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Roberta Caorsi,
Loredana Lepore,
Francesco Zulian, Maria Alessio,
Achille Stabile,
Antonella Insalaco,
Martina Finetti,
Antonella Battagliese,
Giorgia Martini,
Chiara Bibalo,
Alberto Martini,
Marco Gattorno
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ABSTRACT: INTRODUCTION: Interleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data is available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype. METHODS: 13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation. RESULTS: 7 patients with Chronic Infantile Neurological Cutaneous Articular (CINCA) syndrome, 4 patients with as Muckle-Wells syndrome (MWS) and 2 patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced an higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab. CONCLUSIONS: The use of canakinumab in daily practice is associated with a persistent satisfactory control of disease activity but needs a progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age, represents the main variable able to determine the need of more frequent administrations of the drug at higher dosage.
Arthritis research & therapy 02/2013; 15(1):R33. · 4.27 Impact Factor
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Paivi M Miettunen,
Angela Pistorio,
Elena Palmisani,
Angelo Ravelli,
Earl Silverman,
Sheila Oliveira, Maria Alessio,
Ruben Cuttica,
Dimitrina Mihaylova,
Graciela Espada,
Srdjan Pasic,
Antonella Insalaco,
Seza Ozen,
Oscar Porras,
Flavio Sztajnbok,
Dragana Lazarevic,
Alberto Martini,
Nicolino Ruperto
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ABSTRACT: 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.
Annals of the rheumatic diseases 10/2012; · 8.11 Impact Factor
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ABSTRACT: BACKGROUND: Recent studies report that methotrexate (MTX) is beneficial in the treatment of juvenile localized scleroderma (JLS) but little is known about its long-term effectiveness. OBJECTIVE: We assessed the therapeutic role of MTX in children with JLS who were followed up for a prolonged period. METHODS: A cohort of patients with JLS, previously enrolled in a double-blind, randomized controlled trial and treated with oral MTX (15 mg/m(2)/wk) and prednisone (1 mg/kg/d, maximum 50 mg) for the first 3 months, were prospectively followed up. Lesions were evaluated clinically, with infrared thermography, and by a computerized skin score. Response to treatment was defined as: (1) no new lesions; (2) skin score rate less than 1; and (3) decrease in lesion temperature by at least 10% compared with baseline. Clinical remission (CR) on medication was defined when response was maintained, on treatment, for at least 6 months, and complete CR when response was maintained, without treatment, for at least 6 months. RESULTS: Of 65 patients treated with MTX, 48 (73.8%) were responders, 10 (15.4%) relapsed by 24 months since MTX start, and 7 (10.8%) were lost to follow-up. Among the responders, 35 (72.9%) maintained CR for a mean of 25 months and 13 (27.1%) were in CR on medication. Adverse effects seen in 28 patients (48.3%) were generally mild and never required treatment discontinuation. LIMITATIONS: The use of objective measures not widely available, such as infrared thermography and computerized skin score, makes it difficult to compare data from previous studies. CONCLUSIONS: Long-term MTX therapy is beneficial and well tolerated for JLS.
Journal of the American Academy of Dermatology 05/2012; · 3.99 Impact Factor
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ABSTRACT: Aim of the present study was to validate a statistical model to predict a severe course of anterior uveitis (AU) in patients with juvenile idiopathic arthritis (JIA).
Consecutive patients with newly diagnosed uveitis have been followed for at least 1 year with a standardized protocol. For each patient, demographic, clinical and laboratory characteristics, including time interval between arthritis and uveitis onset, α(2)-globulins level at arthritis onset, number of uveitis relapses/year, ocular complications and therapy and visual acuity, have reported. The validation procedure included the assessment of sensitivity, specificity and efficiency of previously published statistical model (Zulian et al. J Rheumatol 2002; 29: 2446-2453) in a new inception cohort of patients during a short length follow-up.
Sixty patients with JIA, followed at 14 paediatric rheumatology-ophthalmology centres in Italy, entered the study. The mean age at arthritis onset was 4.4 years (range 1.2-15.8 years), and the mean interval time between arthritis and uveitis onset was 1.8 years (range: 0.0-14.2 years). After the first AU, patients, followed for a mean of 3.2 years, had a mean of 2.9 uveitis relapses. Twenty-two patients (36.7%) presented at least one complication. Using a probability cut-off value = 0.7, the statistical model revealed 80% sensitivity, 58% specificity and 65% efficiency.
The time interval between arthritis and uveitis onset resulted as the main predictor of severe course uveitis in JIA. The statistical model was able to predict the development of a severe course in 8 of 10 patients.
Acta ophthalmologica 02/2012; 90(1):91-5. · 2.44 Impact Factor
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Alessandro Consolaro,
Nicolino Ruperto,
Angela Pistorio,
Bianca Lattanzi,
Nicoletta Solari,
Roberta Galasso,
Silvia Pederzoli,
Giulia C Varnier,
Pavla Dolezalova, Maria Alessio,
Ruben Burgos-Vargas,
Richard Vesely,
Alberto Martini,
Angelo Ravelli
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ABSTRACT: To develop and validate a parent-centered and a child-centered composite disease assessment index for juvenile idiopathic arthritis (JIA): the Juvenile Arthritis Parent Assessment Index (JAPAI) and the Juvenile Arthritis Child Assessment Index (JACAI), respectively.
The JAPAI and the JACAI include 4 measures: parent/child rating of overall well-being, pain, physical function, and health-related quality of life (HRQOL). Validation analyses were conducted on nearly 5,000 patients and included assessment of construct validity, discriminant validity, responsiveness to change, and reliability. Besides the 4-item version, a 3-item version of both indices, which did not include HRQOL, was tested.
The JAPAI and the JACAI demonstrated good construct validity, yielding high correlations with the Juvenile Arthritis Disease Activity Score and moderate correlations with physician global rating and joint counts. Correlations obtained for the JAPAI and the JACAI and for the 4-item and the 3-item versions were comparable. Factorial analysis by principal component analysis showed that both indices are monodimensional. Both the JAPAI and JACAI discriminated well between different disease states and courses and between different levels of American College of Rheumatology Pediatric criteria in a clinical trial, and revealed fair responsiveness to clinical change. Internal consistency was satisfactory, with a Cronbach's alpha of >0.80 in all but 1 of the patient samples tested.
The JAPAI and the JACAI were found to be valid instruments for assessment of disease status in JIA and suitable surrogates of physicians' evaluations. Both indices are potentially applicable in clinical practice, observational studies, and therapeutic trials.
Arthritis care & research. 05/2011; 63(9):1262-70.
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ABSTRACT: T helper 17 cells (T(H)-17) represent a lineage of effector T cells critical in host defence and autoimmunity. In both mouse and human IL-1β has been indicated as a key cytokine for the commitment to T(H)-17 cells. Cryopyrin-associated periodic syndromes (CAPS) are a group of inflammatory diseases associated with mutations of the NLRP3 gene encoding the inflammasome component cryopyrin. In this work we asked whether the deregulated secretion of IL-1β secondary to mutations characterizing these patients could affect the IL-23/IL-17 axis.
A total of 11 CAPS, 26 systemic onset juvenile idiopathic arthritis (SoJIA) patients and 20 healthy controls were analyzed. Serum levels of IL-17 and IL-6 serum were assessed by ELISA assay. Frequency of T(H)17 cells was quantified upon staphylococcus enterotoxin B (SEB) stimulation. Secretion of IL-1β, IL-23 and IL-6 by monocyte derived dendritic cells (MoDCs), were quantified by ELISA assay. A total of 8 CAPS and 11 SoJIA patients were also analysed before and after treatment with IL-1β blockade. Untreated CAPS patients showed significantly increased IL-17 serum levels as well as a higher frequency of T(H)17 compared to control subjects. On the contrary, SoJIA patients displayed a frequency of T(H)17 similar to normal donors, but were found to have significantly increased serum level of IL-6 when compared to CAPS patients or healthy donors. Remarkably, decreased IL-17 serum levels and T(H)17 frequency were observed in CAPS patients following in vivo IL-1β blockade. On the same line, MoDCs from CAPS patients exhibited enhanced secretion of IL-1β and IL-23 upon TLRs stimulation, with a reduction after anti-IL-1 treatment.
These findings further support the central role of IL-1β in the differentiation of T(H)17 in human inflammatory conditions.
PLoS ONE 01/2011; 6(5):e20014. · 4.09 Impact Factor
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Francesco Zulian,
Giorgia Martini,
Cristina Vallongo,
Fabio Vittadello,
Fernanda Falcini,
Annalisa Patrizi, Maria Alessio,
Francesco La Torre,
Rosa A Podda,
Valeria Gerloni,
Mario Cutrone,
Anna Belloni-Fortina,
Mauro Paradisi,
Silvana Martino,
Giorgio Perilongo
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ABSTRACT: Juvenile localized scleroderma is a chronic progressive fibrotic disorder of the skin that causes permanent disability and aesthetic damage. This study was undertaken to assess the safety and efficacy of methotrexate (MTX) in the treatment of juvenile localized scleroderma.
In this double-blind study, patients with active juvenile localized scleroderma were randomized (2:1) to receive oral MTX (15 mg/m², maximum 20 mg) or placebo once weekly, for 12 months or until treatment failure. Both groups received oral prednisone (1 mg/kg/day, maximum 50 mg) for the first 3 months. A target lesion was evaluated clinically, with infrared thermography and using a computerized scoring system with skin score rate (SSR) evaluation. Response to treatment was defined as the absence of new lesions, SSR ≤ 1, and a decrease in lesion temperature of at least 10% compared to baseline. Treatment failure was defined as the occurrence of new lesions, SSR > 1, or increased lesion temperature. All analyses were done on the intent-to-treat population.
Of the 85 patients screened, 70 (ages 6-17 years) were randomized (46 to the MTX group, 24 to the placebo group). The mean disease duration was 2.3 years. After an initial response in all patients, disease relapsed in 15 MTX-treated patients (32.6%) and 17 placebo-treated patients (70.8%) (P < 0.005). New lesions appeared in 3 MTX-treated patients (6.5%) versus 4 placebo-treated patients (16.7%). The mean SSR decreased from 1 to 0.79 in the MTX group and increased from 1 to 1.1 in the placebo group, and the mean target lesion temperature decreased by 44.4% in the MTX group versus 12.1% in the placebo group. Twenty-six patients in the MTX group (56.5%) and 11 patients in the placebo group (45.8%) developed mild side effects related to treatment. None of the side effects were severe enough to necessitate treatment discontinuation.
Our findings indicate that MTX is efficacious in the treatment of juvenile localized scleroderma and is well tolerated.
Arthritis & Rheumatism 01/2011; 63(7):1998-2006. · 7.87 Impact Factor
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Nicolino Ruperto,
Daniel J Lovell,
Tracy Li,
Flavio Sztajnbok,
Claudia Goldenstein-Schainberg,
Morton Scheinberg,
Inmaculada Calvo Penades,
Michael Fischbach,
Javier Orozco Alcala,
Philip J Hashkes, [......],
Anne Eberhard,
Gabriele Simonini,
Irene Lemelle,
Elizabeth Candell Chalom,
Leonard H Sigal,
Alan Block,
Allison Covucci,
Marleen Nys,
Alberto Martini,
Edward H Giannini
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ABSTRACT: To assess health-related quality of life (HRQOL) in abatacept-treated children/adolescents with juvenile idiopathic arthritis (JIA).
In this phase III, double-blind, placebo-controlled trial, subjects with active polyarticular course JIA and an inadequate response/intolerance to ≥1 disease-modifying antirheumatic drug (including biologics) received abatacept 10 mg/kg plus methotrexate (MTX) during the 4-month open-label period (period A). Subjects achieving the American College of Rheumatology Pediatric 30 criteria for improvement (defined "responders") were randomized to abatacept or placebo (plus MTX) in the 6-month double-blind withdrawal period (period B). HRQOL assessments included 15 Child Health Questionnaire (CHQ) health concepts plus the physical (PhS) and psychosocial summary scores (PsS), pain (100-mm visual analog scale), the Children's Sleep Habits Questionnaire, and a daily activity participation questionnaire.
A total of 190 subjects from period A and 122 from period B were eligible for analysis. In period A, there were substantial improvements across all of the CHQ domains (greatest improvement was in pain/discomfort) and the PhS (8.3 units) and PsS (4.3 units) with abatacept. At the end of period B, abatacept-treated subjects had greater improvements versus placebo in all domains (except behavior) and both summary scores. Similar improvement patterns were seen with pain and sleep. For participation in daily activities, an additional 2.6 school days/month and 2.3 parents' usual activity days/month were gained in period A responders with abatacept, and further gains were made in period B (1.9 versus 0.9 [P = 0.033] and 0.2 versus -1.3 [P = 0.109] school days/month and parents' usual activity days/month, respectively, in abatacept- versus placebo-treated subjects).
Improvements in HRQOL were observed with abatacept, providing real-life tangible benefits to children with JIA and their parents/caregivers.
Arthritis care & research. 11/2010; 62(11):1542-51.
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Loredana Lepore,
Giulia Paloni,
Roberta Caorsi, Maria Alessio,
Donato Rigante,
Nicola Ruperto,
Marco Cattalini,
Alberto Tommasini,
Francesco Zulian,
Alessando Ventura,
Alberto Martini,
Marco Gattorno
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ABSTRACT: To evaluate the quality of life and long-term follow-up of patients enrolled in the Italian registry of cryopyrin-associated periodic syndromes (CAPS).
Since 2004, 20 patients with CAPS were enrolled in a common registry from different Italian Centers of Pediatric Rheumatology; 14 patients were treated with Anakinra in an open fashion. Both treated and untreated patients were routinely followed according to standard of care. The Child Health Questionnaire (CHQ-PF 50) was used to assess the health-related quality of life.
The mean duration of follow-up was 37.5 months. In all treated patients, a complete and persistent control of the inflammatory manifestations was observed with no further progression of the disease. At enrollment in the registry, patients showed a poorer health-related quality of life than healthy children in both physical and the psychosocial summary scores. Treatment was associated with a dramatic and sustained amelioration of a variety of measures of poor quality of life, particularly in those concerning the global health perception, bodily pain-discomfort, and other physical domains.
Long-term IL-1 blockade produces a significant and persistent improvement in the clinical manifestations associated with the disease and on the overall quality of life.
The Journal of pediatrics 08/2010; 157(2):310-315.e1. · 4.02 Impact Factor
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Angelo Ravelli,
Lucia Trail,
Cristina Ferrari,
Nicolino Ruperto,
Angela Pistorio,
Clarissa Pilkington,
Susan Maillard,
Sheila K Oliveira,
Flavio Sztajnbok,
Ruben Cuttica, [......],
Maria Giannina Alpigiani,
Valeria Gerloni,
Claudia Saad-Magalhaes,
Rosanna Podda,
Clovis A Silva,
Loredana Lepore,
Enrico Felici,
Federica Rossi,
Elena Sala,
Alberto Martini
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ABSTRACT: To investigate the long-term outcome and prognostic factors of juvenile dermatomyositis (DM) through a multinational, multicenter study.
Patients consisted of inception cohorts seen between 1980 and 2004 in 27 centers in Europe and Latin America. Predictor variables were sex, continent, ethnicity, onset year, onset age, onset type, onset manifestations, course type, disease duration, and active disease duration. Outcomes were muscle strength/endurance, continued disease activity, cumulative damage, muscle damage, cutaneous damage, calcinosis, lipodystrophy, physical function, and health-related quality of life (HRQOL).
A total of 490 patients with a mean disease duration of 7.7 years were included. At the cross-sectional visit, 41.2-52.8% of patients, depending on the instrument used, had reduced muscle strength/endurance, but less than 10% had severe impairment. Persistently active disease was recorded in 41.2-60.5% of the patients, depending on the activity measure used. Sixty-nine percent of the patients had cumulative damage. The frequency of calcinosis and lipodystrophy was 23.6% and 9.7%, respectively. A total of 40.7% of the patients had decreased functional ability, but only 6.5% had major impairment. Only a small fraction had decreased HRQOL. A chronic course, either polycyclic or continuous, consistently predicted a poorer outcome. Mortality rate was 3.1%.
This study confirms the marked improvement in functional outcome of juvenile DM when compared with earlier literature. However, many patients had continued disease activity and cumulative damage at followup. A chronic course was the strongest predictor of poor prognosis. These findings highlight the need for treatment strategies that enable a better control of disease activity over time and the reduction of nonreversible damage.
Arthritis care & research. 01/2010; 62(1):63-72.
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ABSTRACT: To evaluate the safety and efficacy of abatacept in patients with severe juvenile idiopathic arthritis (JIA)-related uveitis refractory or intolerant to immunosuppressive and anti-tumor necrosis factor alpha (anti-TNFalpha) agents.
Patients with JIA-related uveitis refractory to immunosuppressive and anti-TNFalpha agents were treated with intravenous abatacept (10 mg/kg monthly). Side effects, frequency of uveitis flares, and ocular complications before and after treatment were reported.
Seven patients (6 females and 1 male) with a mean uveitis duration of 11.6 years entered the study. All patients had failed previous immunosuppressive therapy and >or=2 anti-TNFalpha treatments. All patients responded to abatacept and 6 maintained a clinical remission after a mean of 9.2 months of treatment. One patient withdrew from the study with oral mycosis and arthritis flare; no other patients had side effects. The mean frequency of uveitis flares during the 6 months before and after treatment decreased from 3.7 to 0.7 episodes. No new ocular complications or worsening of preexisting ones were reported.
Abatacept treatment led to sustained improvement in severe anti-TNFalpha-resistant JIA-related uveitis and was well tolerated in all but 1 patient. These results provide new insights into a possible indication of abatacept for the treatment of uveitis.
Arthritis care & research. 01/2010; 62(6):821-5.
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Silvia Meiorin,
Angela Pistorio,
Angelo Ravelli,
Silvia M Iusan,
Giovanni Filocamo,
Lucia Trail,
Sheila Oliveira,
Ruben Cuttica,
Graciela Espada, Maria Alessio,
Dimitrina Mihaylova,
Elisabetta Cortis,
Alberto Martini,
Nicolino Ruperto
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ABSTRACT: To validate the Childhood Health Assessment Questionnaire (C-HAQ) as a measure of disability in patients with active juvenile systemic lupus erythematosus (SLE).
Of 557 patients with juvenile SLE included in the Paediatric Rheumatology International Trials Organisation (PRINTO) database, 504 (90.5%) were included in the present study and underwent C-HAQ assessment at the time of a major therapeutic intervention and then after 6 months. Validation procedures, according to the Outcome Measures in Rheumatology Clinical Trials filter for outcome measures in rheumatology, included assessment of responsiveness, feasibility, internal consistency, construct validity, collinearity, and discriminative ability. Response to therapy was evaluated with the PRINTO/American College of Rheumatology (ACR) juvenile SLE definition of improvement.
At baseline, patients showed a high level of disease activity (mean physician global 5.8) and moderate disability (mean C-HAQ 0.83); both disease activity and disability improved after 6 months of treatment. The change in C-HAQ score correlated moderately with the Systemic Lupus Activity Measure (r(s) = 0.42), parent's global assessment of pain and well-being (r(s) = 0.55 and 0.53, respectively), and the physical summary score of the Child Health Questionnaire (r(s) = -0.61), and poorly with other clinical and laboratory parameters. The absolute change in C-HAQ demonstrated a significant ability to discriminate between patients who improved and those who did not improve based on the PRINTO/ACR definition of improvement. Responsiveness of the C-HAQ was moderate (standardized response mean 0.74). Internal consistency was excellent (Cronbach's alpha = 0.96).
The C-HAQ showed moderate responsiveness to clinical change, construct validity, good feasibility, internal consistency, and discriminative ability. These findings demonstrate that the C-HAQ represents a good measure to capture disability in patients with active juvenile SLE.
Arthritis & Rheumatism 09/2008; 59(8):1112-9. · 7.87 Impact Factor
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Marco Gattorno,
Sara Tassi,
Sonia Carta,
Laura Delfino,
Francesca Ferlito,
Maria Antonietta Pelagatti,
Andrea D'Osualdo,
Antonella Buoncompagni,
Maria Giannina Alpigiani, Maria Alessio,
Alberto Martini,
Anna Rubartelli
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ABSTRACT: To examine the synthesis, processing, and secretion of interleukin-1beta (IL-1beta), as well as the clinical and biologic effects of IL-1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle-Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL-1beta hypersecretion, and the underlying response to IL-1 receptor antagonist (IL-1Ra).
Six patients with CINCA syndrome or MWS were treated with IL-1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL-1beta levels were determined by Western blotting and enzyme-linked immunosorbent assay before and after exposure to exogenous ATP.
LPS-induced IL-1beta secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL-1beta was not induced by exogenous ATP. Treatment with IL-1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down-regulation of LPS-induced IL-1beta secretion by the patients' cells in vitro.
Our results showed that the requirements of ATP stimulation for IL-1beta release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL-1Ra treatment is at least partly due to the strong decrease in IL-1beta secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL-1beta.
Arthritis & Rheumatism 10/2007; 56(9):3138-48. · 7.87 Impact Factor
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Nicolino Ruperto,
Angelo Ravelli,
Sheila Oliveira, Maria Alessio,
Dimitrina Mihaylova,
Srdjan Pasic,
Elisabetta Cortis,
Maria Apaz,
Ruben Burgos-Vargas,
Florence Kanakoudi-Tsakalidou, [......],
Carolina Duarte,
Troels Herlin,
Gerd Horneff,
Loredana Lepore,
Marion van Rossum,
Lucia Trail,
Angela Pistorio,
Boel Andersson-Gäre,
Edward H Giannini,
Alberto Martini
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ABSTRACT: To use the Pediatric Rheumatology International Trials Organization (PRINTO) core set of outcome measures to develop a validated definition of improvement for the evaluation of response to therapy in juvenile systemic lupus erythematosus (SLE).
Thirty-seven experienced pediatric rheumatologists from 27 countries, each of whom had specific experience in the assessment of juvenile SLE patients, achieved consensus on 128 patient profiles as being clinically improved or not improved. Using the physicians' consensus ratings as the gold standard measure, the chi-square, sensitivity, specificity, false-positive and false-negative rates, area under the receiver operating characteristic curve, and kappa level of agreement for 597 candidate definitions of improvement were calculated. Only definitions with a kappa value greater than 0.7 were retained. The top definitions were selected based on the product of the content validity score multiplied by its kappa statistic.
The definition of improvement with the highest final score was at least 50% improvement from baseline in any 2 of the 5 core set measures, with no more than 1 of the remaining worsening by more than 30%.
PRINTO proposes a valid and reproducible definition of improvement that reflects well the consensus rating of experienced clinicians and that incorporates clinically meaningful change in core set measures in a composite end point for the evaluation of global response to therapy in patients with juvenile SLE. The definition is now proposed for use in juvenile SLE clinical trials and may help physicians to decide whether a child with SLE responded adequately to therapy.
Arthritis & Rheumatism 07/2006; 55(3):355-63. · 7.87 Impact Factor
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Nicolino Ruperto,
Irina Nikishina,
Evgueni D Pachanov,
Ynessa Shachbazian,
Anne Marie Prieur,
Richard Mouy,
Rik Joos,
Francesco Zulian,
Rudolf Schwarz,
Valeria Artamonova, [......],
Fernanda Falcini,
Eileen Baildam,
Isabelle Kone-Paut, Maria Alessio,
Valeria Gerloni,
Alessandro Lenhardt,
Alberto Martini,
Gertraud Hanft,
Ralf Sigmund,
Stefan Simianer
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ABSTRACT: In an international, multicenter, double-blind, randomized clinical trial we evaluated the short-term (3 months) and long-term (12 months) efficacy and safety of 2 different doses of meloxicam oral suspension compared with the efficacy and safety of naproxen oral suspension in children with oligoarticular-course (oligo-course) or polyarticular-course (poly-course) juvenile idiopathic arthritis (JIA).
Children ages 2-16 years who had active oligo-course or poly-course JIA and who required therapy with a nonsteroidal antiinflammatory drug were eligible for this trial. Patients were randomly allocated to receive therapy with meloxicam oral suspension, 0.125 mg/kg body weight in a single daily dose; meloxicam oral suspension, 0.25 mg/kg body weight in a single daily dose; or naproxen, 10 mg/kg body weight in 2 daily doses. The trial drugs were administered in a double-blind, double-dummy design for up to 12 months. Response rates were determined according to the American College of Rheumatology pediatric 30% improvement criteria (ACR pediatric 30). Safety parameters were assessed by evaluating the frequency of adverse events in the 3 groups.
Of 232 patients enrolled, 225 received treatment, 6 were not eligible for randomization, and 1 randomized patient was not treated. One hundred eighty-two patients (81%) completed the 12-month treatment period. Response rates according to the ACR pediatric 30 criteria improved from month 3 to month 12, as follows: from 63% to 77% in the meloxicam 0.125 mg/kg group, from 58% to 76% in the meloxicam 0.25 mg/kg group, and from 64% to 74% in the naproxen group. No statistically significant differences in response rates were observed between the groups. There were no differences in the frequency of adverse events or abnormal laboratory values between the 3 groups.
The short- and long-term safety and efficacy of meloxicam oral suspension appear to be comparable with the safety and efficacy of naproxen oral suspension in the treatment of oligo-course and poly-course JIA. The once-daily administration of meloxicam oral suspension might represent an improvement in the treatment of JIA.
Arthritis & Rheumatism 03/2005; 52(2):563-72. · 7.87 Impact Factor
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Nicolino Ruperto,
Kevin J Murray,
Valeria Gerloni,
Nico Wulffraat,
Sheila Knupp Feitosa de Oliveira,
Fernanda Falcini,
Pavla Dolezalova, Maria Alessio,
Ruben Burgos-Vargas,
Fabrizia Corona, [......],
Francesco Zulian,
Line Asplin,
Eileen Baildam,
Julia Garcia Consuegra,
Huri Ozdogan,
Rotraud Saurenmann,
Rik Joos,
Angela Pistorio,
Pat Woo,
Alberto Martini
[show abstract]
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ABSTRACT: To compare the safety and efficacy of parenteral methotrexate (MTX) at an intermediate dosage (15 mg/m(2)/week) versus a higher dosage (30 mg/m(2)/week) in patients with polyarticular-course juvenile idiopathic arthritis (JIA) who failed to improve while receiving standard dosages of MTX (8-12.5 mg/m(2)/week).
In the screening phase, 595 patients who were newly started on a standard dose of MTX were followed up for 6 months. Subsequently, the nonresponders, defined according to the American College of Rheumatology (ACR) pediatric 30% improvement criteria (pediatric 30), were randomized to receive an intermediate dose or higher dose of parenteral MTX for an additional 6 months. Improvement in the screening and randomization phase was defined by the ACR pediatric 30 response, as well as by the 50% and 70% response levels (ACR pediatric 50 and ACR pediatric 70, respectively).
In the screening phase, after receiving standard doses of MTX, 430 patients (72%) improved according to the ACR pediatric 30, while 360 (61%) met the ACR pediatric 50 and 225 (38%) met the ACR pediatric 70; among these patients, 69 (12%) also met the definition of complete disease control. Of the 133 nonresponders, 80 were randomized to receive an intermediate dose or higher dose of MTX. In the randomization phase, the ACR pediatric 30 response rate was 25 of 40 children (62.5%) in the intermediate-dose group versus 23 of 40 children (57.5%) in the higher-dose group. An ACR pediatric 50 response rate was attained by 23 patients (57.5%) receiving an intermediate dose versus 22 (55%) in the higher-dose group. An ACR pediatric 70 response rate was seen in 18 children (45%) receiving an intermediate dose versus 19 (47.5%) receiving a higher dose. Five children (12.5%) in the intermediate-dose group versus 4 (10%) receiving the higher dose of MTX also met the definition of complete disease control. None of the intergroup differences in response rate were significant. There were no significant differences in the frequency of adverse events or laboratory abnormalities between the 2 randomized groups.
This study shows that the plateau of efficacy of MTX in JIA is reached with parenteral administration of 15 mg/m(2)/week and that a further increase in dosage is not associated with any additional therapeutic benefit. MTX should be administered for up to 9-12 months to appreciate its full therapeutic effect.
Arthritis & Rheumatism 08/2004; 50(7):2191-201. · 7.87 Impact Factor
