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Reumatologia/Rheumatology
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1/2015
vol. 53
 
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Original paper
Influence of biologic therapy on growth in children with chronic inflammatory connective tissue diseases

Joanna Świdrowska
,
Agnieszka Zygmunt
,
Małgorzata Biernacka-Zielińska
,
Jerzy Stańczyk
,
Elżbieta Smolewska

Reumatologia 2015; 53, 1: 14–20
Online publish date: 2015/04/10
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Introduction

Connective tissue diseases (CTD) in children are a heterogeneous group of chronic inflammatory conditions mostly including juvenile idiopathic arthritis (JIA), autoimmune vasculitis, dermatomyositis, and systemic lupus erythematosus. One of their complications is the inhibition of growth velocity [1]. Due to direct inflammation within the musculoskeletal system, this feature is the most essential and is mainly expressed in the course of juvenile spondyloarthropathies and JIA [2]. Duration of the disease, but predominantly the activity of the inflammatory process, seems to have a significant impact on the abnormal growth profile in children [3]. Excessive stimulation of pro-inflammatory cytokines, especially interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor  (TNF-), causes abnormal secretion of hormones, including growth hormone (GH) and insulin-like growth factor (IGF) [4]. It also causes fluctuations of cortisol concentration in serum. These disorders are significantly worsened by steroids, which are used as a first-line therapy in children with systemic inflammatory CTD [5]. By inhibiting the ongoing inflammatory process, glucocorticosteroids (GCS) improve the general condition of the patient, but used chronically they significantly affect the growth rate through an adverse effect on the hypothalamic-pituitary-adrenal axis (HPAX) [6, 7]. A group of drugs successfully used in the treatment of chronic inflammatory CTD are biological agents [8, 9]. Their mechanisms of action involve inhibition of the activity of pro-inflammatory cytokines: TNF- (etanercept, adalimumab, golimumab) and IL-6 (tocilizumab). Biological therapy causes rapid remission of the inflammatory process and enables faster reduction of daily doses of GCS. According to reports of recent studies, effective biological therapy not only brings improvement of the patient’s clinical condition, but through the extinction of disease activity and reduction of GCS doses it gradually accelerates and normalizes the growth rate in children with chronic inflammatory CTD [10].

Material and methods

Patients

The profile of 24 patients (15 girls, 9 boys) aged 7–21 with chronic inflammatory CTD (polyarteritis nodosa, dermatomyositis, juvenile idiopathic arthritis – polyarticular, oligoarticular and systemic) was retrospectively analyzed. The mean disease duration was 6.5 years (3–17 years). Patients were initially treated with GCS (prednisone at a dose of 0–0.9 mg/kg/day) and selected disease-modifying anti-rheumatic drugs (DMARDs) (methotrexate at a dose of 10–20 mg/m2 body surface area/week; sulfasalazine at a dose of 20 mg/kg/day, hydroxychloroquine at a dose of 200 mg/day, cyclosporine at a dose of 3 mg/kg/day, azathioprine at a dose of 2 mg/kg/day) (Table I). Due to the severe course of disease, refractory to standard treatment, biological therapy was implemented – etanercept subcutaneously at a dose of 0.8 mg/kg per week (12 patients), adalimumab subcutaneously at a dose of 40 mg per two weeks (9 patients, 4 of them after ineffective etanercept treatment), golimumab subcutaneously at a dose of 30 mg/m2 body surface per month (2 patients) and tocilizumab intravenously at a dose of 8 or 12 mg/kg per two weeks or 10 mg/kg per month (5 patients). Duration of biological therapy was 12–96 months (mean 43.2 months). All patients have never received growth hormone treatment.
All patients were treated with biological agents according to the guidelines of the National Health Fund Therapeutic program. Golimumab was administered under the program of a clinical trial, after obtaining approval from the local bioethics committee.

Growth assessment

Growth profile was evaluated using standardized Polish growth charts developed by the Institute of Mother and Child in Warsaw (2007). A pediatrician or a registered nurse made the measurements. The height standard deviation score (height SDS; z score), was defined as the observed height minus mean height for age divided by SD, where SD was the standard deviation for the normal population of the same chronological age and gender. Growth rate was evaluated at the time of the disease onset, during the initiation of biological therapy and after at least 12 months up to 2 years of its duration. The rate of growth was correlated with the daily doses of GCS, and the type and duration of biological therapy.

Results

Median height, expressed as the SD score (SDS), was 0.36 ±1.07 at disease onset, and 0.13 ±1.02 at the time of biological treatment induction. Acceleration of growth velocity was observed in 17 patients (70.1%) with chronic inflammatory CTD two years after biological therapy initiation. Mean height SDS improvement between biological treatment initiation up to two years of its duration was 0.51 ±0.58 (Fig. 1).
In the group where improvement of the growth profile was seen, 1 patient was treated for systemic JIA (33.3%), 5 patients for oligoarticular JIA (62.5%), 9 patients for polyarticular JIA (90%) and 2 patients for polyarteritis nodosa (100%). The height SDS changes in children with particular diagnoses are shown in Figures 2, 3, 4 and 5. Four children (23.5%) were treated with tocilizumab, 2 children (11.7%) with golimumab, 5 children (29.4%) with etanercept, 4 children (23.5%) with adalimumab, and 2 children (11.7%) firstly with etanercept and secondly with adalimumab. In 47% of patients (8 out of 17 with an improved growth rate) daily doses of GCS were reduced to 0 mg/kg/day. In 2 patients (11.7%) doses of steroids were minimized to less than 0.05 mg/kg/day. Unfortunately, in 4 children the GCS therapy was continued at a dose of more than 0.05 mg/kg/day. Three patients (17.6%) had never received steroids. At the latest follow-up, the mean height SDS was –0.03 ±1.09.
In 7 children (29.2%), despite biological agent administration, the growth velocity did not improve. In that group, 2 patients were treated for systemic JIA (28.5%), 3 patients for oligoarticular JIA (42.8%), 1 patients for polyarticular JIA (14.3%) and 1 patient for dermatomyositis (14.3%). Three patients were treated with etanercept (42.8%), 2 patients with etanercept and secondly with adalimumab (28.6%), 1 patient with tocilizumab (14.3%), and 1 patient with adalimumab (14.3%).
In 3 patients the daily dose of GCS was reduced to 0 mg/kg/day. Four patients were treated with GCS at a mean dose of 0.1 mg/kg/day (0.003–0.25 mg/kg/day).
Between the time of disease onset up to biological therapy initiation 6 children (25%) had significant growth inhibition (more than 1 height-SDS). All but one patient received GCS at a dose of 0.5 mg/kg/day or more during that time. After biological treatment induction only 2 of them had only a slight growth rate increase. Significant growth delay was observed in 2 patients (8%) before the diagnosis of CTD.

Discussion

There are various factors that may contribute to growth retardation in patients suffering from chronic inflammatory CTD. Disease type and duration, functional joint involvement, age of puberty and severity of the inflammatory process appear to be risk factors for growth impairment [11]. Glucocorticosteroids, being a first-line therapy, are a frequent cause of deteriorating linear growth in children even if they are administered at low doses [12].
Biological therapy might be effective for both inhibiting the inflammatory process and reducing the daily doses of GCS [13]. By achieving this goal the acceleration of growth velocity might be expected. There are only a few recent studies on the influence of antiTNF treatment on growth in children with JIA. Giannini et al. [14] reported that even without DMARD therapy, a significant increase in height, weight and BMI in children was observed during long-term etanercept therapy. Moreover, the improvement in growth velocity is the best in patients with the greatest growth retardation. On the other hand, Uettwiller et al. [15] recently found that biologic therapy may be insufficient to restore normal growth velocity. Tynjälä et al. and Schmeling et al. [16] reported that the variation of inflammation activity remains a significant predictor of growth velocity. It simply means that the improvement in growth velocity may be observed due to inflammation inhibition and not by a direct effect of biological agents on growth. It is also proven that there is a significant relation between the variations in GCS doses and the change in growth velocity. The results from our study showed the significant acceleration of growth velocity in children with CTD treated with various biological agents. There were no significant differences between the particular therapies. In around half of the children with growth rate improvement the daily dose of GCS could be reduced to 0 mg/kg/day or less than 0.05 mg/kg/day.

Conclusions

In conclusion, to our best knowledge, this is the first study reporting the impact of biological therapy on growth velocity and GCS consumption not only in JIA, but also in other CTD in children. We have shown that biological drug treatment allows one to control the inflammatory process and also to reduce or withdraw the daily doses of GCS. Normal growth is one of the most important goals in CTD treatment, and biological agents might play a crucial role in achieving it.

The authors declare no conflict of interest.
Financing of the work – the statutory program of the Medical University of Lodz (503/8-000-01/503-01).

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Copyright: © 2015 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.





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