ORIGINAL ARTICLE: GASTROENTEROLOGY
Biological Therapy in a Pediatric Crohn Disease Population at a Referral Center Federica Nuti, Franca Viola, Fortunata Civitelli, Claudia Alessandri, Marina Aloi, Anna Dilillo, Emanuela Del Giudice, and Salvatore Cucchiara ABSTRACT Objective: The antitumor necrosis factor a (TNFa) antibodies infliximab and adalimumab are effective in inducing and maintaining remission in pediatric patients with Crohn disease (CD). The aim of the study was to evaluate the long-term efficacy and safety of biological therapy in pediatric patients with CD followed at a referral center. Methods: This work is a retrospective observational study enrolling patients with CD treated with infliximab or adalimumab beyond the induction protocol. The patients’ data were collected from the unit’s IBD database (maximum follow-up evaluation after 36 months of treatment). The efficacy was evaluated by the Pediatric Crohn Disease Activity Index score and by analysis of the cumulative probability of continuing therapy; the safety was assessed in terms of adverse events. Results: We enrolled 78 patients; the mean therapy duration was 27.2 16.7 months, and the mean age at enrollment was 15 3.1 years. The KaplanMeier analysis showed a cumulative probability of continuing therapy of 81%, 54%, and 33% at 1, 2, and 3 years, respectively, from the introduction of therapy. No association between the patients’ baseline characteristics and the long-term outcome was found. The evaluation of the concomitant therapy with immunomodulators and anti-TNFa therapy versus antiTNFa alone did not show a different outcome. No serious adverse events were recorded. Conclusions: The study indicates that biological therapy is effective and safe in pediatric patients with CD in a longer follow-up period. The response to treatment was not influenced by the patients’ baseline characteristics or by the immunomodulator association. Key Words: adalimumab, Crohn disease, infliximab, long-term outcome, pediatrics
(JPGN 2014;58: 582–587)
A
ccording to recent epidemiological data, inflammatory bowel diseases (IBDs) such as Crohn disease (CD) affect an increasing number of pediatric patients, with the most recent reports indicating an incidence of approximately 10 to 12/100,000/year in a range age from 0 to 16 years (1–3). Because it appears that pediatric disease presents a more aggressive phenotype not
infrequently, efforts have been made to identify those patients in whom a disease-modifying therapy should be introduced early in the disease course to alter the natural history of the disorder in depth (4–6). Antitumor necrosis factor a (TNFa) antagonists have been used in pediatric patients with IBD since the beginning of the last decade. The first licensed drug of this class, infliximab (IFX), was approved for pediatric use in 2006 (6). This chimeric antibody has been shown in pediatric studies to be a valid tool in achieving and maintaining remission for up to 1 year (7–9), whereas more recent reports show its efficacy in achieving a long-term response ranging from 50% to 80% (10–14). Adalimumab (ADA), the other anti-TNFa antagonist agent used in pediatric IBD, is a fully humanized antibody, initially used as a second-line biological therapy for IFX failures or nonresponders in patients with CD and now, not uncommonly, as the antiTNFa antagonist of first choice (15–19). A 41% remission rate at 1 year has been reported (19). Pediatric studies evaluating its efficacy are available; however, long-term data are limited. Protracted follow-up programs in children with IBD are of pivotal importance for efficacy and safety, particularly following the description of the occurrence of hepatosplenic T-cell lymphoma, which is a rare but frequently fatal non-Hodgkin lymphoma, in young patients treated with a prolonged combination therapy of high doses of thiopurines and anti-TNFa antagonists (20–22). A recently emphasized topic is the search for variables that may be predictive of the treatment outcome. Some clinical characteristics in adult patients such as colonic disease location and younger age at therapy initiation have been associated with a better outcome; however, no specific predictive factors have been confirmed to be related to the outcome in pediatric IBD populations (5,6,10,13). The primary aim of our study was to analyze the short- and long-term efficacy and safety of anti-TNFa antagonists in a pediatric CD population studied at a single tertiary IBD unit. We aimed to identify the clinical parameters that could be related to the clinical outcome.
METHODS Received March 4, 2013; accepted December 3, 2013. From the Pediatric Gastroenterology and Liver Unit, La Sapienza University of Rome, Rome, Italy. Address correspondence and reprint requests to Salvatore Cucchiara, MD, PhD, Pediatric Gastroenterology and Liver Unit, La Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy (e-mail: salvatore.cucchiara @uniroma1.it). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000276
This work is a retrospective, single-center, cohort study on pediatric patients with CD who underwent biological therapy. The data on all of the patients who received at least a full induction protocol for IFX or ADA between January 2001 and December 2011 were selected for analysis from the IBD database of our unit. The database includes all of the data (demographic information, hospital admissions, blood examinations, therapies, adverse events, and diagnostic and follow-up procedures) of the patients diagnosed as having IBD and followed at our center. The data collected at diagnosis and subsequently every 6 months to a maximal follow-up of 3 years included the age at
582 JPGN Volume 58, Number 5, May 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 58, Number 5, May 2014
diagnosis, sex, age at the beginning of therapy, disease duration, disease location and behavior, extraintestinal manifestations, and previous and concomitant therapy. Regarding the latter, the concomitant immunomodulator (IMM) use and the length of the combination therapy were recorded; for the biologics, the age and disease duration at the first infusion, indication, dose, and dose modulation were recorded. The administration of IFX included an induction protocol of 3 infusions of 5 mg/kg at weeks 0, 2, and 6 followed by maintenance infusions every 8 weeks. For the patients taking ADA, the induction protocol was 160 mg followed by 80 mg after 2 weeks and then 40 mg every other week as maintenance therapy. The indicated dose escalation was an increased dose (from 5 to 10 mg/kg for IFX and from 40 to 80 mg every other week for ADA) or as a decreased interval between doses (6 weeks for IFX and every week for ADA). The disease phenotype was defined according to the Montreal classification (23). The laboratory evaluations included the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) serum levels at the initiation of the anti-TNFa therapy, at the end of induction and every 6 months thereafter for up to 36 months of follow-up. All of our patients were screened for tuberculosis and examined for hepatitis and the EBV immunological status before the therapy introduction; the patients routinely underwent other serological evaluations such as liver and pancreatic enzymes, renal function, albumin, anti-nuclear antibody and complete blood cell count. These data were not further analyzed because they were not complete for all of the patients. All of the serious adverse events, as well as the need and time for surgery, were recorded. The reasons for and the time to therapy discontinuation were recorded.
Outcome Measures The clinical outcome was assessed at the end of the induction phase and after 6 months and 1, 2, and 3 years of treatment in the patients who received and completed at least the induction protocol of anti-TNFa maintenance therapy. The disease activity was defined by the Pediatric Crohn Disease Activity Index (PCDAI) at time 0, at the end of the induction phase, and at 6, 12, 24, and 36 months from the first administration of therapy (24). The primary endpoint criteria included the efficacy of therapy as defined by the reduction of PCDAI at every time point, with an evaluation of the response and remission rates and the cumulative probability of maintaining the biological therapy until the maximum follow-up. Response was defined as a reduction of at least 15 points on the PCDAI from the baseline, whereas remission was
Biological Therapy in a Pediatric Crohn Disease Population at a Referral Center Federica Nuti, Franca Viola, Fortunata Civitelli, Claudia Alessandri, Marina Aloi, Anna Dilillo, Emanuela Del Giudice, and Salvatore Cucchiara ABSTRACT Objective: The antitumor necrosis factor a (TNFa) antibodies infliximab and adalimumab are effective in inducing and maintaining remission in pediatric patients with Crohn disease (CD). The aim of the study was to evaluate the long-term efficacy and safety of biological therapy in pediatric patients with CD followed at a referral center. Methods: This work is a retrospective observational study enrolling patients with CD treated with infliximab or adalimumab beyond the induction protocol. The patients’ data were collected from the unit’s IBD database (maximum follow-up evaluation after 36 months of treatment). The efficacy was evaluated by the Pediatric Crohn Disease Activity Index score and by analysis of the cumulative probability of continuing therapy; the safety was assessed in terms of adverse events. Results: We enrolled 78 patients; the mean therapy duration was 27.2 16.7 months, and the mean age at enrollment was 15 3.1 years. The KaplanMeier analysis showed a cumulative probability of continuing therapy of 81%, 54%, and 33% at 1, 2, and 3 years, respectively, from the introduction of therapy. No association between the patients’ baseline characteristics and the long-term outcome was found. The evaluation of the concomitant therapy with immunomodulators and anti-TNFa therapy versus antiTNFa alone did not show a different outcome. No serious adverse events were recorded. Conclusions: The study indicates that biological therapy is effective and safe in pediatric patients with CD in a longer follow-up period. The response to treatment was not influenced by the patients’ baseline characteristics or by the immunomodulator association. Key Words: adalimumab, Crohn disease, infliximab, long-term outcome, pediatrics
(JPGN 2014;58: 582–587)
A
ccording to recent epidemiological data, inflammatory bowel diseases (IBDs) such as Crohn disease (CD) affect an increasing number of pediatric patients, with the most recent reports indicating an incidence of approximately 10 to 12/100,000/year in a range age from 0 to 16 years (1–3). Because it appears that pediatric disease presents a more aggressive phenotype not
infrequently, efforts have been made to identify those patients in whom a disease-modifying therapy should be introduced early in the disease course to alter the natural history of the disorder in depth (4–6). Antitumor necrosis factor a (TNFa) antagonists have been used in pediatric patients with IBD since the beginning of the last decade. The first licensed drug of this class, infliximab (IFX), was approved for pediatric use in 2006 (6). This chimeric antibody has been shown in pediatric studies to be a valid tool in achieving and maintaining remission for up to 1 year (7–9), whereas more recent reports show its efficacy in achieving a long-term response ranging from 50% to 80% (10–14). Adalimumab (ADA), the other anti-TNFa antagonist agent used in pediatric IBD, is a fully humanized antibody, initially used as a second-line biological therapy for IFX failures or nonresponders in patients with CD and now, not uncommonly, as the antiTNFa antagonist of first choice (15–19). A 41% remission rate at 1 year has been reported (19). Pediatric studies evaluating its efficacy are available; however, long-term data are limited. Protracted follow-up programs in children with IBD are of pivotal importance for efficacy and safety, particularly following the description of the occurrence of hepatosplenic T-cell lymphoma, which is a rare but frequently fatal non-Hodgkin lymphoma, in young patients treated with a prolonged combination therapy of high doses of thiopurines and anti-TNFa antagonists (20–22). A recently emphasized topic is the search for variables that may be predictive of the treatment outcome. Some clinical characteristics in adult patients such as colonic disease location and younger age at therapy initiation have been associated with a better outcome; however, no specific predictive factors have been confirmed to be related to the outcome in pediatric IBD populations (5,6,10,13). The primary aim of our study was to analyze the short- and long-term efficacy and safety of anti-TNFa antagonists in a pediatric CD population studied at a single tertiary IBD unit. We aimed to identify the clinical parameters that could be related to the clinical outcome.
METHODS Received March 4, 2013; accepted December 3, 2013. From the Pediatric Gastroenterology and Liver Unit, La Sapienza University of Rome, Rome, Italy. Address correspondence and reprint requests to Salvatore Cucchiara, MD, PhD, Pediatric Gastroenterology and Liver Unit, La Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy (e-mail: salvatore.cucchiara @uniroma1.it). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000276
This work is a retrospective, single-center, cohort study on pediatric patients with CD who underwent biological therapy. The data on all of the patients who received at least a full induction protocol for IFX or ADA between January 2001 and December 2011 were selected for analysis from the IBD database of our unit. The database includes all of the data (demographic information, hospital admissions, blood examinations, therapies, adverse events, and diagnostic and follow-up procedures) of the patients diagnosed as having IBD and followed at our center. The data collected at diagnosis and subsequently every 6 months to a maximal follow-up of 3 years included the age at
582 JPGN Volume 58, Number 5, May 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 58, Number 5, May 2014
diagnosis, sex, age at the beginning of therapy, disease duration, disease location and behavior, extraintestinal manifestations, and previous and concomitant therapy. Regarding the latter, the concomitant immunomodulator (IMM) use and the length of the combination therapy were recorded; for the biologics, the age and disease duration at the first infusion, indication, dose, and dose modulation were recorded. The administration of IFX included an induction protocol of 3 infusions of 5 mg/kg at weeks 0, 2, and 6 followed by maintenance infusions every 8 weeks. For the patients taking ADA, the induction protocol was 160 mg followed by 80 mg after 2 weeks and then 40 mg every other week as maintenance therapy. The indicated dose escalation was an increased dose (from 5 to 10 mg/kg for IFX and from 40 to 80 mg every other week for ADA) or as a decreased interval between doses (6 weeks for IFX and every week for ADA). The disease phenotype was defined according to the Montreal classification (23). The laboratory evaluations included the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) serum levels at the initiation of the anti-TNFa therapy, at the end of induction and every 6 months thereafter for up to 36 months of follow-up. All of our patients were screened for tuberculosis and examined for hepatitis and the EBV immunological status before the therapy introduction; the patients routinely underwent other serological evaluations such as liver and pancreatic enzymes, renal function, albumin, anti-nuclear antibody and complete blood cell count. These data were not further analyzed because they were not complete for all of the patients. All of the serious adverse events, as well as the need and time for surgery, were recorded. The reasons for and the time to therapy discontinuation were recorded.
Outcome Measures The clinical outcome was assessed at the end of the induction phase and after 6 months and 1, 2, and 3 years of treatment in the patients who received and completed at least the induction protocol of anti-TNFa maintenance therapy. The disease activity was defined by the Pediatric Crohn Disease Activity Index (PCDAI) at time 0, at the end of the induction phase, and at 6, 12, 24, and 36 months from the first administration of therapy (24). The primary endpoint criteria included the efficacy of therapy as defined by the reduction of PCDAI at every time point, with an evaluation of the response and remission rates and the cumulative probability of maintaining the biological therapy until the maximum follow-up. Response was defined as a reduction of at least 15 points on the PCDAI from the baseline, whereas remission was
