Infliximab use in children and adolescents with inflammatory bowel disease

Infliximab is a chimeric monoclonal antibody (75% human, 25% murine) against tumor necrosis factor-alpha, a cytokine with a central role in the pathogenesis of inflammatory bowel disease. Large randomized controlled trials have shown the efficacy and safety of infliximab for the induction and maintenance of remission in adult patients with active Crohn disease (CD). In children and adolescents, mostly small, nonrandomized, non-placebo-controlled studies have supported the notion that infliximab is a potent drug in a population that does not respond to standard therapies. The safety of infliximab is of major concern, and the most frequent severe adverse events are related to severe infections and reactivation of tuberculosis. Non-life-threatening infusion reactions occur rather frequently and seem to be related to the formation of antibodies. The indications for infliximab treatment are therapy-resistant luminal CD (no efficacy or insufficient efficacy of conventional treatment) and therapy-resistant fistulas. An efficient remission induction strategy consists of 3 initial infliximab infusions at 0, 2, and 6 weeks in a dosage of 5 mg/kg to sustain remission. Patients needing maintenance therapy are subsequently treated with an infliximab infusion every 8 weeks. There are indications that the early stages of CD may be more susceptible to immunomodulation, and the natural history of CD may be altered by the introduction of infliximab early in the disease process instead of waiting until conventional therapy has failed. Major points of discussion are whether infliximab maintenance treatment should be episodic (on demand) or scheduled and when infliximab therapy can be discontinued.     

Erythropoietin levels in children and adolescents with inflammatory bowel disease

Iron deficiency anemia (IDA) and anemia of chronic disease (CDA) are often encountered in patients with inflammatory bowel disease (IBD). Inadequate intake or loss of iron is a clear cause of IDA, but mechanisms of CDA induction are multifactorial and involve erythropoiesis disturbance due to circulating inflammation mediators. The authors investigated erythropoietin (Epo) levels in children and adolescents with IBD and correlated them to disease activity, with the aim of gaining an improved understanding of the role of Epo in CDA. Thirty-three patients with IBD were examined (18 boys, 15 girls) ages 4 to 15 years (median 11 years). Two study groups related to the disease activity were formed: group A, those with active disease (n = 21), and group B, those in remission (n = 12). Epo levels were measured using a two-site chemiluminescence immunoassay. Predictive Epo values in response to the degree of anemia were calculated by the equation: logEpo = (3.48 - 0.20) x Hb. According to the results, CDA anemia was present only in patients with active disease. These patients also had a significantly higher possibility of altered Epo levels than expected compared with patients with inactive disease (16/21 vs. 4/12, P < 0.05). It was also interesting that most of the patients with anomalous Epo concentrations presented with an elevated Epo value compared with that expected from the calculation (14/20). It seems that disturbed Epo concentrations are correlated with disease activity in children and adolescents with IBD. It is possible that failure of the bone marrow to respond to increased Epo levels leads to further incremental response. These in turn lead to the high Epo concentrations detected in most of the authors' patients. Impaired Epo production is another mechanism of CDA development and is the one mainly expressed in patients with low Epo values.     

Chronic inflammatory bowel disease in children in western Norway

The incidence of Crohn's disease (CD) and ulcerative colitis (UC) in children in western Norway was estimated in a prospective epidemiological study during the years 1984 and 1985. The total population in the area was 807,000 and the child population was 198,570 (1984). There were 27 new cases of chronic inflammatory bowel disease (IBD) in children aged 15 years or less, 10 new cases of CD, and 17 of UC. The mean annual incidence of CD in the child population was 2.5/100,000/year, whereas the incidence of UC in the child population was 4.3/100,000/year. Nearly all the children had abdominal symptoms. In this study, we found an incidence of CD in children that is the highest hitherto reported, to our knowledge. To the contrary, the incidence of UC was considerably lower than previously reported from northern Europe.     

Incidence and prevalence of inflammatory bowel disease in children in South-Western Sweden

Hildebrand H, Brydolf M, Holmquist L, Krantz I, Kristiansson B. Incidence and prevalence of inflammatory bowel disease in children in South-Western Sweden Acta PEdiatr 1994;83:640–5. Stockholm. ISSN 0803–5253
The incidence and prevalence of inflammatory bowel disease were estimated in all children less than 16 years of age living in the city of Göteborg and in three counties in South-Western Sweden, from 1983 to 1987. One hundred and thirty-two patients were classified according to set criteria into one of four diagnostic categories: ulcerative colitis, Crohn's disease, probable Crohn's disease and indeterminate colitis. The crude incidence of inflammatory bowel disease was 5.3 per 100 000 children per year and the prevalence 21.5 per 100000 children. This study lends support to the hypothesis that Crohn's disease has increased among Swedish children. Crohn's disease now appears to be at least as common as ulcerative colitis. Thirty-five of 55 patients first classified as indeterminate colitis or probable Crohn's disease later fulfilled the criteria of ulcerative colitis or Crohn's disease during a mean follow-up period of 4.6 years. This study emphasizes the importance, in epidemiological studies of inflammatory bowel disease, of inciuding those cases where a definite diagnosis of ulcerative colitis or Crohn's disease cannot be established initially and of re-evaluating the initial diagnosis regularly.     

Recognition and management of inflammatory bowel disease in children and adolescents

Until such time as an etiology and specific therapy can be established, it is critical for the pediatrician to recognize the early clinical manifestations of IBD and to initiate appropriate therapy. Most affected children require consultative care with a gastroenterologist comfortable with the unique requirements of the child with IBD. It is our hope that early diagnosis and treatment will not only reduce the frequency and severity of complications, but also allow minimal interference in the child's quality of life.     

Serum transferrin receptor in children and adolescents with inflammatory bowel disease

Iron studies are difficult to interpret in patients with chronic inflammatory states such as inflammatory bowel disease (IBD). Serum transferrin receptor (TfR) has been reported to be a reliable tool for the diagnosis of iron deficiency in adults. Our aim was to evaluate the role of serum TfR in diagnosing iron deficiency in children and adolescents with IBD. A total of 63 consecutive patients with IBD, aged 9 to 22 years (median 15 years), were tested for serum haemoglobin level, mean corpuscular volume (MCV), and serum iron, transferrin, ferritin and serum TfR levels. Those found to be anaemic were compared with seven age-matched subjects with iron deficiency anaemia (IDA) and 24 age-matched children without signs of anaemia or inflammation. Of the 63 patients with IBD, 26 had anaemia. Based on ferritin levels and MCV indices, anaemia was classified as IDA in 11 patients and as anaemia of chronic disease (ACD) in 15 patients. Mean serum TfR level in normal controls was 3.5 mg/l (range 1.2–8.2 mg/l). Mean (±SD) serum TfR levels were significantly lower in the IBD patients with ACD (5.3 ± 2.3 mg/l) than in the IBD patients with IDA (8.2 ± 3.1 mg/l) (P < 0.05). Serum TfR levels above 5 mg/l identified 10/11 IBD patients with IDA. The calculated TfR/ferritin ratio was 84 (range 17–367) for controls and 133 (range 6.4–1840) for IBD patients. A cut-off level of 350 (91% sensitivity, 100% specificity, 100% positive predictive value, 98% negative predictive value) was established for the diagnosis of IDA in IBD. Conclusion The results suggest that serum transferrin receptor is a useful parameter for the diagnosis of iron deficiency in inflammatory bowel disease, in particular, the transferrin receptor/ferritin ratio with a cut-off level ≥350. Received: 1 June 1999 / Accepted: 16 February 2000     

Skeletal health of children and adolescents with inflammatory bowel disease

Current evidence points to suboptimal bone health in children and adolescents with inflammatory bowel disease (IBD) when compared with their healthy peers. This compromise is evident from diagnosis. The clinical consequences and long-term outcome of this finding are still unknown. The mechanism of suboptimal bone health in children and adolescents with IBD lays mainly in reduced bone formation, but also reduced bone resorption, processes necessary for bone growth. Factors contributing to this derangement are inflammation, delayed growth and puberty, lean mass deficits, and use of glucocorticoids. We recognize that evidence is sparse on the topic of bone health in children and adolescents with IBD. In this clinical guideline, based on current evidence, we provide recommendations on screening and monitoring bone health in children and adolescents with IBD, including modalities to achieve this and their limitations; monitoring of parameters of growth, pubertal development, and reasons for concern; evaluation of vitamin D status and vitamin D and calcium intake; exercise; and nutritional support. We also report on the current evidence of the effect of biologics on bone health in children and adolescents with IBD, as well as the role of bone active medications such as bisphosphonates. Finally, we summarize the existing numerous gaps in knowledge and potential subjects for future research endeavors.     

Inflammatory bowel disease in children and adolescents in Sweden, 1984-1995

BACKGROUND: A prospective study of inflammatory bowel disease (IBD) in Sweden was performed to investigate whether the incidence and morbidity have changed from 1984 through 1995. METHODS: Children 15 years of age or less with IBD were included--i.e., those with a definite diagnosis of ulcerative colitis (UC) and Crohn's disease (CD) and those classified as having indeterminate colitis (IC) and probable Crohn's disease (PCD). The study covered 56.5% of the pediatric population of Sweden. RESULTS: The diagnosis of IBD was made in 639 children, which corresponds to a mean annual incidence of 5.8 per 100,000. The incidence increased from 4.6 per 100,000 per year from 1984 through 1986 to 7.0 from 1993 through 1995. It reflected an increase in UC from 1.4 to 3.2 per 100,000 per year, which is a significant yearly percentage of increase (8%; confidence interval, 2-14%; P < 0.05). In contrast, no change occurred in the incidence of CD (1.2-1.3 per 100,000). The incidence of IC and PCD also remained fairly stable. The percentages of children who underwent surgery decreased from 17.3% in the first 6 years to 4.6% in the last 6 years (P < 0.001). Surgery was performed in 27.7% of CD and 5.3% of UC cases. The median age at diagnosis was 12.2 years for UC, 13.0 years for CD, 11.2 for IC, and 11.2 for PCD. At diagnosis, 48 children (7.5%) were 5 years of age or less, whereas most of the patients were 11 years of age or more (398 children, 62.3%). CONCLUSIONS: In Sweden, the incidence of UC has increased, whereas that of CD remains the same. A significant number of children were classified with IC and PCD. In most children, IBD was diagnosed when they were 11 years old or more, but some cases were detected even in those below 6 years of age. A decrease in the frequency of surgery occurred during the study.     

Bone metabolism in 53 children and adolescents with chronic inflammatory bowel disease

BACKGROUND: Osteopathy is a common clinical feature of chronic inflammatory bowel disease (IBD) in children and young adults at the time of primary diagnosis. The aim of the following study was to address the question of prevalance of a decreased bone density or increased bone metabolism in children with IBD. PATIENTS:We examined 63 patients (mean age 13 years; 5 - 18 years): 36 Crohn's disease (MC) patients, 16 colitis ulcerosa (CU) patient and one patient with colitis indeterminata (CID). 10 children who had been referred to the gastroenterological outpatient department due to suspected IBD symptoms were later found not to suffer from IBD. These 10 patients therefore were included in the study as controls. RESULTS: 8 of 10 CU patients and 18 of 28 MC patients showed a pathological bone density and abnormalities in bone metabolism. Repetitive bone density measurement was performed in 18 patients. In MC patients a - 0.39 SDS decrease of bone mineral density was found, without a simultaneous deterioration of clinical stage and inspite of a decreased cumulative prednisolon dosage. However in CU patients a + 0.06 SDS increase of bone mineral density was detected. These patients had a lower cumulative prednisolon dosage and a stable clinical course. CONCLUSIONS: In conclusion, pediatric IBD patients often show abnormalities in bone metabolism and decreased bone density. There is a need for multicentre, prospective randomised control trials to further identify therapeutic tools on the basis of the multifactorial etiology of bone disease in pediatric IBD patients.     

Antigranulocyte monoclonal antibody immunoscintigraphy in inflammatory bowel disease in children and young adolescents

Aim: Diagnostic delay for inflammatory bowel disease (IBD) is frequent, especially in paediatric patients. Scintigraphy with labelled leucocytes has been proposed as a very sensitive diagnostic tool for detecting bowel inflammation. The aim of this study was to evaluate the sensitivity and specificity of immunoscintigraphy in the diagnosis and follow-up of children with IBD and to compare this technique with other diagnostic techniques.

Methods: Sixty-six children with histologically confirmed IBD were enrolled in the study. Twenty-one children in whom IBD was suspected but subsequently not confirmed were used as controls. A total of 138 immunoscintigraphies were performed using 99m Technetium-labelled monoclonal anti-granulocyte antibodies. Immunoscintigraphy was also compared with other diagnostic techniques.

Results: Overall sensitivity of monoclonal antibody immunoscintigraphy (MoAb-IS) in patients with clinically active disease was 94% for Crohn's disease (CD) and 85% for ulcerative Ultrasonography, endoscopy and radiology were carried out at the same time in 29 patients with CD and in 6 patients with UC: sensitivity of IS was 90% compared with 76% of colonoscopy, 75% for enemas, and 55% for sonography. IS was negative (specificity) in 24% of patients with CD and in 67% of patients with UC during remission, and in 64% of controls with other causes of intestinal inflammation. Diagnostic delay was significantly shorter when compared with a historical cohort of patients.

Conclusion: Immunoscintigraphy is a highly sensitive detector of intestinal inflammation in young patients with IBD and can be useful for reducing diagnostic delay. However, its specificity is low and all positive cases must be confirmed histologically. colitis (UC).     

Use of complementary and alternative medicines by children and adolescents with inflammatory bowel disease

OBJECTIVES: The use of complementary and alternative medicines (CAM) appears increasingly prevalent in children and adolescents. Individuals with chronic illness may have patterns of greater usage. This questionnaire-based study aimed to ascertain the frequency of use by a group of children with proven inflammatory bowel disease (IBD) and to consider the reasons for their use. METHODS: A questionnaire was sent by mail to the parents of patients currently attending a paediatric IBD clinic. Parents were asked to describe their child's usage of alternative and probiotic therapies and to comment on a number of aspects of such therapies. RESULTS: Forty-six (77%) of 60 mailed questionnaires were returned. The mean age of the children was 10.9 (+/- 4.1) years and they were taking an average of 1.7 (+/- 0.8) prescribed medications. Thirty-three (72%) of the children were said by their parents to be having CAM, with four having five or more such therapies (average 2.4 +/- 1.3 agents per child). The most commonly used agents were probiotics (78%) and fish oils (56%). A minority (12%) of respondents reported that their child's CAM was very effective, although many (50%) noted partial benefits. The 13 children who had never used any CAM therapies ('non-users') did not differ from the 'users' in terms of gender, age, disease or duration of disease. As expected, non-users expressed greater concerns about use of CAM and described different attitudes towards such therapies. CONCLUSION: Complementary and alternative medicines, especially probiotic therapies, frequently are administered to children and adolescents with inflammatory bowel disease. Often this appears to be due to parental frustration with managing their child's chronic illness. Practitioners caring for children and adolescents with IBD need to be aware that their patients may be using alternative therapies and adopt an open attitude in this situation.     

Coagulation and fibrinolysis in children, adolescents, and young adults with inflammatory bowel disease

BACKGROUND: Patients with Crohn's disease and ulcerative colitis have an increased risk of thromboembolic events. METHODS: Data were collected from 24 patients aged 4.5 to 23 years who had inflammatory bowel disease. Platelet count, antithrombin, fibrinogen, prothrombin fragment F1+2, soluble thrombomodulin, tissue plasminogen activator, D-dimer, and plasminogen activator inhibitor-1 antigen were investigated. In addition the response to activated protein C, the factor V R506Q mutation, protein C, free protein S antigen, and lipoprotein (a) were analyzed. These data were compared with medical treatment, duration, and disease activity, estimated with the Pediatric Crohn's Disease Activity Index or the Clinical Colitis Activity Index. RESULTS: Forty-five percent of our patients showed an increase in fibrinogen, 29% in prothrombin fragment F1+2, and 20% in platelet count, plasminogen activator inhibitor- antigen, and soluble thrombomodulin. Thrombomodulin was higher in active disease than in inactive disease and in Crohn's disease than in ulcerative colitis. Fibrinogen was also higher with Crohn's disease and tended to be higher in active disease than in ulcerative colitis and inactive disease. Plasminogen activator inhibitor-1 antigen was significantly higher in patients with Crohn's disease than in those with ulcerative colitis and was higher in the patient group treated with steroids. CONCLUSION: As has been shown in adults, young patients with active and inactive inflammatory bowel disease were found to have abnormal coagulation and fibrinolysis. The relevance as a thromboembolic risk factor is discussed.     

Amyloidosis in children with inflammatory bowel disease

Reactive systemic or secondary amyloidosis occurs in 1-29% of adults with Crohn's disease, but only sporadic cases of amyloidosis have been recognized in children with inflammatory bowel disease. We therefore have studied operative specimens (ileal, ileocolonic, and colonic) from 46 children (30 with Crohn's disease and 16 with ulcerative colitis) to determine the frequency of amyloid deposits. Sections of bowel, skin, and lymph nodes (n = 940) were stained by Congo red and examined by light microscopy and by polarized light. Amyloid deposits were found in only one of 46 subjects, an 18-year-old girl who had had Crohn's disease for 6 years. Intestinal amyloid deposits, present 16 months before the clinical diagnosis of amyloidosis, were patchy and seen predominantly in the intestinal mucosa. We conclude that amyloidosis is rare in children requiring surgery for Crohn's disease and ulcerative colitis. Examination of Congo red-stained sections can detect even subclinical amyloidosis. The amyloid deposits in our patient, which were both patchy and consistently mucosal, suggest that multiple endoscopic biopsy samples, not necessarily containing submucosa, are sufficient for diagnosis.     

Hyperhomocystinemia in children with inflammatory bowel disease

OBJECTIVES: Thromboembolism is a significant cause of morbidity and mortality in patients with inflammatory bowel disease (IBD). Plasma total homocysteine (tHcy) is a risk factor for vascular disease and has been implicated as a mediator of thromboembolic events in adults with IBD. The authors studied the link between tHcy and IBD in children, in whom associations may be clearer, and investigated associations with plasma von Willebrand factor antigen, a marker of vascular damage. METHODS: This cross-sectional study included 43 patients with IBD (27 Crohn disease, 9 ulcerative colitis, and 7 indeterminate colitis) and 46 control subjects from a pediatric gastroenterology clinic. Plasma tHcy, plasma 5-methyl tetrahydrofolate, red cell folate, plasma vitamin B12, plasma von Willebrand factor antigen, and methylene tetrahydrofolate reductase (MTHFR) genotype (for the C677T mutation) were measured. RESULTS: Plasma tHcy concentrations were higher in children with IBD than in control subjects, when corrected for age (P < 0.05), and plasma tHcy was negatively correlated with plasma 5 methyl tetrahydrofolate (P < 0.0005). Plasma 5 methyl tetrahydrofolate and age were the main predictors of plasma tHcy. Neither MTHFR genotype nor von Willebrand factor showed any association with any other measure, and there were no differences between children with IBD and control subjects. CONCLUSIONS: Elevated plasma tHcy is a consequence of IBD in children, probably mediated by poor folate status associated with diet or the pathophysiology of the disease.     

Carditis complicating inflammatory bowel disease in children

A 10-year-old child with ulcerative colitis is described who during the quiescent phase of his disease suffered from pericarditis with pleuropericardial effusion. The literature on cardiac involvement in inflammatory bowel disease is reviewed with emphasis on the paediatric age group.