Rheumatoid Arthritis: Ruperto N

Ruperto N, Martini A. · IRCCS Istituto G. Gaslini, Pediatria II, Reumatologia, Genoa, Italy. · World J Pediatr. · Pubmed #18822926 No free full text.

Abstract: BACKGROUND: Pediatric rheumatic diseases (PRDs) are rare conditions associated with significant sequelae affecting the quality of life and long-term outcome. The research aimed at studying new therapeutic approaches is difficult because of logistic, methodological and ethical problems. DATA SOURCES: To address these problems, two international networks, the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Pediatric Rheumatology International Trials Organization (PRINTO) were established. The two networks share the goal to promote, facilitate and conduct high quality research for PRDs. RESULTS: The PRINTO and PRCSG networks have standardized the evaluation of response to therapy in juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus, and juvenile dermatomyositis, drafted clinical remission criteria in JIA, and provided cross-cultural adapted and validated quality of life instruments including the Childhood Health Assessment Questionnaire and the Child Health Questionnaire into 32 different languages. In this paper we reviewed how the networks of the PRINTO and PRCSG have created the basic premises for the best future assessment of PRDs. CONCLUSIONS: The PRINTO and PRCSG networks can be regarded as a model for international cooperation or collaboration in other pediatric subspecialties.

Ruperto N, Meiorin S, Iusan SM, Ravelli A, Pistorio A, Martini A. · IRCCS G. Gaslini, Pediatria II-PRINTO, University of Genoa, Largo Gaslini, 5, 16147 Genova, Italy. · Curr Rheumatol Rep. · Pubmed #18460270 No free full text.

Abstract: The Delphi Technique and Nominal Group Technique are two well-recognized consensus-formation methodologies specifically designed to combine judgments from a group of experts. The Delphi Technique utilizes a series of well-defined questionnaire-based surveys, whereas Nominal Group Technique is a structured face-to-face meeting designed to facilitate consensus. Consensus-formation techniques require that each step build on the results of the previous steps. In this review, we describe these techniques, how they work, and their practical application in pediatric rheumatology, where they have been widely used to develop the outcome measures of several chronic rheumatic diseases, including juvenile idiopathic arthritis, rheumatoid arthritis, systemic lupus erythematosus, and idiopathic inflammatory myopathies, as well as the classification criteria for juvenile systemic sclerosis and juvenile vasculitides.

Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, Viola S, Martini A. · Department of Pediatrics, Division of Pediatrics II, University of Genoa, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genoa, Italy. · J Pediatr. · Pubmed #15870661 No free full text.

Abstract: OBJECTIVE: To develop diagnostic guidelines for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (S-JIA). STUDY DESIGN: We followed the classification criteria approach that is based on the comparison of patients with the index disease with patients with a "confusable" disease. The former group included 74 patients with S-JIA-associated MAS reported in the literature or seen by the authors; the latter group included 37 patients with S-JIA who had 51 instances of "high disease activity" seen by the authors. The relative power of clinical, laboratory, and histopathologic variables in discriminating patients with MAS from patients with high disease activity was evaluated by calculating the sensitivity rate, specificity rate, area under the receiver operating characteristic curve, and diagnostic odds ratio (DOR). The combinations of variables that led to best separation between patients and control subjects were identified through "the number of criteria present" method. RESULTS: The strongest clinical discriminators were hemorrhages (DOR = 67) and central nervous system dysfunction (DOR = 63); the strongest laboratory discriminators were decreased platelet count (DOR = 1092), increased aspartate aminotransferase (DOR = 247), leukopenia (DOR = 70), and hypofibrinogenemia (DOR = 165). The best separation between patients and control subjects occurred when any 2 or more laboratory criteria (DOR = 1309) were simultaneously present; the second best performance was provided by the presence of any 2, 3, or more clinical and/or laboratory criteria (DOR = 765 and 743, respectively). CONCLUSION: We identified preliminary diagnostic guidelines for MAS complicating S-JIA. These guidelines deserve prospective validation.

Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Pérez N, Silva CA, Abud-Mendoza C, Burgos-Vargas R, Gerloni V, Melo-Gomes JA, Saad-Magalhães C, Sztajnbok F, Goldenstein-Schainberg C, Scheinberg M, Penades IC, Fischbach M, Orozco J, Hashkes PJ, Hom C, Jung L, Lepore L, Oliveira S, Wallace CA, Sigal LH, Block AJ, Covucci A, Martini A, Giannini EH, Anonymous00184, Anonymous00185. · IRCCS G Gaslini, PRINTO, Genoa, Italy. · Lancet. · Pubmed #18632147 No free full text.

Abstract: BACKGROUND: Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. METHODS: We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6-17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. FINDINGS: Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0.0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0.0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0.31, 95% CI 0.16-0.95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0.47); only two serious adverse events were reported, both in controls (p=0.50). INTERPRETATION: Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. FUNDING: Bristol-Myers Squibb.

Ruperto N, Lovell DJ, Cuttica R, Wilkinson N, Woo P, Espada G, Wouters C, Silverman ED, Balogh Z, Henrickson M, Apaz MT, Baildam E, Fasth A, Gerloni V, Lahdenne P, Prieur AM, Ravelli A, Saurenmann RK, Gamir ML, Wulffraat N, Marodi L, Petty RE, Joos R, Zulian F, McCurdy D, Myones BL, Nagy K, Reuman P, Szer I, Travers S, Beutler A, Keenan G, Clark J, Visvanathan S, Fasanmade A, Raychaudhuri A, Mendelsohn A, Martini A, Giannini EH, Anonymous00187, Anonymous00188. · IRCCS, Istituto G. Gaslini, Genoa, Italy. · Arthritis Rheum. · Pubmed #17763439 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis (JRA). METHODS: This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received MTX plus infliximab 3 mg/kg through week 44, or MTX plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44. RESULTS: Although a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), the between-group difference in this primary efficacy end point was not statistically significant (P = 0.12). By week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients. Infliximab was generally well tolerated, but the safety profile of infliximab 3 mg/kg appeared less favorable than that of infliximab 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double-stranded DNA observed with the 3 mg/kg dose. CONCLUSION: While infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy end point at 3 months did not differ significantly between infliximab-treated and placebo-treated patients. Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile. These results warrant further investigation in children with JRA.

Ruperto N, Ravelli A, Castell E, Gerloni V, Haefner R, Malattia C, Kanakoudi-Tsakalidou F, Nielsen S, Bohnsack J, Gibbas D, Rennebohm R, Voygioyka O, Balogh Z, Lepore L, Macejkova E, Wulffraat N, Oliveira S, Russo R, Buoncompagni A, Hilário MO, Alpigiani MG, Passo M, Lovell DJ, Merino R, Martini A, Giannini EH, Anonymous00431, Anonymous00432. · IRCCS G. Gaslini, Pediatria II-Reumatologia, PRINTO, Genova, Italy. · Clin Exp Rheumatol. · Pubmed #17181934 No free full text.

Abstract: OBJECTIVE: To investigate the clinical use patterns, clinical effect and safety of cyclosporine A (CSA) in juvenile idiopathic arthritis (JIA) in the setting of routine clinical care. METHODS: An open-ended, phase IV post marketing surveillance study was conducted among members of the Pediatric Rheumatology Collaborative Study Group (PRCSG) and of the Paediatric Rheumatology International Trials Organisation (PRINTO) to identify patients with polyarticular course JIA who had received CSA during the course of their disease. RESULTS: A total of 329 patients, half of whom had systemic JIA, were collected in 21 countries. Data were collected during 1240 routine clinic visits. CSA was started at a mean of 5.8 years after disease onset and was given at a mean dose of 3.4 mg/kg/day. The drug was administered in combination with MTX in 61% and along with prednisone in 65% of the patients who were still receiving CSA. Among patients who were still receiving CSA therapy at the last reported visit, remission was documented in 9% of the patients, whereas in 61% of the patients the disease activity was rated as moderate or severe. The most frequent reason for discontinuation of CSA was insufficient therapeutic effect (61% of the patients); only 10% of the patients stopped CSA because of remission. In 17% of the patients, side effects of therapy was given as the primary reason for discontinuation. CONCLUSION: This survey suggests that CSA may have a less favourable efficacy profile than MTX and etanercept, whereas the frequency of side effects may be similar. The exact place of CSA in the treatment of JIA can only be established via controlled clinical trial.

Ruperto N, Nikishina I, Pachanov ED, Shachbazian Y, Prieur AM, Mouy R, Joos R, Zulian F, Schwarz R, Artamonova V, Emminger W, Bandeira M, Buoncompagni A, Foeldvari I, Falcini F, Baildam E, Kone-Paut I, Alessio M, Gerloni V, Lenhardt A, Martini A, Hanft G, Sigmund R, Simianer S, Anonymous00240. · IRCCS G. Gaslini, Pediatria II, Reumatologia, Genoa, Italy. <> · Arthritis Rheum. · Pubmed #15692986 links to  free full text

Abstract: OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Ruperto N, Murray KJ, Gerloni V, Wulffraat N, de Oliveira SK, Falcini F, Dolezalova P, Alessio M, Burgos-Vargas R, Corona F, Vesely R, Foster H, Davidson J, Zulian F, Asplin L, Baildam E, Consuegra JG, Ozdogan H, Saurenmann R, Joos R, Pistorio A, Woo P, Martini A, Anonymous00439. · IRCCS G. Gaslini, University of Genoa, Genoa, Italy. · Arthritis Rheum. · Pubmed #15248217 links to  free full text

Abstract: OBJECTIVE: 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). METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Ruperto N, Ravelli A, Falcini F, Lepore L, Buoncompagni A, Gerloni V, Bardare M, Cortis E, Zulian F, Sardella ML, Giovanni Strano C, Alessio M, Alpigiani MG, Migliavacca D, Pistorio A, Viola S, Martini A. · Laboratorio di Informatica Medica, IRCCS S. Matteo, Pavia, Italy. · Rheumatology (Oxford). · Pubmed #10342633 links to  free full text

Abstract: OBJECTIVE: To examine the responsiveness of the disease activity measures more commonly used in juvenile chronic arthritis (JCA) clinical trials. METHODS: Data were obtained from an open-label, non-controlled, multicentre trial designed to investigate the efficacy of methotrexate (MTX) in children with JCA. Outcome measures, including physician and parent global assessments, functional ability measures, articular variables, and laboratory indicators of systemic inflammation, were assessed at baseline and after 6 months of MTX treatment in 132 patients. Responsiveness of endpoint variables was evaluated by assessing the effect size (ES) and the standardized response median (SRM). RESULTS: Physician and parent global assessments were the more responsive instruments, showing ES and SRM above 1.0. Erythrocyte sedimentation rate, C-reactive protein, functional status measures and articular variables showed intermediate responsiveness. Morning stiffness, haemoglobin and platelet count were the least responsive instruments. CONCLUSION: The results of our analysis indicate that subjective estimations of the disease activity, either by the physician or parents, are the most responsive instruments in the assessment of the therapeutic response in children with JCA. The responsiveness of outcome measures in JCA should be further investigated in prospective controlled studies.

Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G, Malattia C, Viola S, Martini A, Ravelli A, Anonymous00061. · Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genoa, and the Università degli Studi di Verona, Verona, Italy. · Arthritis Rheum. · Pubmed #19405003 No free full text.

Abstract: OBJECTIVE: To develop and validate a composite disease activity score for juvenile idiopathic arthritis (JIA), the Juvenile Arthritis Disease Activity Score (JADAS). METHODS: The JADAS includes 4 measures: physician global assessment of disease activity, parent/patient global assessment of well-being, active joint count, and erythrocyte sedimentation rate. These variables are part of the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, and Pedi 70 criteria for improvement. Validation analyses were conducted on >4,500 patients and included assessment of construct validity, discriminant validity, and responsiveness to change. Three versions of the JADAS were tested based on 71-joint (range 0-101), 27-joint (range 0-57), or 10-joint (range 0-40) counts. Statistical performances of the JADAS were compared with those of 2 rheumatoid arthritis composite scores, the Disease Activity Score in 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI). RESULTS: The JADAS demonstrated good construct validity, yielding strong correlations with JIA activity measures not included in the score and moderate correlations with the Childhood Health Assessment Questionnaire. Correlations obtained for the 3 JADAS versions were comparable, but superior to those yielded by the DAS28 and CDAI. The area under the curve of the JADAS predicted long-term disease outcome, measured as radiographic progression over 3 years. In 2 clinical trials, the JADAS discriminated well between ACR Pedi 30, Pedi 50, and Pedi 70 response and revealed strong responsiveness to clinical change. CONCLUSION: The JADAS was found to be a valid instrument for assessment of disease activity in JIA and is potentially applicable in standard clinical care, observational studies, and clinical trials.

Bazso A, Consolaro A, Ruperto N, Pistorio A, Viola S, Magni-Manzoni S, Malattia C, Buoncompagni A, Loy A, Martini A, Ravelli A, Anonymous00093. · Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy. · J Rheumatol. · Pubmed #19208532 No free full text.

Abstract: OBJECTIVE: To develop and test reduced joint counts in children with juvenile idiopathic arthritis (JIA). METHODS: Four reduced joint counts including 45, 35, 27, and 10 joints were devised by a panel of experienced pediatric rheumatologists, who selected the joints to be included based on the ease of technical assessment, functional relevance, and frequency of involvement. Three large samples of patients with JIA (total n=4353) who had a detailed joint assessment available were used to develop and test reduced joint counts. Performance of reduced counts was examined by comparing their Spearman correlation with the standard (i.e., complete) joint count. Construct validity was evaluated by calculating Spearman correlation with other JIA outcome measures. Responsiveness to clinical change was determined through the standardized response mean (SRM). RESULTS: Spearman correlations of reduced joint counts with the whole joint count and with the other JIA outcome measures were comparable, revealing that they had similar ability to serve as surrogate for the whole joint count and construct validity. Responsiveness to clinical change was also comparable across reduced counts (SRM 0.83-1.09 for active joint counts and 0.63-0.81 for restricted joint counts). Based on these results and considering the relative feasibility of the different counts, the 27-joint reduced count is proposed for use in JIA. This joint count includes the cervical spine and the elbow, wrist, metacarpophalangeal (from first to third), proximal interphalangeal, hip, knee, and ankle joints. CONCLUSION: Reduced joint counts appear to be as reliable as standard joint counts in assessment of the severity of joint disease and its change over time in children with JIA.

Solari N, Viola S, Pistorio A, Magni-Manzoni S, Vitale R, Ruperto N, Ullmann N, Filocamo G, Martini A, Ravelli A. · Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genoa, Italy. · Arthritis Rheum. · Pubmed #18975357 No free full text.

Abstract: OBJECTIVE: To investigate the disease outcomes of a cross-sectional sample of children with longstanding juvenile idiopathic arthritis (JIA) seen between September 2002 and December 2006, and to provide a benchmarking of outcomes obtained with current treatment. METHODS: All consecutive patients were included if they met the following criteria: diagnosis of JIA, disease duration > or = 5 years, and informed consent. Outcome assessments included disease activity, inactive disease, minimal disease activity, pain, physical function, health-related quality of life (HRQOL), auxometric measurements, and articular and extraarticular damage. RESULTS: A total of 310 patients were included. At study visit, patients had on average a low level of disease activity. However, only 21.8% met the criteria for inactive disease, and less than 50% met the definition of minimal disease activity. Additionally, 19.2% had moderate to severe Childhood Health Assessment Questionnaire disability and 3.6% were in Steinbrocker class III-IV. Approximately 10% had major impairment in HRQOL. A total of 34.2% had damage in > or = 1 joint or joint group and 26.1% showed extraarticular damage. Of the 125 patients who underwent a wrist radiograph, 35.2% had significant structural damage and 8.7% had growth retardation. CONCLUSION: Our patients had on average a low level of disease activity, little or no physical disability, and a satisfactory HRQOL. However, a sizable proportion of patients had persistently active disease, impaired function, and damage. These findings underscore the critical need for treatments and treatment strategies that have the ability to better control disease activity and to reduce the development of disease-related morbidities.

Nielsen S, Ruperto N, Gerloni V, Simonini G, Cortis E, Lepore L, Alpigiani MG, Zulian F, Corona F, Alessio M, Barcellona R, Gallizzi R, Rossi F, Magni-Manzoni S, Lombardini G, Filocamo G, Raschetti R, Martini A, Ravelli A, Anonymous00024. · Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genova, Italy. · Clin Exp Rheumatol. · Pubmed #18799107 No free full text.

Abstract: OBJECTIVE: To investigate the rate of radiographic progression, as measured with the carpo-metacarpal ratio (Poznanski score), during etanercept (ETN) therapy in children with polyarticular juvenile idiopathic arthritis (JIA). METHODS: Patients included in the Italian ETN registry who had a standard radiograph of both hands and wrists in the posteroanterior view made at start of treatment and after 1 year were included in the study. The clinical response was assessed by means of the ACR Pediatric definition of improvement. Radiographic progression was determined by calculating the change in the Poznanski score between the baseline and the 1-year radiographs. RESULTS: A total of 40 patients were studied. The frequency of ACR pediatric 30, 50, and 70 response at 1 year was 77%, 72%, and 50%, respectively. The median change in the Poznanski score between baseline and 1 year was + 0.3 units, meaning that, on average, patients experienced improvement in radiographic progression. CONCLUSION: Our pilot study provides evidence that ETN is potentially capable of reducing the progression of radiographic joint damage in JIA. This finding deserves confirmation in a controlled trial.

Lovell DJ, Ruperto N, Goodman S, Reiff A, Jung L, Jarosova K, Nemcova D, Mouy R, Sandborg C, Bohnsack J, Elewaut D, Foeldvari I, Gerloni V, Rovensky J, Minden K, Vehe RK, Weiner LW, Horneff G, Huppertz HI, Olson NY, Medich JR, Carcereri-De-Prati R, McIlraith MJ, Giannini EH, Martini A, Anonymous00113, Anonymous00114. · Cincinnati Children's Hospital Medical Center, Division of Rheumatology, Location E, Rm. 2-129, MLC 4010, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA. · N Engl J Med. · Pubmed #18716298 links to  free full text

Abstract: BACKGROUND: Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. METHODS: Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. RESULTS: Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients. CONCLUSIONS: Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542.)

Magni-Manzoni S, Ruperto N, Pistorio A, Sala E, Solari N, Palmisani E, Cugno C, Bozzola E, Martini A, Ravelli A. · Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy. · Arthritis Rheum. · Pubmed #18668599 No free full text.

Abstract: 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.

Céspedes-Cruz A, Gutiérrez-Suárez R, Pistorio A, Ravelli A, Loy A, Murray KJ, Gerloni V, Wulffraat N, Oliveira S, Walsh J, Penades IC, Alpigiani MG, Lahdenne P, Saad-Magalhães C, Cortis E, Lepore L, Kimura Y, Wouters C, Martini A, Ruperto N, Anonymous00360. · IRCCS G Gaslini, Pediatria II, Reumatologia, PRINTO, Largo Gaslini, 5, 16147 Genova, Italy. · Ann Rheum Dis. · Pubmed #17875547 No free full text.

Abstract: OBJECTIVES: To examine the change in health-related quality of life (HRQOL) and its determinants in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX). METHODS: Patients were extracted from the PRINTO clinical trial which aimed to evaluate the efficacy and safety profile of MTX administered in standard, intermediate or higher doses (10, 15 and 30 mg/m(2)/week respectively). Children with polyarticular-course JIA, who were less than 18 years and had a complete HRQOL assessment were included. RESULTS: A total of 521 children were included. At baseline, patients with JIA showed poorer HRQOL (p<0.01) than healthy children. In 207/412 (50%) and 63 (15%) children, HRQOL values were 2 standard deviations below the mean of healthy controls in the physical and psychosocial summary scale, respectively. After 6 months of treatment with standard dose MTX, there was a statistically significant improvement in all HRQOL health concepts, particularly the physical ones. Similar improvements were observed in those who did not respond to a standard dose of MTX and were subsequently randomised to a higher dose. The presence of marked disability at baseline was associated with a fivefold increased risk of retaining poor physical health after 6 months of active treatment with standard dose MTX. Other less important determinants of retaining poor physical well-being were the baseline level of systemic inflammation, pain intensity and an antinuclear-antibody-negative status. CONCLUSIONS: MTX treatment produces a significant improvement across a wide range of HRQOL components, particularly in the physical domains, in patients with JIA.

Ravelli A, Ioseliani M, Norambuena X, Sato J, Pistorio A, Rossi F, Ruperto N, Magni-Manzoni S, Ullmann N, Martini A. · Università degli Studi di Genoa, and IRCCS, Istituto G. Gaslini, Genoa, Italy. · Arthritis Rheum. · Pubmed #17763418 links to  free full text

Abstract: OBJECTIVE: To develop adapted versions of the Sharp/van der Heijde radiographic scoring system for use in juvenile idiopathic arthritis (JIA), and to investigate their validity in JIA patients with polyarticular disease. METHODS: The study group comprised 177 patients with polyarticular JIA. Radiographs of the wrist/hand of each patient were obtained at baseline (first observation) and then at 1, 3, 5, 7/8, and 10 years and were assessed independently by 2 pediatric rheumatologists according to different adaptations of the Sharp/van der Heijde method. To facilitate score assignment, the radiograph for each patient was compared with a bone age-related standard. Validation procedures included analysis of reliability, construct validity, and score progression over time. RESULTS: Interobserver and intraobserver agreement on longitudinal score values and score changes was good for all of the adapted scoring versions (intraclass correlation coefficient >0.85). Score changes over time were moderately to strongly correlated with the clinical indicators of long-term joint damage and with the amount of long-term radiographic damage as measured with the carpo:metacarpal ratio, thereby demonstrating good construct validity. A steady increase in scores over time was observed, with joint space narrowing being the most common form of damage throughout the disease course. The inclusion of 5 new areas appeared to increase the overall construct validity of erosion scores. CONCLUSION: Our results show that the adapted versions of the Sharp/van der Heijde score are reliable and valid for the assessment of radiographic progression in patients with JIA.

Filocamo G, Sztajnbok F, Cespedes-Cruz A, Magni-Manzoni S, Pistorio A, Viola S, Ruperto N, Buoncompagni A, Loy A, Martini A, Ravelli A. · Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genoa, Italy. · Arthritis Rheum. · Pubmed #17665481 links to  free full text

Abstract: OBJECTIVE: To develop and validate a new short and simple measure of physical function in children with juvenile idiopathic arthritis (JIA). METHODS: The Juvenile Arthritis Functionality Scale (JAFS) is a 15-item questionnaire that explores physical function in 3 body areas (lower limbs, hand/wrist, and upper segment). Validation of the Italian version of the instrument was accomplished by evaluating 211 consecutive JIA patients ages 2.2-18 years. The instrument's feasibility, face and content validity, construct and discriminative ability, internal consistency, interrater reliability, and responsiveness to clinical change were examined. JAFS psychometric properties were compared with those of the Childhood Health Assessment Questionnaire (C-HAQ). RESULTS: The JAFS was found to be feasible and to possess both face and content validity. The JAFS score correlated with most of the other JIA outcome measures in the range predicted, thereby demonstrating good construct validity, and discriminated well among different levels of disability. The internal consistency (Cronbach's alpha) was 0.82. The intraclass correlation coefficients between raters (mothers, fathers, and children) and between reported and observed level of function ranged from 0.65 to 0.84. The JAFS revealed fair responsiveness, with a standardized response mean ranging from 0.42 to 0.56. Comparison with the C-HAQ indicated that the JAFS may be superior in terms of construct validity and reliability, and at least as good in terms of discriminant validity and responsiveness. CONCLUSION: The JAFS exhibited good reliability, construct validity, and discriminative ability and fair responsiveness, and is therefore a valid instrument for the assessment of physical function in children with JIA.

Consolaro A, Vitale R, Pistorio A, Lattanzi B, Ruperto N, Malattia C, Filocamo G, Viola S, Martini A, Ravelli A. · Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genova, Italy. · J Rheumatol. · Pubmed #17611978 No free full text.

Abstract: OBJECTIVE: To investigate discrepancies between physicians' and parents' ratings of inactive disease in children with juvenile idiopathic arthritis (JIA) and the determinants of the discrepancy. METHODS: Study data were obtained from the clinical database generated at the study unit. Each patient visit included a standardized assessment of JIA outcome measures. One visit for each patient was selected for analysis. Three definitions of inactive disease were applied to the data: a physician-based definition (physician global assessment = 0); a parent-based definition (parent global assessment = 0); and a formal definition, based on fulfillment of newly developed criteria for inactive disease in JIA. RESULTS: Of 1237 visits made by 537 patients that included both physician and parent global assessments, 265 fulfilled the physician-based definition and/or the parent-based definition of inactive disease. Concordance between physicians and parents in rating the disease as inactive was seen in 40% of the visits, whereas in 60% of visits the 2 assessments were discordant. Parents tended to disagree with physicians in rating the disease as inactive if the child had pain or functional impairment, whereas physicians tended to disagree with parents in the presence of active joint symptoms. Only 2/3 of the 79 visits that fulfilled the formal definition of inactive disease also met the parent-based definition of inactive disease. CONCLUSION: We found frequent discordance between physicians' and parents' ratings of inactive disease in children with JIA, which suggests that the parent's rating of a child's disease activity should be considered for inclusion in the definition of clinical remission for JIA.

Oliveira S, Ravelli A, Pistorio A, Castell E, Malattia C, Prieur AM, Saad-Magalhães C, Murray KJ, Bae SC, Joos R, Foeldvari I, Duarte-Salazar C, Wulffraat N, Lahdenne P, Dolezalova P, de Inocencio J, Kanakoudi-Tsakalidou F, Hofer M, Nikishina I, Ozdogan H, Hashkes PJ, Landgraf JM, Martini A, Ruperto N, Anonymous00868. · IRCCS G. Gaslini, Pediatria II, Reumatologia, Pediatric Rheumatology International Trials Organization, Genoa, Italy. · Arthritis Rheum. · Pubmed #17266064 links to  free full text

Abstract: OBJECTIVE: To investigate the proxy-reported health-related quality of life (HRQOL) and its determinants in patients with juvenile idiopathic arthritis (JIA). METHODS: In this multinational, multicenter, cross-sectional study, HRQOL of patients with JIA was assessed through the Child Health Questionnaire (CHQ) and was compared with that of healthy children of similar age from the same geographic area. Potential determinants of HRQOL included demographic data, physician's and parent's global assessments, measures of joint inflammation, Childhood Health Assessment Questionnaire (CHAQ), and erythrocyte sedimentation rate. RESULTS: A total of 6,639 participants (3,324 with JIA and 3,315 healthy) were enrolled from 32 countries. The mean +/- SD physical and psychosocial summary scores of the CHQ were significantly lower in patients with JIA than in healthy children (physical: 44.5 +/- 10.6 versus 54.6 +/- 4.0, P < 0.0001; psychosocial: 47.6 +/- 8.7 versus 51.9 +/- 7.5, P < 0.0001), with the physical well-being domain being most impaired. Patients with persistent oligoarthritis had better HRQOL compared with other subtypes, whereas HRQOL was similar across patients with systemic arthritis, polyarthritis, and extended oligoarthritis. A CHAQ score >1 and a pain intensity rating >3.4 cm on a 10-cm visual analog scale were the strongest determinants of poorer HRQOL in the physical and psychosocial domains, respectively. CONCLUSION: We found that patients with JIA have a significant impairment of their HRQOL compared with healthy peers, particularly in the physical domain. Physical well-being was mostly affected by the level of functional impairment, whereas the intensity of pain had the greatest influence on psychosocial health.

Rossi F, Di Dia F, Galipò O, Pistorio A, Valle M, Magni-Manzoni S, Ruperto N, Tomà P, Martini A, Ravelli A. · Istituto di Ricovero e Cura a Carattere Scientifico G Gaslini, Genoa, Italy. · Arthritis Rheum. · Pubmed #17013855 links to  free full text

Abstract: OBJECTIVE: To investigate the applicability of the Sharp and Larsen scoring methods for radiographic damage in juvenile idiopathic arthritis (JIA). METHODS: Wrist/hand radiographs of 25 patients with polyarthritis obtained at first observation and then yearly for 4-5 years were assessed independently by 2 pediatric rheumatologists according to the Sharp and Larsen methods. To facilitate score assignment, each patient radiograph was compared with a bone age-related standard. A third pediatric rheumatologist measured the Poznanski score, and a pediatric radiologist provided a semiquantitative assessment of radiographic damage severity. RESULTS: Interobserver and intraobserver agreement on longitudinal scores were good for both Sharp and Larsen methods, with intraclass correlation coefficient >0.9. Agreement on change assessment was good for the Sharp method and moderate for the Larsen method. Both methods yielded a steady increase in scores during the study, with score change being more marked in the first year. Sharp and Larsen scores were highly correlated (r(s) = 0.96). Correlations of both scores with the Poznanski score were moderate to high (r(s) from -0.62 to -0.72). Radiologist score was correlated at borderline-high level with both Sharp (r(s) = 0.70) and Larsen (r(s) = 0.71) scores. Sharp and Larsen score change from baseline to final visit was moderately to highly correlated with the number of joints with active arthritis and restricted motion and the Childhood Health Assessment Questionnaire score at final visit. CONCLUSION: Our results demonstrate that the Sharp and Larsen scoring systems are potentially reliable and valid for assessment of radiographic progression in patients with polyarticular JIA.

Gutiérrez-Suárez R, Pistorio A, Cespedes Cruz A, Norambuena X, Flato B, Rumba I, Harjacek M, Nielsen S, Susic G, Mihaylova D, Huemer C, Melo-Gomes J, Andersson-Gare B, Balogh Z, De Cunto C, Vesely R, Pagava K, Romicka AM, Burgos-Vargas R, Martini A, Ruperto N, Anonymous00034. · IRCCS G. Gaslini, Università di Genova, Pediatria II - Reumatologia, Largo Gaslini, 5 16147 Genova, Italy. · Rheumatology (Oxford). · Pubmed #16877459 links to  free full text

Abstract: OBJECTIVES: To compare health-related quality of life (HRQL) and to identify clinical determinants for poor HRQL of patients with juvenile idiopathic arthritis (JIA) coming from three geographic areas. METHODS: The HRQL was assessed through the Child Health Questionnaire (CHQ). A total of 30 countries were included grouped in three geographic areas: 16 countries in Western Europe; 10 in Eastern Europe; and four in Latin America. Potential determinants of poor HRQL included demographic data, physician's and parent's global assessments, measures of joint inflammation, disability as measured by Childhood Health Assessment Questionnaire (CHAQ) and erythrocyte sedimentation rate. Poor HRQL was defined as a CHQ physical summary score (PhS) or psychosocial summary score (PsS) <2 S.D. from that of healthy children. RESULTS: A total of 3167 patients with JIA, younger than 18 yrs, were included in this study. The most affected health concepts (<2 S.D. from healthy children) that differentiate the three geographic areas include physical functioning, bodily pain/discomfort, global health, general health perception, change in health with respect to the previous year, self-esteem and family cohesion. Determinants for poor HRQL were similar across geographic areas with physical well-being mostly affected by the level of disability while the psychosocial well-being by the intensity of pain. CONCLUSION: We found that patients with JIA have a significant impairment of their HRQL compared with healthy peers, particularly in the physical domain. Disability and pain are the most important determinants of physical and psychosocial well-being irrespective of the geographic area of origin.

Sztajnbok F, Coronel-Martinez DL, Diaz-Maldonado A, Novarini C, Pistorio A, Viola S, Ruperto N, Buoncompagni A, Martini A, Ravelli A. · Pediatria II, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy. · Rheumatology (Oxford). · Pubmed #16782733 links to  free full text

Abstract: OBJECTIVE: To investigate the discrepancy between physician's and parent's global assessments of disease status and the factors explaining discordance in patients with juvenile idiopathic arthritis (JIA). METHODS: The mothers of 197 patients with JIA rated the child's overall well-being on a 10 cm visual analogue scale (VAS) and the attending physician rated the child's overall disease activity on a 10 cm VAS. A discordance score was calculated by subtracting the physician's global assessment from that of the parent's, leading to the definition of three patient groups: (1) no discordance, when physician's and parent's assessments were within 1 cm of each other; (2) negative discordance, when parent's assessment was underrated relative to the physician; and (3) positive discordance, when parent's assessment was over-rated relative to the physician. Negative and positive discordance was defined as 'marked' when the difference between the two assessments was greater than 3 cm. RESULTS: No discordance was found in 40.6% of the patients. Negative discordance was found in 51.3% of the patients, with 34% showing marked discordance. Positive discordance was found in 8.1% of the patients, with 2% showing marked discordance. Significant differences between groups included a shorter disease duration among patients with a markedly positive discordance (P = 0.02) and a greater frequency of ongoing second-line drug therapy among patients with no discordance or with positive discordance (P = 0.008). Patients with no discordance or with marked positive discordance had a significantly lower joint counts (P = 0.02-0.004). CONCLUSION: Parents and physicians often perceive the health status of children with JIA differently, with parents providing most frequently lower rating.

Garcia-Munitis P, Bandeira M, Pistorio A, Magni-Manzoni S, Ruperto N, Schivo A, Martini A, Ravelli A. · Unità Operativa Pediatria II, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Università di Genova, Largo G. Gaslini 5, 16147 Genoa, Italy. · Arthritis Rheum. · Pubmed #16583392 links to  free full text

Abstract: OBJECTIVE: To investigate the level of agreement between patients, mothers, fathers, and physicians in rating pain intensity in juvenile idiopathic arthritis (JIA), and to identify factors explaining discrepancies between raters. METHODS: Ninety-four children with JIA and their mothers and fathers were asked to rate independently the intensity of present pain and pain in the previous week on a visual analog scale. The physicians rated pain intensity after physical examination. Agreement between raters was determined using intraclass correlation coefficient and Bland and Altman method. Correlations of explanatory variables with discordance in rating pain intensity were determined by univariate and multivariate analyses. Explanatory variables included sex, age, JIA category, disease duration, results of study ratings, joint inflammation measures, and erythrocyte sedimentation rate. RESULTS: Agreement in rating present pain was moderate between children and mothers, but was poor between children and fathers and children and physicians. The agreement in rating pain in the previous week was moderate between children and mothers and children and fathers. Mother-father agreement was good. Parents and physicians agreed at a moderate level. In multiple regression analyses, only intensity of present pain was significantly associated with discordance within child-mother, child-father, and child-physician dyads. CONCLUSION: Children's ratings of pain were only in moderate agreement with those of their parents and were in poor agreement with those of the physicians, whereas the father and mothers agreed at a good level. The intensity of pain was the strongest determinant of discordance between children and other raters.

Bandeira M, Falcone A, Pistorio A, Ruperto N, Magni-Manzoni S, Buoncompagni A, Sala E, Loy A, Martini A, Ravelli A. · Departimento di Pediatria, Università di Genova, Istituto di Ricovero e Cura a Carattee Scientifico G. Gaslini, Genova, Italy. · Rheumatology (Oxford). · Pubmed #16234273 links to  free full text

Abstract: OBJECTIVE: To develop a scoring system for juvenile idiopathic arthritis (JIA) in which joints are weighted to reflect their relative importance to children's function and to examine whether weighting increases the correlation of joint counts with subjective and laboratory outcome measures. METHODS: A weighted joint score was devised by a panel of experienced paediatric rheumatologists, who assigned a weight from 1 (not very important) to 10 (essential for key functional activities) to each joint based on its functional importance to children's physical and daily activities. The associations of simple and weighted counts of swollen, tender, limited and active joints with the physician's global assessment of overall disease activity, the parent's global assessment of the child's overall well-being and intensity of pain, the Childhood Health Assessment Questionnaire (C-HAQ), the Child Health Questionnaire (CHQ) and the erythrocyte sedimentation rate were compared using Spearman's correlation analysis in 60 unselected patients seen in the clinic and in 61 consecutive patients with disease duration > or = 5 yr. RESULTS: Weighted counts of swollen and active joints yielded greater correlation with the physician's global assessment than did simple counts. The correlation of weighted counts of swollen, painful and active joints with the parent's assessment of overall well-being and intensity of pain was superior to that provided by simple counts. Weighting increased most of the correlations between joint counts and the C-HAQ score and the physical component of the CHQ. CONCLUSION: Weighting improves the information provided by joint counts on the severity of arthritis and its impact on patients' well-being.