Real-life Anti-tumor Necrosis Factor Experience in More Than 500 Patients: High Co-immunosuppression Rates But Low Rates of Quantifying Treatment Response.

OBJECTIVE: The aim of this study was to measure the effectiveness, safety, and use of anti-tumor necrosis Factor (TNF) therapy in pediatric inflammatory bowel disease in the United Kingdom (UK). METHODS: Prospective UK audit of patients newly starting anti-TNF therapy. Disease severity was assessed using Physician Global Assessment +/or the Paediatric Crohn Disease Activity Index. RESULTS: A total of 37 centers participated (23/25 specialist pediatric inflammatory bowel disease sites). A total of 524 patients were included: 429 with Crohn disease (CD), 76 with ulcerative colitis (UC), and 19 with IBD unclassified (IBDU). Eighty-seven percent (488/562) of anti-TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co-immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (interquartile range 0.63-2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by Physician Global Assessment compared to 41% (88/217) by Paediatric Crohn Disease Activity Index (Kappa (κ) 0.28 = only "fair agreement"; P < 0.001.Where documented, 77% (53/69) of patients with CD responded to induction; and 65% (46/71) entered remission. A total of 2287 infusions and 301.96 years of patient' follow-up (n = 385) are represented; adverse events affected 3% (49/1587) infliximab and 2% (2/98) adalimumab infusions (no deaths or malignancies). Peri-anal abscess drainage was less common after anti-TNF initiation (CD), that is 26% (27/102) before, 7% (3/42) after (P = 0.01); however, pre and post anti-TNF data collection was not over equal time periods. CONCLUSIONS: Anti-TNFs are effective treatments, usually given with thiopurine co-immunosuppression. This study highlights deficiencies in formal documentation of effect and disparity between disease severity scoring tools, which need to be addressed to improve ongoing patient care.

Contemporary outcomes for ulcerative colitis inpatients admitted to pediatric hospitals in the United Kingdom.

BACKGROUND: Pediatric ulcerative colitis (UC) care is variable with a lack of appropriate guidelines to guide practice until recently. METHODS: UC inpatients <17 years old admitted to 23 U.K. pediatric hospitals had clinical details collected between September 2010 and 2011. Comparative data for 248 patients were available from a previous audit in 2008. RESULTS: One hundred and seventy-six patients (98 males) of median age 13 years (interquartile range, 10-13) were analyzed; 23 were elective surgical admissions, 47 new diagnoses, and 106 needed acute medical care for established UC. Median length of stay was 6 days (interquartile range, 3-10) with no deaths. Eighty-eight of 126 patients (70%) with active disease had standard stool cultures performed (3 [2%] were positive), and 57 (45%) had Clostridium difficile toxin tested (none positive). Twenty-five of 66 (38%) emergency admissions had an abdominal x-ray on admission, and 13 of 66 patients (20%) had a Pediatric Ulcerative Colitis Activity Index score. There were 3 cases of toxic megacolon and 2 thromboses. Eighty-one of 116 patients (71%) responded to steroids. Nineteen patients who did not respond adequately to steroids received rescue therapy (7 infliximab, 11 ciclosporin, and 1 both) with overall response rate of 90%; 7 patients needed surgery acutely, 5 without previous rescue therapy. Compared with the 2008 data, stool culture rates improved significantly (86 of 121 [71%] versus 76 of 147 [52%], P = 0.001) as did heparinization rates (15 of 150 [10%] versus 5 of 215 [2%], P = 0.002) and rescue therapy usage (17 of 33 [52%] versus 10 of 38 [26%], P = 0.03). CONCLUSIONS: There were signs of improving UC care with significantly increased rates of stool culture and rescue therapy. The majority of sites, however, did not use Pediatric Ulcerative Colitis Activity Index scores.

Prevalence and management of anemia in children, adolescents, and adults with inflammatory bowel disease.

BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) are more likely to have Crohn's disease (CD) than ulcerative colitis (UC) and their disease tends to be more extensive and severe than in adults. We hypothesized that the prevalence of anemia would therefore be greater in children and adolescents than in adults attending IBD outpatient clinics. METHODS: Using the WHO age-adjusted definitions of anemia we assessed the prevalence, severity, type, and response to treatment of anemia in patients attending pediatric, adolescent, and adult IBD clinics at our hospital. RESULTS: The prevalence of anemia was 70% (41/59) in children, 42% (24/54) in adolescents, and 40% (49/124) in adults (P < 0.01). Overall, children (88% [36/41]) and adolescents (83% [20/24]) were more often iron-deficient than adults (55% [27/49]) (P < 0.01). Multivariate logistic regression showed that both active disease (odds ratio [OR], 4.7 95% confidence interval [CI], 2.5, 8.8) and attending the pediatric clinic (OR 3.7; 95% CI, 1.6, 8.4) but not the adolescent clinic predicted iron deficiency anemia. Fewer iron-deficient children (13% [5/36]) than adolescents (30% [6/20]) or adults (48% [13/27]) had been given oral iron (P < 0.05); none had received intravenous iron compared with 30% (6/20) adolescents and 41% (11/27) adults (P < 0.0001). CONCLUSIONS: Anemia is even more common in children than in older IBD patients. Oral iron was given to half of adolescents and adults but, despite similar tolerance and efficacy, only a quarter of children with iron-deficient anemia. Reasons for the apparent underutilization of iron therapy include a perceived lack of benefit and concerns about side effects, including worsening of IBD activity.

Natural history of paediatric inflammatory bowel diseases over a 5-year follow-up: a retrospective review of data from the register of paediatric inflammatory bowel diseases.

OBJECTIVES: The natural history of paediatric inflammatory bowel diseases (IBDs) is poorly understood. We aim to describe the disease course in this cohort and generate prognostic information for patients and clinicians. MATERIALS AND METHODS: Patient records from 6 tertiary paediatric gastroenterology centres were reviewed to generate data concerning original diagnosis, change in diagnosis, family history, surgical interventions, growth, and presence of extragastrointestinal manifestations. RESULTS: Data were collected on 116 children with Crohn disease (CD), 74 with ulcerative colitis (UC), and 20 with indeterminate colitis (IC), followed for a mean period of 3.42, 3.3, and 2.9 years from date of diagnosis, respectively. A male predominance is demonstrated in CD. Revision of diagnosis in patients with IC is mainly to UC, with most children receiving a definitive diagnosis within 2 years of initial presentation. Of the children with UC, 17.6% underwent 1 or more major operations with a median time to surgery of 1.92 years. Of children with CD, 11.6% underwent 1 or more major intraabdominal procedures with a median time to surgery of 1.83 years. We recorded a positive family history in 2.7%, 8.2%, and 10% of cases for CD, UC, and IC, respectively. For both boys and girls with CD, but only for boys with UC, height standard deviation score became more negative over time. CONCLUSIONS: This retrospective study quantifies certain distinctions between IBDs diagnosed in paediatric and adult populations. We document a trend toward male predominance in children with CD. We also note impaired linear growth in children with CD, whereas it appears maintained in girls with UC. We also have recorded a low incidence of IBDs in the families of this cohort and suggest that environmental influences may be of greater importance. We document that major intraabdominal surgery may be required in about 15% of patients with either UC or CD within 2 years of diagnosis, and that the majority of those diagnosed initially with IC will be reclassified as either UC or CD within 2 years.

Genetically modified enterotoxigenic Escherichia coli vaccines induce mucosal immune responses without inflammation.

OBJECTIVE: Enterotoxigenic Escherichia coli (ETEC) is a major cause of acute diarrhoea in children in the developing world, in travellers and in the military. Safe, effective vaccines could reduce morbidity and mortality. As immunity to ETEC is strain specific, the ability to create vaccines in vitro which express multiple antigens would be desirable. It was hypothesised that three genetically attenuated ETEC strains, one with a genetic addition, would be immunogenic and safe, and they were evaluated in the first licensed UK release of genetically modified oral vaccines. METHODS: Phase 1 studies of safety and immunogenicity were carried out at a Teaching Hospital in London. Varying oral doses of any of three oral vaccines, or placebo, were administered to volunteers of both sexes (n = 98). Peripheral blood responses were measured as serum antibodies (IgG or IgA) by ELISA, antibody-secreting cell (ASC) responses by enzyme-linked immunospot (ELISPOT), and antibody in lymphocyte supernatant (ALS) by ELISA. Mucosal antibody secretion was measured by ELISA for specific IgG and IgA in whole gut lavage fluids (WGLFs). RESULTS: Significant mucosal IgA responses were obtained to colonisation factors CFA/I, CS1, CS2 and CS3, both when naturally expressed and when genetically inserted. Dose-response relationships were most clearly evident in the mucosal IgA in WGLF. Vaccines were well tolerated and did not elicit interleukin (IL) 8 or IL6 secretion in WGLF. CONCLUSIONS: Genetically modified ETEC vaccines are safe and induce significant mucosal IgA responses to important colonisation factors. Mucosal IgA responses were clearly seen in WGLF, which is useful for evaluating oral vaccines.

Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the -174 IL-6 G/C polymorphism in children.

Inflammatory diseases frequently impair linear growth. Crohn's disease inhibits growth in up to one third of affected children. In rats with trinitrobenzenesulphonic acid-induced colitis, 40% of growth impairment is attributable to inflammation, with the rest being due to undernutrition. In transgenic mice without inflammation, raised IL-6 retards growth, suppressing insulin-like growth factor (IGF)-I. We hypothesized that IL-6, induced by intestinal inflammation, suppresses growth and inhibits IGF-I expression. Therefore, an anti-IL-6 Ab was given to rats with trinitrobenzene-sulphonic acid colitis. The Ab did not improve nutrient intake or decrease inflammation compared with untreated disease controls, but it significantly restored linear growth (P = 0.023) and increased IGF-I (P = 0.05). In humans, the IL-6 -174 G/C promoter polymorphism affects IL-6 transcription, with the GG genotype inducing the greatest IL-6 levels. Because IL-6 is increased in Crohn's disease, we further hypothesized that growth failure would vary with the IL-6 -174 genotype. At diagnosis, among 153 children with Crohn's disease, those with the IL-6 GG genotype were more growth-retarded than those with the GC or CC genotypes (height SD score, -0.51 vs. -0.10; P = 0.031). Also, the patients with the IL-6 GG genotype had higher circulating levels of C-reactive protein, an IL-6-induced product (36 vs. 18 mg/dl, P = 0.028). However, their risk of developing Crohn's disease was similar to other genotypes when compared with 351 healthy controls (P = 0.7). Thus, the IL-6 -174 genotype mediates growth failure in children with Crohn's disease.

IgM: mucosal response in acute diarrhoeal disease of infants.

OBJECTIVE: Investigating the secretory immune response during the acute phase of diarrhoeal disease is hampered by difficulty in collecting suitable control specimens. This is particularly the case in infants, as they are the most severely affected by this disease. In this study we examined the mucosal immunoglobulin response during the acute phase of diarrhoeal disease in infants. MATERIAL AND METHODS: The intestinal outputs of secretory immunoglobulins (IgA, IgM) and non-secretory proteins (IgG, albumin, A1AT, eosinophil cationic protein (ECP)) were measured in 14 African children with acute watery diarrhoea (less than 3 days). These data were compared with those of 38 controls from the same area who had undergone whole-gut lavage (WGL) (inducing non-pathogenic watery diarrhoea) in a previous study of intestinal immunity and inflammation. Intestinal secretion rates were measured by multiplying the concentration of the substances by the rate of administration of WGL fluid (equal to the output) or by the output of diarrhoea. Statistical comparison was made using the Mann-Whitney U-test. RESULTS: IgA output in subjects with diarrhoea was 1.8-fold greater (80.7 versus 45.6 mg/kg/day, p=0.03), whereas IgM output was 10-fold greater (21 versus 2.1 mg/kg/day, p=0.0001). Albumin, A1AT and IgG were all also greater to varying degrees (2.5-6.8-fold). ECP was unchanged. Increases in the non-secretory proteins would suggest increased permeability of the gastrointestinal tract but transudation of serum was insufficient to explain the rise in immunoglobulin output. CONCLUSIONS: The 10-fold increase in IgM secretion compared with a smaller relative increase in IgA suggests that this is the primary mucosal immune response in acute diarrhoeal disease.