© Borgis - Postępy Nauk Medycznych 3/2014, s. 166-171
*Anna Wiernicka, Maciej Dądalski, Monika Szychta, Grzegorz Oracz, Jarosław Kierkuś
Adalimumab w terapii wrzodziejącego zapalenia jelita grubego u dzieci
Adalimumab in pediatric ulcerative colitis
Department of Gastroenterology, Hepatology and Feeding Disorders, Children’s Memorial Health Institute, Warszawa
Head of Department: prof. Józef Ryżko, MD, PhD
Streszczenie
Wstęp. Skuteczność adalimumabu (ADA) u pacjentów dorosłych ze średnio ciężką i ciężką postacią wrzodziejącego zapalenia jelita grubego została potwierdzona. Niestety brakuje danych na temat roli ADA u dzieci.
Cel pracy. Celem badania było podsumowanie doświadczeń własnych w leczeniu adalimumabem (ADA) wrzodziejącego zapalenia jelita grubego u dzieci.
Materiał i metody. Retrospektywnie przeanalizowano dane sześciu pacjentów ze średnio ciężką i ciężką postacią wrzodziejącego zapalenia jelita grubego leczonych ADA. Zebrano dane dotyczące dotychczasowej terapii, leczenia stosowanego w czasie rozpoczęcia kuracji ADA oraz przeanalizowano parametry biochemiczne. Oceniono odpowiedź krótkoterminową na leczenie adalimumabem oraz opisano długoterminowe wyniki. Do oceny odpowiedzi klinicznej wykorzystano skalę PUCAI. Odpowiedź endoskopową oceniono za pomocą skali Baron.
Wyniki. Średni wiek w momencie diagnozy wyniósł 11,83 ± 2,78 roku. Średni wiek w momencie rozpoczęcia terapii adalimumabem wyniósł 14 ± 2,22 roku. Średni czas trwania choroby przed pierwszą iniekcją ADA wyniósł 23,8 ± 20,8 roku. 5 pacjentów było wcześniej leczonych infliksymabem (IFX). Wskazaniami do terapii adalimumabem były: reakcja nadwrażliwości na IFX (2 osoby), nieskuteczność leczenia IFX (3 osoby), sterydozależność (1 osoba). Jeden pacjent nie zareagował na leczenie ADA, ostatecznie miał wykonaną kolektomię. W 8 tygodniu 2 z 6 pacjentów uzyskało odpowiedź kliniczną. Średni wynik w skali PUCAI na początku leczenia wynosił 32,5 ± 24,23 (5-75), zaś w 8 tygodniu 19 ± 19,49 (0-50). 5 pacjentów ukończyło fazę indukcji i zostało włączonych do fazy podtrzymującej leczenia ADA. Jeden pacjent został wykluczony z analizy długoterminowej odpowiedzi z uwagi na ukończenie 18 roku życia. 4 pacjentów włączono do dalszej analizy. Po 6 miesiącach leczenia wszyscy pacjenci byli w remisji klinicznej (PUCAI < 10), w dwóch przypadkach remisję potwierdzono endoskopowo (Baron 0). Po 12 miesiącach 3 pacjentów pozostawało w remisji klinicznej, u 2 wykonano kolonoskopię (Baron 1 i 0). PUCAI po 6 i 12 miesiącach wyniósł odpowiednio 2,5 ± 2,88; 7,5 ± 11,9.
Wnioski. Adalimumab jest skutecznym i dobrze tolerowanym lekiem u pacjentów pediatrycznych z wrzodziejącym zapaleniem jelita grubego, którzy nie tolerowali leczenia IFX lub utracili odpowiedź na IFX. Adalimumab powinien być rozważany w terapii UC u dzieci przed decyzją o wykonaniu kolektomii.
Summary
Introduction. Adalimumab (ADA) has been shown to be effective in adult patients with moderately to severely active ulcerative colitis. Unfortunately, data about its role in pediatric patients are sparse.
Aim. The aim of our study was to summarize the experience with adalimumab (ADA) used in therapy of pediatric patients with ulcerative colitis (UC) in our center.
Material and methods. We retrospectively analyzed data of six children with active UC who have been treated with ADA in our hospital. Data about treatment history, concomitant therapy, and biochemical parameters were collected. We evaluated short term response to ADA as well as long term outcomes. PUCAI index was used to assess clinical condition of the subjects. Endoscopic features were classified according to Baron scale.
Results. The mean age at diagnosis was 11.83 ± 2.78 years. The mean age at the time of first ADA injection was 14 ± 2.22 years. Mean duration of disease before ADA therapy was 23.8 ± 20.8 months. 5 patients were previously treated with infliximab. Indications for ADA were: hypersensitivity reaction to IFX (2 pts.), infliximab refractory UC (3 pts.), steroid dependency (1 pt.). One child didn’t response to ADA and had colectomy. At week 8, 2 of 6 patients had a clinical response. Mean PUCAI score at baseline was 32.5 ± 24.23, at week 8 was 19 ± 19.49. Five patients competed the induction phase and were entered into maintenance phase of the ADA therapy. One child has been excluded from long-term analysis. He received five injections of ADA and has been transferred to the center for adults. 4 patients after 6 months of ADA therapy maintained clinical remission (PUCAI < 10), in 2 cases remission was endoscopically assessed (grade O in Baron scale). After 12 months 3 patients were in clinical remission, in 2 cases colonoscopy has been performed (Baron scale 0 or 1). PUCAI index after 6 and 12 months were retrospectively 2.5 ± 2.88; 7.5 ± 11.9.
Conclusions. Adalimumab is effective and safe treatment in pediatric ulcerative colitis intolerant to or with loss of effect to infliximab therapy. Should be considered as the rescue treatment before colectomy in this age group.
Introduction
Adalimumab (Humira, Abbott) is a humanized antitumor necrosis factor monoclonal antibody that blocks proteins that play an important role in abnormal inflammatory and immune responses. It has been shown to be effective in adult patients with moderate-to-severe active ulcerative colitis (UC) who were nonresponders or intolerant to standard therapy. After the publication of the results of the two randomized, placebo-controlled, double-blind trials (ULTRA 1 and ULTRA 2) (1, 2) it has been approved by U.S. Food and Drug Administration (FDA) in UC adult patients. Adalimumab is not currently licenced for use in pediatric inflammatory bowel disease and data on its role in pediatric ulcerative colitis are sparse. However, based on evidence derived from adult studies, it is used off-label in clinical practice. In this report we summarize our experience with adalimumab in six pediatric UC patients.
Aim
The aim of the study was to evaluate short term clinical response and remission as well as efficacy in maintaining clinical remission.
Material and methods
We retrospectively reviewed medical charts of children affected with ulcerative colitis treated with ADA in our hospital. Six children with moderately to severely active UC were included in this study. We evaluated short term response to ADA as well as long term analysis. Patient’s data about treatment history, concomitant therapy, biochemical parameters: hemoglobin (Hb), hematocrit (Htc), platelet blood count (PBC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) at baseline, 8 weeks, than 6 and 12 months after first ADA injection were collected. PUCAI index was used to assess clinical condition of the subjects (3). Clinical response was defined as reduction in PUCAI index ≥ 20 points and clinical remission as PUCAI index less than 10 points. Endoscopic features were classified according to Baron scale (4), mucosal healing was defined as either completely normal (score 0) or mild (score 1) in Baron scale. Disease location was classified according to Paris Classification (5).
Initial adalimumab dosages were either 40 mg (1 patient) subcutaneously or 80 mg (5 patients) subcutaneously followed by maintenance dose of 40 mg after 2 weeks than every 2-4 weeks.
Statistical analysis
The data were collected from patient’s medical charts and analyzed retrospectively. The frequency of findings was presented in numbers and in percentages. All statistical tests were performed with Statistica 10.0 (StatSoft Inc., 2011). Distribution of analyzed variables was tested using Shapiro-Wilk Normality test. The Wilcoxon signed-rank test was used to verify the hypothesis. The p value < 0.05 was considered as significant.
Results
Six children (2 female), with confirmed UC were treated with ADA from November 2010 to May 2013. The mean age at diagnosis was (Mean ± SD) 11.83 ± 2.78 (range 8-16) years, the mean age at the time of first ADA injection was 14 ± 2.22 (range 11-17.5) years. The mean duration of disease before ADA therapy was 23.8 ± 20.8 (range 3-60) months. Disease distribution was pancolitis (E4) in 2 cases, left-sided UC (E2) in 3 cases and extensive UC (E3) in one subject. All patients were previously treated with corticosteroids, azathiopryne and mesalazine. 5 of 6 patients failed cyclosporine therapy. One child with diagnosed UC and juvenile idiopatic arthritis (JIA) has been treated in the past with etanercept. The vast majority of patients, without one child with coexisting JIA, were previously treated with infliximab. Mean number of infliximab infusions before ADA was 2.8 ± 0.83 (range 2-4). Indications for starting adalimumab were a hypersensitivity reaction to infliximab (IFX) in 2 patients (after second infusion in one child and after third in another one), failure to achieve clinical remission with IFX in 3 subjects, steroid dependency in one case.
Short term response
From the all investigated subjects one child with steroid dependant UC, previously ineffectively treated with 3 infusions of IFX, didn’t response to ADA. Due to lack of clinical and endoscopic remission temporarily required glucocorticosteroid (GKS) until colectomy. Data of five remaining patients were assessed at week 8. Generally, at week 8, 2 of 6 patients included to this study had a clinical remission, measured with PUCAI index. Mean PUCAI score at baseline was 32.5 ± 24.23 (range 5-75, n = 6) (Mean ± SD, n = number of variables), at week 8 was 19 ± 19.49 (range 0-50, n = 5). Patient with coexisting JIA after 4 ADA injections shoved clinical relapse (PUCAI 50) simultaneously drug-induced (probably aztathiopryne related) pancreatitis has been diagnosed. After a course of intravenous GKS ADA therapy has been successfully continued. Changes in biochemical parameters at week 8 are presented in table 1. There were no statistically significant differences in the analyzed variables.
Table 1. Comparison of clinical and biochemical parameters at baseline and at week 8.
| Variable (Mean ± SD) | N | At baseline | At week 8 | p-value |
| PUCAI index | 5 | 32.5 ± 24.23 | 19 ± 19.49 | 0.68 |
| Body weight (kg) | 5 | 45.61 ± 8.64 | 47 ± 8.88 | 0.34 |
| Hb (g/dl) | 5 | 10.38 ± 1.73 | 10.06 ± 2.28 | 0.68 |
| Hct (%) | 5 | 32.56 ± 4.29 | 33.04 ± 5.32 | 0.22 |
| PBC (k/uI) | 5 | 445.16 ± 98.26 | 401.60 ± 205.98 | 0.50 |
| ESR (mm/h) | 5 | 33.40 ± 23.21 | 22.20 ± 4.43 | 0.14 |
| CRP (mg/dl) | 5 | 2.13 ± 3.28 | 2.15 ± 2.90 | 0.13 |
SD – standard deviation, N – number of variables, Hb – hemoglobin, Hct – hematocrit, PBC – platelet blood count, ESR – erythrocyte sedimentation rate, CRP – C-reactive protein
Long-term follow-up
Five patients competed the induction phase and were entered into maintenance phase of the ADA therapy. One child has been excluded from long-term analysis. He has been treated from May 2013 to August 2013, until age eighteen. Before transferring patient to the center for adults, after receiving five injections of ADA, endoscopy has been performed. Pancolitis has been diagnosed; disease activity endoscopically assessed as grade 3 in endoscopic Baron scale.
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