Therapies with enteral nutrition, corticosteroids, and immunomodulators are the mainstay of management protocols for children and adolescents with severe Crohn's disease (CD) (1). The disease course in children and adolescents is relapsing, interspersed with remission periods (2-4). In a Danish cohort (4) including adult patients, approximately 12% experienced only one attack, 1% a chronic continuous course, and the vast majority (87%) an intermittent course (relapsing periods interspersed with remission intervals). In the patients with continuous disease activity, the course was characterized by prolonged medical or surgical management. The most severe side effects of current management protocols include impaired growth, osteoporosis, risk of hepatic as well as pancreatic inflammation, and bone marrow suppression. The 20 year cumulative probability of intestinal resections was 47% in pediatric- compared with 71% in adult-onset CD patients in a regional unselected Danish cohort study (3,5).
A new approach to the management of CD has been the use of biologic response modifiers such as infliximab treatment in combination with azathioprine. Infliximab is a chimeric mouse-human monoclonal antibody that binds to soluble and membrane-bound tumor necrosis factor (TNFα), thus blocking its biologic effects. TNFα is a pro-inflammatory cytokine, which plays a key role in the pathophysiology of a number of inflammatory disorders, including CD. The efficacy of infliximab in short-term therapy as well as in maintenance therapy has been documented for adults with moderate to severe CD (6,7) and in fistulizing CD (8). In the ACCENT I trial (7), only 17% of the total number of patients were in remission after 8 weeks maintenance infusion regimen at the 54th week, indicating the advantage of a putative treatment algorithm to choose the patients who would benefit from such a regimen. In children, the beneficial clinical efficacy including a steroid sparing effect and healing of mucosa has been confirmed after infusions of infliximab given at weeks 0, 2, and 6 (9-12). In two studies, growth appeared to accelerate in response to infliximab (10,11). However, the clinical effect of infliximab can be transitory, with frequent relapses (up to 90%) within the first year despite concomitant immunosuppression (10). Infliximab treatment appears to be well tolerated (10), but anaphylactic symptoms in connection with the infusion, and symptoms caused by immunosuppression such as upper respiratory tract infections, herpes zoster, severe acute bacterial infections, and an increased risk of tuberculosis, have been described after treatment with infliximab (13-15). The side effects of corticosteroids are well known. In two studies of unselected cohorts of CD patients in Denmark and Minnesota, the clinical response to steroids was assessed as prolonged response (PRO) to steroids or steroid dependency (the need for repeated courses with prolonged outcome) (16,17). PRO was obtained in 44% (Denmark) versus 32% (U.S.) and steroid dependency in 32% versus 28%, respectively. These data were accessed by pattern recognition of the patient disease course after treatment with corticosteroids. Similarly, some CD patients may also benefit from a single infusion of infliximab, obtaining PRO, whereas others need repetitive treatment of infliximab in a dose-dependent way.
The aim of this study was to describe a clinical response to infliximab by pattern recognition in an unselected cohort of all Danish children and adolescents with active intestinal CD, thus being able to identify a pattern of the response to infliximab. Another aim was to report the side effects of infliximab treatment.
MATERIAL AND METHODS
The national Danish Crohn and Colitis Database of Infliximab was initiated in December 1998 to include all adult as well as pediatric CD patients treated with infliximab (18). During the study period from the 7th of September 2000 to the 7th of August 2003 all Danish CD patients treated at pediatric departments with infliximab were included in the database. This database includes all pediatric patients treated with infliximab treatment at the departments of Paediatrics, H:S Hvidovre Hospital and Odense University Hospital, Denmark. These two centers are the main referral institutions for treatment of inflammatory bowel disease of childhood in Denmark. During the same period, according to the database, a limited number of pediatric patients (4 patients aged 15-17 years) were treated at different adult gastroenterologic departments. The medical records of this population based pediatric cohort were reviewed. Data were extracted from the files as to sex, age, duration of disease, localization of disease, previous surgery, medical treatment before infliximab infusion and indications for infliximab, individual dosages, schedules, possible side effects, time to relapse, and subsequent treatment. Patients were considered eligible for treatment with infliximab, if the pediatric gastroenterologist considered their CD to be unresponsive or poorly responsive to current therapy or if they were dependent on corticosteroids (16). As a part of the routine of the pediatric departments, each patient and the family were verbally informed before treatment of the published experience with infliximab and the possible side effects.
A pilot study including 20 nonfistulizing CD patients (10 children and 10 adults) was undertaken to evaluate the definition of immediate and long-term outcome by pattern recognition in CD patients treated with infliximab (18). Thirty days after the first infliximab infusion, the clinical response was evaluated. Complete remission (CR), defined as total regression of symptoms (≤2 stools/day, no blood, pus, mucus, abdominal pain, and weight loss) (16), was seen in 45% and partial remission (PR) defined as regression of symptoms (≤4 stools/day, blood, pus, mucus, or abdominal pain less than daily, no fever, and weight loss) was obtained in 40% (16). Thirty days after intended end of infliximab treatment, PRO, defined as maintenance of CR or PR, was seen in 55% of the patients, infliximab dependence (ID), defined as relapse of symptoms within 30 days resulting in repeated infliximab infusions, was seen in 30%, and no response (NR) was seen in 15%.
The final definition of clinical outcome in the present study was subsequently assessed by the same pattern recognition as validated above. The immediate response was assessed 30 days after the first infliximab infusion, but the time for evaluation of long-term response was adjusted to 90 days after end of intended treatment. The definitions are outlined in Table 1 and illustrated in Figures 1 and 2. The definition of clinical activity in Table 1 was in accordance with previous published adult criteria (19). We were able to fulfill these criteria with our retrospective data. Duration of response was calculated as the number of days between the last intended infliximab infusion and the clinical relapse/end of the study period.
Data are presented as median (range) and mean (standard variation) values. Nonparametric statistics were used.
During the 3 year period, 24 pediatric patients with CD were treated with infliximab (Table 2). They were 9 (37%) boys and 15 (63%) girls, aged a median 15.4 (range 9.8-18.6) years with a history of CD of a median 26 (range 0.7-93) months. CD was localized in the colon and ileum in 11 (46%) patients, in the colon only in 10 (42%), in the oral cavity (aphthoid lesions or hyperplasia of gingiva or lips) and in the colon in 2 (8%), and in the ileum only in 1 (4%). Three (12%) patients had, in addition to their colonic involvement, concomitant perianal disease. The indication for infliximab treatment was steroid dependency, defined as the need for repeated courses of steroid to obtain prolonged outcome, in 8 (33%) patients and intolerance or insufficient response to nutritional treatment and azathioprine, despite having optimized treatment by monitoring white blood count and metabolite levels, in 16 (67%) (Table 2). All patients were treated intravenously with dosages of infliximab of 5 mg/kg to induce remission of disease. The treatment schedule was planned individually, and no increased dosage to 10 mg/kg was given. Seven patients were treated initially with infusions at 0, 2, and 6 weeks followed by infusions on demand, 12 patients had infusions every 6 to 8 weeks, and 5 patients had infusions on demand.
The growth was evaluated in the 10 children who had growth failure as a part of the indication for infliximab treatment. Growth failure was cessation of growth during a 6 month period. No significant effect on growth velocity was noted when comparing growth velocity before (mean 0.32 cm/month) and after treatment (0.42 cm/month) (P = 0.36). The growth was also evaluated in all children 17 years or younger, but no significant improvement was seen (before treatment mean: 0.35 cm/month, after treatment mean: 0.38 cm/month; P = 0.7).
A total number of 116 infusions were given (median 4/patient, range 2-11/patient). Thirty days after first infliximab infusion, 8 (33%) patients achieved CR, 10 (42%) PR, and 6 (25%) NR (Fig. 2). Ninety days after intended cessation of infliximab treatment, 7 (29%) patients obtained PRO, 10 (42%) became ID, and 6 (25%) had NR (Fig. 3). Two patients received only two infusions because of complete lack of response. The patients are described in Table 3. One patient emigrated and was lost to follow-up. Side effects were seen in four (17%) patients. Three developed anaphylactic symptoms, and the infusions were discontinued. In one patient, the treatment was later reintroduced successfully, supported with concomitant use of antihistamines and corticosteroids intravenously. One patient had episodes of serum sickness after each infusion and an episode of herpes zoster after the seventh infusion.
In this study, we have defined a pattern recognition of disease course to assess the responsiveness of infliximab in a national cohort of children with CD. This approach has not been attempted before neither in adults nor in children, nor have the results of infliximab treatment been reported in an unselected nationwide cohort of children. Several conclusions can be drawn about the responsiveness to infliximab from this retrospective study of children and adolescents with active intestinal CD. First, 71% percent of the children appeared to benefit (PRO or ID) from infliximab treatment with minor side effects when given episodically. Two patterns of prolonged responders were recognized, either a PRO after ending infliximab (29%) or dependency on repetitive infusions of infliximab (42%). The latter response was obtained in a dependent way because CR or PR was continuously accessible on repetitive infliximab infusions. Finally, side effects were noticed in four (17%) patients.
A few studies have described the immediate and long-term clinical course after infliximab treatment in children and adolescents with CD. Baldassano et al. (13) treated 21 pediatric patients with a single infusion of infliximab and obtained 50% improvements in Pediatric Crohn's Disease Activity Index (PCDAI) by week 2 and 30% improvement by week 12. Cezard et al. (10) reported a significant decrease in Harvey-Bradshaw index 3 months after three infusions with infliximab (weeks 0, 2, 6) in 21 children. However, 90% of their patients relapsed within 1 year despite continued immunosuppressant therapy. Lionetti et al. (9) also reported a significant decrease of PCDAI 4 weeks and 18 weeks after termination of treatment. In the patients with fistulas, CR (fistula completely closed) was reported in 54%, PR (a reduction of >50% in fistula diameter) in 23%, and minimal response (a reduction of <50% in fistula diameter) in 23%. The infliximab treatment was most effective in those patients with disease duration less than 1 year.
Our data support these studies, concluding that the initial clinical response to infliximab treatment was very good. However, in this study, many of the patients needed further infusions to maintain the initial response and thus became ID with the need of more infusions. We introduce the term “infliximab dependency” (ID) as an analogue term to steroid dependency. We have described the first pediatric CD patients in Denmark treated with infliximab, and they probably have a more complicated and longer lasting disease course compared with the subsequently treated patients. However, when initiating infliximab treatment, it has to be considered that a substantial number of patients will need repetitive infusions to maintain the response.
A significant effect on growth was demonstrated in the study of 10 children by Cezard et al. (10) and in the study of 18 children by Borrelli et al. (11). Our data does not support that infliximab improves growth velocity. However, this might be because of several reasons: all patients were having a chronic, continuous, active disease course, sufficient remission of CD may not have been induced to allow growth, the patients might have received corticosteroids preventing growth, or the observation period (0.5 year before and 0.5 year after) may have been too short. Our study and the studies by Cezard et al. (10) and Borrelli et al. (11) contain too a small number of patients to draw any final conclusions about growth improvement and infliximab treatment.
Infusion reactions to infliximab have previously been studied in children by Crandall and Mackner (20). They reported of 35 of 355 (10%) infusion reactions in 57 patients, of whom 13 needed medical treatment. The most common symptoms of immediate infusion reaction were flushing and shortness of breath, and the most common symptom of delayed infusion reaction were joint pain and swelling. Most reactions occurred during or after the second or third infusion. Our data of 3 patients having an immediate infusion reaction and 1 patient having a delayed reaction of a total of 24 patients do not differ from the previous pediatric studies.
In conclusion, a pattern recognition of disease course to infliximab treatment was identified. Infliximab was an effective treatment of severe CD also in pediatric patients, resulting in an immediate improvement in 71% (PRO + ID). However, a substantial number of the patients (42%) needed repetitive infusions to regain the initial response and as such, became dependent of infliximab (ID).
To justify repetitive infusions of infliximab, it is necessary in the future (1) to achieve data concerning the possible long-term side effects, (2) to evaluate whether the natural course of CD may be modified by infliximab and thus, whether it should be introduced earlier in the disease course, (3) to clarify the effect on growth, (4) to study whether the clinical effect vanishes over time, and (5) to elucidate whether the best long-term result are obtained when infliximab is used episodically (“on demand”) or as maintenance treatment given at regular intervals. The maintenance regimen probably gives the best outcome when soluble and membrane bound TNF is present at a certain level in the patients (21). Considering the lack of knowledge of the possible long-term side effects and the high cost of the treatment, we suggest that maintenance treatment may be given to children who benefit from infliximab in a dependent way.
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