we identified 6 patients (7%) with typical histologic findings only in the bulb (Marsh 3), but also 1 patient (1.1%) with findings only in the distal duodenum (Marsh 2). In 20 patients (23%) the histological changes were more severe in the bulb. One patient had more prominent findings in the second part of the duodenum. None of the control patients had histological changes compatible with CD in the bulb or the second part of the duodenum. CONCLUSIONS: Our findings suggest that when CD is suspected, biopsies should be taken from both locations (bulb and second part) as mucosal changes may emerge only at one site. Nevertheless, the presence of characteristic histology on duodenal bulb biopsies might be sufficient for the diagnosis of CD.

Adalimumab treatment in children with refractory Crohn's disease.

Information on safety and efficacy of adalimumab in children with Crohn's disease (CD) is limited. We present a case-series of 14 children with severe CD treated with adalimumab during a 3.5-year period. Fourteen children (nine boys, five girls), aged 13.9 years (range 1.9-19.1) were treated with adalimumab during 12.5 months (range 7-42). All had steroid or immunosuppression-drugs refractory disease. Ten patients (71%) had been previously treated with infliximab, 13/14 were treated with different immunosuppressive drugs and all were steroid-dependent or resistant. Seven children (50%) showed full clinical response and 5/14 (35%) improved partially. Two children (15%) had loss of response after a period of transient improvement. Adalimumab treatment enabled complete steroids withdrawal in 8/14 (57%) of steroid-dependent children. Currently, five children are in complete remission with adalimumab monotherapy for a median 14 months (range 9-24). Adalimumab may induce and maintain remission in children with severe, refractory CD. Prospective safety and efficacy confirmation of this data in children is necessary.