Efficacy of Adalimumab in Moderate-to-Severe Pediatric ... - Nature

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Efficacy of Adalimumab in Moderate-to-Severe Pediatric Crohn’s Disease Franca Viola, MD1, Fortunata Civitelli, MD1, Giovanni Di Nardo, MD1, Maria Beatrice Barbato, MD1, Osvaldo Borrelli, MD1, Salvatore Oliva, MD1, Francesca Conte, MD1 and Salvatore Cucchiara, MD, PhD1

OBJECTIVES:

The use of tumor necrosis factor-alpha (TNF-) antagonists has changed the therapeutic strategy for Crohn’s disease (CD). Adalimumab (ADA), a fully human anti-TNF- monoclonal antibody, is an effective therapy for patients with CD, both naive patients and those intolerant or refractory to Infliximab (IFX), a chimeric anti-TNF- agent. However, the use of ADA is rarely reported in pediatric CD. We performed an open prospective evaluation of short- and long-term efficacy and safety of ADA in children with moderate-to-severe CD.

METHODS:

A total of 23 pediatric CD patients (9 naive and 14 intolerant or unresponsive to IFX) received ADA subcutaneously as a loading schedule at weeks 0 and 2, and at every other week (eow) during a 48-week maintenance phase. Loading and maintenance doses were 160/80 and 80 mg eow in 13 cases, 120/80 and 80 mg eow in 2, and 80/40 and 40 mg eow in 8 cases. The primary efficacy outcomes were clinical remission and response at different scheduled visits along the maintenance phase. At baseline, 13 patients also received immunomodulators (IMs).

RESULTS:

At weeks 2, 4, 12, 24, and 48, remission rates were 36.3, 60.8, 30.5, 50, and 65.2%, respectively, whereas response rates were 87, 88, 70, 86, and 91%, respectively. Four patients at week 24 and 2 at week 48 received IMs; the mean daily corticosteroid dose, disease activity index, C-reactive protein level, and erythrocyte sedimentation rate decreased significantly throughout the trial. No serious adverse events were recorded.

CONCLUSIONS: ADA can be an effective and safe biological agent for inducing and maintaining remission in

children with moderate-to-severe CD, even in those with previous IFX therapy. Am J Gastroenterol 2009; 104:2566–2571; doi:10.1038/ajg.2009.372; published online 23 June 2009

INTRODUCTION Patients with Crohn’s disease (CD) show recurrent attacks intermingled with phases of quiescence (1,2), and most of them require long-term medications for maintaining remission and managing acute events (3). The disease in children often results in malnutrition, growth and pubertal failure, and debilitating complications (4). Traditional treatment of CD, consisting of corticosteroids (CSs), nonspecific anti-inflammatory agents, and immunomodulators (IMs), seem to be unable to alter the natural course of the disease (5). Recently, the management of the disorder has changed dramatically because of the advent of biological therapies, created using genetic technology and directed against specific inflammatory mediators (6). Antibodies that neutralize

the cytokine tumor necrosis factor-alpha (TNF-) are the most commonly used biological agents in CD (7). Several trials in adults and in children with CD have shown the efficacy of Infliximab (IFX) (Remicade, Centocor, Malvern, PA), a chimeric monoclonal anti-TNF- antibody, to induce and maintain remission (8,9). Unfortunately, either episodic or continuous administration of IFX leads to the development of antibodies against itself (ATI, anti-IFX antibodies) which have been associated with attenuated or lost clinical response to the drug (10), as well as to the development of immediate and delayed-type hypersensitivity events (11). Adalimumab (ADA) (Humira, Abbott Laboratories, Abbott Park, IL) is a fully human monoclonal anti-TNF- antibody

1

Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, University Hospital Umberto I, Sapienza University of Rome, Rome, Italy. Correspondence: Salvatore Cucchiara, MD, PhD, Department of Pediatrics, University Hospital Umberto I, Sapienza University of Rome, Viale Regina Elena, Rome 324 – 00161, Italy. E-mail: [email protected] Received 28 December 2008; accepted 24 May 2009 The American Journal of GASTROENTEROLOGY

VOLUME 104 | OCTOBER 2009 www.amjgastro.com

with a mechanism of action similar to that of IFX (12). It has been reported to be more effective than placebo as an induction and maintenance therapy for adult CD patients (13–15), naive or intolerant to IFX (16). In comparison with IFX, ADA is believed to possess some advantages, namely the fully human nature with a reduced risk of developing neutralizing antibodies; the subcutaneous method of administration; effectiveness and safety in patients loosing response or intolerant to IFX (17). There are very few studies on ADA in pediatrics; they are retrospective and have a short follow-up period (18,19). Recently, however, a North American multicenter retrospective study, including 100 CD children, has evaluated the short- and longterm efficacy of ADA (20). Thus, we reported a prospective study that was carried out at a single tertiary referral center of Pediatric Gastroenterology, in a cohort of patients with moderate-to-severe CD, necessitating biological therapy. We assessed the clinical value of ADA for inducing and maintaining clinical remission; the safety of the drug was also evaluated. The study was funded independently of the pharmaceutical industry.

METHODS Subjects and protocol

This prospective study included 23 patients with CD (age range: 9–20 years, median age: 16.0; median age at diagnosis: 12.0) who were followed up at the Pediatric Gastroenterology and Liver Unit of the Sapienza University of Rome. Inclusion criteria were active moderate-to-severe CD, with a Pediatric Crohn’s Disease Activity Index (PCDAI) score of >30 (21), refractory or intolerant to conventional treatment (CS, IM) or to IFX, and diagnosed at least 6 months before the trial, according to widely agreed criteria (22). Exclusion criteria were infections, inadequate functions of the heart, lungs, kidneys or liver, neurological disorders, immunodeficiency, short bowel syndrome, symptomatic strictures, intra-abdominal abscesses, and bowel resection performed within the last 6 months. Intestinal bacterial infections, including Clostridium difficile, were excluded with appropriate stool analyses. Cytomegalovirus and Epstein–Barr virus infections were excluded by PCR analysis of virus genoma in the biological liquids. ADA was administered as a loading schedule of two subcutaneous injections at 0 and 2 weeks, followed by a 48-week maintenance phase with the drug injected every other week (eow). Before the trial, all patients tested negative for a purified protein derivative (PPD) skin test and showed a normal chest X-ray. Maintenance phase commenced at week 4, the participants were then evaluated as outpatients at weeks 8 and 12, and every 6 weeks thereafter. During the trial, the clinical staff of the Unit was in contact with the families of the patients to manage every therapy-related event quickly. The first two doses of ADA were injected under supervision of the medical team of the Unit, and the patients were monitored for 2 h after injection. Maintenance doses were injected at home after patients and caretakers had received appropriate instructions. © 2009 by the American College of Gastroenterology

At each visit, the patients were assessed through the PCDAI (score ≤10: inactive disease; >10–30: mild disease; >30: moderate-to-severe disease). Before the trial and at each visit, the following tests were determined: full blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum albumin, urea, iron, creatinine, electrolytes, and pancreatic and liver function tests. Urinary protein and glucose levels were also evaluated. The incidence of adverse events was also assessed. Of the 23 patients who entered into the trial, 14 had previously received IFX (11 had loss of response and 3 were intolerant to the drug). The former was defined as a condition with an initial response to IFX (baseline schedule of three infusions at 0.2 and 6 weeks, dose of 5 mg/kg) with a subsequent clinical flare-up despite a maintenance schedule of infusions every 8 weeks and a trial to optimize the IFX treatment either by decreasing the infusion intervals or by doubling the dose (10 mg/kg). Patients were classified as intolerant to IFX if they discontinued treatment due to infusion reactions, classified as either acute (within 24 h of an IFX infusion) or delayed (occurring more than 24 h later and < 15 days after an IFX infusion). Nine patients were naive to biological agents. The loading and the maintenance doses of ADA differed according to the body weight: 160/80 and 80 mg eow in patients weighing ≥40 kg and 80/40 and 40 mg eow in those weighing < 40 kg. An attempt to reduce the maintenance dose from 80 to 40 mg eow was made at week 12 if the disease was clinically controlled. At the beginning of the trial, 18 patients received oral CS (methylprednisolone) with a mean dosage (mg/kg per day) of 0.9 ± 0.2 mg, and 13 patients were on IM (11 on azathioprine, 2.5 mg/kg per day and 2 on methotrexate, 15 mg per week, subcutaneously). CSs were decreased in a gradual manner starting at week 4, whereas IMs were ceased between 8 and 12 weeks, starting from patients with a more stable condition. The primary end point was the proportion of patients who reached clinical remission (i.e., the absence of symptoms and a PCDAI score of ≤10) and clinical response (i.e., a decrease in the PCDAI score of ≥50% compared with the baseline value). The secondary outcomes were (i) the reduction in oral CS dosage; (ii) the mean change in PCDAI score; (iii) the change in the mean values of CRP and ESR; and (iv) the proportion of patients with adverse drug reaction. Data were calculated as meas ± s.d. The final efficacy analysis was carried out after all patients had completed their follow-up assessment. The baseline characteristics of the patients were evaluated by a simple descriptive analysis. For the primary outcome, the proportion of patients in clinical remission and the proportion of those with clinical response at weeks 2, 4, 12, 24, and 48 were analyzed using Fisher’s exact test. For this purpose, intention-to-threat analysis including all patients who had received at least one dose of the study treatment was carried out. The mean scores over time on the PCDAI, CRP, ESR, as well as the mean oral CS daily dose were analyzed using a mixed model of ANOVA (analysis of variance), followed by post hoc analyses using the Bonferroni post test. The 2-test or Fisher’s exact test were used when appropriate. All statistical The American Journal of GASTROENTEROLOGY

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tests were two-tailed using a 0.05 level of significance. Analysis was carried out using the Prism software version 4.00 (GraphPad, San Diego, CA). The study protocol was defined in accordance with the Declaration of Helsinki and approved by the ethical committee of the University Hospital Umberto I in Rome. Written informed consent was obtained from parents of all children; children older than 12 years of age signed a statement of assent.

RESULTS The baseline characteristics of the patients are shown in Table 1. The disease was classified according to the Montreal Criteria (23). The time interval between the last infusion of IFX and the commencement of ADA was 19.2±15.5 months; the disease duration before ADA was 52.2±42.5 months. The loading schedule was 160/80 mg in 13 patients and 80/40 mg in 8. In 2 patients weighing < 40 kg and with a PCDAI score of 40, the initial schedule was 120/80 mg with a maintenance dose of 80 mg eow. One of the 13 patients on the highest induction dose dropped out due to fever and features of systemic infection that occurred within 10 days from the first dose of ADA. As shown in Figure 1, 14 patients, with the highest initial doses, had a reduction in the maintenance dose from 80 to 40 mg eow; however, in 6 of them, the dose was increased to 80 mg eow at week 24 due to a flare-up of the disease. Of the eight patients on the initial schedule of 80/40 mg, the maintenance dose was increased at week 12 from 40 to 80 mg in five. Figure 2 shows the percentage of patients in clinical response and in clinical remission throughout the study period. As shown in Figure 3, there was a significant reduction in the PCDAI, ESR (mm/h), and CRP (mg/ml) by the second week after the commencement of ADA. The mean values of PCDAI, ESR, and CRP at baseline and at subsequent visits are reported in Table 2. There was also a marked decrease in the oral CS dose

(mg/kg per day) during the study period (0.59±0.17, P < 0.05; 0.27±0.2, P < 0.01; 0.08±0.1, P < 0.01; 0.07±0.1, P < 0.01, at weeks 4, 12, 24, and 48 after starting ADA, respectively). Only 4 and 2 patients received IM at weeks 24 and 48, respectively. One patient with anal stenosis at the follow-up, underwent anal dilatations without interrupting ADA. Three patients with perianal fistulae underwent seton placement before the trial and had complete fistulae closure as documented by magnetic

Table 1. Demographics and baseline disease characteristics of patients treated with adalimumab No. of cases

23

Age (years; median and range)

16.1 years (9–20)

Age at diagnosis (years; median and range)

12.0 years (7–15.8)

Gender Male (%)

12 (52.17)

Female (%)

11 (47.83)

Disease duration (months) Mean±s.d.

52.2±42.5

Disease location (Montreal classification) L1 = terminal ileum

2 (8.7%)

L2 = colon

4 (17.4%)

L3 = ileocolon

9 (39.1%)

L3 + L4 = ileocolon + upper GI

8 (34.8%)

Disease behavior B1 = non-stricturing, non-penetrating

10 (43.5%)

B2 = stricturing

9 (39.1%)

B3p = penetrating

4 (17.4)

Patients recruited (23) Induction phase 0, 2 weeks

160/80 mg (13)

Withdrawn (1)

80 mg (12)

4

120/80 mg (2)

80 mg (2)

80/40 mg (8)

40 mg (8)

8 40 mg (12)

12

40 mg (2)

40 mg (3)

80 mg (5)

18

Maintenance phase (week)

24

40 mg (6)

80 mg (6)

30 36 42 48

Figure 1. Flow chart of patient progress throughout the study.

The American Journal of GASTROENTEROLOGY


An episode of psoriasis occurred in a patient at week 8 and disappeared after a decrease in the eow dose of ADA (from 80 to 40 mg). Finally, six patients had transient upper respiratory tract infections that resolved with conservative treatment and did not require ADA cessation.

resonance imaging; these patients had also received a course of metronidazole and ciprofloxacin in addition to ADA. Adverse events

Pain at the injection site was reported in four cases. No abnormal values occurred in the complete blood count and in liver and renal function tests. There were no serious infections or malignancies in the population study. Two patients had infectious episodes requiring a short cessation of ADA (two consecutive doses). A lower abdominal abscess was detected by magnetic resonance imaging in one, with resolution on a prolonged parenteral antibiotic course without surgery. In the other patient, with an underlying PMN cell dysfunction, a staphylococcal folliculitis occurred responding to specific antibiotics. Clinical remission

100

70 65, 2

60, 8

60 40

91

86

80

% of patients

Clinical response

88

87

DISCUSSION Our results indicate that ADA is an efficacious and safe biological agent for inducing and maintaining remission in moderate-to-severe pediatric CD. ADA was associated with a rapid effectiveness as shown by the high levels of clinical remission and response at weeks 2 and 4. These rates are comparable with those from trials in CD adults, either naive or previously treated with IFX (13–15). Clinical remission rates at week 2 were somewhat higher than recent pediatric reports, likely because of higher loading doses used in the most of our patients (18,19). The remission rate was lower than clinical response at week 2, likely because of the severe degree of the disease at baseline, as shown by the PCDAI. In our study, ADA was efficacious regardless of previous treatment with IFX. In all, 14 patients were previously treated with IFX; 11 had loss of response and 3 were intolerant to the drug. Antibodies to IFX seem to account for intolerance and for the loss or attenuated response to the drug. However, other variables (i.e., resistance of lymphocytes to apoptosis, changes in the mucosal cytokine scenario, development of strictures) have been claimed to account for loss of responses to IFX (10,11). Before the trial, all patients with loss of response underwent an optimizing IFX strategy consisting of either reducing interval administration (every 4–6 weeks) or escalating IFX dose to 10 mg/kg. Trials in CD adults with intolerance or loss of response to IFX have shown remission and response rates to ADA statistically similar to IFX-naive patients (24–26). These observations support the view that at least in our patients, unresponsiveness to IFX could be due to specific antibodies to IFX, with TNF- still having a prominent role in the mechanisms underlying CD. There are no sound reports on ADA dosing in pediatrics. We chose the loading doses on the basis of the body weight. The highest induction dose (160/80 mg) was administered to patients weighing >40 kg. Interestingly, clinical effectiveness was paralleled by a decrease in CRP and ESR, which are often related to the inflammatory process itself (27); the improve-

50 36, 3 30, 5

20 0 2

4

12

24

48

Weeks from the beginning of the trial Figure 2. Percentage of patients in clinical response and in clinical remission at different weeks of follow-up.

PCDAI

60

ESR (mm/h)

CRP (mg/ml)

Mean values

50 40 30

**

**

*

* *

** 20

**

*

10

*

*

* *

* * *

0 Baseline

2

4

12

24

48

Weeks Figure 3. Mean values of Pediatric Crohn’s Disease Activity Index (PCDAI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) during the study period. *P < 0.01; **P < 0.05.

Table 2. PCDAI, ESR, and CRP values in the investigated patients at baseline and throughout the follow-up (values as mean ± s.d.) Weeks

0

2

4

PCDAI ESR (mm/h) CRP (mg/ml)

12

24

48

36.5 ± 5.7

14.7 ± 5.05*

11.5 ± 2.38*

16.6 ± 4.7*

13.7 ± 6.4*

9.9 ± 2.7*

54.0 ± 36

22.0 ± 11.1**

27.0 ± 19**

27.0 ± 14**

20.0 ± 14.8**

13.1 ± 4.4*

31.2 ± 24

6.5 ± 5.8*

7.3 ± 6.2*

11.2 ± 5.6*

8.8 ± 4.8*

2.7 ± 1.3*

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; PCDAI, Pediatric Crohn’s Disease Activity Index. *P < 0.01 vs. baseline, **P < 0.05 vs. baseline.

© 2009 by the American College of Gastroenterology


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ment in these variables was as rapid as the clinical response, thus suggesting that responsiveness to ADA can be evaluated early during a therapeutic course. Our data on the short-term efficacy of ADA can hardly be compared with previous pediatric reports; the latter are mostly retrospective and did not assess effectiveness in terms of disease score. Furthermore, they did not report information on the timing of response to the drug. Our study emphasizes the usefulness of ADA in the maintenance of remission. Interestingly, the maintenance doses were handily adjustable according to the clinical and biochemical variables of the patients. On the basis of clinical behavior, patients on a maintenance dose of 80 mg eow were administered 40 mg eow at week 12; however, in 6 of them the dose was again escalated to 80 mg eow at week 24, because of clinical and biochemical worsening. Five of 8 patients who started the maintenance phase with 40 mg eow received at week 12 a doubled dose (80 mg eow) that was kept until the end of the trial. This flexibility in adapting the maintenance dose to the course of the disease is a chance useful for clinicians and makes ADA a versatile agent in managing the unpredictable course of CD. ADA was also effective in allowing weaning for CS, as documented by the dramatic decrease in the CS dose throughout the trial. This is of clinical importance as one of the main expectations from irritable bowel syndrome therapy in pediatrics is maintaining remission, as well as promoting growth and pubertal development avoiding CS as much as possible (28). Indeed, the latter do not alter the course of the disease and cause many harmful effects on health status (29,30). Recent epidemiological data in North American children with CD indicate that 1 year after the beginning of therapy, 31% show CS dependency and 8% require surgery (31). Moreover, reports from a database indicate that the prolonged use of CS in inflammatory bowel disease (IBD) is independently associated with serious infections and with increased mortality (32,33). Interestingly, the use of IMs in our patients decreased remarkably throughout the trial. These drugs are commonly used in adult and pediatric CD both for CS sparing and maintaining remission (34–36). However, the potential benefits with the early initiation of IM must be balanced with their toxicity. A recent meta-analysis, addressing the question whether azathioprine/6-mercaptopurine might increase the risk of lymphoma in IBD concluded that these drugs enhanced approximately fourfold the risk of developing a non-Hodgkin’s lymphoma (37). Additional concern has risen from the report of cases of hepatosplenic T-cell lymphoma, a rare and aggressive form of peripheral non-Hodgkin’s lymphoma, in young adults and adolescents with CD receiving a combination of IFX and azathioprine/6-mercaptopurine (38,39). Description of these cases has questioned the attitude of combining biological agents and IM, suggesting a strategy of biological monotherapy (40,41). A fully humanized anti-TNF antibody, such as ADA, can be of value as sole therapy for IBD without concomitant IM. In adult trials, no apparent difference in efficacy was found at weeks 26 and 56 between patients on ADA alone and those on ADA combined with IM (14,15). The American Journal of GASTROENTEROLOGY

In our study, the ADA safety profile compares well with previous pediatric observations. No serious infective events occurred, and no features of intolerance to the drug were detected. The most common adverse event was a transient (lasting < 2 h) discomfort at the injection site in four cases. ADA was briefly interrupted in two cases because of infective events (abdominal abscess and cutaneous infection). Intriguingly, an episode of psoriasis occurred in a patient at the eighth week of therapy and disappeared after reduction of the maintenance dose (from 80 to 40 mg eow). In conclusion, children with moderate-to-severe active CD can benefit from ADA to induce and maintain remission. Patients with attenuated response or intolerance to IFX can also successfully be treated with ADA. The latter has a rapid clinical effectiveness, allows weaning from CS, and does not necessarily require combination with IM. Of practical importance is the possibility of adjusting the maintenance dose according to the course of the disease. It is reasonable to support large prospective multicenter trials to answer unsettled questions, such as the optimum loading and maintenance dose, as well as safety profile and immunogenicity, of this anti-TNF- agent. CONFLICT OF INTEREST

Guarantor of the article: Salvatore Cucchiara, MD, PhD. Specific author contributions: Recruitment and follow-up evaluation of the patients: Franca Viola, Fortunata Civitelli, and Maria Barbato; endoscopy: Osvaldo Borrelli and Giovanni Di Nardo; data collection, statistical analysis, evaluation of safety profiles of ADA, and maintenance of contact (by telephone and e-mail) with the families: Salvatore Oliva and Francesca Conte. Financial support: None. Potential competing interests: None.

Study Highlights WHAT IS CURRENT KNOWLEDGE Biological therapy has dramatically changed the therapeutic approach to Crohn’s disease and has been shown to be highly efficacious in inducing and maintaining remission of the disease. There are very few studies on the use of Adalimumab, a fully human monoclonal anti-tumor necrosis factoralpha (TNF-) antibody, in pediatric Crohn’s disease; these reports are retrospective, include small-size populations, and measure only few variables. WHAT IS NEW HERE Adalimumab is a very efficacious and safe biological agent for inducing and maintaining remission in children with moderate-to-severe Crohn’s disease, both naive patients and those with attenuated or lost response to Infliximab, the chimeric monoclonal anti-TNF- antibody. Maintenance of remission in pediatric Crohn’s disease by Adalimumab is associated with withdrawal of corticosteroids and reduced exposure to immunomodulators.

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