[show abstract][hide abstract] ABSTRACT: Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children.
To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease.
Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy.
Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks.
Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response.
Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event.
In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment.
clinicaltrials.gov Identifier: NCT00720538.
JAMA The Journal of the American Medical Association 11/2013; 310(20):2164-73. · 29.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inflammatory bowel disease (IBD) is often associated with extraintestinal manifestations (EIMs) such as optic neuritis (ON), although this has been described in only a few adult patients so far, all of whom were affected with Crohn's disease (CD). Furthermore, ON and demyelinating diseases have been demonstrated to be more frequent in IBD patients than in control populations. In our current case report, we describe a child with active CD who developed sudden blindness due to bilateral ON that was not related to any known cause, and that promptly responded to a high dose of steroids. Investigations and a clinical follow-up have so far ruled out the development of demyelinating diseases in this patient. To our knowledge, this is the first report of ON in a pediatric patient with CD. Possible explanations for this case include an episodic EIM of an active bowel disease, an associated autoimmune disorder such as a recurrent isolated ON, the first manifestation of multiple sclerosis, or another demyelinating disease that could appear in a later follow-up.
World Journal of Gastroenterology 10/2011; 17(38):4344-6. · 2.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chronic intestinal failure is a condition causing severe impairment of intestinal functions; long-term total parenteral nutrition is required to provide adequate nutritional support.
This is a 15-year follow-up study of paediatric patients with intestinal failure receiving long-term home parenteral nutrition.
Thirty-six patients were included in the study, all aged <16 years. Total parenteral nutrition and home parenteral nutrition were administered respectively to 100.97 and 85.20 patients-year. Today, 12 out of 36 patients are still on parenteral nutrition. A total of 99 central venous catheters were inserted, for mean 2.75 catheters/patient. The overall incidence rates of catheter-related complications was 1.79 per 1000 days-catheter for sepsis and 3.37 per 1000 days-catheter for mechanical complications. Two multivariate Cox-models have been used to examine the role of some predictors for septic or mechanical complications. The only risk factor for septic complications was the indication for parenteral nutrition, and the only predictor of mechanical complications was the insertion period.
Our experience in the treatment of paediatric patients with gastrointestinal diseases confirms that long-term parenteral nutrition has become a safe and appropriate method in the treatment of severe chronic intestinal failure.
Digestive and Liver Disease 01/2011; 43(1):28-33. · 3.16 Impact Factor
[show abstract][hide abstract] ABSTRACT: To correlate multiple intraluminal esophageal impedance recording with pH-monitoring with symptoms.
Symptoms occurring within a 2-minute window of a reflux were considered to be associated with reflux. Analyses were performed in 1- to 6-, 6- to 12-, and >12-months-old patients for crying, pain, cough, and vomiting.
A total of 70 of 225 tracings were discarded. Of 2172 symptoms, 1136 (52%) were reflux-associated (45% acid reflux [AR], 51% weakly AR, 3% alkaline reflux). The strongest reflux-symptom association was found for vomiting. Cough-reflux association was higher in infants than in older children. In older patients, symptom-reflux association was more with AR. Symptoms were associated with proximal reflux in 70% of patients. The symptom index and symptom association probability (SAP) were positive (>50% for symptom index and >95% for SAP) for all refluxes in 83% and 46% of patients and for AR in 49% and 47% of patients, respectively. In 1- to 6-month-old infants, symptom index and SAP were higher for weakly AR than for AR. For crying, SAP was independent of AR or weakly AR. For cough, SAP was positive in one-third of patients, predominantly with AR in 6- to 12-month-old infants and with weakly AR in the other infants.
Multiple intraluminal esophageal impedance recording with pH-monitoring doubles the probability of documenting an association between symptoms and reflux compared with pH monitoring. In young infants, symptoms are more frequently associated with weakly AR than with AR.
The Journal of pediatrics 12/2010; 157(6):949-954.e1-2. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Enteropathy defines abnormalities of the small intestinal mucosa of various etiologies in which nutrition has a causal or a therapeutic role. Breast milk is the gold-standard feeding during infancy for optimal nutrition in health and the majority of diseases. Therapeutic formulae have decreased the need for enteral or parenteral support. Gastrointestinal infections are worldwide the most frequent cause of enteropathy by increasing mucosal permeability, local expression of costimulatory molecules allowing antigen penetration in the mucosa, and T-cell activation leading sometimes to disruption of oral tolerance. Concomitant malnutrition impairs not only the immunologic response but also the recovery of damaged mucosa with secondary intestinal and pancreatic enzymatic reductions. Optimal nutritional rehabilitation is the cornerstone of the management of persisting diarrhea. Celiac disease and cow's milk protein allergy are examples of chronic enteropathy. Multiple food allergies, even during breast-feeding, are increasingly reported due to an impaired development of oral tolerance. The dietary approach to allergic disease is currently evolving from passive allergen avoidance to active modulation of the immune system to (re)establish tolerance. The gastrointestinal flora provides maturational signals for the lymphoid tissue, improves balance of inflammatory cytokines, reduces bacterial invasiveness and dietary antigen load, and normalizes gut permeability. The clinical effects of nucleotides and zinc merit further clinical evaluation. Major attention has recently focused on the immune effects of dietary lipids in terms of possible prevention of allergic sensitization by downregulating inflammatory response and protecting the epithelial barrier and host-microbe interactions modifying the adherence of microbes to the mucosa.