Ulcerative Colitis: Mamula P

Mamula P. · No affiliation provided · J Pediatr Gastroenterol Nutr. · Pubmed #14676587 No free full text.

This publication has no abstract.

Veres G, Baldassano RN, Mamula P. · First Department of Pediatrics, Semmelweis University, Budapest, Hungary. · Drugs. · Pubmed #17683171 No free full text.

Abstract: This review summarises the present knowledge of infliximab therapy in children with inflammatory bowel disease (IBD) based on the available published literature. Infliximab, the chimeric monoclonal IgG(1) antibody to tumour necrosis factor-alpha, is indicated for medically refractory luminal and fistulising paediatric Crohn's disease. Recently, ulcerative colitis case series in children and adolescents suggested that infliximab might also be effective for treatment of ulcerative colitis resistant to standard medical therapy. Induction therapy with infliximab 5 mg/kg at weeks 0, 2 and 6 is routinely used. Since the majority of patients will relapse if not re-treated, a long-term approach with systematic re-treatment with 5 mg/kg every 8-12 weeks is recommended. Maintenance therapy every 8 weeks was superior to 12 weeks' administration in maintaining response and remission in the largest-to-date paediatric randomised trial. Concomitant immunosuppressive therapy reduces the risk of infliximab antibody formation and infusion reactions, and prolongs the duration of treatment success. Severe reactions may not be an absolute contraindication to future infliximab therapy. Premedication does not prevent the development of infusion reactions; however, it is indicated for prevention of subsequent infusion reactions. Adverse events and safety findings in children are comparable to those observed in adults. Latent tuberculosis needs to be screened for. Malignancy rates in paediatric patients treated with infliximab do not seem to be increased. However, newly reported cases of hepatosplenic T-cell lymphoma in young patients with IBD treated with infliximab and mercaptopurine therapy raise concern, and long-term follow-up studies are necessary to determine the true malignancy risk.

Urlep D, Mamula P, Baldassano R. · Pediatric Department, Divison of Gastroenterology and Nutrition, Maribor Teaching Hospital, Maribor, Slovenia. · Minerva Gastroenterol Dietol. · Pubmed #15990704 No free full text.

Abstract: Inflammatory bowel disease (IBD) predominantly affects the gastrointestinal system but it is associated with a large number of extraintestinal manifestations (EIM). These extraintestinal disorders can significantly contribute to morbidity and impair the overall life quality. EIM may be diagnosed before, concurrently with, or after the diagnosis of IBD is made. The precise etiology of EIM remains unknown. It currently is believed that mucosa from the underlying bowel disease may provide associated immune responses for the inflammatory process in the extraintestinal sites. The involvement of autoimmune mechanisms has been suggested when the shared and unique epitopes in the human colon, eye, joint and biliary epithelium were detected. Recently, the presence of long-lived populations of memory lymphocytes has been discovered which arise as a consequence of bowel inflammation and express homing receptors that direct their migration not only to the gut but also to the extraintestinal sites. The most common extraintestinal disorders associated with IBD include dermatologic, ophthalmologic, musculoskeletal and hepatobiliary diseases, although virtually every organ system may be involved. If these disorders can be considered as the real extraintestinal manifestations of IBD or represent just association between different syndromes of autoimmune etiology, is still not clear. It is important to acquire knowledge on these extraintestinal manifestations of Crohn's disease and ulcerative colitis to start the respective treatment early.

Orel R, Kamhi T, Vidmar G, Mamula P. · University Children's Hospital, Department of Gastroenterology, Vrazov trg 1, Ljubljana 1000, Slovenia. · J Pediatr Gastroenterol Nutr. · Pubmed #19367184 No free full text.

Abstract: BACKGROUND: The aim of this study was to determine the epidemiological and clinical characteristics of inflammatory bowel disease (IBD) in children in central and western Slovenia during a 12-year period (1994-2005). MATERIALS AND METHODS: The medical records of patients with newly diagnosed IBD during the period of 1994-2005 were retrospectively reviewed. RESULTS: In the 12-year study period, 137 children received new diagnoses of IBD, 60% had Crohn disease (CD), 28% had ulcerative colitis (UC), and 12% had indeterminate colitis (IC). The mean annual incidence of IBD for the whole 12-year period was 4.03/100,000 children; for CD 2.42, for UC 1.14, and for IC 0.47. The annual incidence of IBD rose from 3.04 in the period 1994-1999 to 5.14 in the period 2000-2005. The incidences of CD, UC, and IC rose from 1.99, 0.77, and 0.28, respectively, in the first 6 years to 2.88, 1.57, and 0.69, respectively, in the second 6-year period. The most common type of CD at presentation was inflammatory. Pancolitis was the most frequent form of UC. Almost half of the patients had a severe form of CD at its onset. CONCLUSIONS: The incidence of total pediatric IBD in central and western Slovenia is high and seems to be still rising. CD is the most prevalent form of IBD; its incidence is comparable with that reported in other central and western European countries. The incidences of UC and IC are rising more rapidly than the incidence of CD.

Turner D, Hyams J, Markowitz J, Lerer T, Mack DR, Evans J, Pfefferkorn M, Rosh J, Kay M, Crandall W, Keljo D, Otley AR, Kugathasan S, Carvalho R, Oliva-Hemker M, Langton C, Mamula P, Bousvaros A, LeLeiko N, Griffiths AM, Anonymous00063. · Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Jerusalem, Israel. · Inflamm Bowel Dis. · Pubmed #19161178 No free full text.

Abstract: BACKGROUND: We evaluated the psychometric performance of the Pediatric Ulcerative Colitis Activity Index (PUCAI) in a real-life cohort from the Pediatric IBD Collaborative Research Group. METHODS: Two consecutive visits of 215 children with ulcerative colitis (UC) were included (mean age 11.2 +/- 3.6 years; 112 (52%) males; 63 (29%) newly diagnosed and the others after disease duration of 24 +/- 15.6 months). Validity was assessed using several constructs of disease activity. Distributional and anchor-based strategies were used to assess the responsiveness of the PUCAI to change over time following treatment. RESULTS: Reflecting feasibility, 97.6% of 770 eligible registry visits had a completed PUCAI score versus only 47.6% for a contemporaneously collected Pediatric Crohn's Disease Activity Index (odds ratio = 45.8, 95% confidence interval [CI] 28.6-73.5) obtained for children with Crohn's disease accessioned into the same database. The PUCAI score was significantly higher in patients requiring escalation of medical therapy (45 points [interquartile range, IQR, 30-60]) versus those who did not, (0 points [IQR 0-10]; P < 0.001), and was highly correlated with physician's global assessment of disease activity (r = 0.9, P < 0.001). The best cutoff to differentiate remission from active disease was 10 points (area under receiver operating characteristic curve [AUC] 0.94; 95% CI 0.90-0.97). Test-retest reliability was excellent (intraclass correlation coefficient = 0.89; 95% CI 0.84-0.92, P < 0.001) as well as responsiveness to change (AUC 0.96 [0.92-0.99]; standardized response mean 2.66). CONCLUSION: This study on real-life, prospectively obtained data confirms that the PUCAI is highly feasible by virtue of the noninvasiveness, valid, and responsive index. The PUCAI can be used as a primary outcome measure to reflect disease activity in pediatric UC.

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.

Grossman AB, Mamula P. · Division of GI, Hepatology and Nutrition, Children's Hospital of Philadelphia, PA 19104, USA. · Nat Clin Pract Gastroenterol Hepatol. · Pubmed #18725910 No free full text.

This publication has no abstract.

Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, Walters TD, Zachos M, Mamula P, Beaton DE, Steinhart AH, Griffiths AM. · Division of Gastroenterology, Hepatology and Nutrition, the Hospital for Sick Children, University of Toronto, Toronto, Canada. · Gastroenterology. · Pubmed #17681163 No free full text.

Abstract: BACKGROUND AND AIMS: Colonoscopic appearance, the primary measure of disease activity in adult ulcerative colitis, is less acceptable to children. Our aim was to develop a noninvasive activity index of pediatric ulcerative colitis. METHODS: Item selection was performed judgmentally using a Delphi group of 36 experts in pediatric inflammatory bowel disease. Item weighting was performed by regression modeling using a prospective cohort of 157 pediatric ulcerative colitis patients. Validation was assessed on a separate prospective cohort of 48 children with ulcerative colitis undergoing complete colonoscopy. Responsiveness was evaluated at a follow-up visit of 75 children using effect size statistics and diagnostic utility approaches. RESULTS: A list of 41 items was generated and reduced to 11 by rank order. Two physicians completed the Pediatric Ulcerative Colitis Activity Index (PUCAI) on each of the patients in the weighting cohort. Six clinical items were significant in the regression analysis; the laboratory items and an endoscopic appearance item did not improve the PUCAI performance. In the validation cohort, the PUCAI was highly correlated with the Physician's Global Assessment (r = 0.91, P < .001), Mayo score (r = 0.95, P < .001), and colonoscopic appearance (r = 0.77, P < .001). Correlations were higher than 2 noninvasive adult indices calculated concurrently. Interobserver and test-retest reliability were excellent (intraclass correlation coefficient = 0.95; 95% CI: 0.93-0.97). Cut-off points were established using receiver operator characteristic curves on the full cohort. Excellent responsiveness was found at repeated visits (effect size = 1.9, area under the receiver operator characteristic curve = 0.97). CONCLUSIONS: The rigorously developed PUCAI is a noninvasive, valid, highly reliable, and responsive index with which to assess disease activity in pediatric ulcerative colitis.

Shepanski MA, Hurd LB, Culton K, Markowitz JE, Mamula P, Baldassano RN. · Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. · Inflamm Bowel Dis. · Pubmed #15677910 No free full text.

Abstract: PURPOSE: To describe the reported health-related quality of life (HRQOL) in children and adolescents with inflammatory bowel disease (IBD) after attending an IBD summer camp. METHODS: A prospective analysis of quality of life was completed at an overnight camp that was exclusively for patients with IBD, which was sponsored by the Crohn's and Colitis Foundation of America. The IMPACT-II questionnaire (Canada and United States) and the State-Trait Anxiety Inventory for Children were administered to the campers at the beginning and at the end of a 1-week camp to assess HRQOL and anxiety. The IMPACT-II questionnaire consists of 35 questions measuring 6 quality-of-life domains (i.e., bowel domain, systemic symptoms, emotional functioning, social functioning, body image, and treatment/interventions). The State-Trait Anxiety Inventory for Children consists of 2 different 20-item sets of questions. One set assesses state anxiety, and the other, trait anxiety. A repeated-measures multivariate analysis of variance was performed to determine the differences between scores attained before and after camp on the IMPACT-II questionnaire and in each of its domains. Paired sample t tests were performed on state and trait anxiety before and after camp. RESULTS: A total of 125 individuals consented to participate, but 61 patients (50 girls and 11 boys; age range, 9 to 16 y) completed the IMPACT-II questionnaire in full. Of those 61 patients, 47 had Crohn's disease and 14 had ulcerative colitis. There was statistically significant improvement between the mean (+/-SD) precamp total score (172.95 +/- 36.61) and the mean postcamp total score (178.71 +/- 40.97; P = 0.035), bowel symptoms scores (P = 0.036), social functioning scores (P = 0.022), and treatment interventions scores (P = 0.012). No difference was found between anxiety scores before and after camp on either the state or trait anxiety inventories (n = 55; P > 0.05). CONCLUSIONS: Overall, HRQOL improved in children after attending IBD summer camp. This exploratory study suggests that contributing factors for these improvements may be an increase in social functioning, a better acceptance of IBD symptoms, and less distress regarding treatment interventions, suggesting that a camp that is specifically designed for children with IBD may normalize the chronic illness experience. However, future research using a multimodal measurement approach is warranted to support these conclusions.

Miele E, Markowitz JE, Mamula P, Baldassano RN. · The Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #15097438 No free full text.

Abstract: INTRODUCTION: Pediatric studies on immunogenicity of infliximab have not been published. The aim of the study was to evaluate the prevalence of human antichimeric antibody (HACA), relationship to infusion reactions (IR), and the role of concomitant immunomodulatory therapies. METHODS: An inflammatory bowel disease (IBD) database was queried, and a retrospective review of patients who had HACA performed was undertaken. RESULTS: HACA was conclusively determined in 34 patients with IBD (14 male, Crohn disease/ulcerative colitis: 30/4), median age 14.8 years (range, 6.4-22.5 years). Twenty-nine (85.3%) patients were receiving immunomodulatory therapy. A total of 234 infliximab infusions were administered (mean, 6.9; range, 1-26). HACA was detected in 12 (35.3%) patients. IR occurred in 8 (23.5%) patients. HACA-positive patients had a higher proportion of infusions associated with IR than did HACA-negative patients (P < 0.01). HACA levels > or =8.0 microg/mL were more likely to be associated with IR (P = 0.03). Levels of > or = 8.0 microg/mL were more common in patients who had an average interval between infliximab infusions of 8 weeks or less (P = 0.04). Concomitant immunomodulatory therapy was associated with a lower risk of developing HACA (P = 0.02) and lower titer of HACA (P = 0.04). Patients did not have HACA at a greater rate when there was an extended interval (more than 12 weeks) between infliximab infusions (P = 0.89). CONCLUSIONS: In children and adolescents with IBD, HACA formation is related to IR and to the duration of response to treatment. Immunomodulatory agents seem to have a protective role against development of HACA or high titers of antibodies. The interval between infusions does not influence the development of HACA.

Mamula P, Markowitz JE, Cohen LJ, von Allmen D, Baldassano RN. · Division of GI & Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. · J Pediatr Gastroenterol Nutr. · Pubmed #15076630 No free full text.

Abstract: OBJECTIVES: The role of infliximab in treating pediatric ulcerative colitis (UC) is not defined. The authors previously have described their experience with the open label use of infliximab in nine children with moderate to severe UC. The aim of this study was to describe the outcome of these patients after a minimum 2-year follow-up and to describe the responses of eight additional patients to this medication. METHODS: The authors reviewed all pediatric patients with UC who received infliximab at The Children's Hospital of Philadelphia from its first use until February 2003. Tolerance of the infusions and adverse events were recorded. RESULTS: Follow-up information for a minimum of 2 years was reviewed for the nine initial patients. A total of 73 infliximab infusions were administered to these patients. Seven of nine (78%) patients were considered to be responders to the initial dose of infliximab. Two of these patients became nonresponders within 9 months of the first dose of infliximab and underwent colectomy. Of the remaining five (56%) patients with sustained response, two continue to receive infliximab infusions and three are doing well without infliximab. One patient experienced an infusion reaction, and one experienced herpes zoster infection. We have treated eight additional UC patients with infliximab. Seven (88%) patients were considered responders. One responder experienced relapse within 2 months. Overall, a short-term improvement was seen in 14 of 17 (82%) patients, and sustained improvement in 10 of 16 (63%) patients followed up for more than 9 months. All five patients with severe or fulminant UC, unresponsive to 2 weeks of intravenous corticosteroid therapy, experienced improvement with infliximab. Infliximab was well tolerated. CONCLUSION: Infliximab is associated with short- and long-term clinical improvement in children and adolescents with moderate to severe UC.

Kao A, Dlugos D, Hunter JV, Mamula P, Thorarensen O. · Division of Neurology, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. · J Child Neurol. · Pubmed #12269725 No free full text.

Abstract: We describe four pediatric patients with ulcerative colitis and cerebral sinovenous thrombosis and review the pediatric and adult literature on the treatment of sinovenous thrombosis. All of our patients had headache as the initial complaint with onset during an ulcerative colitis flare. Evaluation for hypercoagulable states revealed heterozygosity for prothrombin gene mutation and increased homocysteine level in one patient and mild elevation of anticardiolipin antibodies in two patients. Treatment in the acute period included thrombolysis, heparin, and low-molecular-weight heparin. Chronic therapy included warfarin, low-molecular-weight heparin, and aspirin. Peripheral vein thrombosis occurred in two patients while not on antiplatelet or anticoagulation therapy. Neurologic outcome was positive in this series without complications of therapy, suggesting that aggressive therapy should be considered. Although anticoagulation therapy of sinovenous thrombosis is controversial, particularly in the context of intestinal hemorrhage, it can be beneficial given the possibility of an ongoing hypercoagulable state.

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.