Crohn disease (CD) in children is a chronic inflammatory bowel disease, and patients suffer frequent relapses. Its evolution in children and adults is similar, but children can fail to grow, depending on the severity of the disease and steroid treatment (1–3). Approximately 20% to 30% of children and adults become steroid dependent or steroid resistant despite the use of immunosuppressors (4).
Recent randomized placebo-controlled trials in adults with moderate to severe CD have shown that a single infusion of a chimeric monoclonal antibody to tumor necrosis factor-α (TNFα; infliximab, Remicade, Centocor, Malvern, PA), 5 mg/kg, produced a clinical response in 81% of patients and remission in 50% (5,6). One study showed that the endoscopic and histologic appearance of the intestine improved in patients given infliximab but not in those given placebo (6). Similar good results were obtained in patients with perianal fistula who were given 3 injections on days 0, 15, and 45 (7). Relapses were frequent in all these studies, occurring in approximately 50% of patients 3 to 6 months after the first infusion. Re-treatment every 2 months maintained remission with no increase in side effects at a significantly higher rate (72%) compared to patients re-treated with placebo (44%) (8). The few studies published on children treated with infliximab have shown improvement in all patients and remission in more than 50% (9,10). One study suggested that the efficacy and duration of response were better when treatment was given early in the course of the disease (10).
This prospective study was done to evaluate the long-term efficacy and medication side effects of infliximab, particularly its effect on growth, in children with refractory CD.
MATERIAL AND METHODS
Infliximab became available in France in January 2000. This study was done on children with severe CD enrolled between January 2000 and March 2001 in two pediatric gastroenterology units in Paris. They all fulfilled the criteria determined by the French Medical Agency and had corticosteroid-resistant or -dependent CD with or without a fistula. No patient had bacterial or viral infection, particularly tuberculosis, when given infliximab.
Twenty-one children (11 boys and 10 girls) aged 15 ± 2 years with severe CD for a mean of 48 months (range, 12–84 months) were treated with infliximab, 5 mg/kg, on days 0, 15, and 45 (Table 1). One child was given only a single injection. Six patients had been receiving parenteral nutrition and were being treated for corticosteroid dependence (>0.15 mg/kg/d) with azathioprine (2–2.5 mg/kg/d; n = 5) or methotrexate (0.4 mg/kg/wk intramuscularly; n = 2) for more than 3 months. Four of these patients had perianal fistulas. Twelve other patients had been treated for corticosteroid dependence (>0.2 mg/kg/d) with azathioprine (2–2.5 mg/kg/d; n = 8) or methotrexate (0.4 mg/kg/wk intramuscularly; n = 4) for more than 3 months. Six of these patients had a perianal fistula. The last 3 patients were corticosteroid resistant (1 mg/kg/d) for 15 days despite immunosuppressor therapy (azathioprine, 2 mg/kg/d for 3 months) in 2. Two of these patients had a perineal fistula. All the patients, except one on parenteral nutrition, had a Harvey-Bradshaw index (HB) of ≤5 (mean, 8).
Three patients had disease in the terminal ileum and right colon. Four patients had extensive lesions of the small intestine (jejunum + ileum), with associated colon disease in two. Fourteen had pancolitis, with terminal ileitis in 5 patients. Sixteen had anal and perineal lesions, and 12 of these had fistulas. Lesions of the stomach or esophagus were detected endoscopically or histologically in 12 patients.
Laboratory and Clinical Measurements
Patients satisfying the inclusion criteria underwent clinical evaluation with measurement of their HB (11) plus laboratory tests, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), plasma albumin, TNFα in stools, and abdominal tomodensitometry. They were also checked for viral and bacterial infection, antinuclear and anti–double-stranded DNA antibodies, Epstein-Barr virus (EBV) serology, and EBV polymerase chain reaction (PCR). Patients were evaluated on days 0, 15 and 45, and then every 3 months or earlier if necessary.
We recorded the number of patients remaining in remission (HB, ≤4) every 3 months and the decrease or tapering of steroids. Additional immunosuppressing medications were given to all patients. These included azathioprine (2–2.5 mg/kg/d) in 13, methotrexate (0.4 mg/kg/wk intramuscularly) in 4, and mycophenolate mofetil (15 mg/kg/d) in 4.
A relapse (HB, ≤5) was always managed with steroids (0.5–1 mg/kg/d) plus a new injection of infliximab (5 mg/kg) if rapid improvement was not obtained after 10 days of steroid therapy. The immunosuppressor therapy was also changed in five patients who suffered a relapse during the follow-up period. Three were given methotrexate instead of azathioprine, and two were given mycophenolate mofetil instead of methotrexate. All patients were followed for at least 1 year (mean, 21.6 months).
The symptoms of all 21 patients treated with infliximab improved after 2 injections. The HB index decreased from 8 ± 3 on day 0 to 1 ± 2 on day 45 and 3 ± 1.9 after 3 months (P = 0.001). Nineteen children were in remission (HB, <4) on day 45, and 2 had improved (HB, −6 points). Steroid dose decreased from 17.7 ± 5 mg/d to 2 ± 5 mg/d at 3 months (P = 0.001). Fourteen patients had stopped taking steroids at 3 months, and all were off parenteral nutrition by day 45. All perianal fistulae (n = 12) were closed at 3 months (Table 2).
These clinical results were confirmed by a significant decrease in TNFα in the stools (n = 16), from 438 ± 887 pg/g on day 0 to 85 ± 147 pg/g on day 45 (P = 0.04). Inflammatory indicators also decreased: ESR from 28 ± 20 on day 0 to 9 ± 13 at 3 months (P = 0.001), and serum albumin increased from 32 ± 5 g/L on day 0 to 39 ± 4 g/L at 3 months (P = 0.002;Table 2). The growth velocities (Z score) of 10 patients who had not finished pubertal growth were measured. Z score was greater after infliximab treatment (+0.5 SD) than in the year before treatment (−0.45 SD;P = 0.0004;Table 3).
During the follow-up period, 19 of the 21 patients experienced relapses (90%): before 3 months in 7 patients, between 3 and 6 months for 7, and between 6 and 12 months for 5, despite continuing immunosuppressive treatment in all patients. The probability of relapse over time is shown in Figure 1. All patients who relapsed, except two who underwent surgery, were given steroids (0.5–1 mg/kg/d), and 12 were given a new infliximab injection (5 mg/kg; 1–5 injections during follow-up period). Seven patients underwent surgery because of a stenosis (1), a relapsed ileovesical fistula (1), or an uncontrolled pancolitis despite a new infliximab injection (5). Two patients had no relapse after a 24-month follow-up period; they were dependent on corticosteroids before infliximab administration, and one had a perineal fistula.
Eighty-two injections of infliximab were given (2–7 injections/patient). Side effects always occurred during the first 3 months of treatment (Table 4). One patient had anaphylactic shock during the second injection of infliximab. The patient was treated with solumedrol, and the infliximab infusion was stopped. No further adverse reaction occurred in these patients after increasing the infusion time from 2 to 4 hours and systematic pretreatment with dexchlorpheniramine. One case of catheter-related sepsis on day 20 was easily controlled with antibiotics and catheter removal. Six patients developed antinuclear antibodies (1/40–1/640) associated with double-stranded DNA (1/40–1/240) in two but without any clinical symptoms. These antibodies disappeared within 6 months after discontinuing infliximab. The EBV PCR of the 8 patients who were EBV-positive increased 100-fold (Eqv/105c) in 4 patients, 200-fold in 2 patients, and 1,000-fold in 2 others. All patients had a negative EBV PCR before infliximab treatment, and their EBV PCRs were all negative 6 months after stopping infliximab.
This prospective open-label study of 21 patients confirms the efficacy of infliximab for treating children with severe refractory or corticoid-dependent CD (9,10). Complete remission was obtained in 90% of patients, as in other pediatric studies. All perianal fistulae closed after 3 months, with a significant decrease in TNFα in the stools and improved inflammatory markers. The long-term follow-up evaluation (mean, 21.6 months) confirms the findings in studies of adults (5–8): a high rate of relapses (90% at 1 year), despite the maintenance of immunosuppressors. The number of relapses and the duration of remissions in patients with early (<2 years) and late (>2 years) CD were similar, contrary to a previous report (10). Whereas steroid administration alone easily controlled 37% of relapses, a new infusion of infliximab was required for 63% of patients. Seven children (33%) needed surgery within 1 year, 5 because of an uncontrolled relapse despite infliximab re-treatment (41%). This high rate of failure of infliximab re-treatment raises questions about the preventive management of these relapses. Should re-treatment with infliximab be routine every 2 months, as suggested for adults (8), or only when an exacerbation occurs? Despite this question, treating children with severe CD with infliximab increased their growth velocity (P = 0.004), which is a major complication of CD in this age group (1–3).
There were few adverse clinical effects, as in other studies on pediatric patients (9,10), provided that the exclusion criteria were respected (12). However, two adverse biological effects occurred frequently. The first was the presence of antinuclear antibodies in 28% of patients, with antibodies to double-stranded DNA in 10%. The second adverse effect was the reactivation of EBV infection in 28% of patients, demonstrated by 100-fold to 1,000-fold increases in their EBV PCR. All of these abnormalities disappeared within 6 months after discontinuing infliximab. These observations suggest that prolonged re-treatment with infliximab could have adverse effects, leading to autoimmune diseases or an EBV-induced lymphoma, particularly if re-treatment becomes the rule (12–14).
We conclude that the use of infliximab to manage refractory CD in children produces excellent immediate results and is well tolerated. The short duration of its beneficial effects, despite immunosuppressor treatment, suggests that prolonged systematic re-treatment with infliximab should be considered, despite its potential significant biological side effects.
1. Motil KJ, Grand RJ, Davis-Kraft L, et al. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993; 105:681–91.
2. Markowitz J, Grancher K, Rosa J, et al. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993; 16:373–80.
3. Cezard JP, Touati G, Hugot JP, et al. Nutritional treatment in paediatric inflammatory bowel disease. In: Tytgar GNJ, Bartelsman JF, Van Deventer SJH. Inflammatory Bowel Disease. Lancaster, UK: Kluwer Academic Publishers; 1995:619–25.
4. Modigliani R, Mary JY, Simon JF, et al. Clinical biological and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Gastroenterology 1990; 98:811–8.
5. Targan SR, Hanauer SB, Van Deventer SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. N Engl J Med 1997; 337:1029–35.
6. D'Haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with Infliximab
anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial. Gastroenterology 1999; 116:1029–34.
7. Present DH, Rutgeert P, Targan S, et al. Infliximab
for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398–405.
8. Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (Infliximab
) to maintain remission in Crohn's disease. Gastroenterology 1999; 117:761–9.
9. Hyams JS, Markowitz J, Wyllie R. Use of Infliximab
in the treatment of Crohn's disease in children and adolescents. J Pediatr 2000; 137:192–6.
10. Kugathasan S, Werlin SL, Martinez A, et al. Prolonged duration of response to Infliximab
in early but not late pediatric Crohn's disease. Am J Gastroenterol 2000; 95:3189–94.
11. Harvey RF, Bradshaw JM. A simple index of Crohn's disease activity. Lancet 1980; 1:514.
12. Onrust SV, Lamb HM. Infliximab
: a review of its use in Crohn's disease and rheumatoid arthritis. BioDrugs 1998; 10:397–422.
13. Bickston SJ, Lichtenstein GR, Arseneau KO, et al. The relationship between Infliximab
treatment and lymphoma in Crohn's disease. Gastroenterology 1999; 117:1433–7.
14. Dayharsh GA, Loftus EV, Sandborn WJ, et al. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology 2002; 122:72–7.