Infliximab therapy in 30 patients with refractory pediatric crohn disease with and without fistulas in The Netherlands.
ABSTRACT The purpose of this study was to describe the clinical experience with the anti-tumor necrosis factor chimeric monoclonal antibody, infliximab, in pediatric patients with Crohn disease in The Netherlands.
Clinical response and adverse effects of infliximab were recorded for pediatric patients with Crohn disease treated from October 1992 to January 2003.
Thirty patients (aged 7-18 years) with refractory Crohn disease (with or without severe fistulas) were treated with infliximab. Patients were treated with up to 30 infusions. Mean follow-up was 25.3 months. A total of 212 infusions were administered. Thirteen patients had refractory Crohn disease without fistulas. Six patients showed good long-term response to infliximab treatment (defined as clinical index < or =10 points). Sixteen patients had refractory Crohn disease with draining fistulas. Nine showed good long-term response (closure or nonproductiveness of fistulas). One patient with metastatic Crohn disease in the skin had a good long-term response. Six patients developed an allergic reaction during infusion. In one patient, the allergic reaction occurred after an infliximab-free interval of 9 years. One patient died of sepsis.
Infliximab was an effective therapy in 53% of patients with refractory pediatric Crohn disease, with or without fistulas. Approximately half of the patients become unresponsive to infliximab therapy. Randomized controlled studies are mandatory to assess long-term efficacy and safety to define the optimal therapeutic strategy of infliximab therapy in children with Crohn disease.
- [show abstract] [hide abstract]
ABSTRACT: Crohn's disease is often poorly responsive to conventional therapy with corticosteroids and immunomodulators. A novel chimeric antibody to tumor necrosis factor-alpha, infliximab, has shown utility in the treatment of refractory Crohn's disease in adults. To evaluate the efficacy of open-label administration of infliximab in children and adolescents with active intestinal Crohn's disease. Chart review of the experience with 19 subjects (mean age 14.4 years, range 9 to 19 years) receiving 1 to 3 infusions of infliximab (5 mg/kg/dose) over a 12-week period for corticosteroid-resistant disease (n = 7) or corticosteroid dependence (n = 12). Disease activity was monitored by physician global assessment and the Pediatric Crohn's Disease Activity Index. Significant initial improvement (first 4 weeks after infusion) was noted in all subjects, with Pediatric Crohn's Disease Activity Index values decreasing significantly (mean +/- SD, 42.1 +/- 13.7 to 10.0 +/- 5.6, P <.0001). Over the subsequent 8-week period, 8 of 19 treated subjects had worsening of symptoms, although none deteriorated to severe activity. The mean Pediatric Crohn's Disease Activity Index at 12 weeks was 26.8 +/- 16. 4. The mean daily prednisone dosages at baseline, 4 weeks, and 12 weeks were 28 +/- 14 mg, 20 +/- 12 mg, and 8 +/- 12 mg, respectively (P <.01). Adverse effects were noted in 3 patients during infusion (dyspnea, rash) and were self-limited. Infliximab is associated with short-term clinical improvement in children and adolescents with severe Crohn's disease. The rapid return of disease activity in some patients suggests that additional dosing strategies may be required. Long-term safety necessitates close monitoring.Journal of Pediatrics 08/2000; 137(2):192-6. · 4.04 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Enterocutaneous fistulas are a serious complication of Crohn's disease and are difficult to treat. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease. The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months' duration as a complication of Crohn's disease. Patients were randomly assigned to receive one of three treatments: placebo (31 patients), 5 mg of infliximab per kilogram of body weight (31 patients), or 10 mg of infliximab per kilogram (32 patients); all three were to be administered intravenously at weeks 0, 2, and 6. The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits. A secondary end point was the closure of all fistulas. Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point, as compared with 26 percent of the patients in the placebo group (P=0.002 and P=0.02, respectively). In addition, 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13 percent of the patients assigned to placebo (P=0.001 and P=0.04, respectively). The median length of time during which the fistulas remained closed was three months. More than 60 percent of patients in all the groups had adverse events. For patients treated with infliximab, the most common were headache, abscess, upper respiratory tract infection, and fatigue. Infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.New England Journal of Medicine 06/1999; 340(18):1398-405. · 51.66 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Although effective in the treatment of refractory Crohn's disease, episodic retreatment with the antitumor necrosis factor a chimeric monoclonal antibody infliximab (Remicade, Centocor, Malvern, PA) can be associated with severe acute and delayed systemic reactions. We analyzed episodic infliximab retreatment over 30 months in 86 adult and pediatric patients receiving 304 infusions to determine factors associated with the development of severe systemic reaction. Overall, 14% of patients experienced severe systemic reactions with episodic infliximab retreatment. There was a significant difference in the rates of severe systemic reaction observed in adults (11/52 [21%]) and pediatric patients (1/34 [3%]) (p < 0.02). Delayed systemic reactions, characterized by arthralgia, fever, and myalgia requiring corticosteroid treatment, were found exclusively in adults (age > 17 yr) and occurred in eight patients treated for luminal Crohn's disease. Acute systemic reactions, characterized by hypotension, mucosal irritability, and laryngospasm requiring epinephrine, diphenhydramine, and/or methylprednisolone treatment, occurred sporadically in three adults and one child, treated for both luminal and fistulizing disease. Second infliximab infusions were associated with two thirds of severe systemic reactions, and a distant second infusion (> or = 20 wk from first infusion) was poorly tolerated relative to earlier retreatment (p < 0.001). Concomitant medications were similar in adults and children. Episodic infliximab retreatment--specifically, a distant second infusion--is associated with high rates of severe systemic reaction in adults, but not children. We recommend multiple early infusions of infliximab if retreatment is anticipated in adult patients to avoid the development of delayed severe systemic reactions.The American Journal of Gastroenterology 06/2002; 97(6):1408-14. · 7.55 Impact Factor
Downloaded from UvA-DARE, the Institutional Repository of the University of Amsterdam (UvA)
SOURCE, OR PART OF THE FOLLOWING SOURCE:
TitlePaediatric inflammatory bowel disease: scoping the future : genetics, diagnostics and
AuthorL. de Ridder
FacultyFaculty of Medicine
FULL BIBLIOGRAPHIC DETAILS:
It is not permitted to download or to forward/distribute the text or part of it without the consent of the copyright holder
(usually the author), other then for strictly personal, individual use.
UvA-DARE is a service provided by the Library of the University of Amsterdam (http://dare.uva.nl)
060449 omslag.indd 1060449 omslag.indd 113-12-2006 07:18:46 13-12-2006 07:18:46
Paediatric Inflammatory Bowel Disease:
Scoping the Future
Genetics, Diagnostics and Therapeutics
Paediatric Inflammatory Bowel Disease: Scoping the Future.
Genetics, Diagnostics and Therapeutics.
Thesis, University of Amsterdam, The Netherlands
For the publication of this thesis, financial support is gratefully acknowledged from the
pharmaceutical companies: Schering-Plough BV, Centocor, AstraZeneca BV, Ferring, Solvay
Pharma, Nutricia Nederland BV en Tramedico.
Marga Duin, artist, www.margaduin.com
Chris Bor, Medical photography, AMC
Buijten & Schipperheijn, Amsterdam
@ 2006 Lissy de Ridder
No part of this thesis may be reproduced or transmitted in any form or by any means without
permission of the author.
Paediatric Inflammatory Bowel Disease:
Scoping the Future
Genetics, Diagnostics and Therapeutics
ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam
op gezag van de Rector Magnificus prof. mr P.F. van der Heijden
ten overstaan van een door het college voor promoties ingestelde commissie,
in het openbaar te verdedigen in de Aula der Universiteit
op woensdag 24 januari 2007 te 14.00 uur
Lissy de Ridder
geboren te Uitgeest
Promotor: Prof. dr H.S.A. Heymans
Dr M.A. Benninga
Dr D.W. Hommes
Dr J.A.J.M. Taminiau
Prof. J.F. Bartelsman
Prof. dr H.J. Verkade
Prof. dr A.M. Griffiths
Prof. dr H.N. Caron
Prof. dr T.W. Kuijpers
Dr J.C. Escher
Faculteit der Geneeskunde
Partly published as:
Genpolymorfismen en inflammatoire darmziekten
Chapter 2 Differences in genotype and phenotype in paediatric-onset
Inflammatory Bowel Disease and adult-onset Inflammatory Bowel
Rectal bleeding in children: Endoscopic evaluation re-visited
Pharmacogenetics of thiopurine therapy in paediatric IBD patients
Azathioprine maintains first remission in newly diagnosed paediatric
Chapter 6 Infliximab use in children and adolescents with inflammatory bowel
Infliximab as first line therapy in severe paediatric Crohn’s disease
Chapter 8 Infliximab therapy in 30 patients with refractory paediatric Crohn’s
disease with and without fistulas in The Netherlands
Chapter 9 Infliximab in paediatric Crohn’s disease: long-term follow-up of an
Chapter 10 Summary
C h a p t e r1
Lissy de Ridder,
Pieter C.F. Stokkers,
Edmond H.H.M. Rings
Part of this chapter is published as:
Genpolymorfismen en inflammatoire darmziekten
Nederlands Tijdschrift voor Kindergeneeskunde 2004;5:179-184
Paediatric Inflammatory Bowel Disease
Crohn’s Disease (CD), Ulcerative Colitis (UC) and indeterminate colitis (IC) are chronic inflam-
matory bowel diseases (IBD). CD is a segmental, transmural inflammation that can concern
the whole digestive tract, from mouth to anus. The terminal ileum is the most commonly
affected site. Presenting complaints often are abdominal pain, weight loss, diarrhoea and
poor appetite. However, the classical triad of abdominal pain, weight loss, diarrhoea is present
in only 25% of children with CD.(1) Many children with CD present with vague complaints,
such as lethargy, anorexia and mild abdominal complaints.(1,2) Perianal complaints such as
skin tags, fistulas and abscess formation can occur. Systemic complaints such as fatigue, fever
and extraintestinal manifestations can occur. Osteoporosis can already be present when the
disease is diagnosed. Growth failure and delay in puberty development are specific problems
for paediatric CD and sometimes precede other symptoms.
UC mainly concerns inflammation of the mucosa, limited to the colon and rectum. In contrast
to the segmental inflammation of CD, UC has continuous involvement, extending from the
rectum proximally. Presenting complaints often are diarrhoea, rectal bleeding and abdominal
pain. Sometimes systemic signs such as fever and weight loss are present. Osteoporosis,
growth failure and delay in puberty development can occur, but much less frequent than in
Sometimes it is not possible to make a distinction between CD and UC, because patients
present with colitis, without specific features of either CD or UC. These patients are classified
as having IC.
In 20-25% of patients the disease presents before the age of 20. The incidence of paediatric
IBD (under the age of 18) in The Netherlands is recently assessed and concerns 5.2/100.000
children.(3) In the UK and Republic of Ireland 5.2/100 000 children less than 16 years of age
were newly diagnosed as having IBD. Sixty percent had CD, 28% had UC and 12% IC.(4) In
South Wales comparable data were found.(5) The incidence has increased over the last 30-40
years.(6) In the seventies and eighties UC was diagnosed more frequently in children and ado-
lescents, while nowadays CD is diagnosed more frequently. The cause of the rising incidence
and changing disease pattern is unknown but may well be related to environmental factors
playing a role in the aetiology of IBD.
Clinical features of paediatric IBD are different from adult IBD. In adults diarrhoea (CD) or rectal
bleeding (UC) is the most frequently presenting symptom while in children this is abdominal
pain. In adults UC is predominantly confined to the rectum or left-sided colon while children
usually present with pancolitis.(1,7) Linear growth retardation and pubertal delay of course
are very specific problems for the paediatric IBD population.(8)
Aetiology of IBD
IBD is a multi-factorial disorder with a complex interaction between immunological, genetic
and bacterial factors, leading to inflammation of the gut and the gut mucosa.
CD is characterized by a T-helper type-1 (TH1) immune response. Probably an abnormal reactivity
against luminal and mucosal antigens gets pro-inflammatory and regulating CD4
lymfocytes out of balance. This causes a disturbance between TH1-associated inflammatory
cytokines on one hand, such as ‘tumor necrosis factor-alpha’ (TNF-α), interferon-gamma
(IFN-γ), interleukin-12 (IL-12) and interleukin-18 (IL-18) and anti-inflammatory cytokines such
as interleukin-10 (IL-10) and ‘transforming growth factor-beta’ (TGF-β) on the other hand. In
UC evidence suggests that an excessive T helper 2-cell response occurs rather than the Th1-cell
pattern typical of CD.(9)
During the last years many factors of aetiology and pathophysiology in IBD are elucidated.
Epidemiological studies have shown the important role of genetic factors in the development
of IBD. Prevalence of IBD differs by race and ethnicity. In monozygotic twins a higher concor-
dance is found than in dizygotic twins. There is also clustering of IBD within families.
About 5% -10% of IBD patients have a positive family history for IBD.(10,11) A positive family
history therefore is the most important risk factor for the development of IBD. The prob-
ability to develop IBD before the age of 30 years when both parents are known with IBD
is about 33%.(12) The relative risk to develop IBD in a sibling of an IBD patient is estimated
between 15 en 35 for CD and between 7 and 17 for UC.(12,13) The genetic influence in CD is
stronger than in UC.(14) A large part of genetic research and new developments concern CD.
However, genetic factors alone are not sufficient to cause CD; after all, concordance in mono-
zygotic twins is only 50%.(14) It is very important to identify the genes playing a role in IBD,
because both understanding of aetiology and pathogenesis and know-how on diagnostics
and response on therapy will be improved.
In concordance with the multi-factorial character of IBD there are multiple phenotypes.
Amongst others, phenotypic diversity is expressed in time of first presentation of disease,
disease localization and disease severity.
Polymorphisms and an increased susceptibility for CD
Genome screening yielded several susceptibility loci by now. The first gene identified that is
clearly associated with the risk of development of CD is the ‘caspase-activation recruitment’
domain (CARD15)/ the ‘nucleotide-binding’ domain (NOD2) gene.(15-17) The NOD2/CARD15
gene is located on chromosome 16. Mutations of the NOD2/CARD15 gene are associated
with ileal disease activity, the presence of disease at a younger age, more frequent formation
of granulomas and the occurrence of fistulizing or stenotizing phenotypes.(17-22) Mutations
of the NOD2/CARD15 gene can be demonstrated in 10-20% of the Caucasian patients. Homo-
zygous carriage of a NOD2/CARD15 gene mutation does not always lead to the development
of CD.(23) As can be foreseen in a complex, multifactorial disorder a mutation of the NOD2/
CARD15 gene is neither essential nor sufficient to develop CD.
The NOD2/CARD15 gene encodes for a protein that is expressed in the human being in the
cytosol of monocytes, granulocytes and dendritic cells, but also in epithelial cells of the gut.(24)
These cells all are important in the process of inflammation in CD.(9) The N-terminal part of
the NOD2 protein contains two ‘caspase-activation recruitment’ domains, a centrally located
‘nucleotide-binding’ domain and ‘leucine-rich repeats’ (LRR) on the C-terminal end of the
protein. Both CARD regions seem to play a role in the activation of the ‘nuclear factor kappa-
B’ (NF-κB) and in the initiation of apoptosis (programmed cell death). NF-κB is a transcription
factor that plays a crucial role in the expression of inflammatory cytokines in CD.(9,25) Glu-
cocorticoids can inhibit NF-κB. This mechanism possibly explains the positive effect of steroid
treatment in CD. Before NF-κB can be activated, the binding of bacterial components (such as
lipopolysaccharide) via LRR is essential.
Three polymorphisms in the NOD2/CARD15 gene are positively associated with an increased
risk of susceptibility for CD. It concerns two ‘single nucleotide polymorphisms’ (SNPs), causing
a change of amino acid (Arg702Trp or R702W and Gly908Arg or G908R) and a ‘frame shift’
mutation with the insertion of the nucleotide cytosine (Leu1007fsinsC or 3020Cins), by which
the gene cannot be encoded properly anymore and by which the protein is strongly short-
ened. The three polymorphisms are all located in the LRR, that are involved in the recognition
The LRR jointly are a structure in a protein, that can function as a receptor for microbial
elements.(27) In the case of the NOD2 protein this element is a protein, the muramyl dipep-
tide, that is found in the bacterial cell wall.(28) NOD2 is a part of a protein family that occurs
in many organisms. In plants these proteins often are involved in resistance against patho-
gens. In human beings the protein is considered to play a role in the innate immunity. This
part of the immune system is not life long ‘programmed’, in contrast to the adaptive humoral
and cellular immunity. It concerns evolutionary, very ancient receptors for pathogens, that, in
higher organisms, play a role in the first recognition of microbial invasion.(27)
In vitro studies on functional consequences of the three mutations in the gene have shown
that they cause a diminished capacity to activate NF-κB.(17,29) Another argument to the ‘loss
of function hypothesis’ is the observation that humans with homozygous expression of the
fore mentioned mutations have a tenfold higher risk than humans with a heterozygous expres-
As the NOD2/CARD15 proteins, Toll-like receptors (TLR’s) are pattern recognition receptors
that signal presence of bacterial antigens, and play a key role in innate immunity system.
NOD2 is located intracellular, whereas TLR’s are extra cellular proteins. Both NOD2 and the
TLR’s are activated by pathogen-associated molecular patterns (PAMP) such as endotoxins.
TLR’s are usually membrane bound. These molecules are present on epithelial cells and
involved in the first phase of host-response to micro-organisms. Each of these receptors (TLR
1-10) recognizes another molecule of a specific group of micro-organisms.
However, the question remains how a defect in a pro-inflammatory cascade of signals can
lead to an inflammatory condition such as CD.
Relevance for clinical practice
The discovery of the NOD2/CARD15-gene caused acceleration in the clarification of the
aetiology of CD. By now other loci for vulnerability of CD are examined. Loci are found on
chromosome 5, 6, 12 and 14. Next to the current knowledge already acquired with the dis-
covery of abovementioned SNPs in the NOD2/CARD15-gene, it is likely that in the near future
more clarity will arise concerning the aetiology of the disease as soon as the genes concerned
will be identified on these chromosomes.
Up till now, these findings are of little importance for clinical practice. In The Netherlands
7.4 % of the adult Crohn patients are homozygote or ‘compound heterozygote’ for the SNPs
in the NOD2/CARD15-gene.(30) The risk that comes along with homozygous expression
is calculated on a relative risk of 23 with a confidence interval of 6 tot 84.(19) This risk is
comparable to the risk that arises as one has a first grade family member with CD (relative
risk = 15).(29) Therefore, it seems too early for genetic counselling. It should be noted that
in calculating the risk of homozygous expression relatively small control groups, in which no
homozygous expression was found, were used. It can be expected that the calculation of the
relative risk will be higher if larger control groups are used. If in the near future this risk can
be calculated more precisely it is imaginable that a parent suffering from severe CD wants
to involve the NOD2/CARD15-genotype of oneself and the life partner in the decision to get
pregnant. Genotyping also could be useful in characterizing the phenotype of the disease
more precisely; in patients with IC the NOD2/CARD15-genotype could be decisive in the final
The recent understandings in molecular mechanisms concerning the aetiology of inflamma-
tory bowel diseases are of crucial importance for the future therapies of these diseases.
Analysis of molecular and cellular processes in normal and disordered immune response has
clarified the biological function of cells that are involved in the resistance of the gut. Besides,
important knowledge on inflammation is gathered. At the moment this knowledge is used to
develop specific therapies. Immunobiologic remedies, such as antibodies against TNF-α and
interleukine-12 and antisense oligonucleotides against specific subunits of NF-κB are already
being tested in clinical trials. This development has only just started and will increase in interest
the next years.
Genetic susceptibility may have a more important role in the aetiology and severity of early-,
than of late-onset IBD. If so, a higher frequency of the gene mutations can be expected in
paediatric IBD patients. Besides, since phenotype of paediatric IBD differs from adult-onset
IBD, genotype-phenotype associations also may differ. Therefore, it is important to perform
genetic studies in paediatric IBD populations.
Investigation and diagnosis of IBD
The diagnosis and classification of IBD is based on the clinical presentation, endoscopy, radiol-
ogy and histology. Distinction between CD and UC is important as prognosis, clinical course
and treatment options vary. Besides distinction of the type of inflammatory disease, assess-
ment of disease severity is important to identify patients with active inflammation so that
optimal therapy may be prescribed.(31) Current diagnostic standard of care in paediatric
patients suspected of IBD consists of ileocolonoscopy and gastroduodenoscopy with tissue
sampling for histological analysis and barium enteroclysis.(32)
Colonoscopy is very important in diagnosing IBD. It enables to inspect the gut mucosa mac-
roscopically and to take mucosal biopsies for histo-pathology. It should always be attempted
to reach the terminal ileum, since 10% of paediatric Crohn patients present with isolated
terminal ileitis.(1) Moreover, in case of a pancolitis, presence of terminal ileitis may be sug-
gestive for CD instead of UC. It is advised to perform a gastroduodenoscopy in the same
diagnostic session, since 10-30% of paediatric-onset CD can only be diagnosed due to
histological changes in the upper gastrointestinal tract.(33-35) Since endoscopy is of high
importance in diagnosing IBD it is important to evaluate endoscopic strategies and diagnostic
yield in children, suspected of IBD.
Small bowel barium enteroclysis or barium meal follow through is currently considered the
most sensitive technique for imaging of the small bowel and will be able to detect inflam-
mation, stenotizing and/or internal fistulizing. However, radiation exposure and patient
discomfort are clear disadvantages, especially in children and adolescents suffering from a
chronic disease such as IBD. In their future, these patients are potentially exposed to much
more of these investigations.
Therefore, Magnetic Resonance Imaging (MRI) maybe a better alternative. Another advantage
of MRI as against enteroclysis is the non-invasive transmural assessment of the bowel, thus
theoretically facilitating both the diagnosis of IBD and differentiation between CD and UC.
In the past poor contrast resolution and motion artefact precluded the use of MRI for bowel
imaging. Technological advances, including the use of intravenous gadolinium, fat suppression
and respiration-suspended sequences have extended the role of MRI in the evaluation of the
Although a distinction between CD and UC can often be made based on well-established
clinical, endoscopic and histological criteria, in 5-23% of cases differentiation between these
two entities is not possible, particularly when disease is limited to the colon.(40) MRI may be
a very valuable tool in both diagnosing IBD and follow-up. However, to perform and inter-
pret MRI in children and adolescents with IBD optimally more experience and well-performed
studies are needed.
Therapy in paediatric IBD
Little published evidence on treatment in paediatric IBD is available. A lot of paediatric practice
comes from studies in adult IBD populations, small paediatric populations or expert opinion.
Conventional remission induction consists of either sustained enteral nutrition, 5-aminosalicyl-
ic acid or high-dose corticosteroids for a minimum of three weeks. Conventional maintenance