Abstract

Objective. To compare the efficacy and safety of intra-articular triamcinolone hexacetonide (TH) and triamcinolone acetonide (TA) in children with oligoarticular juvenile idiopathic arthritis (JIA).

Methods. One hundred and thirty joints of 85 patients undergoing intra-articular injections were randomly treated with either TH or TA depending on the availability of the drug. The efficacy of both treatments was evaluated prospectively in a blinded fashion. A good response was defined as a decrease in the articular score of ≥60% from baseline. Clinical, laboratory and immunological variables were noted in order to examine possible factors, other than treatment, predictive of the result.

Results. Seventy injections were performed using TH and 60 with TA. The two groups were comparable for clinical, immunological and laboratory characteristics. The rate of response was significantly higher with TH than with TA: 81.4% vs 53.3% (P = 0.001) at 6 months, 67.1 vs 43.3% (P = 0.006) at 12 months, and 60 vs 33.3% (P = 0.002) at 24 months.

Conclusion. At comparable doses TH appeared to be much more effective than TA for intra-articular use, in both short- and long-term follow-up. This result was not affected by disease duration or degree of local and systemic inflammation.

Intra-articular corticosteroids (IACS) have been employed for the treatment of rheumatoid arthritis (RA) in adults since 1951 [1], and have recently also become an important therapeutic tool for the treatment of juvenile arthritis. IACS are recommended by some authors as first-line therapy for the oligoarticular type of juvenile idiopathic arthritis (JIA), rather than for selective use in active synovitis resistant to non-steroidal anti-inflammatory drugs (NSAIDs) [2]. Furthermore, recent data show that early, continued use of IACS may help prevent the development of leg length discrepancies and other deformities in children with JIA [3, 4].

The beneficial effect and duration of effect of single-dose injection are dependent on the preparation used. The longest-lasting effects have been observed with less soluble compounds [5, 6]. The long-acting steroids most commonly used in JIA are triamcinolone hexacetonide (TH) and triamcinolone acetonide (TA). The choice of preparation is often arbitrary, in many cases depending on where the rheumatologist has been trained [7] and on the commercial availability of the drug. This can be partially explained by the rarity of studies comparing the efficacy of different preparations, particularly in children.

To our knowledge, no prospective studies have been performed to date to compare the short- and long-term efficacy of the two most commonly used IACS drugs, TH and TA, in reducing joint inflammation in children with JIA.

In this prospective study, we compared the efficacy and safety of TH and TA, given intra-articularly, in a cohort of children with oligoarticular JIA.

Patients and methods

Patients

The study groups consisted of patients managed at the Paediatric Rheumatology Unit of the University of Padua. These children had received intra-articular steroid injections between January 1996 and December 2000, either for an unsatisfactory response to NSAIDs and/or for persistent isolated single-joint involvement. All the patients fulfilled the revised diagnostic criteria for JIA of the persistent or extended oligoarticular types [8]. Patients who had a history of any clinically significant adverse reaction to steroids, ongoing chronic disease or erosive findings on joint X-ray or who had received IACS treatment during the previous 12 months were excluded from the study.

Procedure

One hundred and thirty joints of 85 patients were injected with either triamcinolone hexacetonide (TH) (Lederspan®) or triamcinolone acetonide (TA) (Kenacort A Retard®). The choice of drug was dependent on the availability of TH during the study period. TH has to be imported into Italy via neighbouring countries, and sometimes there are shortages of the drug. For this reason, we have used TA as an alternative long-lasting steroid preparation. We were thus able to compare the efficacies of these two drugs.

After preparing the skin with antiseptic solution, the joint fluid was aspirated and then TH or TA at the dose of 1 mg/kg body weight (up to 40 mg) was injected. Children were advised not to bear weight for at least 72 h after the injection. The same physicians (FZ and CG) always performed arthrocentesis. Children under the age of 6 yr and very anxious older children were sedated in the intermediate setting of the Paediatric Intensive Care Unit using a combination of a low dose of ketamine (Ketalar®, 0.5 mg/kg) and propofol (Diprivan®, 2 mg/kg). This type of sedation has been shown to be safe, well tolerated and effective in achieving analgesia, anaesthesia and amnesia with respect to the procedure and can be performed in an out-patient setting [9].

Clinical evaluation

Clinical assessment of synovitis was performed at baseline, before the injection, and 1, 3, 6, 9, 12, 18 and 24 months after the procedure, or if relapse occurred.

The physician performing the clinical examination (GM) was unaware of which drug had been used for injection.

On each observation occasion, four variables were recorded: swelling on inspection, limitation of range of motion, pain on passive movement and warmth to touch, as proposed as part of the Preliminary Core Set of Outcome Measures developed at the Consensus Conference held at Marco Island (Florida, USA) [10]. For each joint, a score ranging from 0 to 3 was attributed to each variable: 0 normal, 1 mild, 2 moderate, 3 severe. The articular score was then obtained by summing the scores of each variable.

A good response was defined as the absence of synovitis or as a decrease in joint inflammation leading to a reduction in the articular score of more than 60% from baseline. Relapse was defined as the reappearance of arthritis after a period of good response, defined as above. If relapse occurred the patient was withdrawn from the study and the time to relapse was recorded.

Data analysis

The two treatment groups were compared according to the following parameters: age at the time of treatment, age at disease onset, disease duration, sex, type of joint injected, first treatment or retreatment, articular score before the procedure, antinuclear antibodies (ANA) (tested using the HEp2 cell line; ≥1:80 was a positive result according to our laboratory standards), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values at baseline, and concomitant therapy with NSAIDs and/or methotrexate (MTX). All these variables were considered for their potential effect on the outcome. The differences between the groups were analysed by the t-test, the χ2 test or Fisher’s exact test, as appropriate.

The primary outcome variable was the articular score at 6, 12 and 24 months after the procedure. The efficacy of treatment was expressed as the percentage of positive result or as the relative risk of relapse (RR). The 95% confidence interval (CI) defined the degree of significance and the accuracy of the estimate.

A secondary analysis was performed to assess the potential role of each variable as a predictor of positive response at 6, 12 and 24 months. Furthermore, to assess the hypothesis that the effect of one of the two drugs could be influenced by other clinical variables, a stratified analysis was performed and the interaction was studied with the likelihood-ratio χ2 test.

The analysis of time to flare in each treatment group was undertaken according to the Kaplan–Meier procedure and compared using the log rank test.

Finally, to compare the effect of TH and TA by the time to flare, a Cox proportional hazards model was used, by including all the clinical and laboratory parameters.

The Stata statistical package (Stata Corp., College Station, TX, USA) was used for data evaluation.

Results

The clinical characteristics of the patients are summarized in Table 1. Eighty-five patients entered the study; 42 were treated with TH and 43 with TA. The average age at disease onset was 58.5 months, ranging from 13 to 144 months. Sixty-six (77.6%) were female and 19 (22.4%) were male. Seventy-four patients (87%) had persistent oligoarticular JIA and 11 had extended-oligoarticular JIA. ANA were positive in 57 (67%), while HLA B27 was positive in 4 (4.7%).

Table 1.

Clinical characteristics of the patients with oligoarticular JIA

Characteristic No. (%) 
No. of patients 85 
No. of joints injected 130 
Age at onset (months)  
    Average 58.5 
    Range 13–144 
Sex  
    Female 66 (77.6) 
    Male 19 (22.4) 
JIA subtype  
    Persistent oligoarticular 74 (87) 
    Extended oligoarticular 11 (13) 
ANA-positive (>1:80) 57 (67) 
HLA B27-positive 4 (4.7) 
Characteristic No. (%) 
No. of patients 85 
No. of joints injected 130 
Age at onset (months)  
    Average 58.5 
    Range 13–144 
Sex  
    Female 66 (77.6) 
    Male 19 (22.4) 
JIA subtype  
    Persistent oligoarticular 74 (87) 
    Extended oligoarticular 11 (13) 
ANA-positive (>1:80) 57 (67) 
HLA B27-positive 4 (4.7) 

The characteristics of the two treatment groups are summarized in Table 2. One hundred and thirty joints were injected: 115 knees and 15 ankles. TH was used in 70 procedures and TA in 60. None of the children was lost to follow-up. Mean follow-up time was 32.2 months (range 24–71 months).

Table 2.

Characteristics of the two treatment groups

 TH (n = 70) TA (n = 60) P 
Age (months): mean ± s.d53.7 ± 37.9 64.7 ± 42.7 n.s. 
Disease duration    
    Months: mean ± s.d42.7 ± 44.3 32.7 ± 34.6 n.s. 
    <12 months (%) 34.3 38.3 n.s. 
Sex (M:F) 1:3.6 1:3.3 n.s. 
ANA >1:80 (%) 65.7 73.3 n.s. 
Injected joints 64 knees, 6 ankles 51 knees, 9 ankles n.s. 
First injection (%) 81.4 80.0 n.s. 
Articular score at baseline (%)    
     ≥5 35.7 36.7 n.s. 
42.6 45.0 n.s. 
23.5 18.3 n.s. 
ESR at baseline (mm)    
    Mean ± s.d39.6 ± 27.0 39.6 ± 31.5 n.s. 
    >30 mm (%) 55.7 53.3 n.s. 
CRP at baseline (mg/l)    
    Mean ± s.d19.0 ± 21.5 13.0 ± 15.9 n.s. 
    >6 mg/l (%) 48.3 46.9 n.s. 
NSAIDs before injection (%) 64.3 51.7 n.s. 
NSAIDs after injection (%) 65.7 48.3 n.s. 
MTX before injection (%) 11.4 n.s. 
MTX after injection (%) 11.5 6.6 n.s. 
Response rate (%)    
      6 months 81.4 53.3 0.001 
    12 months 67.1 43.3 0.006 
    24 months 60.0 33.0 0.002 
 TH (n = 70) TA (n = 60) P 
Age (months): mean ± s.d53.7 ± 37.9 64.7 ± 42.7 n.s. 
Disease duration    
    Months: mean ± s.d42.7 ± 44.3 32.7 ± 34.6 n.s. 
    <12 months (%) 34.3 38.3 n.s. 
Sex (M:F) 1:3.6 1:3.3 n.s. 
ANA >1:80 (%) 65.7 73.3 n.s. 
Injected joints 64 knees, 6 ankles 51 knees, 9 ankles n.s. 
First injection (%) 81.4 80.0 n.s. 
Articular score at baseline (%)    
     ≥5 35.7 36.7 n.s. 
42.6 45.0 n.s. 
23.5 18.3 n.s. 
ESR at baseline (mm)    
    Mean ± s.d39.6 ± 27.0 39.6 ± 31.5 n.s. 
    >30 mm (%) 55.7 53.3 n.s. 
CRP at baseline (mg/l)    
    Mean ± s.d19.0 ± 21.5 13.0 ± 15.9 n.s. 
    >6 mg/l (%) 48.3 46.9 n.s. 
NSAIDs before injection (%) 64.3 51.7 n.s. 
NSAIDs after injection (%) 65.7 48.3 n.s. 
MTX before injection (%) 11.4 n.s. 
MTX after injection (%) 11.5 6.6 n.s. 
Response rate (%)    
      6 months 81.4 53.3 0.001 
    12 months 67.1 43.3 0.006 
    24 months 60.0 33.0 0.002 

n.s., not significant.

As shown in Table 2, the two groups were comparable for age at the time of the injection, disease duration, male/female ratio, ANA positivity, articular score at baseline, average ESR and CRP values, and NSAIDs or MTX treatments before or after the IACS injections.

The rate of response was significantly higher with TH than with TA, being 81.4 and 53.3% respectively (P = 0.001) at 6 months, 67.1 and 43.3% at 12 months (P = 0.006) and 60% and 33.3% (P = 0.002) at 24 months.

Table 3 shows that the drug used was the most important predictive variable for the response at 6, 12 and 24 months. The relative risk of relapse with TA compared with TH was 2.5 (95% CI 1.4–4.4) at 6 months, 1.7 (1.2–2.6) at 12 months and 1.7 (95% CI 1.2–2.3) at 24 months. Ankles showed a significantly worse response at 6, 12 and 24 months (RR 2.0, 1.6 and 1.4 respectively). No other variable significantly affected the result at these times.

Table 3.

Variables predictive of clinical response at 6, 12 and 24 months

 Relapse at 6 months
 
 Relapse at12 months
 
 Relapse at 24 months
 
 
 n (%) RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI) 
Treatment       
    TH 13 (18.6) 23 (32.9) 28 (40.0) 
    TA 28 (46.7) 2.5 (1.4–4.4) 34 (56.7) 1.7 (1.2–2.6) 40 (66.7) 1.7 (1.2–2.3) 
Age at onset       
    <42 months 19 (30.2) 24 (38.1) 31 (49.2) 
    >42 months 22 (32.8) 1.1 (0.6–1.8) 33 (49.2) 1.3 (0.9–1.9) 37 (55.2) 1.1 (0.8–1.6) 
Disease duration       
    ≤12 months 16 (34.0) 18 (38.3) 21 (44.7) 
    >12 months 25 (30.1) 0.9 (0.5–1.5) 39 (47.0) 1.2 (0.8–1.9) 47 (56.6) 1.3 (0.9–1.8) 
ESR at baseline       
    ≤ 30 mm 19 (32.2) 29 (49.2) 31 (52.5) 
    >30 mm 22 (31.0) 1.0 (0.6–1.6) 28 (39.4) 0.8 (0.6–1.2) 37 (52.1) 1.0 (0.7–1.4) 
CRP at baseline       
    ≤6 mg/l 16 (26.7) 23 (38.3) 27 (45) 
    >6 mg/l 25 (35.7) 1.3 (0.8–2.3) 34 (48.6) 1.3 (0.8–1.9) 41 (58.6) 1.3 (0.9–1.8) 
Articular score       
    3 11 (40.7) 14 (51.8) 15 (55.6) 
    4 14 (25.0) 0.6 (0.3–1.2) 19 (33.9) 0.7 (0.4–1.1) 24 (42.9) 0.8 (0.5–1.2) 
    ≥5 16 (34.0) 0.8 (0.5–1.5) 24 (51.1) 1.0 (0.6–1.6) 29 (61.7) 1.1 (0.7–1.7) 
ANA       
    ≤1:80 16 (40.0) 20 (50.0) 23 (57.5) 
    >1:80 25 (27.8) 0.7 (0.4–1.2) 37 (41.1) 0.8 (0.6–1.2) 45 (50.0) 0.9 (0.6–1.2) 
NSAID       
    No 16 (29.6) 24 (44.4) 27 (50.0) 
    Yes 25 (32.9) 1.1 (0.7–1.9) 33 (43.4) 1.0 (0.7–1.4) 41 (53.9) 1.1 (0.8–1.5) 
MTX       
    No 38 (32.5) 50 (42.7) 60 (51.3) 
    Yes 10 (23.1) 0.7 (0.2–2.0) 7 (53.8) 1.3 (0.7–2.2) 8 (61.6) 1.2 (0.8–1.9) 
Joint injected       
    Knee 30 (27.3) 44 (40.0) 54 (49.1) 
    Ankle 11 (55.0) 2.0 (1.2–3.3) 13 (65.0) 1.6 (1.1–2.4) 14 (70.0) 1.4 (1.0–2.0) 
First injection 34 (31.2) 48 (44.0) 57 (52.3) 
Retreatment 7 (33.3) 1.1 (0.6–2.1) 9 (42.9) 1.0 (0.6–1.7) 11 (52.4) 1.0 (0.6–1.6) 
 Relapse at 6 months
 
 Relapse at12 months
 
 Relapse at 24 months
 
 
 n (%) RR (95% CI) n (%) RR (95% CI) n (%) RR (95% CI) 
Treatment       
    TH 13 (18.6) 23 (32.9) 28 (40.0) 
    TA 28 (46.7) 2.5 (1.4–4.4) 34 (56.7) 1.7 (1.2–2.6) 40 (66.7) 1.7 (1.2–2.3) 
Age at onset       
    <42 months 19 (30.2) 24 (38.1) 31 (49.2) 
    >42 months 22 (32.8) 1.1 (0.6–1.8) 33 (49.2) 1.3 (0.9–1.9) 37 (55.2) 1.1 (0.8–1.6) 
Disease duration       
    ≤12 months 16 (34.0) 18 (38.3) 21 (44.7) 
    >12 months 25 (30.1) 0.9 (0.5–1.5) 39 (47.0) 1.2 (0.8–1.9) 47 (56.6) 1.3 (0.9–1.8) 
ESR at baseline       
    ≤ 30 mm 19 (32.2) 29 (49.2) 31 (52.5) 
    >30 mm 22 (31.0) 1.0 (0.6–1.6) 28 (39.4) 0.8 (0.6–1.2) 37 (52.1) 1.0 (0.7–1.4) 
CRP at baseline       
    ≤6 mg/l 16 (26.7) 23 (38.3) 27 (45) 
    >6 mg/l 25 (35.7) 1.3 (0.8–2.3) 34 (48.6) 1.3 (0.8–1.9) 41 (58.6) 1.3 (0.9–1.8) 
Articular score       
    3 11 (40.7) 14 (51.8) 15 (55.6) 
    4 14 (25.0) 0.6 (0.3–1.2) 19 (33.9) 0.7 (0.4–1.1) 24 (42.9) 0.8 (0.5–1.2) 
    ≥5 16 (34.0) 0.8 (0.5–1.5) 24 (51.1) 1.0 (0.6–1.6) 29 (61.7) 1.1 (0.7–1.7) 
ANA       
    ≤1:80 16 (40.0) 20 (50.0) 23 (57.5) 
    >1:80 25 (27.8) 0.7 (0.4–1.2) 37 (41.1) 0.8 (0.6–1.2) 45 (50.0) 0.9 (0.6–1.2) 
NSAID       
    No 16 (29.6) 24 (44.4) 27 (50.0) 
    Yes 25 (32.9) 1.1 (0.7–1.9) 33 (43.4) 1.0 (0.7–1.4) 41 (53.9) 1.1 (0.8–1.5) 
MTX       
    No 38 (32.5) 50 (42.7) 60 (51.3) 
    Yes 10 (23.1) 0.7 (0.2–2.0) 7 (53.8) 1.3 (0.7–2.2) 8 (61.6) 1.2 (0.8–1.9) 
Joint injected       
    Knee 30 (27.3) 44 (40.0) 54 (49.1) 
    Ankle 11 (55.0) 2.0 (1.2–3.3) 13 (65.0) 1.6 (1.1–2.4) 14 (70.0) 1.4 (1.0–2.0) 
First injection 34 (31.2) 48 (44.0) 57 (52.3) 
Retreatment 7 (33.3) 1.1 (0.6–2.1) 9 (42.9) 1.0 (0.6–1.7) 11 (52.4) 1.0 (0.6–1.6) 

The stratified analysis by clinical and laboratory characteristics did not show any significant interaction: TH was more effective than TA for each stratum of the variables at 6, 12 and 24 months.

The survival curves for the analysis of time to disease flare are shown in Fig. 1. The Kaplan–Meier estimate of incidence rate of arthritis flare was 1.4/100 months of follow-up for the TH group and 4.2/100 months for the TA group (incidence rate ratio 3.0, 95% CI 1.9–4.8; log rank test P = 0.0007).

Fig. 1.

Kaplan–Meier survival estimates of the time to arthritis flare in TA and TH groups (P = 0.0007, log rank test).

Fig. 1.

Kaplan–Meier survival estimates of the time to arthritis flare in TA and TH groups (P = 0.0007, log rank test).

When all the variables were included in a Cox proportional analysis model, the result confirmed that the type of treatment was the only parameter significantly associated with the clinical response. In fact, the rate of relapse in the TA group was 2.7 times greater than in the TH group (95% CI 1.6–4.8).

Side-effects

IACS were fairly safe in our population: only two patients in each group developed skin atrophy at the injection site. No other known complications, such as joint infections and chemical synovitis, were noted. Two patients experienced reversible apnoea (<20 s duration) during the induction phase of the sedation procedure.

Discussion

IACS have been shown to be an effective therapy for adults and children with inflammatory joint disease [3, 4, 6, 11, 12, 13]. The intra-articular approach delivers a high concentration of corticosteroids to the primary site of pathology, where they interfere with many immunological functions. In particular, they inhibit the cell receptor transcription and down-regulate the expression of adhesion molecules and the production of cytokines (e.g. interleukins 1 and 6 and tumour necrosis factor α) [14]. Suppression of adhesion molecule expression reduces migration into the joint of lymphocyte [15], an effect that includes reduction of memory T-cell expansion, which is believed to be important in the pathogenesis of this disease.

TH and TA are the long-acting steroids that are most commonly used in JIA for intra-articular treatment. In the present study we compared our experience with the use of TH and TA prospectively in a homogeneous population of children with oligoarticular JIA. Although this was not a true randomized trial, we utilized to our advantage the random availability of these two preparations in our hospital. The fact that the examining physician did not know which of the preparations was being used makes this a blinded comparison.

The results clearly show that TH is more effective than TA in both short- and long-term follow-up.

After 6 months, 81.4% of joints injected with TH and 53.3% of joints injected with TA had no sign of inflammation. For TH, the response rate at 6 months was similar to that reported in other studies, ranging from 67.6 to 82% [3, 11, 16]. For TA, we observed a response rate lower than reported previously by Hertzberger-ten Cate [17]. This difference might be related to the size of the study sample, which was greater in our study (60 joints) than the study by Hertzberger-ten Cate (27 joints).

To date there are no data on longer follow-up results in children, and this is another important point in our study. We showed that TH maintained excellent efficacy 12 months after the procedure, with 67.1% responding joints vs 43.3% for joints treated with TA. Similar efficacy was observed 24 months after the injection, with a response rate of 60% and 33% respectively. This difference in outcome was not influenced by other variables, such as disease duration, age at onset, age at time of treatment, immunological profile, and degree of systemic or local inflammation. In addition, there were no differences in concomitant systemic treatment.

This result was clearly confirmed by univariate, stratified and Cox proportional analyses, which all indicated that the only predictive variable for the clinical response was the use of TH.

Most of the clinical information on the use of IACS in children comes from observational or retrospective analyses or, by inference, from studies in adult patients with arthritis. When TH has been compared with other agents for intra-articular injection in adults with RA, it was more effective in reducing pain and other signs of joint inflammation.

In a study of 270 adults with RA in which hydrocortisone succinate (HC), TA and TH were compared, the authors found that TH was significantly more effective than HC and TA in reducing pain and joint inflammation in the first 12 weeks after injection [11/18]. Similar results were achieved in a comparative study of betamethasone and TH in children with oligoarticular JIA [5].

In a retrospective study of children with JIA, Gerloni et al. [19] reported much better control of joint inflammation with TH than with TA, with a response rate at 6 months of 84 and 30% respectively.

In earlier studies, no clear relationship between age at disease onset and efficacy of IACS was found [5, 17/20]. However, some authors reported longer-lasting remission in early-onset oligoarticular JIA compared with late-onset and systemic onset subtypes [3, 18/21]. We did not find such a relationship.

With regard to disease duration, the overall response rate was not significantly different in patients with short (<12 months) or long disease duration (>12 months). This is in agreement with two earlier studies [6, 16], but in contrast with other studies, which showed an indirect relationship between disease duration and response to IACS [3, 17].

We did not find any significant difference in markers of inflammation, such as ESR and CRP, or in clinical findings, such as articular score, between responders and non-responders. This observation is in agreement with other studies [6, 11]. Only one author reported elevation of ESR as the strongest predictor of complete clinical response to IACS injection [20]. The heterogeneity of the JIA patients in that study, which also included systemic and polyarticular subtypes, may account for this different result.

It is worth pointing out that in our population no major side-effects were observed. In four patients (3.0%), two in each group, the patients developed a small area of atrophy at the injection site. This rate is lower than the incidence reported by Job-Deslandre et al. (8.3%) [22] but similar to that reported by other authors [3, 21].

In trying to explain the reasons for the difference in efficacy between these compounds, previous pharmacokinetic studies showed that, although there was no significant difference in the amount of triamcinolone absorbed into the circulation after intra-articular injection of TH and TA, the mean residence time in the joint was calculated to be 6 days for TH and 3.2–4.3 days for TA [23]. This was considered to be due to the slower release of TH, which in turn was related to its lower solubility. This chemical characteristic of the drug may explain its greater efficacy in reducing local joint inflammation and the longer duration of response. A higher TA dose is probably needed to obtain a result similar to that given by TH.

In conclusion, this study shows that IACS are effective and safe for the treatment of joint inflammation in JIA and may be used as the first-line therapy for the oligoarticular subtype. Effective control of arthritis with this local treatment may also preclude the need for oral anti-inflammatory treatment, with consequent adverse effects, in this subgroup of patients [24].

TH clearly appears much more powerful than TA, at a comparable dose, in both short- and long-term follow-up.

We thank B. H. Athreya (Jefferson University, Philadelphia, PA, USA) for reading the manuscript and for helpful suggestions.

Conflict of interest

The authors have declared no conflicts of interest.

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Author notes

Departments of Paediatrics and 1Orthopaedics, University of Padua, Italy.

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