Factors associated with nonadherence to thiopurines in adolescent and adult patients with inflammatory bowel disease.

OBJECTIVES: We hypothesised that nonadherence to thiopurines is more common in adolescents than in adults with inflammatory bowel disease. METHODS: We sought factors associated with thiopurine nonadherence defined by thiopurine metabolite levels. RESULTS: Multivariate logistic regression confirmed that adolescents (odds ratio [OR] 4.6 [95% confidence interval [CI] 1.9-11.5]; P < 0.01) compared with adults, patients with Crohn disease (OR 3.3 [CI 1.1-10.5] P = 0.04) compared with ulcerative colitis, and patients living in more socially deprived areas (OR 1.03 [CI 1.0-1.1] P = 0.02) were more likely to be nonadherent to thiopurines. CONCLUSIONS: Adolescents are more frequently nonadherent than adults: prospective studies are required to determine the reasons for nonadherence in adolescents.

Do children with IBD really respond better than adults to thiopurines?

BACKGROUND AND OBJECTIVES: Children and adolescents with inflammatory bowel disease (IBD) have more extensive and severe disease than adults. Despite a lack of comparative studies, thiopurines are frequently cited as being more efficacious in children. To test this assertion, we compared the efficacy of thiopurines in children with IBD with that in adults matched for disease phenotype. PATIENTS AND METHODS: Fifty paediatric and adult patients with IBD started on a thiopurine were matched for sex, disease type, and extent. Retrospective data were obtained by electronic case note review, and corticosteroid-free clinical remission and tolerance rates at 6 months as well as relapse rates during the subsequent year were recorded. RESULTS: Adverse effects caused discontinuation of thiopurines in 1 of 50 children and 16% (8/50) of adults (P < 0.05). At 6 months, steroid-free remission was achieved in 30% (15/50) of children and 38% (19/50) of adults (P = 0.53). No differences in remission rates were seen according to disease type. At the end of the following year, 73% (11/15) of children and 68% (13/19) of adults remained in remission (P = 1). CONCLUSIONS: Thiopurines are tolerated better by children. When phenotype is matched, there is no difference in the therapeutic response to thiopurines between children and adults with IBD.

Systematic review of the evidence base for the medical treatment of paediatric inflammatory bowel disease.

OBJECTIVE: To systematically review the evidence base for the medical (pharmaceutical and nutritional) treatment of paediatric inflammatory bowel disease. METHODS: Key clinical questions were formulated regarding different treatment modalities used in the treatment of paediatric (not adult-onset) IBD, in particular the induction and maintenance of remission in Crohn disease and ulcerative colitis. Electronic searches were performed from January 1966 to December 2006, using the electronic search strategy of the Cochrane IBD group. Details of papers were entered on a dedicated database, reviewed in abstract form, and disseminated in full for appraisal. Clinical guidelines were appraised using the AGREE instrument and all other relevant papers were appraised using Scottish Intercollegiate Guidelines Network methodology, with evidence levels given to all papers. RESULTS: A total of 6285 papers were identified, of which 1255 involved children; these were entered on the database. After critical appraisal, only 103 publications met our criteria as evidence on medical treatment of paediatric IBD. We identified 3 clinical guidelines, 1 systematic review, and 16 randomised controlled trials; all were of variable quality, with none getting the highest methodological scores. CONCLUSIONS: This is the first comprehensive review of the evidence base for the treatment of paediatric IBD, highlighting the paucity of trials of high methodological quality. As a result, the development of clinical guidelines for managing children and young people with IBD must be consensus based, informed by the best-available evidence from the paediatric literature and high-quality data from the adult IBD literature, together with the clinical expertise and multidisciplinary experience of paediatric IBD experts.

Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease.

TGF-beta1 functions as a negative regulator of T cell immune responses, signaling to target cells using the Smad family of proteins. We show here that Smad7, an inhibitor of TGF-beta1 signaling, is overexpressed in inflammatory bowel disease (IBD) mucosa and purified mucosal T cells. Both whole tissue and isolated cells exhibit defective signaling through this pathway, as measured by phospho-Smad3 immunoreactivity. Specific antisense oligonucleotides for Smad7 reduce Smad7 protein expression in cells isolated from patients with IBD, permitting the cells to respond to exogenous TGF-beta1. TGF-beta1 cannot inhibit proinflammatory cytokine production in isolated lamina propria mononuclear cells from patients with Crohn disease (CD), but inhibition of Smad7 restores TGF-beta1 signaling and enables TGF-beta1 to inhibit cytokine production. In inflamed mucosal tissue explants from patients with CD, inhibition of Smad7 also restores p-Smad3 and decreases proinflammatory cytokine production, an effect that is partially blocked by anti-TGF-beta1. These results show that Smad7 blockade of TGF-beta1 signaling helps maintain the chronic production of proinflammatory cytokines that drives the inflammatory process in IBD and that inhibition of Smad7 enables endogenous TGF-beta to downregulate this response.

Cardiac dysfunction in paediatric HIV infection.

A child under long term surveillance for vertically acquired HIV-I infection developed respiratory symptoms. Dilated cardiomyopathy was diagnosed. Clinical and echocardiographic assessment of six other children with symptomatic HIV disease showed no evidence of cardiac dysfunction. The exact prevalence of this complication in paediatric HIV infection is unknown, but the potential diagnostic difficulties are highlighted.

Factors associated with thiopurine non-adherence in patients with inflammatory bowel disease.

BACKGROUND: Medication non-adherence seems to be a particular problem in younger patients with inflammatory bowel disease (IBD) and has a negative impact on disease outcome. AIMS: To assess whether non-adherence, defined using thiopurine metabolite levels, is more common in young adults attending a transition clinic than adults with IBD and whether psychological co-morbidity is a contributing factor. We also determined the usefulness of the Modified Morisky 8-item Adherence Scale (MMAS-8) to detect non-adherence. METHODS: Seventy young adults [51% (36) male] and 74 [62% (46) male] adults were included. Psychological co-morbidity was assessed using the Hospital Anxiety Depression Scale (HADS) and self-reported adherence using the MMAS-8. RESULTS: Twelve percent (18/144) of the patients were non-adherent. Multivariate analysis [OR, (95% CI), P value] confirmed that being young adult [6.1 (1.7-22.5), 0.001], of lower socio-economic status [1.1 (1.0-1.1), <0.01] and reporting higher HADS-D scores [1.2 (1.0-1.4), 0.01] were associated with non-adherence. Receiver operator curve analysis of MMAS-8 scores gave an area under the curve (95% CI) of 0.85 (0.77-0.92), (P < 0.0001): using a cut-off of <6, the MMAS-8 score has a sensitivity of 94% and a specificity of 64% to predict thiopurine non-adherence. Non-adherence was associated with escalation in therapy, hospital admission and surgeries in the subsequent 6 months of follow up. CONCLUSIONS: Non-adherence to thiopurines is more common in young adults with inflammatory bowel disease, and is associated with lower socio-economic status and depression. The high negative predictive value of MMAS-8 scores <6 suggests that it could be a useful screen for thiopurine non-adherence.

The phenotype and course of inflammatory bowel disease in UK patients of Bangladeshi descent.

BACKGROUND: We have tested the hypotheses that compared with local white Caucasians, UK-resident patients of Bangladeshi descent develop inflammatory bowel disease (IBD) at a younger age; more often have Crohn's disease than ulcerative colitis (UC); and have a more aggressive disease course. AIM: To test the hypotheses that compared to white Caucasian patients of English, Scottish or Welsh descent, patients of Bangladeshi descent develop IBD at a younger age; more often have Crohn's disease; and have a more aggressive disease course by screening case-records of these patients. METHODS: We screened the case-records of 132 Bangladeshi and 623 white Caucasian consecutive out-patients. We then matched each Bangladeshi to a patient of white Caucasian descent for age at diagnosis and disease duration. Data on migration status, phenotype, disease course, treatments and extra-intestinal manifestations and complications were obtained. RESULTS: No differences were seen in the adjusted age at diagnosis of IBD between Bangladeshi and white Caucasian patients. More Bangladeshis than white Caucasian patients (P < 0.01) were diagnosed with Crohn's disease than UC. Crohn's phenotype at diagnosis was similar in both groups. However, multivariate Cox logistic regression analyses showed that Bangladeshis developed perianal complications (HR [95% confidence interval CI] 8.6 [1.4, 53.1], P = 0.02), and received anti-TNFs (HR [95% CI] 3.0 [1.2, 7.7], P = 0.02) earlier and underwent surgery later (HR [95% CI] 0.4 [0.2, 0.9], P = 0.03) than white Caucasians. More Bangladeshis with UC had extensive disease (24/40 [60%]) than white Caucasians (16/49 [33%], P = 0.02). Overall, more Bangladeshis were anaemic and vitamin D deficient. CONCLUSIONS: Bangladeshi patients with IBD more frequently have Crohn's than UC. Bangladeshis with Crohn's more frequently develop perianal disease, have earlier medication escalation and undergo surgery later than white Caucasians. Bangladeshis have more extensive UC than white Caucasians. The relative contributions of genotype and environmental factors, including vitamin D, to these phenotypic differences require additional study.

Adolescents with IBD: the importance of structured transition care.

Children and adolescents with inflammatory bowel disease (IBD) tend to have more extensive and severe disease than adults. IBD presenting in childhood interferes with growth, education and employment as well as psychosocial and sexual development, frequently delaying adolescent developmental milestones. Transition, in the context of healthcare, is the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions to adult-orientated healthcare systems. Although no single model has been widely adopted and despite a paucity of data, recent guidelines from Europe and the USA propose the formation of specialist transition clinics for adolescent patients with IBD. In order to develop a successful transition service, the barriers that arise because of differences between paediatric and adult IBD services need to be identified. In this article, we review the concept of transitional care for adolescents with IBD, highlighting the important differences in not only, paediatric and adult IBD, but also paediatric and adult IBD services. We consider the consequences of failed transition, and describe the limited published data reporting different approaches to transition in IBD, before outlining our own approach.

Inflammatory bowel disease in young people: the case for transitional clinics.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) is increasing among adolescents. In all, 25% of patients are diagnosed before the age of 16, when they are traditionally transferred from the pediatric to the adult service. METHODS: We conducted a retrospective case-controlled study to characterize patients treated in a novel transitional adolescent-young adult IBD clinic. This compared disease extent, radiation exposure, therapeutic strategy, and requirement for surgery in 100 adolescents with controls from our adult IBD clinic matched for disease duration. RESULTS: The median (range) ages for the adolescent and adult population was 19 (16-28) and 43 (24-84), with a median age at diagnosis of 15 (3-26) and 39 (13-82) respectively (P < 0.001). Crohn's disease was significantly more common in the adolescents. Disease distribution was ileocolonic in 69% of adolescents and 28% of adults, restricted to the ileum in 20% of adolescents and 47% of adults, and colonic only in 11% and 22%, respectively. Upper gastrointestinal involvement occurred in 23% of adolescents, but was not seen in adults (P < 0.01). Total ulcerative colitis was seen in 67% of adolescents and 44% of adults (P < 0.01). Contrary to previous data adolescents did not receive more ionizing radiation than adults. Requirement for immunosuppressive therapy was higher in the adolescent group (53% versus 31%, respectively, P < 0.01). Likewise, 20% of adolescents had required biological therapy compared to only 8% in the adult cohort (P < 0.05). CONCLUSIONS: Gastroenterologists should recognize that IBD is more complex when presenting in adolescence and our data support the creation of specific adolescent transitional clinics.

Inflammatory bowel disease.

Twenty five per cent of inflammatory bowel disease presents in childhood. Growth and nutrition are key issues in the management with the aim of treatment being to induce and then maintain disease remission with minimal side effects. Only 25% of Crohn's disease presents with the classic triad of abdominal pain, weight loss, and diarrhoea. Most children with ulcerative colitis have blood in the stool at presentation. Inflammatory markers are usually although not invariably raised at presentation (particularly in Crohn's disease). Full investigation includes upper gastrointestinal endoscopy and ileocolonoscopy. Treatment requires multidisciplinary input as part of a clinical network led by a paediatrician with special expertise in the management of the condition.

High intraluminal fluid flow increases intestinal IgA output.

BACKGROUND: Stool IgA output in normal stool or chronic diarrhoea is a fraction of that recorded in high-output watery diarrhoea due to cholera. We hypothesized that high intestinal fluid flow leads to increased IgA output, and this is not a consequence of reduced degradation/reabsorption. METHODS: Daily intestinal outputs of IgA and other secretory and non-secretory proteins were measured in stool from 14 volunteers with ileostomies and compared with the output during whole-gut lavage, a whole-gut perfusion system. RESULTS: Output into whole-gut lavage was significantly higher for all the proteins (P=0.02 to 0.001). Median IgA output into ileostomy effluent (IE) was 3.6 mg/kg/day compared with 26 mg/kg/day into whole-gut lavage fluid (WGLF). Thus IgA recovery in stool was only 12.7% of the amount in corresponding WGLF. Similar results were found for other proteins: specific IgA and IgM antibodies (5.4%-20.3%), IgM (42.4%), IgG (8.9%), and albumin (9.3%). Six subjects with IE water content >92% had increased recovery of IgA compared with eight with <92% water. In vitro, experiments predict that degradation of IgA within the small bowel results in 80% remaining compared with the 12.7% measured in vivo. CONCLUSIONS: Our data show that high intraluminal fluid flow increases the intestinal output of IgA and other proteins, and this is not a consequence of reduced degradation/reabsorption in the colon or small bowel. This increased protein output may be a non-specific response in the early stages of acute diarrhoea.

Direct assessment of gastrointestinal inflammation and mucosal immunity in children with cystic fibrosis.

Fibrosing colonopathy is a recently described complication of cystic fibrosis, of unknown aetiology but possibly related to treatment with high-dose pancreatic enzyme supplements. We have used a whole gut perfusion technique to study subclinical gut inflammation in cystic fibrosis patients; concentrations of haemoglobin, IgG, albumin, alpha-1-antitrypsin, granulocyte elastase, IL1 beta, and IL8 were measured in whole gut lavage fluid: 23 tests were performed in 17 children with cystic fibrosis (20 elective tests, three lavages to treat distal intestinal obstruction syndrome (DIOS)). None has had fibrosing or haemorrhagic colitis. There were 12 tests in control children with constipation or precolonoscopy. Moderately abnormal results were obtained for many of the parameters studied, in specimens from all the cystic fibrosis children; however there were no significant differences between tests on high-dose and low-dose enzyme supplements of the same brand in the five children who had duplicate tests performed electively. The lavage fluid specimens from two cystic fibrosis children were strikingly abnormal in all tests apart from haemoglobin and alpha-1-antitrypsin. These were two of the three children with DIOS, and were also the only cases in the series taking Nutrizym 22. These data suggest that the majority of cystic fibrosis children, including those on high-dose enzyme supplements, do not have clinically significant colitis, but that there is subclinical mucosal inflammation in a minority (two of 17 in this series), for which DIOS and/or Nutrizym 22 treatment may be risk factors. Alternatively, inflammation and dysmotility in the proximal colon may be directly produced by a drug or other agent, producing a clinical syndrome indistinguishable from DIOS. Tests for indices of inflammation in gut lavage fluid offer a new approach to the detection and measurement of iatrogenic intestinal and colonic injury.

Gut inflammation in children with cystic fibrosis on high-dose enzyme supplements.

We used a whole-gut perfusion technique to study subclinical gut inflammation in children with cystic fibrosis (18 elective tests, three lavages to treat distal intestinal obstruction syndrome); and in 12 control children with constipation or pre-colonoscopy. We assayed for haemoglobin, IgG, albumin, alpha-1-antitrypsin, granulocyte elastase, interleukin-1 beta (IL-1 beta) and IL-8 concentrations in whole-gut lavage fluid. Results for two children with distal intestinal obstruction syndrome, the only children in the series taking Nutrizym 22, were strikingly abnormal. This new test has revealed subclinical gut mucosal inflammation in a minority of CF children, for which distal intestinal obstruction syndrome, Nutrizym 22 treatment, or both, may be risk factors.

Technical report: results of immunological tests on faecal extracts are likely to be extremely misleading.

Clinical investigation of gut immunity is difficult because of the need to study intestinal tissues or secretions directly. Others have reported that immunoglobulins, antibodies and cytokines can be detected in saline extracts of faeces. We have assessed the validity of this approach by measuring immunoglobulins, albumin, alpha 1-antitrypsin and isotype-specific antibodies in matched samples of faeces and whole gut lavage fluid. Results were compared as estimated output per day, and by using haemoglobin as a common reference substance. Samples were obtained from 10 patients with active inflammatory bowel disease and 10 with other benign GI diseases. For immunoglobulins, albumin and antibodies, the amount detected in faeces varied from < 0.01% to 35.5% (based on estimated daily output) and < 0.01% to 18.5% (based on haemoglobin) of the amount known to be produced in the gut from results of assays on whole gut lavage fluid (WGLF); there were significantly higher rates of recovery in faecal specimens from patients with active gut inflammation than from other patients. Detection rates and titres of specific antibody in faeces were even lower than those for immunoreactive IgA. These data indicate that immunological tests on saline extracts of faeces do not represent the true status of the gut humoral immune system, and such studies should be strongly discouraged.

Intestinal inflammation in cystic fibrosis.

BACKGROUND: There is controversy about whether the inflammatory response observed in the cystic fibrosis (CF) lung occurs secondary to bacterial infection or is caused by a dysregulation of the inflammatory response associated with the basic cellular defect of CF. AIMS: To study the inflammatory response in the gastrointestinal tract of children with CF; and to investigate whether there is increased inflammation in the gastrointestinal tract of CF children with fibrosing colonopathy. METHODS: Whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF and fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, alpha(1) antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin 1beta) were measured. RESULTS: Compared to controls, the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1beta, and interleukin 8. Similar values were obtained for the CF patients with fibrosing colonopathy. CONCLUSIONS: These data suggest that there is immune activation in the gastrointestinal mucosa of children with cystic fibrosis, which may result from the basic cellular defect. Fibrosing colonopathy does not appear to be associated with increased inflammation.

Ewing's sarcoma in a child with human immunodeficiency virus (type 1) infection.

A male child with vertically transmitted human immunodeficiency virus type 1 (HIV) infection developed a Ewing's sarcoma of the left fibula at 6.1 years of age. We report the antitumour chemotherapy given and the response of the tumour. Six months after tumour diagnosis the child died of probable HIV encephalopathy. This is the first reported case of Ewing's sarcoma in an HIV-infected child.