What Is Known
- Half of children with Crohn disease treated by infliximab (IFX) present a loss of response.
- Published experiences of adalimumab (ADA) in children come mainly from tertiary centers where ADA is effective in nearly two-thirds of patients with IFX failure.
What Is New
- Approximately two-thirds of children with Crohn disease treated by ADA after failure to IFX had clinical benefit at the population level. Cumulative probability of ADA failure was 55% at 1 year.
- No serious adverse events were observed.
Crohn disease (CD) is a chronic progressive, destructive, and disabling condition (1). The worldwide incidence and prevalence of inflammatory bowel disease (IBD) are increasing in children (2–4). In the largest population-based registry EPIMAD, an increase in annual pediatric-onset CD incidence of 71% (from 6.5 to 11.1/105 inhabitants) was observed in Northern France from 1988 to 2007 (2). Patients with pediatric-onset CD have a more aggressive phenotype and frequently develop disease complications such as growth retardation and delayed puberty (5,6). The advent of anti-TNF agents has allowed significant progress in the treatment of pediatric CD refractory to standard medications. Infliximab (IFX) was the first biologic approved for the treatment of moderate to severe pediatric CD (7). A significant proportion of adult patients with CD—>10% per patient-year of IFX treatment in the long term—will lose response and will require an increase in dose and/or decrease in infusion interval (8).
Adalimumab (ADA) is a fully human monoclonal anti-TNF agent that demonstrated its clinical efficacy in pediatric CD in the IMAgINE trial, a phase III trial of induction and maintenance, associated with an improvement in height velocity and a decrease in C-reactive protein (CRP) (9). The published experiences of ADA in children come mainly from tertiary centers where ADA is effective in nearly two-thirds of patients with IFX failure (10,11). The ADA clinical efficacy, its effect on growth status, on nutritional status, and on biomarkers of inflammation, and its safety profile have never been evaluated at the population level in pediatric CD.
The aim of the present study was therefore to evaluate retrospectively the efficacy and safety profile of ADA after IFX failure in a population-based cohort of pediatric CD.
Cases included all of the patients younger than 17 years of age at CD diagnosis from January 2001 to December 2010 issued from the population-based registry EPIMAD and treated with ADA following IFX failure. Study area was northern France with 2 administrative areas: Nord (2,564,959 inhabitants) and Pas-de-Calais (1,459,531 inhabitants). The population younger than 17 years of age was as follows: Nord, 593,837; Pas-de-Calais, 332,228 (2 regions henceforth referred to as “Nord–Pas de Calais”), with a total of 925,902 children. Methodology of the EPIMAD registry was previously described in detail (12). Briefly, 4 interviewer practitioners collected data of all of the incident patients with IBD diagnosed by all of the adult and pediatric gastroenterologists (GEs) in the private and public sectors. Only children living in the studied area at the time of CD diagnosis were included. Each GE reported all of the patients seeking consultations for the first time with clinical symptoms compatible with IBD; he/she was contacted by phone at least 3 times per year by an interviewing practitioner. This interviewer visited the GE's consulting office and collected data from charts on a standardized questionnaire for each new patient. The main data collected were age, sex, year of diagnosis, interval between onset of symptoms and diagnosis, and clinical, radiological, endoscopic, and histological findings at the time of diagnosis. Final diagnosis of CD was made by 2 expert GEs according to validated and previously published criteria (12). Only definite and probable patients with CD were included in the present study.
All of the data were extracted from charts of adult and pediatric GEs and from hospital medical records, and were collected using a predefined questionnaire specifically designed for the study. All of the records were reviewed for accuracy and completeness by a pediatric investigator (AJ).
The study period was defined as the time between IBD diagnosis and maximal follow-up. Among patients younger than 17 years of age at diagnosis and a CD diagnosis from January 1, 2001 to December 31, 2010 identified throughout the EPIMAD registry, we extracted all of the patients treated with ADA before the age 18 years following IFX failure.
Clinical and biological data were collected retrospectively at CD diagnosis, at ADA initiation, at the end of ADA therapy, and at maximal follow-up, and included age, sex, weight, height, date of IBD diagnosis, disease location, and behavior according to the Montreal classification (13), as well as CRP and orosomucoid levels. The following CD-related medications were recorded before ADA initiation, at ADA initiation, and at maximal follow-up: 5-aminosalicylic acid, systemic steroids, immunosuppressants (ISs) (azathioprine/6-mercaptopurine/methotrexate), and enteral nutrition (enteral). Indication for switching to ADA and all of the adverse events (AEs) were also collected.
Treatment response was assessed using the physician global assessment score (PGA) (14): PGA 1, inactive disease (no clinical activity); PGA 2, weakly active disease (clinical signs without repercussions on daily life); PGA 3, moderately active disease (clinical signs altering daily life); PGA 4, severely active disease (requiring hospitalization).
The primary outcome was “ADA efficacy,” defined as clinical remission (PGA = 1) or clinical response (decrease of at least 2 points of PGA score 6 months after ADA initiation). “Primary failure” was defined by the absence of clinical remission or clinical response at 6 months after ADA initiation. “Secondary failure” was defined by an increase in PGA score after initial ADA efficacy. Patients with steroid dependency were considered to be failure. “Optimization” was defined by an increase in ADA dose and/or a decrease in intervals between ADA injections. Growth and nutritional status were assessed by comparison between means of body mass index (BMI/age), height/age (H/A), and weight/height (W/H) z score from ADA initiation to maximal follow-up.
ADA safety was evaluated by reviewing all of the charts of patients. For every AE, time of onset, severity, concomitant IS therapy, and outcome were recorded. A serious AE was defined as any AE that resulted in hospitalization or prolongation of hospitalization, was fatal or life threatening, or led to significant disability as previously described (15).
Continuous variables were expressed as medians with interquartile ranges (Q1–Q3). Qualitative variables were given as frequencies and percentages. Cumulative probability of failure to ADA was estimated by the Kaplan-Meier method. The start date corresponded to the date of ADA initiation. The time to event was defined as the time between ADA initiation and ADA failure (including both primary and secondary failure). Regarding patients who did not fail to the treatment, the observation was censored at the date of maximal follow-up.
Because of the small sample size, nonparametric statistical tests were performed. Indicators at ADA initiation and maximal follow-up were compared by Wilcoxon signed-rank test for efficacy group on 1 side and for primary failure group on the other side. Data were analyzed with SAS software, version 9.3 (SAS Institute, Cary, NC). Statistical significance was considered to be P ≤ 0.05. The present study followed the regulations and instructions set up by the Comité National des Registres (approval no. 97107 and 983792) and was part of the “Programme Hospitalier de Recherche Clinique” PHRC IR 07 no. 2007-A00468-45.
Between January 2001 and December 2010, a total of 325 patients newly diagnosed as having CD and younger than 17 years of age were enrolled in the EPIMAD registry. A total of 147 patients received IFX treatment. Of them, 27 (8%) required treatment with ADA because of IFX failure, including 14 girls (52%), with a median age at CD diagnosis of 11 years (Q1 = 9; Q3 = 12). Demographic and clinical characteristics of the study population are listed in Table 1. Median disease duration at ADA initiation was 3 years (2; 4). At ADA initiation, a majority of children (n = 14; 60%) had ileocolonic disease (L3) and inflammatory behavior (B1) (n = 21; 78%).
Before ADA initiation, 26 children (96%) had exposure to azathioprine, 20 (74%) to methotrexate, 24 (88%) to systemic steroids, and 16 (59%) to enteral nutrition. Median age at ADA initiation was 15 years (12; 15). Median BMI z score was −0.8 (−1.5; 0.4), median z score W/H −0.7 (−1.2; 0.5), and median z score H/A −0.5 (−1.4; 0.7). When ADA was introduced, median CRP was 24 (5; 44) mg/L and median orosomucoid 1.7 (1.5; 2.6) g/L.
Indication for ADA treatment was loss of IFX response in 16 patients (60%), primary IFX failure in 4 (14%), and IFX intolerance in 7 (26%). IFX intolerance was defined as AE leading to IFX discontinuation. Median duration of IFX treatment was 13 months (8; 19).
Efficacy of ADA Treatment
Median follow-up of this cohort was 16 months (8; 26) after ADA initiation, and median duration of ADA treatment was 10 months (5; 19). ADA was effective in 19 patients (70%) and maintained efficacy was observed in 14 patients (52%) at maximal follow-up (Fig. 1). Primary failure to ADA was observed in 8 patients (30%), and loss of response (secondary failure) in 5 patients (19%). A total of 14 patients (52%) underwent an optimization during follow-up, including dose escalation in 6 patients, reduction of intervals between injections in 1 patient, and both in 7 patients. Response to optimization was observed in 10 patients (71%). According to Kaplan-Meier analysis, cumulative probability of failure to ADA treatment was 38.4% (22.7%; 59.9%) at 6 months and 54.9% (35.7%; 76.1%) at 1 year (Fig. 2). According to the indication of ADA treatment, ADA was effective in 7 of 7 (100%) children intolerant to IFX, in 11 of 16 (68%) children with secondary failure to IFX, and in 1 of 4 (25%) children in primary failure to IFX. At the date of the latest news, 17 patients were receiving ADA. Intestinal resections were performed in 5 patients after ADA initiation.
At ADA initiation, 5 patients (19%) received systemic corticosteroids and 3 patients (11%) received ISs (azathioprine: n = 2; methotrexate: n = 1). At maximal follow-up, 4 patients (15%) were receiving systemic steroids and 4 were receiving ISs (azathioprine: n = 2; methotrexate: n = 2). Concomitant IS was introduced in only 1 patient after ADA initiation. Among the 4 patients with concomitant IS therapy, 3 experienced ADA failure after 6 months.
Effects of ADA Treatment on Nutritional Growth Status and Growth
At maximal follow-up, median BMI z score was −0.2 (−1.5; 0.3), median W/H z score was −0.5 (−1.3; 0.3), and H/A z score was −0.2 (−1.3; 0.6). No significant changes in growth and nutritional status occurred during the study period (Table 2) in both groups (efficacy and failure). In patients with ADA efficacy (n = 19), median BMI z score was −0.2 (−1.1; 0.5), median W/H z score was −0.4 (−1.2; 0.4), and median H/A z score was −0.2 (−1.3; 0.9) at maximal follow-up. No significant changes in growth and nutritional status occurred during the study period (Table 2).
Effect of ADA Treatment on Inflammation
In patients with ADA efficacy (n = 19), a significant decrease in both median CRP (15 mg/L [4; 44] vs 9 mg/L [3; 19]; P = 0.05) and orosomucoid (1.6 g/L [1.5; 2.6] vs 1.1 g/L [0.8; 1.9]; P = 0.001) levels was observed from ADA initiation to maximal follow-up (Table 3). No significant changes were observed among patients with primary failure to ADA (n = 8).
Safety of ADA Treatment
A total of 11 patients (40%) experienced a total of 19 AEs. Main AEs were as follows: cutaneous (xerosis [dry skin], n = 6; depigmentation, n = 3; acne, n = 2; and psoriasis, n = 1), local reactions (pain, inflammatory reaction) at the injection site (n = 3), and transient arthralgia and/or myalgia (n = 4). None of them resulted in ADA discontinuation. There were no opportunistic infections or other infectious complications. AEs were observed in 4 of 7 children intolerant to IFX, 2 of 4 children with primary failure to IFX, and 5 of 16 children with secondary loss of response to IFX. No death or malignancy was observed.
We report on the efficacy and safety profile of ADA therapy in 27 pediatric patients with CD with IFX failure using a well-defined population-based registry. Approximately two-thirds of patients had clinical benefit after a median follow-up of 16 months after ADA initiation. ADA efficacy was observed in 100% of children intolerant to IFX, 68% of children with secondary failure to IFX, and only 25% of children with primary failure to IFX. As observed in adults (16), it appears that switching from IFX to ADA is more efficacious in patients who were IFX intolerant than in those with prior loss of IFX response.
Our results are comparable to reports on the ADA efficacy in pediatric CD (10,11,17,18). The rate of response was higher than in randomized clinical trials (RCTs) in both children treated with IFX and those who were IFX naïve (9). Differences in defining clinical response and clinical remission likely explain such discrepancy between RCTs and real-life experience. Primary nonresponse was observed in one-third of children, as reported in adults (19–21). Similarly to studies performed in adults (19,21), we observed secondary failure of ADA in 18% of children in the present pediatric study. Because of the deleterious impact of corticosteroids on growth in pediatric patients with CD, corticosteroid-free remission is a major therapeutic goal. Only 1 of 5 patients on steroids at ADA initiation could achieve steroid-free remission at maximal follow-up. This may be explained by the relatively short duration of follow-up. Indeed, RCTs had shown a significant positive impact of ADA on corticosteroid-free remission in both adults (22,23) and children (9).
The impact of anti-TNF therapy on biomarkers such as CRP has been extensively studied in IBD (24). There was a significant improvement in CRP and orosomucoid levels among patients who responded to ADA therapy.
Cytokines released from the inflamed intestine may impair growth through interference with insulin-like growth factor 1 (25). Normal growth is a surrogate marker of treatment efficacy in children with IBD. Effect of ADA on growth and nutritional status is poorly known, with no data in population-based cohorts. Our study did not demonstrate a significant improvement in nutritional status and growth of patients on ADA treatment. These results should be interpreted with caution because of small sample size. Furthermore, children included in our study presented no severe growth retardation and all of them were treated with IFX that is known to be associated with an improvement in growth pattern (26). Indeed, a recent study showed that clinical response to ADA therapy is associated with an improvement in linear growth, with a superior efficacy of ADA on growth in anti-TNF–naïve patients (27).
In our study, ADA therapy was well tolerated. No serious AEs were observed and none of them resulted in ADA discontinuation. There was no death or malignancy in the present population-based cohort. No opportunistic infections or others infectious complications were recorded. AEs were observed in 40% of patients. The most common AE was xerosis. No immediate or delayed hypersensitivity reaction requiring discontinuation of ADA was observed. Except in 1 study in which death secondary to sepsis was reported in 2 patients with concomitant therapy with IS and parenteral nutrition (11), no death has been reported in short-term follow-up of children with pediatric-onset CD receiving ADA (10,17,18,28). Prospective studies on ADA therapy with a long-term follow-up are required to better define the safety profile of this agent in pediatric CD.
We are well aware of the limitations of our study, first because of its retrospective nature. Some important variables such as pubertal staging or disease phenotype and localization at the end of follow-up are not available. Second, the available data did not allow the use of the Pediatric Crohn's Disease Activity Index that is more detailed and objective than the PGA score. We used a different definition of treatment response of the previous report not only with a decrease of at least 2 points of PGA but also by a clinical remission defined by PGA = 1. Moreover, no data on trough serum ADA and anti-drug antibodies were available. Despite our small sample size, results are consistent with those of previous studies. Moreover, our patients were identified from a large pediatric-onset IBD population-based registry covering a large area (9.3% of the French population) with well-documented cases allowing an exhaustive inclusion.
In conclusion, the present population-based study evaluating the efficacy and safety profile of ADA therapy in children suggests that ADA may be effective for the induction and maintenance of remission in children with CD who experienced IFX failure. These real-life data need to be confirmed in large prospective population-based cohorts to further assess the efficacy and safety of ADA therapy in children with IBD.
The authors thank the interviewing practitioners who collected data: N. Guillon, I. Rousseau, A. Pétillon, and B. Turck. They also thank all of the adult and pediatric gastroenterologists who participated in the present study and the Digestscience Foundation.
1. Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, et al. The natural history of adult Crohn's disease in population-based cohorts. Am J Gastroenterol
2. Chouraki V, Savoye G, Dauchet L, et al. The changing pattern of Crohn's disease incidence in northern France: a continuing increase in the 10- to 19-year-old age bracket (1988–2007). Aliment Pharmacol Ther
3. Lehtinen P, Ashorn M, Iltanen S, et al. Incidence trends of pediatric inflammatory bowel disease in Finland, 1987–2003, a nationwide study. Inflamm Bowel Dis
4. Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis
5. Vasseur F, Gower-Rousseau C, Vernier-Massouille G, et al. Nutritional status and growth in pediatric Crohn's disease: a population-based study
. Am J Gastroenterol
6. Gupta N, Bostrom AG, Kirschner BS, et al. Incidence of stricturing and penetrating complications of Crohn's disease diagnosed in pediatric patients. Inflamm Bowel Dis
7. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology
8. Gisbert JP, Panés J. Loss of response and requirement of infliximab dose intensification in Crohn's disease: a review. Am J Gastroenterol
9. Hyams JS, Griffiths A, Markowitz J, et al. Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. Gastroenterology
10. Rosh JR, Lerer T, Markowitz J, et al. Retrospective evaluation of the safety and effect of adalimumab therapy (RESEAT) in pediatric Crohn's disease. Am J Gastroenterol
11. Russell RK, Wilson ML, Loganathan S, et al. A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease. Aliment Pharmacol Ther
12. Gower-Rousseau C, Salomez JL, Dupas JL, et al. Incidence of inflammatory bowel disease in northern France (1988–1990). Gut
13. Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol
2005; 19 (suppl A):5–36.
14. Hyams J, Markowitz J, Otley A, et al. Evaluation of the pediatric Crohn disease activity index: a prospective multicenter experience. J Pediatr Gastroenterol Nutr
15. Food and Drug Administration Center for Drug Evaluation and Research. Guideline for industry—clinical safety data management: definitions and standards for expedited reporting. In: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH); 2007.
16. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med
17. Wyneski MJ, Green A, Kay M, et al. Safety and efficacy of adalimumab in pediatric patients with Crohn disease. J Pediatr Gastroenterol Nutr
18. Noe JD, Pfefferkorn M. Short-term response to adalimumab in childhood inflammatory bowel disease. Inflamm Bowel Dis
19. Peyrin-Biroulet L, Laclotte C, Bigard MA. Adalimumab maintenance therapy for Crohn's disease with intolerance or lost response to infliximab: an open-label study. Aliment Pharmacol Ther
20. Cordero Ruiz P, Castro Márquez C, Méndez Rufián V, et al. Efficacy of adalimumab in patients with Crohn's disease and failure to infliximab therapy: a clinical series. Rev Esp Enferm Dig
21. Swoger JM, Loftus EV Jr, Tremaine WJ, et al. Adalimumab for Crohn's disease in clinical practice at Mayo clinic: the first 118 patients. Inflamm Bowel Dis
22. Hanauer SB, Kamm MA, Panaccione R, et al. Steroid-free remission over 2 years in Crohn's patients receiving adalimumab: the open-label extension of the CHARM trial [abstract]. Gastroenterology
2008; 134 (4 suppl 1):A-490.
23. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology
24. Assa A, Hartman C, Weiss B, et al. Long-term outcome of tumor necrosis factor alpha antagonist's treatment in pediatric Crohn's disease. J Crohns Colitis
25. Beattie RM, Camacho-Hubner C, Wacharasindhu S, et al. Responsiveness of IGF-1 and IGFBP-3 to therapeutic intervention in children and adolescents with Crohn's disease. Clin Endocrinol
26. Crombé V, Salleron J, Savoye G, et al. Long-term outcome of treatment with infliximab in pediatric-onset Crohn's disease: a population-based study
. Inflamm Bowel Dis
27. Malik S, Ahmed SF, Wilson ML, et al. The effects of anti-TNF-alpha treatment with adalimumab on growth in children with Crohn's disease (CD). J Crohns Colitis
28. Rosenbach Y, Hartman C, Shapiro R, et al. Adalimumab treatment in children with refractory Crohns disease. Dig Dis Sci