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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References

Background : Infliximab is an effective therapy in adult patients with refractory and fistulizing Crohn's disease. Experience in children is still limited.

Aim : To evaluate the experience in 22 children and adolescents treated with infliximab with refractory and/or fistulizing Crohn's disease, and to compare duration of response in children between early Crohn's disease and late Crohn's disease.

Methods : The experience in 22 children and adolescents treated with a total of 73 infusions was evaluated retrospectively. Treatment indication was refractory Crohn's disease in 9/22 patients, fistulizing Crohn's disease in 7/22 patients and both these conditions in 6/22. All patients with refractory Crohn's disease had late Crohn's disease (> 1 year), whereas 6/13 patients with fistulas had early disease (< 1 year).

Results : Mean Paediatric Crohn's Disease Activity Index (PCDAI) decreased from 41.2 to 16.2 at 4 weeks (P < 0.01), and to 15.4 at 18 weeks (P < 0.01). Mean PCDAI at 18 weeks in children with early Crohn's disease and late Crohn's disease was 5.5 and 18.1, respectively (P < 0.05). Complete closure of fistulas was obtained in 5/6 children with early Crohn's disease and in 2/7 children with late Crohn's disease. Immediate adverse reactions were observed in two children.

Conclusions : Infliximab is a highly effective treatment in children and adolescents with both severe refractory or fistulizing Crohn's disease. Children with early Crohn's disease have a higher chance of prolonged response to infliximab than children with late Crohn's disease.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References

Crohn's disease involves children and adolescents with increasing incidence.1, 2 This chronic relapsing disorder requires prolonged medical therapy. The burden of illness imposed on young patients is considerable, particularly when the disease is accompanied by growth failure, a specific complication for the paediatric population. Corticosteroids often relieve symptoms but do not induce mucosal healing, and growth failure commonly persists.3 Nutritional therapy represents an alternative management strategy for many children. However, acceptability and difficult administration often limit compliance. Long-term immunosuppressive therapy with azathioprine or mercaptopurine is effective in patients with severe and chronically active disease.4 It has been shown recently that the early use of mercaptopurine in newly diagnosed paediatric patients reduces both the percentage of patients with relapse at one year and the cumulative steroid dosage.5 Disadvantages of mercaptopurine therapy include a three to four month delay in response.

With improved understanding of immune mechanisms leading to chronic intestinal inflammation, new therapeutic agents, referred to as biologics, have been developed. Tumour necrosis factor-α is a proinflammatory cytokine that plays a central role in the pathogenesis of Crohn's disease. Many properties of this key cytokine may be relevant for intestinal inflammation and systemic symptoms of Crohn's disease.6 Children with Crohn's disease have an increased number of lamina propria cells producing tumour necrosis factor-α7 and increased stool excretion of this cytokine.8 Infliximab is a chimeric (murine-human) anti-tumour necrosis factor-α monoclonal antibody of IgG-1 isotype (Remicade, Centocor, Malvern, PA, USA) that has shown significant short-term efficacy in adult patients with severe medically refractory and fistulizing Crohn's disease.9, 10 Successful retreatment of patients at eight-week intervals has been reported.11 The ACCENT 1 randomized trial showed that adult patients with active Crohn's disease who respond to an initial dose of infliximab are more likely to be in long-term remission (54 weeks) with a maintenance therapy by infusion every 8 weeks.12 Even though the first patient treated with infliximab was a 12-year-old girl with severe refractory Crohn's disease13 experience in children is still limited. This is due to difficulties in performing placebo-controlled trials in children for ethical reasons. In a retrospective study, short-term clinical improvement was observed in 19 children and adolescents with intractable and corticosteroid dependent Crohn's disease.14 An open label prospective clinical trial was conducted in 15 children with medically refractory Crohn's disease. A remarkably prolonged duration of response after a single infusion was observed in children with early (< 2 years duration from the time of diagnosis) compared with long-standing (> 2 years) Crohn's disease.15 Recently, safety and steroid sparing effects have been reported in larger cohorts of children treated with infliximab.16, 17

Since becoming commercially available in Italy, infliximab has been used in selected paediatric patients with medically refractory and fistulizing Crohn's disease. We report our initial experience in 22 patients. Comparison of the duration of response to infliximab between children with a long-standing disease and children with newly diagnosed Crohn's disease has been specifically studied.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References

A multicentre retrospective survey was carried out by the inflammatory bowel disease study group of the Italian Society of Paediatric Gastroenterology and Hepatology. Medical records of 22 children aged from 3.2 to 17.9 years, treated with infliximab at eight Italian paediatric inflammatory bowel disease referral centres between October 1999 to March 2002, were reviewed retrospectively. Eligibility for treatment was based on the clinical judgement of the prescribing paediatric gastroenterologist. In all patients, treatment indications were refractory to conventional therapy Crohn's disease and/or fistulizing Crohn's disease. The patients' families and the children, depending on their age, were informed about the published experience with infliximab and the possible side effects. Written informed consent was obtained for every infusion.

Infliximab was given by intravenous infusion at a dose of 5 mg/kg over at least 2 h according to the manufacturer's suggestions. Decisions for re-infusion were made on the physician's judgement of the patient's clinical condition. All patients were hospitalized during therapy and monitored for adverse events.

Patients were classified according to disease duration. Onset of Crohn's disease symptoms was identified retrospectively by the patients and their families. Patients were arbitrarily defined as early Crohn's disease when disease duration was less than 1 year and long-standing Crohn's disease when they had more than 1 year of documented history of inflammatory disease. Disease duration in our patient population ranged from 0.1 to 8 years. Six patients had early Crohn's disease. All six had fistulas, and treatment indications were fistulizing Crohn's disease in four and both refractory and fistulizing disease in two. Sixteen patients had long-standing Crohn's disease; nine were treated for refractrory Crohn's disease, three for fistulizing disease, and four for both refractory and fistulizing Crohn's disease. A surgical resection had been performed previously in one patient. At the time of infliximab infusion, 11 patients were receiving daily corticosteroids, 19 were receiving 5-aminosalicylate, 12 either mercaptopurine or azathioprine, two methotrexate, 13 antibiotics, two enteral nutrition and one patient was on total parenteral nutrition. Table 1 shows the clinical characteristics of patients, disease distribution, fistula location and concomitant medications.

Table 1.  Clinical characteristics of patient population
CharacteristicsNumber
No. of patients22
Sex10 M, 12F
Age (years)
 Mean ± s.d.13 ± 3.2
 Range3.2–17.9
Disease localization
 Oesophagus, stomach, colon1
 Oesophagus, stomach, terminal ileum, colon2
 Terminal ileum1
 Terminal ileum, colon11
 Colon5
 All the intestine2
Patients with perianal disease15
Patients with fistula13
Location of fistulas
 Perianal10
 Perianal and rectovaginal1
 Rectovaginal1
 Enterovescical1
Disease duration (years)
 Mean ± s.d.2.8 ± 2.2
 Range0.1–8
 < 1 year6
 > 1 year16
Previous surgery1
Concomitant medications
 6-Mercaptopurine/Azathioprine12
 Corticosteroids11
 5-Aminosalicylate19
 Enteral nutrition2
 Total parenteral nutrition1
 Methotrexate2
 Antibiotics13
Indication for infliximab treatment
 Refractory Crohn's disease9
 Fistulizing Crohn's disease7
 Both refractory and fistulizing Crohn's disease6

Patient disease activity was documented every 2–4 weeks after initial infliximab infusion by the Paediatric Crohn's Disease Activity Index (PCDAI).18 This index is a 0–100 point scale with remission defined as a score ≤15. It has been developed and validated for use in multicentre trials among children and adolescents. It includes growth parameters and more validly reflects the severity of intestinal inflammation in paediatric patients than the Crohn's Disease Activity Index.19 Routine haematology and blood chemistry was performed in each patient. Fistula evaluation was based on the paediatric gastroenterologist's physical and/or endoscopic examination of the patient. A complete response to treatment was defined a priori when a fistula was completely closed or no longer drained despite gentle finger compression. A partial response was defined when a reduction of 50% or more in fistula diameter, discharge, pain and restriction of activity was obtained. A minimal response to treatment was defined when such a reduction was less than 50%.

Results are expressed as mean ± standard deviation (s.d.). Statistical comparisons were made by the Mann–Whitney U-test.

Number of infusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References

Patients received one to eight doses for a total of 73 infusions (mean 3.3 infusions/patient). Four patients received one infusion, four received two infusions, eight received three infusions, three received five infusions, one received six infusions and two received eight infusions. The interval between each infusion ranged from two to 12 weeks.

Patients with early Crohn's disease had an average of 2.3 (range: one to five) infliximab infusions, with three out of six having only one infusion. Patients with long-standing Crohn's disease had an average of 3.6 infliximab infusions (range: one to eight), with one out of 16 having one infusion. With regard to the number of infusions, the difference between early Crohn's disease and long-standing Crohn's disease is not statistically significant.

Disease activity

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References

Significant improvement was observed in all patients after the initial infusion. Mean PCDAI values of the study population decreased from 41.2 ± 21 to 16.2 ± 15 at 2–4 weeks (P < 0.01), 13.8 ± 12 at 8–10 weeks (P < 0.01), and 15.4 ± 14 at 16–18 weeks (P < 0.01). At 18 weeks, mean PCDAI was 5.5 ± 3 and 18.1 ± 14 in children with early Crohn's disease and long-standing Crohn's disease, respectively (P < 0.05) (Figure 1). Similarly, erythrocyte sedimentation rate and serum C reactive protein levels decreased rapidly after initial infliximab infusion. However, they tended to increase at 8–10 and 16–18 weeks, independently of dosing schedule, especially with regard to C reactive protein levels (Figures 2a and 2b). Erythrocyte sedimentation rate and C reactive protein levels at 16–18 weeks were, respectively, 19 ± 15 mm/h and 05 ± 0.4 mg/dL in early Crohn's disease patients, and 39 ± 33 and 2.9 ± 2.6 in patients with long-standing Crohn's disease (P < 0.05) (Figure 2).

image

Figure 1. Mean Pediatric Crohn's Disease Activity Index (PCDAI) in 22 paediatric patients at 2–4, 8–10 and 16–18 weeks after initial infusion. LCSD: long-standing Crohn's disease (disease duration > 1 year); ECD: early Crohn's disease (disease duration < 1 year).

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image

Figure 2. Mean erythrocyte sedimentation rate (a) and C reactive protein (b) in 22 paediatric patients at 2–4, 8–10 and 16–18 weeks after initial infusion. LCSD: long-standing Crohn's disease (disease duration > 1 year); ECD: early Crohn's disease (disease duration < 1 year).

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Response to infliximab treatment in patients with fistulas is shown in Table 2. At 18 weeks after the initial infliximab infusion, independently of the number of infusions, seven out of 13 patients (54%) had a complete response, three out of 13 had a partial response (23%) and three out of 13 (23%) had a minimal response to treatment. At 18 weeks, a complete response to fistula treatment was obtained in five out of six children (83%) with early Crohn's disease and in two out of seven (29%) with long-standing Crohn's disease.

Table 2.  Response to infliximab in 13 paediatric patients with fistulas at 18 weeks after initial infliximab infusion
 All patientsLSCDECD
  1. LCSD: long-standing Crohn's disease (disease duration > 1 year); ECD: early Crohn's disease (disease duration < 1 year).

Complete response7/13 (54%)2/7 (29%)5/6 (83%)
Partial response3/13 (23%)3/7 (42%)0 (0%)
Minimal response3/13 (23%)2/7 (29%)1/6 (17%)

One patient with severe perianal fistulizing early Crohn's disease lasting only one month was treated with a single dose of infliximab. This patient achieved clinical remission and fistula closure within two weeks, and endoscopy performed at eight weeks showed mucosal healing. He was still in remission after 18 weeks.

The follow-up duration ranged from 18 weeks to 2.5 years. Eleven patients out of 22 (two early Crohn's disease and nine long-standing Crohn's disease) had a follow-up period longer than 18 weeks.

The longest time of clinical remission was observed in a girl with severe perianal fistulizing early Crohn's disease and has been reported in detail elsewhere.20 She developed general seizure and cortical blindness during intravenous infusion of ciclosporin, 9 months after the diagnosis of Crohn's disease. Full neurological recovery was rapidly achieved after ciclosporin suspension. She was then treated with a single infusion of infliximab, leading to fistula closure and relapse after two years. The second patient with fistulizing early Crohn's disease received, after the initial infliximab infusion, a second and a third infusion after 4 and 13 weeks, respectively. Fistula closure was achieved and the patient was still in remission after 1.5 years. During the follow-up period, patients with long-standing Crohn's disease, subsequent to the initial 18 weeks, generally relapsed 2–4 months after every infliximab infusion. Two patients with refractory long-standing Crohn's disease received eight infusions. Adopting the 8 week retreatment schedule prevented relapses in these patients. One patient with long-standing Crohn's disease involving the whole intestine, after unsuccessful treatment with steroids, azathioprine, ciclosporin and talidomide, received five infliximab infusions. Colectomy was carried out during infliximab treatment. The patient improved, still maintaining a mild disease activity (PCDAI = 20) for a 6 month follow-up period.

Safety

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References

Each patient was monitored for adverse effects during and after the treatment. Immediate adverse reactions were observed in two children during infliximab infusion, which was then stopped. One patient had a rash and severe dyspnea during the second infusion and one patient had a rash, shortness of breath and hypotension at the third infusion. These patients were not pretreated with diphenhydramine. One patient had chest pain after the first infusion and headache after the second infusion.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References

Published information on experience with infliximab in paediatric patients with Crohn's disease is still limited compared with the adult literature.

Although infliximab is not licensed for patients younger than 18 years, it is now widely used by paediatirc gastroenterologists in selected patients with the same indications as adult patients. Short-term clinical improvement after infliximab treatment was observed in 19 children and adolescents with severe refractory Crohn's disease.14 A prospective clinical trial in a small group of children with medically refractory recent onset Crohn's disease showed a prolonged response after a single infusion.15 The rate of infusion reactions in an adult series receiving infliximab was approximately 4–13%12, 21 and was similar to that observed in children.22 Episodic retreatment with a distant second infusion is associated with a high rate of severe systemic reactions in adults but not in children.23 Very recently, a retrospective review confirmed that the rate of infusion reactions in children is similar to that in adults. Female gender, use of immunosuppressive agents for less than 4 months and previous infusion reactions were reported to be risk factors for subsequent adverse infusion reactions.16 In the largest paediatric cohort published, infliximab was well tolerated over multiple infusions and immediate infusion reactions did not preclude further use of the agent. Serious infections were seen in a small number of patients. A statistically significant steroid-sparing effect was reported at 4 and 8 weeks after infusion.17 It is worth noting that nearly all patients in this cohort were receiving concomitantly mercaptopurine/azathioprine or methotrexate. This may have contributed to the infliximab efficacy, the steroid-sparing effect and the reduced incidence of infusion reactions. In rheumatoid arthritis, a synergy between low dose of immunosuppressive drugs and infliximab was reported together with a reduced production of antichimeric antibodies.24 The ACCENT-1 trial in adult patients with Crohn's disease showed a tendency for a better clinical outcome when combination therapy with immunosuppressive agents was administered.12

Our data show that infliximab is a highly effective short-term treatment in children and adolescents with either severe refractory or fistulizing Crohn's disease. To our knowledge, no studies have been published on infliximab efficacy in children with fistulizing Crohn's disease. Independent of the number of infusions, in seven out of 13 (54%) paediatric patients with fistulas we observed complete fistula healing at 18 weeks, whereas a partial response was observed in three patients and a minimal response in three patients. Although the number of patients is too small to draw conclusions, these data suggest that in children, the efficacy of infliximab in healing fistulas which complicate Crohn's disease is similar to that observed in adults. In 94 adult patients with enterocutaneous fistulas, closure of all fistulas was obtained in 55% of those treated with 5 mg/kg infliximab.10

Remarkably, when we divided patients in two subgroups according to disease duration, children with early Crohn's disease had a higher chance of a prolonged response to infliximab than children with long-standing Crohn's disease. Disease activity was significantly lower in children with a disease duration < 1 year than in children with long-standing disease 4 months after the initial infliximab infusion, independently of dosing schedule. PCDAI score, erythrocyte sedimentation rate and C reactive protein levels at 18 weeks were significantly lower in the sub-group of children with early Crohn's disease than in children with long-standing Crohn's disease. When considering patients with fistulas, a complete response to treatment was obtained in five out of six children with early Crohn's disease and in only two out of seven children with long-standing Crohn's disease. The variability in number of infliximab infusions in the population reported could represent a limit to these data. However, in our population, children with early Crohn's disease received a lower average number of infliximab infusions than children with long-standing Crohn's disease. Three out of six children with early Crohn's disease had only a single infusion and were still in remission 4 months later, along with fistula closure.

An improved duration of response after a single infliximab infusion has already been observed in six children with early refractory Crohn's disease compared with eight children with long-standing Crohn's disease.15 Our data extend such observations to include children with fistulizing Crohn's disease. Mucosal T-cells isolated from children with early Crohn's disease showed susceptibility to IL-12, whereas T-cells from children with late disease did not show the same pattern of response.25 The early introduction of mercaptopurine in newly diagnosed paediatric patients with Crohn's disease reduces disease relapses and cumulative steroid dosage at one year.5 Early use of aggressive immunosuppressive therapy in juvenile rheumatoid arthritis results in improved clinical outcome and decreased need of steroids.26 Taken together, such observations and our results support the hypothesis that a higher susceptibility to immunomodulation is present early in the disease course of immune-mediated diseases and tends to decrease in the late stages. Considering the need in children for a corticosteroid-sparing treatment regimen early in the disease course to promote linear growth velocity, a different approach to infliximab usage in paediatric patients may be suggested.15 A recent editorial by Hyams27 questions whether we should start using infliximab in children with corticosteroid-dependant or refractory Crohn's disease while awaiting a response to azathioprine/mercaptopurine, or even at diagnosis instead of steroids in those with severe disease complicated by growth failure. Enteral nutrition represents a different therapeutic option for paediatric Crohn's disease. It is widely used as a first-line treatment instead of steroids in Europe and Canada whereas it is neglected in the United States. However, exclusive liquid diet is less effective in Crohn's colitis and in relapsing and long-standing disease.28 The existing concerns of long-term safety and risks of malignancy still restrict infliximab usage indications to refractory and fistulizing Crohn's disease not responding to conventional therapy. However, it is time for a prospective trial specifically designed for children to ascertain whether early use of this agent will result in improved long-term clinical outcome.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References

The authors wish to thank Paola Roggero, University of Milan, Coordinator of the IBD study group of the Italian Society of Pediatria Gastroenterology and Hepatology.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Number of infusions
  7. Disease activity
  8. Safety
  9. Discussion
  10. Acknowledgements
  11. References
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