Subra Kugathasan

Prolonged duration of response to infliximab in early but not late pediatric Crohn's disease.

OBJECTIVES:Tumor necrosis factor-α plays a central role in chronic intestinal inflammation of Crohns disease. Targeting this cytokine with the chimeric monoclonal antibody infliximab has emerged as an effective form of therapy in adult Crohns disease patients. We sought to determine whether infliximab treatment would benefit pediatric patients with medically refractory Crohns disease. We also assessed the duration of response, comparing children with early disease to children with long-standing (late) Crohns disease.METHODS:Fifteen consecutive children (mean age 12.8 ± 3.2 yr) with medically refractory Crohns disease were enrolled in a prospective, open-label trial of a single, 5-mg/kg infliximab intravenous infusion. Medically refractory disease was defined as an inability to taper steroids, lack of response to immunomodulator therapy over 4 months, and active disease as measured by the Pediatric Crohns Disease Activity Index (PCDAI). Primary endpoints included measurements of disease activity (PCDAI), steroid use, and duration of clinical response.RESULTS:In all, 14/15 children (94%) improved after infliximab infusion, with a significant decrease of both PCDAI and daily steroid use by 4 wk. Ten patients (67%) achieved complete remission by 10 wk. Among the 14 patients who responded, three of six children (50%) with early disease maintained clinical response through the 12-month trial period, compared to none of eight children with late disease. There were no serious complications associated with the use of infliximab in any of the patients.CONCLUSIONS:Infliximab is safe and effective in the short-term treatment of medically refractory pediatric Crohns disease. More importantly, there is a remarkably prolonged duration of response after infliximab therapy in children with early compared to late Crohns disease.

Infliximab retreatment in adults and children with Crohn's disease: risk factors for the development of delayed severe systemic reaction.

Infliximab retreatment in adults and children with Crohns disease: risk factors for the development of delayed severe systemic reaction

Growth abnormalities persist in newly diagnosed children with crohn disease despite current treatment paradigms

Objectives: We analyzed growth outcomes in children newly diagnosed with Crohn disease and determined whether growth abnormalities persist despite current therapies. Patients and Methods: Clinical and growth data were prospectively obtained on an inception cohort younger than 16 years old at diagnosis and Tanner I to III during the study. Results: In all, 176 children (mean age 10.1 years; 65% male) with mild (33%) or moderate/severe (67%) disease at diagnosis were studied. Disease activity at 1 year was inactive/mild (89%) or moderate/severe (11%). First-year treatments included immunomodulators (60%), corticosteroids (77%), 5-aminosalicylates (61%), infliximab (15%), and enteral nutrition (10%). By 2 years, 86% had received immunomodulators and 36% infliximab. Mean height z scores at diagnosis, 1 year, and 2 years were −0.49 ± 1.2 standard deviations (SDs), −0.50 ± 1.2, and −0.46 ± 1.1, respectively. Of the subjects, 10%, 8%, and 6.5% had height z scores less than −2 SD at diagnosis, 1 year, and 2 years. A height velocity z score less than −1SD was seen in 45% of subjects at 1 year and 38% at 2 years. The mean height velocity z score, however, increased between 1 and 2 years from −0.71 to 0.26 (P < 0.03). Corticosteroid use greater than 6 months in the first year was associated with abnormal height velocity at 1 year (adjusted odds ratio = 4.5; 95% confidence interval [CI] = 2.2–9.6). No statistically significant effect on height velocity z scores was noted when comparing those receiving or not receiving infliximab. Conclusions: Growth delay persists in many children with CD following diagnosis, despite improved disease activity and the frequent use of immunomodulators and biologics. Additional strategies to improve growth outcomes require development.

Fecal calprotectin is useful in predicting disease relapse in pediatric inflammatory bowel disease.

Background: Fecal calprotectin (FC) has been proposed as a noninvasive surrogate marker to determine the degree of intestinal inflammation and predicting relapse in patients with inflammatory bowel disease (IBD). The aim was to compare FC levels in IBD and healthy controls, to correlate FC levels with clinical disease activity, and to assess whether FC levels can be used to predict clinical relapse in children with IBD. Methods: Enzyme‐linked immunosorbent assay (ELISA) determined levels of FC were measured in more than 1 stool samples (n) from 32 IBD patients (n = 97) and from 34 healthy controls (n = 37). Disease activity was assessed by the Harvey–Bradshaw index in Crohns disease (CD) and by Physicians Global Assessment (PGA) in both CD and ulcerative colitis (UC). Clinical events were recorded up to 9 months following stool collection in CD patients. Wilcoxon rank sum test and Fishers exact tests were used to compare FC levels in IBD patients and in control. Kaplan–Meyer analysis was used to determine a risk of clinical relapse in relation to FC levels. Results: The IBD group had higher FC levels (range 17–7500 g/g) compared with control (16–750 g/g, P < 0.0001). FC levels were higher during relapse (CD, 3214 ± 2186; UC, 2819 ± 1610) compared to remission (CD, 1373 ± 1630; UC, 764 ± 869; P < 0.0001). Among those with clinical relapse, 90% had FC levels more than 400 &mgr;g/g in CD. Eighty‐nine percent of CD encounters with FC levels less than 400 &mgr;g/g remained in clinical remission. Conclusions: FC levels differentiate active IBD from controls. Among children with CD and in remission, FC levels may be useful in predicting impending clinical relapse.

Ureteropelvic junction obstruction: an overlooked cause of cyclic vomiting.

Cyclic vomiting syndrome is an unusual cause of recurrent episodes of repetitive vomiting, particularly in children. Although in only a minority of cases can an underlying cause be found, each patient deserves a thorough evaluation for treatable conditions. We present four cases of cyclic vomiting syndrome caused by ureteropelvic obstruction. Surgical correction was followed by resolution of symptoms in all four patients.

Pediatric inflammatory bowel disease: clinical and therapeutic aspects.

Epidemiologic data suggest that the incidences of pediatric ulcerative colitis and Crohn disease continue to evolve with geographic variations. One study suggests that children with autism have a unique inflammatory bowel disorder that is associated with gastrointestinal symptoms. The appropriate use of new diagnostic tests and novel treatments for inflammatory bowel disease (IBD) needs to be clarified in the pediatric population. Because of concerns regarding sensitivity and specificity, serologic markers measuring anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies cannot yet replace conventional diagnostic testing for screening or diagnosis of pediatric IBD. Large, prospective, pediatric population-based studies still need to be performed to ascertain their use as a noninvasive screening tool. Genetic studies using thiopurine methyl transferase and measurement of 6-mercaptopurine metabolites appear to be valuable for management of pediatric patients with IBD, in assisting clinicians in optimizing therapeutic response to 6-mercaptopurine, and in identifying individuals at increased risk for drug-induced toxicity. Newer immunomodulatory agents also are being explored in pediatric IBD. Open pilot trials of infliximab (Remicade; Centocor, Malvern, PA) for the treatment of children with Crohn disease that does not respond to conventional management have demonstrated short-term efficacy and safety. Trials of tacrolimus for treatment of fulminant colitis in children have been disappointing.

Molecular Stratification of Crohn's Disease by Chemokine Receptors: Fractalkine Receptor Polymorphisms Define a Fibrostenosing Ileal Subgroup

The association of NOD2/CARD15 gene mutations with Crohns disease (CD) has also provided proof of principle that anatomic location (ileal disease) and stricturing behavior is associated with specific genetic variants. However, the majority of CD patients of Caucasian descent, and essentially all minority CD patients do not possess NOD2/CARD15 mutations. Although these early lessons from NOD2/CARD15 genotype/phenotype correlations are encouraging, much more needs to be done to adequately understand the CD spectrum of subgroups. The study by Brand et al. demonstrates that a chemokine receptor polymorphism (CX3CR1 T280) can also influence disease location and behavior, suggesting yet another genetic variant that can help to subgroup CD patients. Findings similar to the study by Brand and colleagues in this issue of American Journal of Gastroenterology suggest that panels of susceptibility alleles and polymorphisms will ultimately allow an early genetic determination that will correspond with unique clinical patterns of CD: increased expression of the chemokine fractalkine in Crohns disease and association of the factalkine receptor T280M polymorphism with a fibrostenosing disease phenotype.