Crohn's disease (CD) is a chronic disorder characterised by inflammation of the gastrointestinal tract. Its overall incidence and prevalence in children has increased in recent years: the incidence of CD in Spain has risen from 0.53 to 1.7 per 100,000 individuals <18 years of age in the last 14 years.1,2 Growth failure and delayed puberty are two specific paediatric features. Exclusive enteral nutrition (EEN) and corticosteroids are effective for the induction of clinical remission in children with CD. Anti-TNF therapy is recommended for inducing remission in children with active steroid-refractory disease, for inducing and maintaining remission in children with chronically active luminal CD despite prior optimised immunomodulatory therapy (azathioprine (AZA), mercaptopurine (MP) or methotrexate (MTX)) and as primary induction and maintenance therapy for children with active perianal fistulising disease in combination with appropriate surgical intervention.3

Infliximab (IFX) and adalimumab (ADA) are chimeric human-murine and fully humanised monoclonal antibodies, respectively, which specifically bind to tumour necrosis factor alpha (TNFα). Several studies have shown significant efficacy of IFX in the treatment of CD through sustaining clinical remission and improving overall clinical benefit.4 IFX is the usual first-line anti-TNF administered as therapy in children. ADA was approved later than IFX, and the demonstration of its efficacy in paediatric populations has been based mainly on retrospective studies and just one clinical trial (IMAgINE 1).5–12 In clinical practice, ADA is usually administered in patients who have lost response or developed intolerance to IFX.13 ADA has also shown its efficacy as first-line anti-TNF therapy in adults. Literature about the administration of ADA to paediatric patients with CD is scarce. Moreover, evidence for the short- and long-term efficacy of ADA in anti-TNF naïve patients is even more limited.14

The aim of the present study was to characterise the effectiveness and safety of ADA in achieving clinical remission and maintaining it over time in an anti-TNF-naïve population of paediatric patients with CD.

Three tertiary referral hospitals participated in this multicentre retrospective study. Clinical data from all paediatric CD patients under 18 years of age who had received ADA as first-line anti-TNF treatment were reviewed. All patients were naïve to anti-TNF treatment but might have previously been treated with corticosteroids and/or immunomodulators (AZA, MP, or MTX).

Diagnosis of Crohn's disease was established according to the revised Porto Criteria.15 Infection with tuberculosis was ruled out using the Mantoux and QuantiFERON®-TB Gold In-Tube test (Cellestis Ltd.; Carnegie, VIC, Australia) tests prior to starting treatment. Disease phenotype was established according to the Paris Classification.16

Prior to inclusion, the authors (JMC, GPM, MNR and VMNL) assessed each case and discussed the indication of an anti-TNF: a total (4/4) consensus was needed for each patient to be included in this study. Exclusion criteria were: the presence of active infection; heart, renal or liver failure; and neurological or immunodeficiency disorders. The Haycock formula17 was used for the calculation of body surface area.

The effectiveness of treatment as regards the induction and maintenance of clinical remission was assessed using a paediatric-specific disease activity score, the weighted Paediatric Crohn's Disease Activity Index (remission if wPCDAI<12.5 points). Primary non-response was defined as lack of improvement of clinical signs and symptoms at week 12 after induction therapy (wPCDAI≥12.5),18 mild response as a change of more than 12.5 points from baseline wPCDAI and moderate for more than 37.5 points from baseline wPCDAI changes. In addition to wPCDAI other remission criteria were used.

Dose escalation was indicated in patients with loss of response, defined as recurrence of disease activity (wPCDAI≥12.5) during maintenance therapy after achieving an appropriate induction response.19 The wPCDAI was calculated at baseline, week 12 and week 52. Faecal calprotectin (FC, Calprest®, Eurospital, Trieste, Italy) was used to establish the degree of intestinal mucosal inflammation. Samples for the determination of FC were collected at home by the patient the day before and were delivered refrigerated to the laboratory for analysis. Normal FC levels were considered to be below 50μg/g of faeces.

ADA induction dose (1 dose every other week (EOW)) was established according to basal weight: 160mg and 80mg, or 80mg and 40mg for ≥40kg or <40kg body weight, respectively. The first two doses of ADA were injected at the hospital under medical supervision. Subsequent doses were administered at the patient's home by parents or at their primary care centre. The standard maintenance dose was 40mg EOW. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), haemoglobin (Hb), haematocrit (HCT), platelets, white blood cells (WBC), serum albumin, and FC levels were measured during follow-up. CRP levels were also expressed as the ratio between the value obtained and the upper limit of normal (ULN). Weight and height were measured with the patient barefoot and in underwear. Growth velocity, weight, height and body mass index (BMI) z-scores were calculated using data from Spanish growth Charts.20 Severe growth failure was defined as a growth rate z-score<−2.5 and mild to moderate failure as a growth rate z-score between −1.0 and −2.5.3 Growth velocity was calculated according to Tanner stage and to bone age when delayed puberty was present. Serious Adverse Event (SAE) was defined as any adverse event or adverse reaction that results in death, life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity.

In a first analysis, steroid-free remission at week 12 and 52 was assessed. Secondly, the need for dose escalation and the effect of anti-TNF treatment on the growth rate were also evaluated.

Literature concerning treatment with ADA in anti-TNF naïve paediatric CD patients is very scarce.21 Our data reveal promising results in terms of effectiveness, safety and growth as shown by short- and long-term clinical remission rates after 12 and 52 weeks of treatment. In a study conducted by Hyams et al.,10 including 105 infliximab-naïve patients, a remission rate of 56.9% at week 26 and 45.1% at week 52 was achieved in the high-dose (40mg EOW) group compared with 35.2% at week 26 and 27.8% at week 52 in the low-dose (20mg EOW) group, this was the main reason for not using low ADA dose in our study. Another possible explanation for our better results is the shorter disease duration before the first ADA dose (median 7.3 months in our study, as opposed to 2.9 years in Hyams’ study). A recent prospective study included 12 naïve anti-TNF patients treated with ADA, with a disease progression of 9.4±2.7 months (range 8.6–15.7), remission rate at 9–12 months starting treatment with ADA was 67.5%, the percentage of patients with mucosal healing was 41.7% and with partial mucosal healing 25%.12 Several studies have demonstrated an inverse relationship between disease duration and treatment outcome.21,22

Our results provide further evidence for the hypothesis that ADA may give better results in anti-TNF naïve patients than in IFX-experienced patients. Only one clinical trial has been carried out in a paediatric population, IMAgINE-1 (which includes the largest subgroup of anti-TNF naïve patients so far), and two trials in adult patients, CHARM23 and CLASSIC I,24 which have demonstrated positive results. Two prospective and several retrospective studies focused on the efficacy of ADA in paediatric populations which included a majority of patients with previous anti-TNF failure.5–7,9,21,22 The ADA induction doses in our series were 160/80mg, and 80/40mg for ≥40kg or <40kg body weight, respectively. The maintenance dose used for all patients was 40mg EOW. Our dosing schedule was similar to the higher ADA dose group in Hyams’ study, which was more successful for patients in remission than the lower dose group.10

The median duration of combination therapy in our series was 12 months (IQR 6–14). Although the data on this topic in paediatric populations is scarce, combination therapy during the first months of anti-TNF therapy may be associated with a lower rate of antibody development and loss of response. However, this benefit should be weighed against the potentially increased lymphoma risk with thiopurines.25

Malnutrition and growth failure are detrimental consequences in children with CD. The beneficial effect of anti-TNF on this issue has been reported in some studies.26–37 Nevertheless, some did not find any change in linear growth.26,30,31 One study reported nutritional and developmental effects of ADA in paediatric CD patients, but in this case all patients were IFX-experienced.33 Our study is the first report on growth and nutritional parameters effects of ADA in anti-TNF naïve patients. Furthermore, it confirms the beneficial effect in improving weight, height, BMI and growth rate over a period of one year. In our series, improvement in growth rate z-scores was found in patients with growth failure at baseline. These results are similar to those already published.10,26 One explanation for our results may be the steroid-sparing protocol followed in our study; only two patients used steroids concomitantly with ADA, because of severe extraintestinal manifestations.

Laboratory biomarkers play an important role in the follow-up of paediatric CD patients. Even if they are not as sensitive or specific as faecal biomarkers, they are very useful, in combination with clinical signs, to predict mucosal inflammation.35 The effects of ADA on Hb, HCT, WBC, platelet and albumin levels have also been described. All parameters showed a slow but progressive normalisation, maintaining normal levels until the end of the follow-up. With regard to safety, our experience showed a low rate of major AEs, including no malignancy, opportunistic infections, or surgical interventions. These findings are in accordance with other reports.5–7,9,26 By contrast, two studies described an incidence of 10%–43% of injection site reactions and 20% of serious AEs.10,12

In our series, 12 out of 62 patients (19.3%) had to intensify treatment to 40mg of ADA weekly during the first year of treatment, well below that recently published by Dubinsky et al.38 In this series (from the IMAgINE 1 study), 44% had to be intensified after 12 weeks of treatment, 50.5% of the low-dose group of adalimumab and 37.6% of those who were part of the high-dose group. At 52 weeks of follow-up, 18.8% of the low-dose group and 31.4% of the high-dose group were in remission. These percentages were higher in patients naïve to anti-TNF treated with high dose (15.4% and 44.4%) but much lower than those obtained in our series.

A previously undescribed contribution from paediatric series is the preference of children and their families to receive ADA subcutaneously injected at home instead of IFX administered at hospital. As specified in the European Crohn's and Colitis Organisation-European Society for Paediatric Gastroenterology and Nutrition (ECCO-ESPGHAN) consensus guidelines on the treatment of paediatric CD, considering IFX and ADA to be drugs of similar efficacy and safety profile for the treatment of anti-TNF naïve patients, these should be offered as options to the patient, depending on availability, route of administration, patient preferences, cost, and local regulations. Different series of adult patients with disease subsidiary to anti-TNF treatment have shown ease of use and time spent on administration as the two factors that most influence the choice of treatment.39,40 Furthermore, involving the patient and caregivers in choosing the drug could, apart from strengthening the doctor–patient relationship, allow greater patient responsibility in their treatment and self-care. This strategy, put into practice in our centres, has shown that 90% of our paediatric patients who have been offered the choice prefer ADA to the option of intravenous administration of IFX in hospital.

This study has a number of limitations, including small sample size, its retrospective nature, the lack of a control group, the short follow-up period, absence of drug levels and monitoring of mucosal healing with colonoscopy. However, this series provides important data: the effectiveness of ADA to normalise growth rate in paediatric patients with Crohn's disease and the predictive factors for dose escalation.

In conclusion, ADA as first-line anti-TNF therapy induces and maintains clinical remission in paediatric patients with CD. Moreover, ADA has a beneficial effect on nutritional and growth parameters, and is also well tolerated. Some patients maintain remission for prolonged time periods under monotherapy; however some patients in this situation would require dose escalation.

All authors have made substantial contributions to all of the following:

• (1)

  the conception and design of the study, or acquisition of data, or analysis and interpretation of data: Víctor Manuel Navas-López, Gemma Pujol Muncunill, Enrique Llerena, María Navalón Rubio and J. Martin-de-Carpi

• (2)

  drafting the article or revising it critically for important intellectual content: Víctor Manuel Navas-López, Gemma Pujol Muncunill, Enrique Llerena, María Navalón Rubio, David Gil-Ortega, Vicente Varea-Calderón, Carlos Sierra Salinas and J. Martin-de-Carpi

• (3)

  final approval of the version to be submitted: Víctor Manuel Navas-López, Gemma Pujol Muncunill, Enrique Llerena, María Navalón Rubio, David Gil-Ortega, Vicente Varea-Calderón, Carlos Sierra Salinas and J. Martin-de-Carpi.

This manuscript, including related data, figures and tables, has not been previously published and is not under consideration elsewhere.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent was obtained from all individual participants included in the study.

Dr Victor Manuel Navas-López has received consulting fees and speakers’ fees from Abbvie; Dr María Navalon Rubio has received consulting fees and speakers’ fees from Abbvie; Dr Enrique Llerena declares that he has no conflict of interest. Dr Gemma Pujol declares that she has no conflict of interest; Dr David Gil-Ortega declares that he has no conflict of interest; Dr Vicente Varea-Calderón declares that he has no conflict of interest; Dr Carlos Sierra declares that he has no conflict of interest. Dr Javier Martín-de-Carpi has received consulting fees and speakers’ fees from Abbvie.