Bone status over 1 yr of etanercept treatment in juvenile idiopathic arthritis

G. Simonini, T. Giani, S. Stagi1, M. de Martino1 and F. Falcini

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To evaluate bone mineral status over 1 yr of etanercept treatment in juvenile idiopathic arthritis (JIA).

Methods. Twenty children (13 female, 7 male) aged 5.2–11.4 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Osteopenia/osteoporosis is still a major unsolved complication in juvenile idiopathic arthritis (JIA) and one of the major causes of co-morbidity [1]. As a definitive treatment is still lacking, controlling the underlying disease activity and flare, along with corticosteroid avoidance, encouraging physical activity and ensuring adequate nutrition, seems the best currently available approach [2]. Etanercept, a soluble tumour necrosis factor (TNF) receptor (p75):Fc fusion protein, provides rapid and sustained improvement in disease activity in 39–83% of patients with JIA [3–5].

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
We prospectively enrolled 20 patients (13 females, 7 males, median age 7.6 yr; range 5.2–11.4 yr) affected with active polyarticular JIA. During the first 6 months of disease, four children had had systemic arthritis, two oligoarthritis, then extended, whilst the others had polyarthritis (rheumatoid factor negative) [6]. To be eligible, patients had to have at least five active joints plus abnormalities of at least two of any five remaining JIA core set criteria despite current treatment. Before enrolment, patients had received non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate (10–15 mg/m2 of body-surface area per week). The four patients with systemic onset had received steroids (2 mg/kg, daily), over the first month then tapered within the following 6 months up to control of systemic features.

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 5–12.5). Two patients received just anti-TNF{alpha} 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 5–15 yr (Z score = 0, S.D. = 1). We have, however, also compiled reference values for children aged 3–18 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 5–15 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 Mann–Whitney 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).


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
After 12 months of treatment, 15 JIA patients (75%) met the definition of improvement, and were considered as responders (Table 1).


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TABLE 1. Measures of disease activity and improvement from base line to 1 yr follow-up of etanercept in 20 juvenile idiopathic arthritis children

 
At baseline, there were no significant differences regarding age, gender, type onset of JIA rate, disease duration, methotrexate doses, core-set variables or BUA and Z-score values between responders and non-responders (Table 2).


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TABLE 2. Demographic characteristics, disease history and baseline measures of disease activity in 20 juvenile idiopathic arthritis patients, subdivided, according etanercept efficacy, into 15 responders and 5 non-responders

 
At 6 months and at 1 yr follow-up in the whole group of 20 patients BUA and Z-score values were not significantly different compared with baseline, with just a slight, not statistically significant, increase at a 1-yr follow-up compared with baseline values: BUA at 1 yr 48.8 ± 8.3 vs baseline BUA 43.4 ± 6.3 dB/MHz; Z score at 1 yr –0.8 ± 0.6 vs baseline Z score –1.5 ± 0.8) (Fig. 1).



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FIG. 1. Changes in mean BUA and Z-score values over 1 yr of etanercept treatment in 20 children with JIA: whole group, responders, and non-responders. BUA P value, responders vs non-responders: *P = 0.002; 1 yr follow-up vs baseline, **P = 0.001. Z-score P value, responders vs non-responders: §P = 0.003; 1 yr follow-up vs baseline, §§P = 0.002.

 
Regarding etanercept efficacy, no significant difference was detected between responders and non-responders at 6 month CUBA evaluation (Fig. 1).

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).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In the present study, although with a small sample, etanercept treatment over 1 yr seems to induce beneficial effects on bone status in JIA child responders: it is possible that controlling disease activity with etanercept may positively outweigh the osteopenic effects of JIA.

Due to the significant improvement in patients with active polyarticular JIA with etanercept therapy [3–5], 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{alpha} 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, 14–17].

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{alpha}, IL-1 and RANK-L prevents joint erosions and systemic bone loss caused by the chronic over-expression of these cytokines in a TNF-{alpha} induced arthritis [20, 21].

Our prospective study is not a proper tool and does not attempt to speculate on the close relationship between TNF-{alpha} 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-{alpha} therapy, but potential clinical and long-term treatment implications of our findings seem likely.

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Bianchi ML. Bone problems in rheumatic diseases during childhood and adolescence. Clin Rev Bone Miner Metab 2004;2:63–76.[CrossRef]
  2. Rabinovich CE. Osteoporosis: a pediatric perspective Arthritis Rheum 2004;50:1023–5.[CrossRef][ISI][Medline]
  3. Lovell DJ, Giannini EH, Reiff A et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 2000;342:763–9.[Abstract/Free Full Text]
  4. Lovell DJ, Giannini EH, Reiff A et al. Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multicenter, open-label, extended-treatment trial. Arthritis Rheum 2003;48:218–26.[CrossRef][ISI][Medline]
  5. Quartier P, Taupin P, Bourdeaut F et al. Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum 2003;48:1093–11.[CrossRef][ISI][Medline]
  6. Petty RE, Southwood TR, Manners P et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390–2.[ISI][Medline]
  7. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:1202–9.[ISI][Medline]
  8. Falcini F, Bindi G, Ermini M et al. Comparison of quantitative calcaneal ultrasound and dual energy X-ray absorptiometry in the evaluation of osteoporotic risk in children with chronic rheumatic diseases. Calcif Tissue Int 2000;67:19–23.[CrossRef][ISI][Medline]
  9. Genovese MC, Kremer JM. Treatment of rheumatoid arthritis with etanercept. Rheum Dis Clin North Am 2004;30:311–28.[CrossRef][ISI][Medline]
  10. Allali F, Breban M, Porcher R, Maillefert JF, Dougados M, Roux C. Increase in bone mineral density of patients with spondyloarthropathy treated with anti-tumor necrosis factor alpha. Ann Rheum Dis 2003;62:347–9.[Abstract/Free Full Text]
  11. Marzo-Ortega H, McGonagle D, Haugeberg G, Green MJ, Stewart S, Emery P. Bone mineral density improvement in spondyloarthropathy after treatment with etanercept. Ann Rheum Dis 2003;62:1020–1.[Free Full Text]
  12. Falcini F, Bindi G, Simonini G et al. Bone status evaluation with calcaneal ultrasound in children with chronic rheumatic diseases. A one year follow up study. J Rheumatol 2003;30:179–84.[ISI][Medline]
  13. Roth J, Palm C, Scheunemann I, Ranke M, Schweizer R, Dannecker GE. Musculoskeletal abnormalities of the forearm in patients with juvenile idiopathic arthritis relate mainly to bone geometry. Arthritis Rheum 2004;50:1277–85.[CrossRef][ISI][Medline]
  14. Njeh CF, Shaw N, Gardner-Medwin JM, Boivin CM, Southwood TR. Use of quantitative ultrasound to assess bone status in children with juvenile idiopathic arthritis: a pilot study. J Clin Densitom 2000;3:251–60.[CrossRef][ISI][Medline]
  15. Van den Bergh JP, Noordam C, Ozyilmaz A, Hermus AR, Smals AG, Otten BJ. Calcaneal ultrasound imaging in healthy children and adolescents: relation of the ultrasound parameters BUA and SOS to age, body weight, height, foot dimensions and pubertal stage. Osteoporosis Int 2000;11:967–76.[CrossRef][ISI][Medline]
  16. Hartman C, Shamir R, Eshach-Adiv O, Iosilevsky G, Brik R. Assessment of osteoporosis by quantitative ultrasound versus dual energy X-ray absorptiometry in children with chronic rheumatic diseases. J Rheumatol 2004;31:981–5.[ISI][Medline]
  17. Njeh CF, Fuerst T, Diesel E, Genant HK. Is quantitative ultrasound dependent on bone structure? A reflection. Osteoporosis Int 2001;12:1–15.[CrossRef][Medline]
  18. Simonini G, Cimaz R, Falcini F. Usefulness of bone ultrasound techniques in pediatric rheumatic diseases. J Rheumatol 2005;32:198.[ISI][Medline]
  19. Rabinovich EC. Bone metabolism in childhood rheumatic disease. Rheum Dis Clin North Am 2002;28:655–67.[CrossRef][ISI][Medline]
  20. Zwerina J, Hayer S, Tohidast-Akrad M et al. Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANK-L pathways in tumor necrosis factor induced arthritis: effects on synovial inflammation, bone erosions, and cartilage destruction. Arthritis Rheum 2004;50:277–90.[CrossRef][ISI][Medline]
  21. Redlich K, Gortz B, Hayer S et al. Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin of parathyroid hormone in tumor necrosis factor-mediated arthritis. Am J Pathol 2004;164:543–5.[Abstract/Free Full Text]
Submitted 8 November 2004; revised version accepted 1 February 2005.