Digestive Diseases and Sciences

, Volume 55, Issue 3, pp 747–753

Adalimumab Treatment in Children with Refractory Crohn’s Disease

Authors

  • Yoram Rosenbach
    • Institute of Gastroenterology, Nutrition, and Liver Disease, Schneider Children’s Medical Center of Israel, Sackler Faculty of MedicineTel-Aviv University
    • Institute of Gastroenterology, Nutrition, and Liver Disease, Schneider Children’s Medical Center of Israel, Sackler Faculty of MedicineTel-Aviv University
  • Rivka Shapiro
    • Institute of Gastroenterology, Nutrition, and Liver Disease, Schneider Children’s Medical Center of Israel, Sackler Faculty of MedicineTel-Aviv University
  • Akiva Hirsch
    • Institute of Gastroenterology, Nutrition, and Liver Disease, Schneider Children’s Medical Center of Israel, Sackler Faculty of MedicineTel-Aviv University
  • Yaron Avitzur
    • Institute of Gastroenterology, Nutrition, and Liver Disease, Schneider Children’s Medical Center of Israel, Sackler Faculty of MedicineTel-Aviv University
  • Raanan Shamir
    • Institute of Gastroenterology, Nutrition, and Liver Disease, Schneider Children’s Medical Center of Israel, Sackler Faculty of MedicineTel-Aviv University
Original Article

DOI: 10.1007/s10620-009-0791-7

Cite this article as:
Rosenbach, Y., Hartman, C., Shapiro, R. et al. Dig Dis Sci (2010) 55: 747. doi:10.1007/s10620-009-0791-7

Abstract

Information on safety and efficacy of adalimumab in children with Crohn’s disease (CD) is limited. We present a case-series of 14 children with severe CD treated with adalimumab during a 3.5-year period. Fourteen children (nine boys, five girls), aged 13.9 years (range 1.9–19.1) were treated with adalimumab during 12.5 months (range 7–42). All had steroid or immunosuppression-drugs refractory disease. Ten patients (71%) had been previously treated with infliximab, 13/14 were treated with different immunosuppressive drugs and all were steroid-dependent or resistant. Seven children (50%) showed full clinical response and 5/14 (35%) improved partially. Two children (15%) had loss of response after a period of transient improvement. Adalimumab treatment enabled complete steroids withdrawal in 8/14 (57%) of steroid-dependent children. Currently, five children are in complete remission with adalimumab monotherapy for a median 14 months (range 9–24). Adalimumab may induce and maintain remission in children with severe, refractory CD. Prospective safety and efficacy confirmation of this data in children is necessary.

Keywords

Crohn’s diseaseAdalimumabInfliximabChildren

Introduction

Approximately 25% of inflammatory bowel disease (IBD) patients have the onset of their disease during childhood and adolescence [1]. An increasing number of pediatric and adult patients displaying steroid or immunomodulatory agents-refractory disease have been a major impetus for the development of biological agents. The use of TNF antagonists has changed the therapeutic approach to Crohn’s disease (CD), particularly in patients with severe and refractory disease. All anti-TNF agents studied so far (infliximab, adalimumab, and certolizumab) have been shown to induce and maintain remission or response in adults with CD [2].

Infliximab (Remicade®, Centocor Inc., Malvern, PA, USA) has also been shown to be effective for induction and maintenance of remission in children with CD [3]. However, infliximab is immunogenic, and repeated administration results in the development of antibodies to it, leading to infusion reactions, loss of efficacy, and delayed hypersensitivity reactions [4]. The fully human IgG1 anti-TNF antibody, adalimumab (Humira®, Abbott Laboratories, Parsippany, New Jersey, IL, USA) was shown to be effective in induction and maintenance of remission in adults with CD, as primary or rescue therapy after infliximab failure [2]. However, data on the use of adalimumab in children is limited to a few case reports. We therefore present our center’s experience with adalimumab in children with severe, medically resistant CD.

Patients and Methods

Our cohort included 14 children and adolescents with medically refractory CD who were treated at the Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children’s Medical Center of Israel from 2004 to 2007. The diagnosis of CD was made according to established endoscopic, radiologic, and histopathologic criteria [5]. Medical records of all patients were reviewed for the following information: sex, age, age at diagnosis, previous medical and surgical history, location and behavior of disease, laboratory results, concomitant medication (corticosteroids, azathioprine, mercaptopurine, methotrexate, 5-ASA), previous treatment with infliximab (indication, time and number of infliximab infusions, efficacy, side effects). Primary non-response to infliximab was defined as an absence of clinical response or symptoms’ worsening at least 2–4 weeks after two infliximab’ doses. Loss of response to infliximab was defined as initial response followed by subsequent reduction in the efficacy, requiring a shortening of the interval between infusions to <6 weeks (usually 4 weeks) and eventual loss of response. All patients were screened for tuberculosis using a protein-purified derivative skin test and chest radiograph before the initiation of anti-TNF treatment. Complete medical files were available for all patients. The study was approved by the local institutional review board.

Statistical analysis for continuous variables is given as median with range. The results for non-continuous variables are given as frequency and percentage. Comparison of data from baseline to week 4 (laboratory data), or the last follow-up (anthropometry data) was done using Wilcoxon signed-rank test for matched pairs. P-values <0.05 were considered to indicate statistical significance.

Results

Demographic data of the children and adolescents (nine males, median age 13.9 years, range 1.9–19.1) treated with adalimumab is provided in Table 1. All patients except one had non-stricturizing, non-fistulizing disease, at diagnosis. Re-evaluation of disease extent before the start of adalimumab treatment was performed in 6/14 children and all showed similar disease location and extent as at diagnosis. Disease location and extent at diagnosis according to Montreal classification is presented for each child in Table 2 [6]. Extraintestinal manifestations were present in 7/14 children, and active perianal disease was present in 6/14 children. We could not calculate PCDAI because of the incomplete laboratory data, mainly erythrocyte sedimentation rate, from some patients’ files, but instead used the Harvey-Bradshaw score, a simplified CD activity index that provides scoring for each of the following: well being, abdominal pain, diarrhea, abdominal mass, and each of the extraintestinal manifestations. A score <4 defines remission, between 5 and 8 indicates moderate activity, and a score above 9 represents severe disease [7]. Complete weight and height recordings were present in 13 children. Assessment of weight and height at the last follow-up showed that significant improvement in weight z-score occurred after the start of adalimumab (−1.8 ± 0.9 vs. −1.3 ± 0.9, P = 0.04), while height change was not statistically significant (−1.8 ± 0.8 vs. −1.6 ± 0.9). Albumin, hemoglobin and C-reactive protein blood levels were recorded at baseline and after the induction period (1 month). After three adalimumab doses, there was a marked decrease in C-reactive protein, (4.7 ± 3.4 mg/dL vs. 0.9 ± 0.7, P = 0.0,015) and hemoglobin levels rose significantly, (10.6 ± 1.4 g/dL vs. 11.9 ± 1.2, P = 0.027). There was a slight, but statistically non-significant improvement in albumin levels (3.3 ± 0.7 g/dL vs. 3.7 ± 0.7).
Table 1

Demographic characteristics of children treated with adalimumab

Gender

    Male (%)

9 (64%)

    Female (%)

5 (36%)

Age (years)

    Median (range)

13.4 (1.9–19.1)

Disease duration (years)

    Median (range)

3.9 (1.2–7.1)

Extraintestinal manifestations

7/14

Indication for adalimumab therapy

    Adverse reaction to infliximab

4/14

    Loss of response to infliximab

6/14

    No response to treatment

4/14

Duration of adalimumab treatment (months)

    Median (range)

16.4 (7–42)

Follow-up after the start of adalimumab (months)

    Median (range)

17.3 (7–42)

Table 2

Clinical data and treatment response of children with CD

 

Gender

Age/disease duration (years) and phenotype

Disease manifestations before the start of adalimumab Harvey-Bradshaw score (HB score)

Previous/failed medications

Clinical status at the last follow-up Harvey-Bradshaw score (HB score)

Current medications and doses

Duration of adalimumab treatment (months)

1

SR

M

2.10/2.2

A1

L2

B1p

Diarrhea, gross bleeding

Failure to thrive

Inflamed perianal skin tags and fissures

Fever, oral ulcers

HB score 10

Corticosteroid-depend disease

Infliximab, adverse reaction (fever)

Complete response

HB score 2

Adalimumab monotherapy

20 mg EOW

23

2

SD

F

18.2/7

A1

L2

B1p

Abdominal pain, diarrhea

Weight loss, poor well-being

Perianal skin tags and indolent fissures

HB score 9

AZA, recurrent disease relapses

Corticosteroids, refusal to treatment

Partial response

Infrequent rectal bleeding

HB score 4

Adalimumab

40 mg EOW

Entocort enemas

17

3

VN

F

11.10/2

A1

L3

B1

Abdominal pain

Growth failure

Fever

HB score 12

AZA, recurrent disease relapses

Budeson, corticosteroid-dependent disease

Complete response

HB score 2

Adalimumab monotherapy

40 mg EOW

14

4

AA

M

11.5/4

A1

L3

B3p

Abdominal pain

Diarrhea, gross bleeding

Scrotal/perianal fistula

HB score 13

Corticosteroid-depend disease

AZA, recurrent disease relapses

Infliximab, adverse reaction (shivering)

Thalidomide

Partial response

Indolent perianal fistula

HB score 5

Adalimumab monotherapy

40 mg EOW

18

5

IL

F

8.10/7

A1

L2

B1

Abdominal pain, diarrhea

Arthritis, knee, ankle

HB score 10

Corticosteroid-depend disease

AZA, MTX, recurrent disease relapses

Infliximab, adverse reaction (shivering)

Partial response

Recurrence of arthritis

HB score 5

Adalimumab

40 mg

every 4–5 weeks

MTX

42

6

DI

M

17.2/2

A1

L2

B1

Abdominal pain, diarrhea

HB score 10

Corticosteroid-depend disease

AZA, MTX, no response

Infliximab, loss of response

Complete response

HB score 2

Adalimumab monotherapy

40 mg EOW

11

7

SI

M

1.9/1.5

A1

L2

B1

Diarrhea, gross bleeding

Failure to thrive

Ankle arthritis

Fever, oral ulcers

HB score 13

Corticosteroid-depend disease

AZA, MTX, no response

Partial response

Recurrence of arthritis

HB score 5

Adalimumab

20 mg/week

MTX

Tapering steroids

5 mg EOD

9

8

DO1

M

17.2/4

A1

L3

B1p

Abdominal pain

Severe weight loss

Inflamed perianal skin tags and fissures

Fever

HB score 12

Multiple courses of corticosteroids

AZA, MTX, no response

Infliximab, loss of response

Ileocecal resection

Complete response

HB score 2

Adalimumab monotherapy

80 mg EOW

24

9

VD

M

13.4/2.5

A1

L2

B1p

Diarrhea, gross bleeding

Poor well-being

Weight loss, growth arrest

Inflamed perianal skin tags and fissures

HB score 12

Multiple courses of corticosteroids

AZA, no response

Infliximab, primary non-response

Complete response

HB score 2

Adalimumab monotherapy

40 mg EOW

9

10

DO2

F

19/5

A1

L3

B1

Abdominal pain, diarrhea

Severe weight loss

Fever

HB score 10

Corticosteroid-depend disease

AZA, MTX, no response

Infliximab, loss of response

Partial/transient response

Abdominal abscess

HB score 8

Postsurgery

Corticosteroids

20–30 mg/d

7

11

KA

F

16.5/1.2

A1

L2

B1p

Diarrhea, gross bleeding Poor well-being

Perianal skin tags and fissures

HB score 11

Multiple courses of corticosteroids

AZA, no response

Infliximab, primary non-response

Partial/transient response

Abdominal pain/diarrhea

HB score 10

Corticosteroids

20–30 mg/d

5

12

LL

M

14.4/0.4

A1

L2

B1

Diarrhea, gross bleeding

Poor well-being

Severe weight loss

HB score 130

Corticosteroid-depend disease

CSA, no response

Infliximab, primary non-response

Colectomy

Complete response

HB score 2

Adalimumab

40 mg EOW

Tapering steroids

5 mg/d

7

13

AN

M

19.1/2.5

A2

L3

B1

Ileocolic CD

Abdominal pain, diarrhea

Severe weight loss

HB score 13

Corticosteroid-depend disease

AZA, recurrent relapses

Infliximab, adverse reaction (rash, dyspnea)

Complete response

HB score 2

Adalimumab

40 mg EOW

Tapering steroids

10 mg/d

7

14

GM

M

4.4/4.2

A1

L2

B1p

Diarrhea, gross bleeding

Failure to thrive

Gluteal abscess

Fever, oral ulcers, ankle arthritis

HB score 13

Corticosteroid-depend disease

AZA, MTX, recurrent relapses

Partial response

Perianal disease improved

HB score 8

Adalimumab

20 mg every 3 weeks

MTX

7

A1 age at diagnosis below 16 years; A2 age at diagnosis above 17 years; L2 colonic disease; L3 ileocolonic disease; B1 non-stricturing, non-penetrating; B3 penetrating; p perianal disease modifier; AZA azathioprine; MTX methotrexate, EOW every other week

Table 2 shows the clinical details and the symptomatic response to adalimumab treatment in individual patients. Adalimumab was started in 4/14 children because the development of adverse reactions to infliximab: fever (1/4), dyspnea (1/4), shivering (2/4), and rash (1/4). Three children showed loss of response after 4–12 infliximab doses, in spite of shortening of the interval between doses to 4 weeks. A dose escalation to 10 mg/kg was tried in one of these patients. Three children were primary non-responders to infliximab and were switched to adalimumab when no clinical improvement occurred 2 weeks after the second infliximab dose. Four children were never treated with infliximab due to their parents’ choice (mostly reluctance to hospital admissions and infusions). Adalimumab was administered subcutaneously, every 2 weeks. The dose was calculated as mg/body surface area, by extrapolating from the recommended adult dosage; 160 mg/1.73 m3 first dose, 80 mg/1.73 m3 second dose and 40 mg/1.73 m3 as maintenance dose.

A complete response, defined as the disappearance of all complaints, a decrease of the Harvey-Bradshaw score to <4, weight recovery, and improvement of inflammatory markers, was achieved 7/14 children. A partial response (defined as a reduction in the Harvey-Bradshaw score to <8) occurred in 7/14 children. Five children particularly showed a remarkable improvement of complaints, general well-being, and significant weight gain after the start of adalimumab. All children had abdominal pain and/or diarrhea before the start of adalimumab and these symptoms improved first. Failure to thrive or severe weight loss (>10% of weight) were present in 10/14 and poor well-being in 5/14. Perianal disease improved greatly in two children and partial response to adalimumab in two. The two children with scrotal fistula and gluteal abscess had been treated with thalidomide and MTX, and had already improved at the start of adalimumab. Fever disappeared in all children after the start of adalimumab. Arthritis improved temporary and required maintenance of MTX treatment.

Loss of response to adalimumab (return of previous symptoms or development of new complaints during adalimumab treatment after a period of partial or complete improvement) was recorded in two patients, adalimumab was stopped in both after 7 and 4 months of treatment. Seven months after starting adalimumab treatment (14 doses), one of these adolescents (patient 10, DO2) developed abdominal abscess and underwent surgery and ileocolic resection.

Adjustment of adalimumab (dose escalation or weekly injections) treatment was needed in order to maintain remission in 8/14 children. The children were followed weekly and the decision to increase the adalimumab dose or shorten the treatment schedule (weekly injections) was made immediately at the occurrence of symptoms suggesting a relapse in the presence of an increased level of inflammatory markers. The new dose of adalimumab was the previous dose that induced response. In the absence of improvement, we also shortened the intervals between injections. Rapid return to lower doses and extended intervals between doses was done after the achieving symptoms' remission. In contrast, in two patients who were on stable remission, the intervals between adalimumab injections were increased to 3 weeks in one (patient 14, GM) and to 4–5 weeks in the other (patient 5, IL).

At the start of adalimumab injections, 13/14 children received concomitant stable doses of immunosuppressive medication (azathioprine n = 12, methotrexate n = 6, cyclosporine n = 1) and all were steroid-dependent or resistant (daily prednisone doses varied between 10 and 30 mg). The initiation of adalimumab treatment made possible complete steroid withdrawal in 57% (8/14) of steroid-dependent children, and medication reduction for another ten children. Corticosterois’ tapering was started after the first two induction doses of adalimumab and continued slowly (prednisone dose reduction by 2.5 mg/week), up to complete withdrawal, which usually took 2–4 months, depending on the recovery of adrenal axis. At the last follow-up, five children are in complete remission with adalimumab monotherapy for a median of 14 months (range 9–24), one responded partially to adalimumab, three are concomitantly treated with MTX, and three are on tapering doses of corticosteroids. Overall, subcutaneous injections of adalimumab were well tolerated with no case of anaphylaxis, acute or delayed hypersensitivity reactions, or significant injection site pain. No dermatologic, neurologic, or infectious complications were recorded during the follow-up, so far, with the exception of the development of abdominal abscess in one patient.

Discussion

The use of novel therapies in children had always lagged behind adults. To date, four new biological agents have been studied in adults with CD but only infliximab has been approved so far for the treatment of children with severe CD. The options left for children that failed to respond or lost response to infliximab are limited. We present the largest case-series, so far, of pediatric patients with severe medically refractory CD treated with adalimumab. Adalimumab was used in these patients as rescue therapy after all other treatment failed to achieve remission and also as maintenance therapy. All but one of the patients showed clinical response with significant reduction or end of abdominal pain, diarrhea, systemic symptoms, resumption of growth, and improvement of quality of life for the children and their families.

Four randomized double-blind placebo-controlled trials have evaluated and proved the efficacy and safety of adalimumab treatment for induction and maintenance of remission in patients with CD [710]. Several additional small open studies including 16–50 patients evaluated adalimumab use in adult patients with CD that were intolerant or experienced loss of response to infliximab [1113]. To date, no studies on adalimumab treatment in children with CD have been published except for two case reports [14, 15].

The majority of children presented in the current report were started on adalimumab because of failure of all other therapies to achieve or maintain remission, and in some because of intolerance to infliximab. All children that were started on adalimumab, even the one that developed abdominal abscess, showed some improvement after the beginning of the treatment. The randomized, placebo-controlled studies in adult patients with CD that were intolerant or failed to respond or experienced loss of response to infliximab, showed that compared to placebo, adalimumab was better in induction and maintenance of remission [9, 10]. Observational, non-controlled studies showed a higher response (75%) and remission rate at 4 weeks (42%), 8 weeks (63%), and 2 years (68%) [11, 13, 16]. In our cohort, all children showed some response after the first dose of adalimumab and almost complete response after the second dose (4 weeks). All but two showed remission or partial response during the follow-up, although only 50% maintained complete remission. This is a much higher response rate compared to placebo-controlled studies, but closer to the results of the observational studies. Given the novelty of the treatment, these children were closely followed and adalimumab doses and treatment schedule were immediately and frequently changed on an individual basis in keeping with changes in symptoms. We observed that all children showed quick symptomatic and inflammatory markers’ response after the start of adalimumab which may support the recommendation that, similar to infliximab, efficacy of treatment should be assessed after the induction period, and adalimumab continued only in responders.

The recent dispute surrounding the issue of concomitant immunosuppression as a form of synergy with anti-TNF agents aiming to reduce the induction of anti-TNF antibodies has both pro and con arguments [17]. The above strategy is under re-evaluation because of the concerns of the potential increase in life-threatening infections and malignancies associated with anti-TNF, particularly in children [18].

Our goal was adalimumab monotherapy for all our patients mainly for safety reasons, and thus, half of the children were treated with adalimumab as monotherapy. With the reservation of a small number of patients and short follow-up, we recorded only one severe adverse event.

In spite of our excellent results, we still reserve the adalimumab treatment for severe, medically refractory cases of CD, and almost always after an infliximab trial, mostly because this is the conventional, approved treatment for children.

There are several limitations to this case-series report. First, the data presented are based on a retrospective review that evaluated treatment response at different endpoints. Secondly, we could not present objective measures of patients’ improvement, such as pediatric Crohn’s disease activity index (PCDAI) although we showed definite improvement in clinical and laboratory parameters. Thirdly, although we use a standardized approach, the current data reflect clinical practice of one center, although with considerable experience in difficult IBD cases.

In conclusion, we showed that adalimumab may induce and maintain remission and response in children with severe CD that failed to respond to other therapies, including infliximab. We showed that some children can maintain remission for prolonged time periods with adalimumab monotherapy, although a significant proportion of patients require adalimumab dose escalation. Further, prospective confirmation of our data in children is necessary.

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