Standard medical treatment of mild Crohn disease consists of aminosalicylates. In moderate and severe disease, corticosteroid is the treatment of choice. Steroid dependency is seen in 36% and steroid resistance is seen in 20% of Crohn disease patients (1). Furthermore, long-term use of corticosteroids has many well-known adverse effects (2). The next step in therapy is immuno-modulation with drugs such as azathioprine, 6-mercaptopurine or methotrexate. These drugs have a delayed onset of action and can cause serious adverse effects (pancreatitis, hepatitis and severe leukopenia).
A recent development in refractory Crohn disease (steroid dependent and/or therapy resistant despite immuno-modulators) is the use of the monoclonal antibody anti–tumor necrosis factor (infliximab). Tumor necrosis factor has a key role in the inflammation cascade. Its concentration in the intestinal mucosa is increased in children with active Crohn disease (3). In The Netherlands, in 1992, the first patient with refractory Crohn disease (a 13-year-old girl) was successfully treated with infliximab (4). In the past decade, infliximab has been shown to be effective and safe for the induction and maintenance of remission in adult patients with moderate to severe Crohn disease with or without fistulas (5–10). In children, noncontrolled studies of infliximab have produced similar results (11–15). The aim of this study is to describe the experience with infliximab in all pediatric patients with severe Crohn disease in The Netherlands.
MATERIALS AND METHODS
A study group of the Dutch pediatric gastroenterological society composed a consensus guideline for infliximab treatment of children with severe Crohn disease (Table 1). Subsequently, all pediatric gastroenterology units in The Netherlands were solicited to report data on infliximab-treated children and adolescents with Crohn disease. The participating hospitals were visited, and data on patient characteristics, disease history, previous treatment, surgery, complications, and effect of infliximab treatment were extracted from the medical record. Data collection was closed on January 1, 2003.
A modified Pediatric Crohn Disease Activity Index (PCDAI) (16,17) was calculated before the first infusion of infliximab and 4 weeks after the first infusion (initial response). In patients receiving infliximab maintenance therapy, the modified PCDAI was calculated 4 weeks after the last administered infusion. Clinical response was defined as good if the index was ≤10 or showed a decline of ≥20 points. In fistulous disease, response was considered good if fistula closure or cessation of drainage was maintained for >4 weeks by physical examination.
Between October 1, 1992, and January 1, 2003, 30 patients (15 girls, 15 boys) were treated in seven hospitals according to the treatment guidelines. Thirteen had refractory Crohn disease (without fistulas), 16 had active disease with fistulas and 1 had metastatic Crohn disease (Table 2). The mean age at diagnosis was 11.4 years (range, 2.7–16.8 years). All patients were refractory to drug treatment and had been treated with 5-amino-salicylic acids, high-dose corticosteroids for 3 weeks or more and azathioprine for 4 months or more without success, or they had become intolerant to the above-mentioned drugs.
The mean age at the start of infliximab therapy was 14.1 years (range, 7.2–18.2 years). At the start of treatment, 20 patients (67%) had had Crohn disease for >2 years. The mean duration of follow-up was 25.3 months (range, 4–122 months). During the infliximab treatment, 28 patients also used azathioprine or methotrexate and 18 patients used corticosteroids (Table 2). In total, 212 infliximab infusions were administered, 1–30 per patient (mean, 7.1).
Patients With Refractory Crohn Disease Without Fistulas
Thirteen patients had active Crohn disease despite high-dose corticosteroids and/or azathioprine administration. These refractory patients had a mean MODIFIED PCDAI of 29.2 (range, 15–45) before the first infusion of infliximab. Four weeks after the first infusion, mean MODIFIED PCDAI was 9.2 (range, 0–35). Twelve patients (92%) showed good initial response (MODIFIED PCDAI of ≤10 or a decline of ≥20 points 4 weeks after first infusion). Six patients (46%) had sustained good response to infliximab therapy after a mean period of 20 months (Fig. 1). Two patients (patients 2 and 8) achieved stable clinical remission and infliximab therapy was discontinued (Table 2). Patient 8, diagnosed 11 months before his first infliximab infusion, achieved prolonged remission after one infusion. As in all of the other patients, the patient had first been treated with 5-aminosalicylic acids and corticosteroids. When that failed, he received azathioprine. He received infliximab because remission was still not achieved. The fact that infliximab treatment was given early in the disease course may explain the prolonged remission achieved after only one infusion. The other 4 patients with sustained good response (patients 1, 3, 11 and 12) are still receiving infliximab therapy with modified PCDAI scores of 0–5, four weeks after the last infusion. infusions are given every 8 weeks unless there is evidence of disease exacerbation, then the interval is shortened to sustain remission.
Six of the 13 refractory patients had growth impairment (a change of at least −1.0 SD for height). After the start of infliximab treatment, three (patients 2, 3 and 12) resumed normal linear growth velocity. They are still receiving maintenance infliximab treatment. The other three patients did not resume normal linear growth velocity. Two (patients 4 and 10) became unresponsive to infliximab and the treatment was discontinued. The third patient (patient 13) was the first patient to be treated with infliximab. She was treated with two consecutive infusions, and maintenance therapy was not considered at that time (4).
Seven of the 13 refractory patients had no clinical response to repeated infliximab infusions and therapy was discontinued. Five of these 7 patients underwent total or subtotal colectomy and in one patient, colectomy is planned.
Patients With Active Crohn Disease and Fistulas
Sixteen patients had active Crohn disease with fistulas—11 with perianal fistulas only, 3 with rectovaginal fistulas, 1 with both perianal and rectovaginal fistulas and 1 with abdominal wall fistulas. Continued draining fistulas despite antibiotics and immunomodulatory treatment were the indication for infliximab treatment.
Nine of 16 patients (56%) had good clinical response to infliximab therapy (Fig. 1). In two (patients 24 and 29), fistulas closed after three infliximab infusions. In the first patient, the fistulas are still closed after follow-up of 36 months. In the second patient, a new fistula developed 9 months after infliximab therapy was discontinued. The fistulas of seven patients (patients 14, 18, 22 and 25–28) stopped draining after infliximab therapy. In 2 patients (17 and 23) fistulas did not close or cease draining; however, the Crohn disease activity diminished and infliximab treatment was continued (modified PCDAI not available).
Five patients were unresponsive to therapy. Two patients (15 and 21) underwent colectomy after infliximab failure. In 1 patient (patient 20), surgical correction of the fistulas is planned. Another patient (patient 16) was an 11-year-old boy with refractory colonic Crohn disease (modified PCDAI 55 before infliximab therapy). He had extensive abdominal wall fistulas and had undergone several resections, stoma revisions and fistula correction before he came to The Netherlands for treatment. He was treated for several months with total parenteral nutrition, corticosteroids, azathioprine and repeated surgical intervention before infliximab was started. Five months later, uncontrollable bacterial sepsis developed with multiorgan failure and the patient died. The sepsis may have originated from an abscess located near a stenosis in the colon. The patient was leukopenic, probably because of long-standing azathioprine therapy.
Patient With Metastatic Crohn Disease
Patient 30 had metastatic Crohn disease in the skin of his penis and scrotum with granulomata identified on biopsy of the affected skin. There was no sign of disease in the gastrointestinal tract (18). His edema and tissue inflammation diminished after a single infliximab infusion. The patient received repeated infusions for a year followed by surgery.
Analysis of response of the entire cohort according to total of infliximab infusions received was also performed. The patients showing response to infliximab therapy received 1 to 30 infusions (Fig. 2). The patients who did not show response to infliximab therapy received 2 to 8 infusions (Fig. 3).
Adverse Effects of Infliximab Therapy
Six of the 30 patients (20%) had an immediate allergic reaction during infusion. One of the patients received only corticosteroids as concomitant therapy. The other five patients received azathioprine (three with simultaneous corticosteroids) as concomitant therapy. Corticosteroids and an antihistamine were administered intravenously, after which the reactions resolved. These medications were given as prophylaxis before subsequent infusions. One patient (patient 13) experienced a severe allergic reaction with dyspnea, facial edema and hypoxemia after the fourth infliximab infusion that improved after treatment with corticosteroids, antihistamines and epinephrine intravenously. Nine years had elapsed between her second and third infusions. She received no further infliximab therapy. Antibodies to infliximab were not routinely checked in our patients.
Seven patients (23%) experienced other adverse effects. Six reported headache, muscle ache and nausea after infusions. One boy (patient 23) developed arthritis of the hip joint after the second infliximab infusion. It is unclear whether this adverse event was caused by infliximab. Neither of the patients experienced autoimmune phenomena.
This study describes the experience with infliximab therapy in a cohort of Dutch children and adolescents with refractory Crohn disease. This is the longest followed pediatric cohort receiving repeated infusions of infliximab. After a mean follow-up of 2 years, 53% of the patients have continued good clinical response to infliximab therapy. These results are comparable to other recently reported cohorts of pediatric and adult patients with Crohn disease (10,14).
Because the PCDAI (15) is difficult to apply in daily practice and requires laboratory examinations, we used a modified PCDAI, which was recently validated and proven to be as accurate as the PCDAI (16). In the modified PCDAI, only clinical parameters are evaluated in order to reduce discomfort for the patient. The cutoff score for remission is 15 according to the PCDAI (19) and 10 according to the modified PCDAI.
We observed a good clinical response as shown by regained normal linear growth velocity in three of six patients with growth retardation after initiation of infliximab treatment. Ineffectively controlled inflammation with subsequent chronic malnutrition is an important factor for growth impairment in children with Crohn disease (20). Conversely, normal growth is a marker of treatment success.
In our study, the response of patients with fistulas to infliximab therapy was scored as closure or nondrainage. The fistulas were not routinely imaged on follow-up. However, infliximab treatment does not induce disappearance of fistulous tracts, irrespective of therapeutic response (21).
Nonresponsiveness to infliximab occurred in 47% of our patients. Our results suggest that patients who remain in remission on infliximab after receiving nine infusions will remain responsive to the medication. It is of great importance to find clinical, biochemical, immunologic or genetic markers to predict nonresponsiveness. Early reactivation of the inflammatory cascade, higher serum tumor necrosis factor-levels and antibody formation are influencing factors (22–24). All but two patients (patients 6 and 24) received concomitant immunomodulation. The formation of human antichimeric antibodies was not routinely checked. Therefore, it is not possible to determine whether the absence of concomitant immuno-modulation or the formation of human antichimeric antibodies are factors associated with nonresponsiveness to infliximab.
Allergic reactions during infliximab infusion occurred in 20% of our patients but resulted in discontinuation of therapy in only one patient who experienced a severe systemic reaction after a long infliximab-free interval. The development of systemic reactions after an infliximab-free interval has not been previously reported in a pediatric patient (25). Another adverse effect of infliximab therapy is the increased risk for infections. In our study, one boy died of sepsis after treatment with infliximab. This patient was malnourished, had undergone multiple surgical procedures, and was leukopenic as a consequence of azathioprine therapy. Nonetheless, severe infections have been previously reported in infliximab-treated patients, and they should be diagnosed early and treated promptly. Until now, infliximab therapy has been considered safe in the short term. However, it is clear from our data that maintenance infliximab treatment is associated with a risk for severe infections and a relatively high rate of allergic reactions.
The mean follow-up of our patients was 2 years (maximum, 10 years). No malignancies were seen. However, this is much too short a time to conclude that infliximab is a safe drug in the long term.
The majority of our patients had had Crohn disease for more than 2 years when infliximab treatment was started and all were resistant to conventional therapy. The optimal dosing scheme for infliximab treatment is still unknown. Concomitant immunosuppressive therapy seems to be associated with decreased immunogenicity and fewer adverse effects (26). It may be more effective to introduce infliximab earlier in the disease process instead of waiting until all conventional therapy has failed since the early stages of this condition may be more susceptible to immunomodulation (11). Moreover, debilitating side effects of corticosteroids may be avoided while quality of life is improved. Our results suggest that infliximab maintenance be given at intervals of 6–8 weeks.
Infliximab is an effective therapy in approximately half of the patients with refractory pediatric Crohn disease with or without fistulas. Approximately half of our patients, however, become nonresponsive to infliximab therapy. In children with Crohn disease, randomized controlled studies are mandatory to further assess short and long-term safety, responsiveness and optimal therapeutic strategies of infliximab therapy.
The authors thank Freddy Kokke, Maarten Sinaasappel, Jan E. A. R. de Schryver, Diederik K. Bosman and Marc A. Benninga for their support of this study.
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