Department of Pediatrics-Rheumatology Unit and 1 Department of Pediatrics, University of Florence, Italy.
Correspondence to: G. Simonini, Department of Pediatrics-Rheumatology Unit, Via Pico della Mirandola 24, 50132 Firenze, Italy. E-mail: gabriele.simonini{at}unifi.it
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Abstract |
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Methods. Twenty children (13 female, 7 male) aged 5.211.4 yr, with active polyarticular JIA were prospectively enrolled to receive etanercept (0.4 mg/kg, twice weekly). Responders were defined according to the American College of Rheumatology Pediatric 50 definition of improvement. Broadband ultrasound attenuation (BUA) by bone was determined at the left calcaneus to assess bone status at baseline and at 1-yr follow-up.
Results. After 12 months of treatment, 15 (75%) patients were considered as responders. At baseline, responders and non-responders did not differ with regard to age, disease duration, core-set variables or BUA and Z-score values (patient's value age specific normal value/normal group's S.D.). At 6-month and 1-yr follow-up in the whole group, BUA and Z-score values were not significantly different compared with baseline. At 1-yr follow-up, but not at 6 months, all 15 responders, differently from non-responders, showed a significant increase in both BUA and Z-score values: BUA at 1 yr 55.2 ± 3.3 vs baseline 43.5 ± 3.2 dB/MHz, P<0.001; Z score at 1 yr 0.3 ± 0.2 vs baseline 1.5 ± 0.4, P<0.002.
Conclusion. For the first time in childhood rheumatic disease this pilot prospective study, although in a small group, shows evidence that 1 yr of etanercept therapy by controlling the underlying disease activity induces a sustained benefit on JIA bone loss. Prospective studies in larger patient samples are needed to confirm these data.
KEY WORDS: Juvenile idiopathic arthritis, Etanercept, Bone mineral status
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Introduction |
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Conversely to the well-known osteopenic/osteopathic effects of steroids, and the potential effects on bone metabolism of ciclosporin and methotrexate, although not confirmed in childhood chronic rheumatic diseases (CRD) [1], to our knowledge there is no information about the possible effect of the new biologic drugs on the bone health in CRD.
The aim of our study was to evaluate the bone status in children with polyarticular JIA receiving etanercept over 1 yr.
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Patients and methods |
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At baseline, patients received 0.4 mg of etanercept/kg of body weight, subcutaneously, twice weekly for up to 1 yr, in addition to NSAID treatment and methotrexate (median weekly dose 7.5 mg/m2 body surface area, range 512.5). Two patients received just anti-TNF treatment as they did not tolerate methotrexate. All 20 enrolled patients received etanercept at our unit over the study period. During the course of the study, stable doses of NSAIDs, methotrexate and etanercept were permitted.
According to the American College of Rheumatology Pediatric 50 definition of improvement, patients were considered responders to etanercept if they demonstrated at least 50% improvement from baseline in at least three of any six core set variables with no more than one indicator worsening by more than 30%, considering the JIA core set variables previously reported [7]: global assessment of the severity of disease by the physician, global assessment of overall well-being by the patient or parent, number of active joints (joints with swelling not due to deformity or joints with limitation of motion and with pain, tenderness or both), number of joints with limitation of motion and with pain, tenderness or both, functional ability and erythrocyte sedimentation rate (ESR). As previously reported by Lovell et al. [3], we modified the fourth variable so as to eliminate counting joints with contractures that might not have improved during the short course of treatment.
Methods
Height, expressed as S.D. score, was calculated averaging three measurements performed with a Harpenden stadiometer. Weight was measured on a standard clinical balance. Body mass index was calculated according to the formula weight (kg)/height (m2). Pubertal staging was performed using the criteria of Tanner and Whitehouse.
Bone status was evaluated using quantitative ultrasound technique (QUS) by measurements of ultrasound wave attenuation by bone: broadband ultrasound attenuation (BUA). BUA (dB/MHz) by bone was determined at the left calcaneus using two 12.5 mm diameter, 1 MHz transducers mounted in hand-held callipers linked to a paediatric contact ultrasound bone analyser (CUBA) (McCue Ultrasonics, Winchester, UK). CUBA was determined as described [8], on both sides. The paediatric CUBA is a specific paediatric system containing normative data for children aged 515 yr (Z score = 0, S.D. = 1). We have, however, also compiled reference values for children aged 318 yr with our personal controls: 864 healthy subjects that attended the paediatric out-patient department of A. Meyer Hospital, for arthralgias and/or musculoskeletal pain without signs of inflammation or for minor surgical interventions and received a routine clinical, laboratory and instrumental work-up for possible rheumatic, endocrine or metabolic diseases.
Z scores, the difference between the patient's value and the age-specific normal value divided by the normal group's standard deviation, were calculated for each patient. In patients in whom a significant difference between the two sides was determined, the least compromised side was considered for statistical comparisons. On the basis of the manufacturer's instructions, a difference between the two limbs of 8% was considered significant. Patients were evaluated by CUBA at baseline, then every 6 months. All assessments were performed and analysed by the same person (SS). Each value was the mean of three consecutive determinations. Quality control measurement of QUS equipment was performed daily. The in vitro coefficient of variation for BUA using phantoms was 1.8%, and the in vivo coefficient of variation for BUA in subjects aged 515 yr was 3.8%. The same person (SS), using the same equipment, performed repeated CUBA evaluations, every 6 months.
Approval was obtained from the Ethical Committee of Meyer Hospital and parents gave informed consent.
Statistical analysis
All results are expressed as mean or median ± S.D. The MannWhitney U-test and Wilcoxon signed rank test for paired samples were used to compare data. The Pearson correlation test was used to determine correlation coefficients for different variables (age, pubertal stage, weight, height, disease duration). Multiple stepwise regression was performed to determine variables, including disease severity parameters, that may correlate independently with changes in BUA values. The predictors used in the final model were the parameters showing a significant correlation with BUA in the univariate analysis. Non-parametric tests were used, where necessary, due to the small size of our groups and to the skewness of our data. Levels of P<0.05 were considered statistically significant. All analyses were performed on the SPSS package for Windows, version 11.0 (SPSS, Inc., Chicago, IL).
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Results |
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At a 1-yr follow-up after etanercept treatment, all 15 responders showed a significant increase in both BUA and Z scores (BUA at 1 yr 55.2 ± 3.3 vs baseline BUA 43.5 ± 3.2 dB/MHz, P<0.001; Z score at 1 yr 0.3 ± 0.2 vs baseline Z score 1.5 ± 0.4, P<0.002), whilst non-responders did not change values after 1 yr of treatment (Fig. 1).
After 1 yr, in all patients, BUA increased with height (r = 0.29, P<0.003), weight (r = 0.2, P<0.04), age (r = 0.19, P<0.05) and pubertal stage (r = 0.21, P<0.05). In a multiple stepwise regression analysis, the effect of weight, age and pubertal stage disappeared and changes in BUA values were influenced only by height (F = 14.56, P<0.001), which accounted for 11% of variance in BUA values. After that, BUA values were corrected for height; no other variables were determinants for significant differences in BUA values.
After 1 yr of etanercept treatment, responders showed higher BUA and Z scores than non-responders: BUA in responders 55.2 ± 3.3 vs BUA in non-responders 45.7 ± 3.2 dB/MHz, P<0.002; Z score in responders 0.3 ± 0.2 vs Z score in non-responders 1.2 ± 0.4, P<0.003 (Fig. 1).
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Discussion |
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Due to the significant improvement in patients with active polyarticular JIA with etanercept therapy [35], the increase in BUA coincident with the suppression of the disease activity might be expected, but, so far, it is unknown whether the new biologics available to treat JIA, such as etanercept, have direct effects on bone metabolism and content.
It is already well known that anti-TNF therapy prevents and/or slows the rate progression and cartilage damage [9]; whilst little evidence is available on its potential effects on bone mineral density (BMD) and overall is lacking in children.
Allali et al. [10] suggest a benefit of infliximab on BMD in 29 adults with persistently active spondyloarthropathy, and Marzo-Ortega et al. [11] report a BMD improvement in 10 spondyloarthropathic adults after etanercept treatment. Our study, to the best of our knowledge, in a unique current report in childhood CRD, seems to suggest evidence of bone improvement in JIA on etanercept therapy over 1 yr follow-up.
As previously reported [12], not surprisingly, changes in prospective bone density measures during the course of illness occur as a result of the administered treatment: patients who were taking corticosteroids decreased their bone mass, while those on alendronate or who received an intra-articular steroid injection showed an increase in QUS values after 1 yr.
A potential caveat of our study regards which method of bone assessment is used: dual X-ray absorptiometry still remains the gold standard for measuring bone mineral density, even though its is of limited feasibility in young children and has limitations due to different sizes of bone [2]. Although there are concerns about radiation exposure and cost, peripheral quantitative computed tomography allows for three-dimensional measurement of bone density, separate analysis of trabecular and cortical bone and determination of the geometric parameters of bone along with information about the musculoskeletal system, as recently reported in JIA [13]. However, current literature provides supportive evidence about the reliability of QUS in routine clinical work-up and follow-up of bone status in childhood CRD [7, 11, 1417].
Currently, this radiation-free assessment along with its low cost, portability and short duration of examination seems to indicate QUS to be a useful measurement tool for bone status in CRD. Indeed, QUS gives information not only on bone mineralization but also on bone micro- and macrostructure and elasticity [17].
Assuming appropriate reference values collected on the same type of machine and in an ethnically similar population, providing corrections for age, gender, height, weight and pubertal status, as we actually do at our unit using QUS bone measures [18], the CUBA method seems to be a reliable and appealing alternative for measuring bone status in children with CRD [19].
Since immobility is a well known risk factor for bone loss [19], a potential confounding factor to explain the observed bone gain in JIA responders might be due to increased mobility in these patients. The relationship between the level of physical activity and bone status remains difficult in children; however, the control of disease activity, therefore allowing better physical fitness, might be a potential cause of this bone catch-up whether or not etanercept has a direct beneficial effect on bone health. It has been already shown that the combined blockade of TNF, IL-1 and RANK-L prevents joint erosions and systemic bone loss caused by the chronic over-expression of these cytokines in a TNF-
induced arthritis [20, 21].
Our prospective study is not a proper tool and does not attempt to speculate on the close relationship between TNF- and its antagonists and osteoclast/osteoblast activity. Instead, it seems to provide evidence that over 1 yr of etanercept therapy, control of underlying disease activity induces a sustained benefit on JIA bone loss.
Further and more extensive studies are needed to clarify this issue on larger cohorts and over a prolonged anti TNF- therapy, but potential clinical and long-term treatment implications of our findings seem likely.
The authors have declared no conflicts of interest.
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