Augmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn's disease: a retrospective chart review.

Background: Ustekinumab is a monoclonal antibody that inhibits interleukins 12 and 23. It is approved for treatment of Crohn's disease (CD) in adults; however, there is a paucity of data regarding its use in pediatric CD. We describe our experience using ustekinumab in anti-TNF refractory CD pediatric patients. Methods: We performed a retrospective chart review on pediatric patients with CD who were started on ustekinumab from January 2016 to November 2018. We collected patient's clinical history, previous treatment history, surgeries related to CD, disease severity, as measured by abbrPCDAI, and endoscopic severity as recorded by SES-CD before and after ustekinumab. Results: We identified 10 patients with CD who were started on ustekinumab due to non-response to currently approved agents. Seven patients needed augmented maintenance dosing every 4-6 weeks to achieve clinical response or remission. Six of these seven patients had therapeutic drug monitoring during the course of treatment, with five patients showing subtherapeutic drug levels of <4.5 µg/mL while on standard maintenance dosing every 8 weeks, and four patients showing therapeutic drug levels of >4.5 µg/mL on augmented dosing interval. The remaining three patients were on standard maintenance dosing for the duration of treatment. Conclusion: In this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset CD required augmented maintenance doses of ustekinumab to achieve clinical response or remission. A prospective study is needed to define appropriate ustekinumab dosing and interval in management of pediatric CD.

Impaired intestinal iron absorption in Crohn's disease correlates with disease activity and markers of inflammation.

BACKGROUND: Anemia in patients with Crohn's disease (CD) is a common problem of multifactorial origin, including blood loss, malabsorption of iron, and anemia of inflammation. Anemia of inflammation is caused by the effects of inflammatory cytokines [predominantly interleukin-6 (IL-6)] on iron transport in enterocytes and macrophages. We sought to elucidate alterations in iron absorption in pediatric patients with active and inactive CD. METHODS: Nineteen subjects with CD (8 female, 11 male patients) were recruited between April 2003 and June 2004. After an overnight fast, serum iron and hemoglobin levels, serum markers of inflammation [IL-6, C-reactive protein (CRP), and erythrocyte sedimentation rate], and a urine sample for hepcidin assay were obtained at 8 am. Ferrous sulfate (1 mg/kg) was administered orally, followed by determination of serum iron concentrations hourly for 4 hours after the ingestion of iron. An area under the curve for iron absorption was calculated for each patient data set. RESULTS: There was a strong inverse correlation between the area under the curve and IL-6 (P = 0.002) and area under the curve and CRP levels (P = 0.04). Similarly, the difference between baseline and 2-hour serum iron level (Delta[Fe]2hr) correlated with IL-6 (P = 0.008) and CRP (P = 0.045). When cutoff values for IL-6 (>5 pg/mL) and CRP (>1.0 mg/dL) were used, urine hepcidin levels also positively correlated with IL-6 and CRP levels (P = 0.003 and 0.007, respectively). CONCLUSIONS: Subjects with active CD have impaired oral iron absorption and elevated IL-6 levels compared with subjects with inactive disease. These findings suggest that oral iron may be of limited benefit to these patients. Future study is needed to define the molecular basis for impaired iron absorption.

Celiac disease presenting with chilblains in an adolescent girl.

Chilblains, or pernio, are cutaneous lesions that may accompany systemic illnesses including states of malnutrition and autoimmune diseases. We report an adolescent girl in whom chilblains were the chief presenting sign of celiac disease. A gluten-free diet led to weight gain and resolution of the chilblains. We speculate that in this patient, weight loss due to celiac disease contributed to the development of chilblains.

Pediatric inflammatory bowel disease.

PURPOSE OF THIS REVIEW: The prevalence of early-onset inflammatory bowel disease has been on the rise, with children and adolescents currently accounting for approximately 30% of all patients with this condition. Remarkable new advances in diagnostic modalities and therapy for adults with inflammatory bowel disease, and further information about the role of genetics in determining susceptibility to disease make the review of the recent literature in pediatric inflammatory bowel disease more timely than ever. RECENT FINDINGS: In the area of genetics, new studies provide strong evidence for genetic susceptibility to disease, and match genotype with phenotypic presentation. A few studies examine the use of noninvasive diagnostic modalities, such as MRI, and biomarkers (fecal lactoferrin) in pediatric inflammatory bowel disease. Remarkable new agents in therapy for adults with inflammatory bowel disease have been empirically administered to children with inflammatory bowel disease. The first attempts to systematically study the effects of these agents in children and adolescents are reviewed here. Furthermore, new studies revise our notion of surgical outcomes in pediatric inflammatory bowel disease. SUMMARY: Although premature for clinical practice application, the role of genetic testing in determining disease susceptibility and assisting with prognosis and course of therapy is clearly evolving and needs further study. As new therapeutic agents join the available treatments of inflammatory bowel disease it is imperative to include pediatric patients in clinical trials. The goals of future studies will be to alter the natural history of early-onset inflammatory bowel disease, reduce the frequency of recurrences, and perhaps reduce requirements for surgical intervention.