Ulcerative Colitis: Piccoli DA

Baldassano RN, Piccoli DA. · Division of Gastroenterology and Nutrition, Children's Hospital of Philadelphia, Pennsylvania, USA. · Gastroenterol Clin North Am. · Pubmed #10372276 No free full text.

Abstract: IBD is a chronic pediatric disease that needs to be treated by a team of experts consisting of pediatricians, pediatric gastroenterologists, psychologists, nutritionists, social workers, and nurses. A critical factor in successful management of this disease is the willingness of the patient to participate and cooperate with the team. Parents and patients must be educated and supported to treat these disorders effectively. Much further research is necessary to understand the specific causative and therapeutic issues unique to young patients with IBD.

Kugathasan S, Baldassano RN, Bradfield JP, Sleiman PM, Imielinski M, Guthery SL, Cucchiara S, Kim CE, Frackelton EC, Annaiah K, Glessner JT, Santa E, Willson T, Eckert AW, Bonkowski E, Shaner JL, Smith RM, Otieno FG, Peterson N, Abrams DJ, Chiavacci RM, Grundmeier R, Mamula P, Tomer G, Piccoli DA, Monos DS, Annese V, Denson LA, Grant SF, Hakonarson H. · Department of Pediatrics, Children's Research Institute and Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. · Nat Genet. · Pubmed #18758464 No free full text.

Abstract: Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.

Brown KA, Back SJ, Ruchelli ED, Markowitz J, Mascarenhas M, Verma R, Piccoli DA, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. · Am J Gastroenterol. · Pubmed #12385446 No free full text.

Abstract: OBJECTIVES: Understanding cytokine production patterns in early mucosal lesions of pediatric patients newly diagnosed with inflammatory bowel disease (IBD) may be critical to understanding IBD pathogenesis. Interleukin-6 (IL-6) has a central role in a multitude of immune system reactions; however, inconsistent lamina propria and serum IL-6 has been reported in IBD patients. Newly diagnosed pediatric IBD patients have not previously been evaluated for lamina propria or serum IL-6. METHODS: Serum and intestinal lamina propria biopsy whole organ culture supernatants were evaluated by ELISA for IL-6 obtained from newly diagnosed IBD patients, before initiation of immunomodulatory therapies. RESULTS: Levels of lamina propria IL-6 demonstrated significant correlation with graded severity of histological inflammation (p < 0.001). Log-transformed serum and organ culture IL-6 levels demonstrated significant correlation (p < 0.0001, R2 = 0.6226). Assigning a demarcation level of >400 pg/ml, serum IL-6 concentrations were a superior marker for the presence of microscopic intestinal inflammation than erythrocyte sedimentation rate (ESR), with a sensitivity of 82%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 82%. When evaluating subtypes of IBD, serum IL-6 levels were correlated more significantly with active disease in ulcerative colitis patients (p = 0.01, R2 = 0.74) than in Crohn's disease patients (p = 0.21, R2 = 0.33). CONCLUSIONS: This study outlines graded production of IL-6 in intestinal lamina propria and serum of newly diagnosed pediatric IBD patients, confirming the presence of IL-6 in early IBD patients. In addition, serum IL-6 may be a good predictor of IBD in pediatric patients with suspected or newly diagnosed IBD.

Mamula P, Telega GW, Markowitz JE, Brown KA, Russo PA, Piccoli DA, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. · Am J Gastroenterol. · Pubmed #12190168 No free full text.

Abstract: OBJECTIVES: Clinicians are becoming increasingly aware that inflammatory bowel disease (IBD) can affect all age groups, although it has not been well described in infants and young children. Our aim was to evaluate early onset IBD in patients 5 yr of age and younger. METHODS: Medical records of patients diagnosed with early onset IBD at The Children's Hospital of Philadelphia between 1977 and 2000 were reviewed. Patients were divided into three categories: those with Crohn's disease (CD), those with ulcerative colitis (UC), and those with indeterminant colitis (IC). RESULTS: A total of 82 patients fulfilled the criteria. In 12 patients (15%), the IBD diagnosis was changed during the course of illness. At the end of the follow-up period, linear growth failure was present in 10 of 35 (29%) children with CD, one of 30 (3%) with UC, and three of 17 (18%) with IC. Failure to thrive was a frequent presenting symptom in children with CD (44%) and IC (39%), whereas in all four patients with UC and failure to thrive the diagnosis was subsequently changed to CD or IC. A high proportion of patients with CD had large bowel (89%), and perianal (34%) disease. None of the tested patients were positive for anti-Saccharomyces cerevisiae antibody (ASCA), and 10 tested positive for perinuclear antineutrophil cytoplasmic antibody (three of five patients with CD, five of seven with UC, and two of three with IC). CONCLUSIONS: Failure to thrive, at the time of presentation, is indicative of a final diagnosis of CD or IC, not UC. Linear growth failure is a common finding in patients with early onset CD. A high proportion of patients with CD have failure to thrive, colonic, and perianal disease. The IBD serology panel is of limited clinical relevance in providing definitive diagnostic information in this pediatric population.

Mamula P, Markowitz JE, Brown KA, Hurd LB, Piccoli DA, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #11964959 No free full text.

Abstract: OBJECTIVES: The role of infliximab (anti-tumor necrosis factor alpha antibody) therapy in ulcerative colitis (UC) is not well defined. There are only two reports published describing its use in UC. The authors describe their experience with open-label use of infliximab in children with moderate to severe UC. METHODS: The authors collected data on all consecutive pediatric patients with UC who received infliximab at The Children's Hospital of Philadelphia until July 2001. The primary measured outcome was clinical response at 2 days and 2 weeks after infliximab infusion, as measured by the Lichtiger colitis activity index (LCAI) score and the Physician Global Assessment (PGA). Tolerance of the infusions and adverse events were recorded. RESULTS: Nine patients qualified for clinical response analysis. The median Lichtiger colitis activity index score decreased from 11 before the infusion to 1 at 2 days and 2 weeks after the infusion, respectively (P = 0.01 for 2 days and 2 weeks). Seven of nine (77%) patients had decreased activity of their disease measured by the Physician Global Assessment. Corticosteroid therapy was discontinued in six (66%) patients. An infusion reaction developed (generalized pruritus and facial flushing) in two patients and an elevated anti-nuclear antibody (ANA) titer of 1:1280 developed in one patient. CONCLUSION: Infliximab is associated with short-term clinical improvement in children and adolescents with moderate to severe UC.

Mamula P, Piccoli DA, Peck SN, Markowitz JE, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #11964953 No free full text.

Abstract: BACKGROUND: Iron-deficiency anemia is a frequent complication in children with inflammatory bowel disease (IBD). Parenteral iron therapy is rarely prescribed because of concern about potential side effects. The aim of this study was to retrospectively evaluate the safety and efficacy of total dose intravenous (TDI) iron therapy. METHODS: Charts of all the pediatric patients with IBD who received TDI iron therapy between February of 1994 and February of 2000 were reviewed. RESULTS: Seventy patients (20 with ulcerative colitis and 50 with Crohn disease) received a total of 119 TDI iron dextran infusions. Thirty-four patients qualified for the efficacy analysis. The average increase in hemoglobin concentration was 2.9 g/dL, (P < 0.0001). Eleven immediate hypersensitivity reactions developed in 10 patients (9% of the total number of infusions). None of the reactions was life threatening and none required hospitalization. CONCLUSIONS: Total dose intravenous infusion of iron dextran, when appropriately used, is a safe and potentially efficacious treatment for children with inflammatory bowel disease and iron deficiency anemia who are unresponsive to or noncompliant with oral iron therapy.

Kader HA, Mascarenhas MR, Piccoli DA, Stouffer NO, Baldassano RN. · Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #9890469 No free full text.

Abstract: BACKGROUND: The effectiveness of 6-mercaptopurine combined with azathioprine in treating severe ulcerative colitis has been shown in several adult studies. Reported pediatric experiences are rare. The purpose of this study was to investigate the safety and the potential efficacy of 6-mercaptopurine and azathioprine in the treatment of active ulcerative colitis in a pediatric population. METHODS: The medical records of patients with active ulcerative colitis who were under observation at The Children's Hospital of Philadelphia and its satellite clinics from January 1984 through December 1997 were retrospectively reviewed. Patients were included who had received a diagnosis of ulcerative colitis, who met no criteria for Crohn's colitis, and who had received treatment with 6-mercaptopurine and azathioprine. They were then analyzed for the development of side effects, the indication to use 6-mercaptopurine and azathioprine, and the ability to discontinue corticosteroid use in those patients taking 5-acetylsalicylic acid products who were corticosteroid-dependent or whose disease was refractory to treatment. Excluded from the corticosteroid analyses were patients who underwent surgery for their disease and patients treated with 5-acetylsalicylic acid only. Statistical analysis was performed by the Kaplan-Meier survival curve and paired Student's t-test. RESULTS: In a review of 200 medical records of patients with active ulcerative colitis, 20 patients met the criteria. The patients' average age at the initiation of treatment with 6-mercaptopurine and azathioprine was 13.8 years. Sixteen patients (80%) were corticosteroid dependent and 3 (15%) had ulcerative colitis refractory to corticosteroid treatment. One patient had severe colitis treated with 5-acetylsalicylic acid only. Discontinuation of corticosteroid was accomplished in 12 (75%) of 16 patients. The median time to discontinuation of corticosteroid after initiation of 6-mercaptopurine and azathioprine therapy was 8.4 months. Eight patients (67%), observed from 3 months to 65 months, have continued without corticosteroid therapy. Side effects included pancreatitis and shingles that resulted in discontinuation of 5-acetylsalicylic acid, leukopenia corrected by withholding 6-mercaptopurine, and self-resolved hepatitis. CONCLUSIONS: The data support the safety of 6-mercaptopurine and azathioprine use in the treatment of pediatric patients with ulcerative colitis; side effects were minimal and reversible. Eighteen (90%) of 20 patients tolerated the therapy well. The results also show that 12 (75%) of 16 pediatric patients with ulcerative colitis will benefit from the use of 6-mercaptopurine and azathioprine after initial discontinuation of corticosteroid therapy. Although 6-mercaptopurine and azathioprine may not prevent further relapses, medical management of these flares may be less intense and may not require long-term corticosteroid use. Prospective clinical trials in pediatric patients are necessary to delineate further the role of 6-mercaptopurine and azathioprine in pediatric ulcerative colitis.