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Keywords:

  • Crohn's disease;
  • children;
  • infliximab

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References

Infliximab, a monoclonal antibody against tumor necrosis factor-alpha, has been shown to be effective for the treatment of refractory Crohn's disease in adult patients, but experience in pediatrics is limited. This retrospective study included 88 children and adolescents, 39 girls and 49 boys, with a median age of 14 years (range 3.3–17.9). Infliximab was indicated for active disease (66%) and/or fistulas (42%) that were refractory to corticosteroids (70%), and/or other immunosuppressive (82%) agents, and/or parenteral nutrition (20%). Patients received 1 to 17 infusions (median 4) of 5 mg/kg (range 3.8–7.3) of infliximab during a median time period of 4 months (1–17 months). Infusion reaction was noted in 13 patients (15%), with a total of 16 reactions in 450 infusions (4%). At Day 90 after the first infusion of infliximab, symptoms improved in 49% of patients, whereas 29% of patients were in remission and 13% of patients relapsed. From Day 0 to Day 90, Harvey–Bradshaw score decreased from 7.5 to 2.8 (P < 0.001), C-reactive protein from 36 to 16 mg/L (P < 0.01), and 1-hour erythrocyte sedimentation rate from 35 to 17 mm (P < 0.01). Dosage of corticosteroids decreased from to 0.59 to 0.17 mg/kg/d (P < 0.001); 53% of patients could be weaned of corticosteroids and 92% of parenteral nutrition. Treatment with infliximab is well tolerated and effective in most children and adolescents with Crohn's disease that is refractory to conventional immunosuppressive therapy. Nevertheless, long-term efficacy remains to be shown, and further studies are urgently needed to precisely determine the best modality of continuing treatment.

Crohn's disease (CD) is a chronic inflammatory bowel disease of unknown cause that is characterized by transmural inflammation involving any portion of the gastrointestinal tract. Corticosteroids are effective for inducing remission in adults 1 but are associated with a high prevalence of side effects and lead to altered growth when given for prolonged periods in children. 2,3 Nutritional therapy has been used as an alternative treatment, with efficacy rates ranging from 50% to 82%, especially in children and adolescents with growth failure and/or delayed puberty. 3 Among adult patients receiving corticosteroids, 20% have corticosteroid-refractory disease, and 36% of those with an initial response develop corticosteroid dependence within 1 year, 4 requiring the use of immunomodulatory agents, such as azathioprine or 6-mercaptopurine, methotrexate, mycophenolate mofetil, or cyclosporine. 5

Tumor necrosis factor (TNF)-α has been identified as a key mediator of inflammation in CD. TNF-α production is increased in the intestinal mucosa, 6,7 and the fecal concentration of this cytokine is increased in CD patients. 8 Infliximab, a chimeric (75% human and 25% mouse) monoclonal antibody against TNF-α, 9 binds both the soluble subunit and membrane-bound precursor of TNF-α and inhibits a broad range of its biologic activities. 10 It may also cause lysis of cells that produce TNF-α. 11 The use of infliximab has been well documented in adult CD patients 2,12–15 but pediatric experience is mostly from retrospective, short-term series with a limited number of patients. 16–20 We report herein the experience of the French Speaking Group of Pediatric Gastroenterology, Hepatology and Nutrition through a large series of pediatric patients treated with infliximab for refractory CD.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References

A multicentric retrospective review of CD patients younger than 18 years of age who were treated with infliximab (Remicade; Shering-Plough, Malvern, PA) was undertaken under the direction of the French-Speaking Group for Pediatric Gastroenterology, Hepatology and Nutrition review board. University Hospital Medical Centers who participated in the study were from France: Bordeaux (T. Lamireau), Paris-Robert Debré (J. P. Cézard), Rennes (A. Dabadie), Paris-Necker (O. Goulet), Lyon (A. Lachaux), Lille (D. Turck), Tours (C. Maurage), Nancy (A. Morali), Rouen (J. Stoller), Angers (J. L. Giniès), Paris-Trousseau (S. Viola), Dijon (F. Huet), Limoges (J. Languepin), Amiens (C. Lenaerts), Marseille (J. Sarles); from Belgium: Bruxelles-Saint Luc (E. Sokal), Bruxelles-Reine Fabiola (S. Cadranel), Montegnée (F. Bury); and from Switzerland: Geneve (D. Belli).

The following parameters were collected: gender, age, date of diagnosis of CD, location of CD, use of corticosteroids and/or of other immunosuppressive agents, nutritional therapy; reason for treatment with infliximab, number of infusions of infliximab and, for each infusion, dosage, premedication, infusion reactions, delayed hypersensitivity reactions, and documented infections. Infusion reaction was defined as any adverse events occurring during or within 2 hours after the end of an infusion. One or several of the following symptoms occurring from 2 to 12 days after the infusion were defined as delayed hypersensitive reaction: polyarthralgia and/or myalgia, associated with fever and/or rash, and possibly with pruritus, dysphagia, urticaria, facial edema, sore throat, or headache. As a measure of efficacy, Harvey–Bradshaw (HB) scoring (normal < 5), erythrocyte sedimentation rate (ESR; normal range 2–20 mm), C-reactive protein (CRP; normal range 0–5 mg/L), corticosteroid dosage (expressed as milligram equivalent of prednisone per kilogram per day), were assessed at 90 days after the initiation of treatment with infliximab, and compared with values at Day 0. Patients were classified as improved (decrease of both HB scoring and ESR), in remission (HB ≤ 4 and ESR ≤ 20 mm, or closure of fistulae), or in relapse (increase of HB and ESR, or reopening of fistulae, after initial improvement) The percentage of patients who could be weaned of corticosteroid treatment or parenteral nutrition also was evaluated. Factors such as gender, location of CD, duration of the disease at the time of the first infusion of infliximab, and disease activity were compared between patients weaned or not weaned of corticosteroids. Response to infliximab was also analyzed according to initial CRP level (low <5 mg/L versus high >5 mg/L).

The Student t test was used to compare mean values of each parameter at Day 0 and Day 90. Comparison between patients weaned or not weaned of corticosteroids was performed using the Student t test or the χ2 test as appropriate.

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References

Eighty-eight children were included in the study (Table 1). Indication for treatment with infliximab was active disease in 58 patients (66%) and/or fistula in 37 patients (42%) that were refractory to corticosteroid and/or other immunosuppressive agents. At the time of the first infusion of infliximab, median age was 14 years (range 3.3–17.9 years), and 62 patients (70%) were treated with corticosteroids, 72 patients (82%) with other immunosuppressive drugs, and 18 patients (20%) were on parenteral nutrition.

Table 1. Characteristics of Patients
Sex 
Girls39 (44%)
Boys49 (56%)
Age at beginning of symptoms (years) (mean; range)10 (1–15)
Age at diagnosis of CD (years) (mean; range)11 (2.8–16.2)
Location of CD 
Small intestine alone11 (56%)
Ileum and colon49 (58%)
Colon alone25 (28%)
Upper digestive tract24 (27%)
Perineum40 (45%)
Extradigestive manifestations51 (58%)
Oral cavity19 (21%)
Joint29 (33%)
Skin14 (16%)
Previous treatment 
Azathioprine76 (86%)
Methotrexate27 (30%)
Ciclosporine2 (2%)
Parenteral nutrition22 (25%)
Enteral nutrition27 (30%)
Enteral and parenteral nutrition23 (26%)

Administration of Infliximab

A total of 450 infusions were administered to the 88 patients, ranging from 1 to 17 infusions per patient (median 4) over a median time period of 4 months (range 1–17 months). Eighty-three percent of patients received 3 infusions or more, 36% received more than 5 infusions, and 7% more than 10 infusions. Dosage of infliximab was 5 mg/kg, except in 3 children who received an infusion of 3.8, 4.5, and 7.3 mg/kg, respectively. A premedication, mostly with dexchlorpheniramine, was administered before the initial infusion in 32% of cases and before further infusions in 60% of cases.

Safety

Infusion reaction was noted in 13 patients (14.7%): during the initial infusion in 5 patients (5.6%) and during the further infusions in 9 patients (22.3%). Reactions occurring during the first infusion did not differ from others (Table 2). Among the 13 patients, 10 had further infusions, and a second reaction occurred only in 3 patients. A total of 16 reactions occurred during 450 infusions (3.5%;Table 2). All reactions were limited but required to reduce the flow rate (n = 5) or to stop (n = 5) the infusion or to use intravenous administration of dextrochlorpheniramine (n = 3), acetaminophen (n = 2), or prednisolone (n = 1). Symptoms strongly suggestives of delayed hypersensitive reaction occurred in only 2 patients (2.2%): 1 patient had polyarthralgia and fever 10 days after the third infusion; a second patient had elevated fever and polyarthralgia 14 days after the second and the third infusions. An eruption suggestive of lupus erythematosus, with no other symptoms and negative nuclear antibodies, occurred after the second infusion in 1 patient. This eruption disappeared spontaneously and progressively within 6 months, whereas the patient received 2 other infusions during this time. Henoch–Schoenlein purpura occurred in 1 patient 6 days after the first infusion of infliximab. Two patients developed perineal abscess (1 that was present before infliximab was started and required operation in the first patient; another that occurred after the third infusion of infliximab but improved with further infusions in the second patient), and 1 patient developed an arm abscess 31 days after the fifth infusion. Two patients developed intestinal strictures that required surgery. One patient had neutropenia that disappeared after concomitant azathioprine was stopped.

Table 2. Adverse Reactions During Infusion of Infliximab in 13 Patients
Type of Reaction (n = 16)Treatment
  • *

    *Reaction during the first infusion.

Hypotension*None
Headache*Reduced infusion rate
Fatigue*Infusion stopped
Pruritis*IV diphenhydramine
Hypotension*None
Headache, shiverIV acetaminophen
Chest tightnessNone
FeverIV acetaminophen
Flushing, nauseaReduced infusion rate
HypotensionReduced infusion rate
Flushing, tachycarciaInfusion stopped.
 IV diphenhydramine
Chest tightness, flushingInfusion stopped,
 IV diphenhydramine
HypotensionInfusion stopped, IV prednisolone
Chest tightness, tachycardiaReduced infusion rate
Chest tightness, tachycardiaReduced infusion rate
Hypotension, headacheInfusion stopped

Efficacy

Efficacy could be evaluated 90 ± 7 days after the first infusion of infliximab in 76 patients (86%). Symptoms improved in 40 patients (53%) of patients and 26 patients (34%) were in remission (HB ≤ 4), whereas 10 patients (13%) relapsed. Mean values of HB scoring, CRP, and ESR decreased significantly (Fig. 1). At the time of the first infusion of infliximab, 43 of the 76 patients were treated with corticosteroids and 13 were on parenteral nutrition. At 90 days, dosage of corticosteroids decreased from 0.59 ± 0.51 to 0.17 ± 0.25 mg/kg/d (P < 0.001). Twenty-four patients (53.4%) were weaned of corticosteroids and 12 (92.3%) of parenteral nutrition. Efficacy at 90 days after the first infusion of infliximab was not different in patients treated for active disease, for fistula, or for both (Fig. 1). Gender, location of CD, duration of the disease at the time of the first infusion of infliximab, and disease activity were not different between patients weaned or not weaned of corticosteroids (Table 3). At Day 90, 54% of patients with a low CRP level at the first infusion of infliximab were improved and 31% were in remission, whereas 45% of patients with a high initial CRP level were improved and 35% were in remission (differences not significant). Mean initial CRP level was not significantly different between patients who were in remission (55 ± 74 mg/L), improved (27 ± 26 mg/L), or who relapsed (42 ± 29 mg/L).

Table 3. Predictive Factors of Weaning of Corticosteroids After 3 Months of Treatment with Infliximab
 Patients NotPatients 
 Weaned of CsWeaned of 
 (n = 21)Cs (n = 22)P
  1. CRP indicates C-reactive protein; Cs, corticosteroids; ESR, 1-hour erythrocytc sedimentation rate.

Sex13 M/8 F12M/10FNS
Location of Crohnn's disease   
Ileum23NS
Ileum + colon1113NS
Colon56NS
Disease course   
Age at diagnosis (year)10.9 ±2.710.7 ±2.5NS
Age at first infusion of   
infliximab (year)15.1 ±2.314.9 ±3.3NS
Duration of disease (year)5.2 ±2.84.3 ± 2.9NS
Indication for infliximab   
Active intestinal disease1912NS
Fistulae05NS
Both22NS
Disease activity at first   
perfusion of infliximab   
HB score8.5 ±3.39.5 ±4.1NS
CRP (mg/L)37 ±3136 ±24NS
ESR (mm/h)34 ±2432 ±19NS
Dosage of corticosteroids   
(mg/kg/d)0.71±0.430.51±0.56NS
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Figure FIGURE 1. Efficacy of infliximab at 90 days regarding to the type of disease. Values of HB scoring, CRP, and 1-hour ESR at the beginning of treatment (D0) were similar in the whole population, and in active CD or fistulae. In the 3 groups, values of HB, CRP, and ESR decreased significantly at 90 days after the beginning of treatment with infliximab (D90). **P < 0.01; ***P < 0.001.

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In the 12 patients who could not be evaluated at 90 days, one relapsed and required colectomy, and the remaining patients had only 1 or 2 infusions of infliximab with a short duration of follow-up.

Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References

Controlled studies in adults patients with active and fistulizing CD have undoubtedly shown that inhibition of TNF-α with infliximab provides rapid and prolonged clinical improvement, leading to improved quality of life. 13,15,21 The published experience on infliximab for active CD in pediatric patients is limited by the small number of patients included in retrospective studies. 16,17,19 In the present study, we confirmed in a large cohort of children and adolescents the short-term efficacy of infliximab in patients with severe CD that was refractory to conventional immunosuppressive therapy. Ninety days after treatment was started, activity of disease was significantly reduced, as reflected by the decrease of HB scoring and CRP and ESR values. Nearly all patients dependent of parenteral nutrition could be weaned of this support. The dosage of corticosteroids was significantly reduced, and half of the patients could be weaned of corticosteroids. A corticosteroid-sparing effect of infliximab was also reported by Stephens et al 18 in 82 patients with active disease. A discontinuation of corticosteroids was obtained in 79% of treated patients after a median period of 12 weeks. Nonetheless, a relapse, requiring corticosteroids to be started again, is as frequent as 35% 18 or even 90% of cases. 19 A decrease of response after repeated infusions of infliximab was also reported by de Ridder et al, 22 and fistula tracts may persist on magnetic resonance imaging despite closure of external orifices. 23,24

Response to infliximab seems to be predicted by a high CRP level at the beginning of the treatment 25 or by the duration of the disease, a prolonged response being more likely in early as compared with late CD in children. 17 Nevertheless, in this study, neither the initial CRP level nor the duration of the disease did influence the response to infliximab. The development of antibodies against infliximab also may explain a reduced duration of response to treatment, as well as an increased risk of infusion reactions. 26 The high rate of relapse occurring after the initial treatment with infliximab raises questions about a maintenance therapy. In adults, retreatment every 2 months has been shown to maintain remission in 72% who received infliximab as compared with 48% of those who received placebo. 14

Evolution toward intestinal stenosis occurred in 2 of our patients (2.3%) during the study period, as compared with the 9 cases of stenosis among 82 patients (11%) reported on by Stephens et al. 18 In that study, 8 patients required surgical resection and 1 was treated with endoscopic dilation. Only 1 of these patients received further infusions of infliximab after surgery.

Reaction occurred during infliximab infusion in 15% of our patients, a rate identical to that reported on by Stephens et al 18 but slightly higher than the 9.7% reported on by Cheifetz et al. 27 Three of 10 patients experienced a second reaction during a further infusion as compared with the 23% of recurrence rate reported by Stephens et al. 18 When related to the number of infusions, infusion reaction rate was lower (3.5%) than that reported by Stephens et al 18 and Cheifetz et al. 27 These reactions were self limited and usually did not preclude further infusion of infliximab but should lead to use premedication and slower infusion rate. 18 In some cases, desensitization using dose escalation has been proposed. 28

Hypersensitive delayed reactions, as we observed in 3 of our patients, are reported in approximately 6% of patients treated with infliximab. In adult patients, hypersensitive delayed reactions seem to be more common in patients with a significant interval between infusions, but this factor has not been found in children. 29 Treatment with other immunosuppressive agents, such as 6-mercaptopurine, azathioprine, or methotrexate, could decrease the appearance of anti-infliximab antibodies. 30 Severe infections have been reported in patients treated with TNF-α antagonists. 19,31–34 In our study, 1 child with a central venous line had septicemia with Staphylococcus aureus, 2 patients developed perineal abscesses, and 1 patient developed an arm abscess 1 month after a fifth infusion of infliximab. Only a few patients treated with infliximab develop antinuclear antibodies, which is usually not associated with anti-DNA antibodies. 35 Clinical symptoms of lupus erythematosus are rare and generally limited to skin eruption. 35 Such an eruption was present only in 1 patient in this study, but diagnosis of lupus erythematosus remains doubtful because antinuclear antibodies were absent. Other immunologic disorders such as vasculitis are reported on during treatment with infliximab, 36 as we observed in a patient who presented Henoch–Schönlein purpura within 1 week after the first infusion of infliximab.

In conclusion, treatment with infliximab is well tolerated in children with CD. Anaphylactic reactions and hypersensitive delayed adverse reactions are rare. Although retrospective, this study strongly suggests that short-term treatment is effective in most pediatric patients with CD refractory to conventional immunosuppressive therapy. Nevertheless, longterm efficacy and tolerance remain to be shown, and further studies are needed urgently to precise the best modality of maintenance therapy.

References

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. References
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