Elena Palmisani

Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis

OBJECTIVE To develop and validate a definition of minimal disease activity (MDA) in patients with juvenile idiopathic arthritis (JIA). METHODS The clinical charts of JIA patients followed over a 16-year period were reviewed to identify visits with high disease activity and MDA, defined on the basis of therapeutic decisions made by the attending physician. For each JIA activity measure recorded at the time of the visit, the cutoff value that best identified states of MDA was calculated by means of the area under the receiver operating characteristic curve analysis. A definition of MDA for oligoarthritis and polyarthritis was set up after testing the relative power of each variable in a multivariate analysis. Validation procedures included assessment of discriminant and construct validity. RESULTS The definition that resulted from the analyses led to establish that a state of MDA could be defined as the presence of a physician global assessment < or =2.5 cm and a swollen joint count of 0 in patients with oligoarthritis; and as the presence of a physician global assessment < or =3.4 cm, a parent global assessment < or =2.1 cm, and a swollen joint count < or =1 in patients with polyarthritis. Validation procedures demonstrated that the MDA definition had good discriminant and construct validity in the context of both observational studies and controlled trials. CONCLUSION We developed a preliminary definition of MDA in patients with JIA that represents a useful treatment target state and is proposed for inclusion as an outcome measure in future observational studies and clinical trials in patients with JIA.

The PRINTO criteria for clinically inactive disease in juvenile dermatomyositis

Objectives To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM). Methods The Paediatric Rheumatology International Trials Organisation (PRINTO) database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physicians and parents global disease activity/damage evaluations, inactive disease criteria derived from the literature and other ad hoc criteria were evaluated for sensitivity, specificity and Cohens κ agreement. Results The individual measures that best characterised inactive disease (sensitivity and specificity >0.8 and Cohens κ >0.8) were manual muscle testing (MMT) ≥78, physician global assessment of muscle activity=0, physician global assessment of overall disease activity (PhyGloVAS) ≤0.2, Childhood Myositis Assessment Scale (CMAS) ≥48, Disease Activity Score ≤3 and Myositis Disease Activity Assessment Visual Analogue Scale ≤0.2. The best combination of variables to classify a patient as being in a state of inactive disease on or off therapy is at least three of four of the following criteria: creatine kinase ≤150, CMAS ≥48, MMT ≥78 and PhyGloVAS ≤0.2. After 24 months, 30/31 patients (96.8%) were inactive off therapy and 69/145 (47.6%) were inactive on therapy. Conclusion PRINTO established data-driven criteria with clearly evidence-based cut-off values to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice.

Factors Associated with Achievement of Inactive Disease in Children with Juvenile Idiopathic Arthritis Treated with Etanercept

Objective. To evaluate the rate of inactive disease in children with juvenile idiopathic arthritis (JIA) treated with etanercept, and to identify clinical characteristics associated with attainment of inactive disease. Methods. Clinical charts of patients who were given etanercept between January 2002 and January 2011 were evaluated retrospectively. For each patient, all visits from initiation of etanercept to the last followup evaluation in which the patient was still receiving etanercept were examined to establish whether the patient had reached the state of inactive disease and to identify the first visit in which inactive disease was documented. Clinical characteristics associated with achievement of inactive disease were determined through univariate analyses and Cox regression procedures. Results. A total of 173 patients who received etanercept for a median of 2.2 years (range 0.5–10.5 yrs) were studied. Eighty-seven patients (50.3%) achieved inactive disease after a median of 0.6 years (range 0.1–2.5 yrs) of therapy. At last followup evaluation, 85 patients (49.1%) still had inactive disease and 70 (40.5%) were in clinical remission on medication. The probability of achievement of inactive disease after 6, 12, and 24 months of therapy was 24%, 46% and 57%, respectively. On Cox regression analysis, the attainment of inactive disease was associated with lack of wrist involvement and an age at disease onset < 3.6 years. Conclusion. Around half of our patients with JIA treated with etanercept achieved a state of inactive disease. Children who lacked wrist involvement and were younger at disease onset had a greater likelihood of achieving inactive disease.

MRI versus conventional measures of disease activity and structural damage in evaluating treatment efficacy in juvenile idiopathic arthritis

Objective To compare the American College of Rheumatology paediatric (ACRp) response criteria and conventional radiography with MRI findings in a cohort of patients with juvenile idiopathic arthritis. Methods Forty consecutive patients (30 girls, 10 boys; median age 10.8 years) with arthritis of the wrist starting treatment with disease-modifying antirheumatic drugs or biological agents were recruited. At 1-year follow-up the treatment response was assessed by ACRp criteria and radiographic progression using the adapted Sharp/van der Heijde method. Wrist MRIs were evaluated using both the paediatric-MRI and the OMERACT rheumatoid arthritis MRI scores. Sensitivity to change of clinical and imaging variables was assessed by standardised response mean (SRM) and relative efficiency (RE) was used to compare SRMs. Results ACRp90 responders showed a significantly higher decrease in MRI synovitis score (median change −4) than non-responders (median change 0), ACRp30–50 responders (median change 0) and ACRp70 responders (median change −1) (p=0.0006, Kruskal–Wallis test). Non-responders showed significantly higher radiographic progression than ACRp90 responders (pB=0.016). The MRI synovitis score showed a greater responsiveness to change (SRM 1.69) compared with the majority of ACR core set of variables. MRI erosion scores were less responsive than conventional radiography in detecting destructive changes (RE <1). MRI follow-up revealed no signs of inflammation in four out of 24 wrists with clinically inactive disease. Conclusion Only ACRp90 responders showed a significant decrease in synovitis and the halting of structural damage, suggesting that levels of response higher than ACRp30 are more appropriate for assessing drug efficacy. The excellent responsiveness of MRI and its ability to detect subclinical synovitis make it a promising outcome measure.

Agreement between physicians and parents in rating functional ability of children with juvenile idiopathic arthritis

ObjectiveTo investigate concordance between physicians and parents in rating the degree of functional ability of children with juvenile idiopathic arthritis (JIA).MethodsThe attending physician and a parent were asked to rate independently the level of physical functioning of 155 patients with disease duration ≥ 5 years on a 6-point scale ranging from 1 = no disability (i.e. the child can do without difficulty all activities that children of his/her age can do) to 6 = severe disability (i.e. all activities are difficult for the child). At study visit, measures of JIA activity and damage were assessed. Agreement was evaluated with weighted kappa (<0.40 = poor agreement; 0.41–0.60 = moderate agreement; 0.61–0.80 = substantial agreement; >0.80 excellent agreement). Physician/parent evaluations were divided in 3 groups: 1) concordance; 2) parent over-rating = parent assessment over-rated relative to physician assessment; 3) physician over-rating = physician assessment over-rated relative to parent assessment. Factors affecting concordance/discordance were evaluated by means of Kruskal-Wallis or Chi-square/Fisher exact test.ResultsConcordance, parent over-rating and physician over-rating were observed in 107 (69%), 29 (18.7%) and 19 (12.3%) evaluations, respectively. Kappa value was 0.69. Parent over-rating was associated with greater intensity of pain (p = 0.01) and higher Childhood Health Assessment Questionnaire (C-HAQ) score (p = 0.004), whereas physician over-rating was associated with more severe joint disease (p = 0.04 to <0.001), higher C-reactive protein (p = 0.03) higher frequency of Steinbrocker functional class = II (p < 0.001), and greater articular damage, as measured with the Juvenile Arthritis Damage Index (p < 0.001).ConclusionPhysicians and parents revealed fair concordance in rating functional ability of children with JIA. Parent over-rating was associated with greater childs pain and worse C-HAQ score, whereas physician over-rating was associated with greater severity of joint inflammation and damage.

Temporomandibular Joint Involvement is Associated with Quality of Life, Disability and High Disease Activity in Juvenile Idiopathic Arthritis

To evaluate the demographic, disease activity, disability, and health‐related quality of life (HRQOL) differences between children with juvenile idiopathic arthritis (JIA) and their healthy peers, and between children with JIA with and without clinical temporomandibular joint (TMJ) involvement and its determinants.

Mycophenolate mofetil for the treatment of children with immune thrombocytopenia and Evans syndrome. A retrospective data review from the Italian association of paediatric haematology/oncology

Mycophenolate mofetil (MMF) has been shown to be effective in children with immune thrombocytopenia (ITP) and Evans syndrome (ES), but data from larger series and details on the timing of the response are lacking. We evaluated 56 children treated with MMF for ITP (n = 40) or ES (n = 16), which was primary or secondary to autoimmune lymphoproliferative syndrome ‐related syndrome (ARS). Thirty‐five of the 54 evaluable patients (65%) achieved a partial (18%) or complete (46%) response after a median (range) of 20 (7–137) and 37 (7–192) d, respectively. ITP and ES patients responded in 58% and 81% of cases (P = not significant, ns), with complete response in 32% and 81% (P = 0·01), respectively. 60% and 73% of children with primary disease and ARS responded (P = ns) with complete response in 34% and 68% of cases (P = 0·01), respectively. Six of 35 (17%) children relapsed after a median of 283 d (range 189–1036). Limited toxicity was observed in four patients. The median durations of treatment and follow‐up were seven and 12·7 months, respectively. This is the largest reported cohort of patients treated with MMF for ITP/ES. The results show that MMF is effective and safe and provides a relatively quick response, suggesting that it has a potential role as an alternative to more aggressive and expensive second/further‐line treatments.

Therapeutic approaches for the treatment of renal disease in juvenile systemic lupus erythematosus: an international multicentre PRINTO study

Objectives To evaluate therapeutic approaches and response to therapy in juvenile systemic lupus erythematosus (SLE) with renal involvement in a large prospective international cohort from four geographic areas. Methods New onset and flared patients with active renal disease (proteinuria ≥0.5 g/24 h) were enrolled in 2001–2004. Therapeutic approaches and disease activity parameters were analysed at baseline, 6, 12 and 24 months. Response was assessed by the PRINTO/ACR criteria. Results 218/557 (79.8% female subjects, 117 new onset and 101 flared) patients with active renal disease were identified; 66 patients were lost to follow-up and 11 died. Mean age at disease onset for new onset group was higher than for flared group (13.1 vs 10.2 years, p<0.0001). At baseline, both groups had similar renal activity with similar median doses of corticosteroids (1.0–0.76 mg/kg/day). Cyclophosphamide (43.1%) and azathioprine (22%) were the most common immunosuppressive drugs. At baseline, South American patients received higher doses of corticosteroids than in other areas in new onset (median 1.16 vs 0.8–1 mg/kg/day) while cyclophosphamide use was similar in all four regions in the new onset group. There were no differences regarding the use of azathioprine or mycophenolate mofetil worldwide. PRINTO 70 response was reached in a greater percentage of new onset versus flared patients (74.8% vs 53.3%; p=0.005) at 6 months while at 24 months ACR 90 was reached by 69.9% and 56.1%, respectively. Conclusions New onset and flared juvenile SLE improved similarly over 24 months with minimal differences in therapeutic approaches worldwide.

A Meta‐Analysis to Estimate the Placebo Effect in Juvenile Idiopathic Arthritis in Randomized Controlled Trials

To estimate the placebo effect in juvenile idiopathic arthritis (JIA) through a meta‐analysis of phase III clinical trials with placebo comparator.

A Meta-Analysis to Estimate the Placebo Effect in Randomized Controlled Trials in Juvenile Idiopathic Arthritis.

To estimate the placebo effect in juvenile idiopathic arthritis (JIA) through a meta‐analysis of phase III clinical trials with placebo comparator.