The duration of effect of infliximab maintenance treatment in paediatric Crohn’s disease is limited

Authors


Dr C. I. de Bie, Department of Pediatric Gastroenterology, Erasmus MC – Sophia Children’s Hospital, Dr. Molewaterplein 60, Rotterdam, 3015 GJ, The Netherlands.
E-mail: c.i.debie@erasmusmc.nl

Abstract

Aliment Pharmacol Ther 2011; 33: 243–250

Summary

Background  Infliximab is effective for induction and maintenance of remission in children with moderately to severely active Crohn’s disease (CD).

Aim  To evaluate the long-term efficacy of infliximab treatment in paediatric CD.

Methods  In this observational, multicentre study, all paediatric CD patients in The Netherlands treated with infliximab from October 1992 to November 2009 and with minimal follow-up of 3 months since start of infliximab, were studied.

Results  One hundred and fifty-two CD patients [81M; median age at start of infliximab 15.0 years (IQR 13.1–16.4)] received a median number of 10.5 infliximab infusions (IQR 6–21). Median follow-up after start of infliximab was 25 months (IQR 13–40). Kaplan–Meier analysis showed that the cumulative probability of losing response to infliximab in patients who initially required repeated infusions was 13%, 40% and 50% after 1, 3 and 5 years, respectively. Seventy-four patients (49%) needed dose adjustments, with a median time to any adjustment of 6 months.

Conclusions  Duration of effect of infliximab is limited as 50% of patients on infliximab maintenance treatment lose their therapeutic response after 5 years. Dose adjustments after start of infliximab are frequently needed to regain therapeutic benefit. These findings emphasise the need for effective, long-term treatment strategies for paediatric CD.

Introduction

Infliximab (IFX; Remicade, Centocor, Malvern, PA, USA) is a chimeric monoclonal antibody (75% human, 25% murine) that binds with high affinity and specificity to tumour necrosis factor-α (TNF-α),1 a pro-inflammatory cytokine with increased expression in the inflamed intestinal mucosa of children with active Crohn’s disease (CD).2

Since the first use of IFX for CD in 1992 in a 13-year old girl,3 several small nonrandomised, nonplacebo controlled studies4–9 and a randomised multicentre open-label study10 have demonstrated the efficacy of IFX to induce and maintain clinical remission in children with moderate-to-severe CD. IFX has greatly improved the therapeutic options for refractory paediatric CD. Although IFX has a good short-term safety profile,9–12 there are concerns about the long-term safety aspects, especially since postmarketing surveillance reported on the occurrence of 18 cases of hepatosplenic T cell lymphoma (HSTCL) (data on file, Centocor). This aggressive form of non-Hodgkin’s lymphoma occurred in predominantly male adolescents and young adults with inflammatory bowel disease (IBD; mostly CD) who had been treated with anti-TNF-α and thiopurines.13

To date, data on long-term efficacy of IFX in paediatric CD are still limited. A recent study by Hyams et al.14 showed that during the third year of IFX maintenance therapy, 33% of patients had sustained remission (defined as clinically inactive disease not requiring corticosteroids or surgery). In addition, our previous study9 demonstrated that sustained clinical response after cessation of IFX treatment or on IFX maintenance therapy was seen in 70% of patients after a mean follow-up of 41 months.

To avoid exposure and toxicity in the patients who will not benefit from IFX therapy in the long-term, it is important to find predictors of prolonged response. Episodic treatment has been associated with higher relapse rates compared with scheduled maintenance treatment both in adults and children.12, 15 Other clear risk factors for IFX failure have not been identified in children, except for the possible influence of disease duration before start of IFX treatment. Two paediatric studies have reported prolonged duration of response after IFX treatment when the drug was initiated early in the disease course,4, 7 but we were not able to confirm this difference in our previous study.9

The primary aim of this study was to evaluate the long-term efficacy of IFX treatment in a national cohort of paediatric CD patients treated with IFX. The secondary aim was to examine whether clinical factors, such as gender, age at diagnosis, disease location and disease duration before start of IFX, were associated with treatment outcome.

Materials and methods

Patients

All paediatric CD patients treated with IFX since 1992 by paediatric gastroenterologists in The Netherlands were reviewed. After the appearance of a national consensus guideline on the indications and use of IFX in children with refractory CD, a database was initiated in 2002 with the purpose to audit IFX treatment given by paediatric gastroenterologists in The Netherlands. Patients who received IFX in the period 1992–2002 were retrospectively included in the database (= 22).

Patients were included in this study when IFX was started before the age of 19 years and follow-up was at least 3 months after initiation of IFX treatment. Patients who did not receive a three-dose induction scheme at 0, 2 and 6 weeks and/or were treated episodically, were excluded. Patients who initiated treatment before June 2007, were also included in our previous studies.9, 16

Data on patient characteristics, disease history, previous and concomitant treatments were recorded. In addition, number and schedule of IFX infusions, outcome of IFX treatment, adverse events, surgery and treatment in case of IFX failure were extracted from the medical records. Data were collected until November 2009.

Definitions

The outcome of IFX treatment was defined as prolonged response, IFX requirement, loss of response, or nonresponse. Patients who maintained good clinical response minimally 3 months after IFX treatment stopped, were classified as having a prolonged response. Good clinical response was based on the judgment of the treating paediatric gastroenterologist. IFX requirement indicated that repeated IFX infusions were needed to maintain good clinical response. Adjustments in treatment schedule (dosage increase up to 10 mg/kg and/or shortening of the interval between two infusions) were allowed in these patients. Patients with loss of response had an initial good clinical response to IFX maintenance treatment, but eventually there was a need for surgery or withdrawal of IFX (including patients with recurrent allergic reactions despite prophylaxis) and switch to other medical therapy. Finally, nonresponse was defined as no clinical response to a three-dose IFX induction scheme and withdrawal of IFX after three infusions in total. Treatment outcome was considered successful in case of prolonged response or IFX requirement.

Statistical analysis

Data were collected and analysed in spss (version 15.0, SPSS, Inc., Chicago, IL, USA). Descriptive statistics were calculated as percentages for discrete data and medians with interquartile ranges (IQR) for continuous data. Kaplan–Meier analysis was used to estimate the cumulative probability of losing response to IFX treatment over time. Time to event was analysed from the date of IFX initiation until the date of loss of response to IFX, or last known follow-up. To analyse predictive factors of IFX failure among categorical baseline characteristics (i.e. gender, disease location at diagnosis, initiation of IFX within 1 year after diagnosis, previous bowel surgery), univariate analyses with log-rank test were used. Multivariate Cox proportional hazards regression was used to identify independent variables predictive of IFX failure. The proportional hazards assumption was checked using log-minus-log survival plots. To assess the relation between treatment outcome and adverse events, Fisher’s exact test was used. All reported P-values are two-sided. P-values <0.05 were considered significant.

Results

Patient characteristics

Between October 1992 and November 2009, 188 paediatric patients in The Netherlands were treated with IFX in 13 hospitals. Thirty-six patients were excluded because of the following reasons: follow-up <3 months (= 6), no administration of a three-dose induction scheme (= 26), episodic treatment (= 3) and lost to follow-up (= 1).

Characteristics of the 152 included patients are shown in Table 1. The median age at start of IFX treatment was 15.0 years (IQR 13.1–16.4) after a median disease duration of 1.8 years (IQR 0.8–3.0). All patients but five were refractory to conventional treatment. These five patients received first-line IFX therapy because of severity of colonic disease at presentation (= 1),17 perianal fistulas in the presence of juvenile idiopathic arthritis (= 1) and complex perianal fistulas at presentation (= 3).

Table 1.   Patient characteristics at start of infliximab treatment (= 152)
  1. IQR, interquartile range.

Gender (male), n (%)81 (53)
Age at start treatment (years), median (IQR)15.0 (13.1–16.4)
Disease duration before start of infliximab (years), median (IQR)1.8 (0.8–3.0)
Disease location at diagnosis, n (%)
 Small bowel13 (9)
 Colon43 (28)
 Both95 (63)
 Isolated perianal fistulas1 (1)
Previous surgery, n (%)32 (21)
 Bowel surgery16 (11)
 Fistula correction15 (10)
 Both1 (1)
Previous medication, n (%)
 Corticosteroids136 (90)
 Exclusive enteral nutrition63 (41)
 Thiopurine143 (94)
 Methotrexate38 (25)
 5-Amino-salicylic acids99 (65)
Indication for infliximab, n (%)
 Refractory luminal disease105 (69)
 Refractory luminal disease and perianal fistulas19 (13)
 Refractory luminal disease and growth retardation12 (8)
 Perianal fistulas11 (7)
 First line5 (3)

Majority of patients (= 133) received a three-dose induction scheme at 0, 2 and 6 weeks followed by maintenance treatment. Sixteen patients (11%) received an induction scheme only. In three patients (2%), IFX was stopped after the induction scheme, but treatment was restarted when disease relapsed.

Outcome of IFX treatment

Median duration of IFX treatment was 16 months (IQR 7–34, range 2–132). In total, 2291 infusions were administered (median 10.5, IQR 6–21, range 3–86). Patients were followed for a median of 25 months (IQR 13–40, range 3–132) after start of IFX treatment, with 20 patients (13%) having a follow-up of more than 5 years.

Analysis of the entire cohort demonstrated that 15 patients (10%) had a prolonged response of at least 3 months after cessation of IFX therapy, 92 patients (61%) required repeated IFX infusions, whereas 40 patients (26%) had loss of response and five patients (3%) had no initial response to treatment.

Figure 1 shows follow-up of paediatric CD patients treated with IFX. Number of patients on IFX maintenance treatment decreased during the years due to discontinuation of treatment or reaching the end of the follow-up period. Majority of prolonged responders was treated with IFX because of isolated fistulizing disease (9/15), and received a three-dose induction scheme only (10/15). In the five remaining patients, IFX was stopped because of good clinical effect. CRP levels 3–7 months after cessation of IFX were available in nine patients, with a median level of 4 mg/L (IQR 3–10). Seven patients (47%) remained in remission during a median follow-up of 18 months (range 3–29 months). IFX was restarted in three out of the eight patients with relapse of disease and this was successful in two of them.

Figure 1.

 Outcome of infliximab according to duration of treatment in 152 paediatric Crohn’s disease patients. Patients with infliximab requirement drop out, because treatment is discontinued (prolonged response, loss of response), or end of follow-up is reached.

Forty-six per cent (42/92) of the patients who required repeated IFX infusions, received concomitant medication at the end of the follow-up period: thiopurines (= 26), methotrexate (= 8), 5-amino-salicylic-acids (= 7) and corticosteroids (= 1). Four of the six patients requiring IFX after 5 years continued IFX treatment until the end of the follow-up period (range 61–81 months). The remaining two patients lost response after 69 and 101 months, respectively.

Kaplan–Meier analysis showed that the cumulative probability of losing response to IFX in patients who required repeated infusions, was 13% (±3%), 40% (±6%) and 50% (±9%) after 1, 3 and 5 years, respectively (Figure 2).

Figure 2.

 Kaplan–Meier analysis of duration of infliximab treatment in paediatric Crohn’s disease patients who initially required repeated infusions [= 132: patients with infliximab requirement (= 92) and loss of response (= 40)]. Discontinuation of treatment is caused by loss of response to infliximab maintenance therapy.

Adjustments in treatment schedule

Adjustments in treatment schedule at any time during follow-up were made in 74/152 (49%) of the patients. In 28 of the 40 patients who lost response to IFX (70%), an adjustment in treatment schedule was made before it was decided that IFX treatment had failed. Forty out of 92 (44%) patients with IFX requirement needed intensification of treatment, which was temporary in twelve patients. The median time to any adjustment in treatment schedule was 6 months (IQR 3–11). The timing of adjustments in treatment schedule is displayed in Figure 1.

Fifty-four patients (73%) had initial adjustment with a decreased interval of 4–7 weeks between two infusions, in 16 patients (22%) the initial adjustment was a dosage increase and in two patients both adjustments were made at the same time. In two patients, the sequence of the adjustments was unknown. Eventually, 32 of the 74 patients (43%) needed both a decrease in interval between two infusions and an increase in dosage.

Clinical predictors of IFX failure

None of the following factors were predictive of IFX failure in univariate analysis (log-rank test): disease location (= 0.75), initiation of IFX within 1 year after diagnosis (= 0.73) and previous bowel surgery (= 0.26). There was a trend towards a higher risk of IFX failure in female patients (= 0.063). As gender did not meet the proportional hazards assumption, we had to perform a stratified multivariate proportional hazards analysis, as displayed in Table 2. Again, we found no independent predictors of IFX failure.

Table 2.   Predictors of infliximab failure (i.e. nonresponse or secondary loss of response) in stratified multivariate Cox proportional hazards regression analysis
 HR95% CIP
  1. Analysis was stratified according to gender.

  2. HR, hazard ratio; CI, confidence interval; IFX, infliximab.

Age at diagnosis0.990.88–1.110.86
Disease location at diagnosis
 Small bowel1  
 Colon1.680.38–7.400.50
 Both1.550.36–6.660.55
Initiation of IFX within 1 year after diagnosis0.830.40–1.700.61
Previous bowel surgery1.410.61–3.250.42

Treatment in case of IFX failure

Primary or secondary IFX failure was seen in a total of 45 patients. In most patients (= 35) maintenance treatment with an immunomodulator, including thiopurines (= 20) or methotrexate (= 15), was continued or restarted. Twenty-four patients underwent surgery (53%): bowel surgery in 19 patients, fistula correction in two patients and both bowel surgery and fistula correction in three patients. The median time between start of IFX treatment and surgery was 15.5 months (IQR 4–24). Despite the need for surgery, IFX was continued in twelve patients: eight were still being treated with IFX at the end of the follow-up period, three patients eventually needed other medication and one patient was unsuccessfully treated with adalimumab and switched back to IFX treatment. There was a great variety in other treatment strategies used after IFX failure: adalimumab (= 20), corticosteroids (= 6), exclusive enteral nutrition (= 4) and/or restart of IFX (= 5). This latter treatment strategy was successful in two patients, but they required IFX again at the end of the follow-up period. A small minority of patients was treated with certolizumab (= 2), thalidomide (= 1) or anti-CD3 (= 2).

Adverse events

Among the entire cohort of patients, 17 patients (11%) experienced a type 1 allergic reaction during infusion. Reactions resolved spontaneously or after administration of intravenous corticosteroids and/or an antihistaminic. Treatment with IFX had to be discontinued in three patients because of recurrent allergic reactions despite prophylaxis. In total, 25 patients (16%) developed a mostly mild infection during treatment with IFX (e.g. gastroenteritis, upper respiratory tract infection, pneumonia, herpes infection, fungal infection, Clostridium colitis). However, one patient developed uncontrollable bacterial sepsis 5 months after start of IFX and died (previously published by de Ridder et al.16). Another serious infection (severe reactivation of EBV infection) was seen in a 12-year old patient, who required temporary discontinuation of IFX treatment. A third patient refused further treatment with IFX because of a range of side effects (frequent upper respiratory tract infections, headache and mood swings). There was no significant difference in occurrence of infections between successfully treated patients and patients in whom IFX therapy failed (14% vs. 22%; = 0.24).

Twelve patients (8%) reported a wide variety of skin eruptions (e.g. eczema, psoriasiform lesions) during the course of IFX treatment, but there was no need for discontinuation of treatment. There was no significant relation between the occurrence of skin eruptions and treatment outcome (8% in successfully treated patients; 9% in patients in whom IFX therapy failed; = 0.75). No gender differences were found in the occurrence of allergic reactions, infections and skin eruptions (= 1.0; = 0.38; = 1.0).

One patient developed a basal cell carcinoma on the scalp 27 months after start of IFX therapy. Drug-induced lupus was seen in one patient, who discontinued treatment and switched to adalimumab. No other autoimmune phenomena were observed. Serum sickness-like disease, demyelination and heart failure18 were not observed in this cohort of patients.

Discussion

Our study describes the longest follow-up until now of a large, multicentre cohort of paediatric CD patients receiving induction with IFX followed by scheduled maintenance treatment in a majority of patients. Although IFX treatment is effective in children with refractory CD, our study shows that the therapeutic effect decreases over time with loss of response in 50% of patients who initially required repeated infusions, after 5 years. Adjustments in treatment schedule, decreased intervals and/or dosage increases, were required in 49% of the patients to maintain clinical response, with a median time to any adjustment of 6 months.

Recently, another large multicentre cohort study reported on the long-term outcome of IFX maintenance therapy in paediatric CD.14 This study showed that 33% of patients discontinued IFX treatment after 3 years due to several reasons (elective, loss of response, primary nonresponse, allergy). The results in frequency and timing of dose adjustments were comparable with our data. As our study only examined IFX discontinuation due to loss of response, these outcomes are somewhat difficult to compare. However, it seems that discontinuation of IFX due to loss of response occurred more frequently in our cohort of patients (40% loss of response after 3 years). An explanation for this difference could be the earlier introduction of IFX in the USA: the median interval between diagnosis and start of IFX was 9 months compared to 1.8 years in our study. This probably indicates more severe and complicated disease courses in our patients, which is reflected by the larger proportion of patients who underwent surgery before IFX initiation in our study (21% compared with 6% in the study of Hyams et al.). Another reason for the difference in loss of response could be the higher frequency of concomitant use of corticosteroids (9% at 3 years of follow-up compared to 1% in our study).

Our study found a trend towards a higher risk of IFX failure in female patients. Interestingly, male IBD patients seem to have the highest risk of developing HSTCL. It could be hypothesised that male patients achieve higher serum IFX concentrations compared with female patients. Pharmacokinetic differences have been found in male and female adult IBD patients treated with IFX.19 These findings warrant further investigation. In contrast with two previous studies,4, 7 we did not find an association between treatment outcome and disease duration before start of IFX. This may be explained by several factors. In the first study, only one IFX infusion was administered, whereas all patients in our study received induction with IFX usually followed by scheduled maintenance treatment. Current CD treatment guidelines20, 21 recommend a three-dose induction scheme and scheduled maintenance treatment, indicating that a single infusion is less effective for maintenance of response. In the second study, treatment effect was determined already after 18 weeks, whereas our study assessed treatment outcome after a median of 25 months. In addition to disease duration, disease location has been suggested as a predictor of response to IFX. Two adult studies have shown that patients with isolated colonic disease were more likely to respond to IFX, at least on the short-term.22, 23 In our cohort, we did not find a relation between disease location and treatment outcome, which might have been caused by differences in distribution of disease locations between adults and children.24 A recent study demonstrated that adult patients with objective evidence of inflammation (high CRP level and/or mucosal lesions at endoscopy) had the best clinical results with IFX.25 These factors were not assessed in our study.

Infections and infusion reactions were the most frequently observed complications of IFX treatment in our study. Infections were seen in 16% of patients and were mild, except in two patients. Allergic reactions during IFX therapy occurred in 11% of our patients, which is comparable to previous reports.9, 26 One young man developed a basal cell carcinoma on the scalp at 18 years of age, 27 months after start of IFX therapy. Before IFX monotherapy, he was treated with azathioprine and methotrexate. Nonmelanoma skin cancer (NMSC) has been reported before in adult IBD patients on IFX treatment.18, 27–29 A recent study showed that the increased risk for NMSC was especially associated with thiopurine use, but also, to a lesser extent, with biological treatment.30

Hepatosplenic T cell lymphoma was not observed in our cohort; our patient population is relatively small and follow-up too short to detect this extremely rare complication. The alarming effect that reporting of HSTCL had on paediatric gastroenterologists probably caused a decrease in the concomitant use of thiopurines after initiating IFX therapy. In our study, only 28% of patients, who required repeated infusions, received concomitant thiopurines, compared with 64% of the patients in our previous study.9

Our data should be interpreted in the context of the following limitations. First of all, the number of patients with a follow-up of more than 3 years is limited, which can be explained by the relatively short clinical use of IFX. Long-term studies in larger populations of paediatric CD patients are needed to further determine the long-term effect of IFX. Secondly, our study is observational and thus a reflection of daily practice. Decisions concerning adjustments in treatment schedule or discontinuation of IFX treatment were based on the judgment of the paediatric gastroenterologist and did not follow a standardised protocol. As different schedules for patient visits were used, it was not possible to use the Pediatric Crohn’s Disease Activity Index (PCDAI) or other clinical scores to determine disease activity at set time points. Furthermore, there could be an overlap between patients with a prolonged response to IFX and IFX requirement. Majority of prolonged responders was treated with IFX before paediatric treatment guidelines were available and therefore only received a three-dose induction scheme. Current treatment guidelines do not recommend stopping successful IFX treatment, which has resulted in a decreasing number of prolonged responders in the last 2 years of our study. Vice versa, it was not routinely attempted to stop IFX in patients who required repeated infusions. Seven out of 92 patients (8%) with IFX requirement received IFX every 10 or 12 weeks at the end of the follow-up period. It is possible that these patients would have had a prolonged response after cessation of IFX. In the remaining 85 patients, the risk of flaring was probably considered too high, which is supported by the finding that 46% of these patients required an adjustment in treatment schedule. Another limitation of our study is the absence of data on the formation of antibodies against IFX. Previous adult and paediatric studies have shown that the development of these antibodies is associated with a reduced duration of response to IFX treatment.31, 32 We are also unaware of the effect of changes in concomitant treatment during IFX on treatment outcome. Finally, our study does not include paediatric CD patients older than 16 years whose treatment was initiated by an adult gastroenterologist. However, there is no reason to assume that these patients are different from patients treated by paediatric gastroenterologists.

In conclusion, the present study underlines that IFX is an effective therapy in children with refractory CD. However, there are concerns regarding the durability of long-term IFX maintenance treatment, as 50% of patients on IFX maintenance treatment lose their initial therapeutic response after 5 years. Dose adjustments after start of IFX are frequently needed to regain therapeutic benefit. In contrast to previous studies, loss of response was not found to be associated with disease duration or disease location. These findings emphasise the need for effective long-term treatment strategies for paediatric CD, as well as the need for predictors of response to IFX treatment to select the most suitable patients for this treatment. This will prevent exposure and toxicity in patients who will not benefit from IFX.

Acknowledgement

Declaration of personal and funding interests: None.

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