Rheumatoid Arthritis: Ravelli A

Ravelli A. · No affiliation provided · J Rheumatol. · Pubmed #18398949 links to  free full text

This publication has no abstract.

Ravelli A. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #15144118 No free full text.

Abstract: Over the past four decades, a number of studies have evaluated the long-term outcome of juvenile idiopathic arthritis (JIA) and some of them have also attempted to identify early prognostic factors. This editorial addresses, by reviewing the surveys that have analyzed the outcome of JIA in term of clinical remission, physical disability, and radiographic damage, the clinical questions that are most relevant in this area of study. Altogether, the available data indicate that JIA is not a benign disease because a considerable number of patients still enter adulthood with persistently active disease and a significant proportion of them may develop severe physical disability. Among the different onset forms, the long-term outcome is best in persistent oligoarthritis and worst in RF-positive polyarthritis; the outcome of systemic arthritis is widely variable, perhaps reflecting the heterogeneity of this JIA subtype. The comparison of earlier studies with those published in the last decade shows a decline in the frequency of patients with severe physical disability over the years; however, the proportion of patients who enter adulthood with active disease does not seem to be diminished. Although there is considerable data on prognostic factors in JIA, prediction of long-term outcome early after disease presentation is still difficult because comparisons among studies are hindered for a variety of reasons. Thus, while a considerable body of data is accumulating, the definition of the long-term outcome of JIA remains imperfect. To increase the comparability of future analyses and to obtain generalizable information on the prognosis of JIA and its prediction, a great deal of effort should be directed toward standardizing the study design and the measurement of predictors and outcomes.

Ravelli A, Martini A. · No affiliation provided · J Rheumatol. · Pubmed #10955319 No free full text.

This publication has no abstract.

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, Martini A. · Department of Paediatrics, University of Genoa and Institute G. Gaslini, Genoa, Italy. · Lancet. · Pubmed #17336654 No free full text.

Abstract: Juvenile idiopathic arthritis is a broad term that describes a clinically heterogeneous group of arthritides of unknown cause, which begin before 16 years of age. This term encompasses several disease categories, each of which has distinct methods of presentation, clinical signs, and symptoms, and, in some cases, genetic background. The cause of disease is still poorly understood but seems to be related to both genetic and environmental factors, which result in the heterogeneity of the illness. Although none of the available drugs has a curative potential, prognosis has greatly improved as a result of substantial progresses in disease management. The most important new development has been the introduction of drugs such as anticytokine agents, which constitute a valuable treatment option for patients who are resistant to conventional antirheumatic agents. Further insights into the disease pathogenesis and treatment will be provided by the continuous advances in understanding of the mechanisms connected to the immune response and inflammatory process, and by the development of new drugs that are able to inhibit selectively single molecules or pathways.

Ravelli A, Martini A. · Dirigente Medico, Pediatria II, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genova, Italy. · Clin Exp Rheumatol. · Pubmed #17083772 No free full text.

Abstract: Until recently, no uniform and widely accepted criteria for defining remission in juvenile idiopathic arthritis (JIA) were available. In recent years, a set of preliminary criteria for clinical remission in JIA was developed through an international collaborative effort. These criteria enable the classification of patients in the states of inactive disease, clinical remission with medication, and clinical remission without medication. The first phase of the validation process of the criteria, which was accomplished recently, established that they are feasible and have good face, content and construct validity, and strong discriminant properties. A few studies have applied the new remission criteria in series of patients with JIA, with results that concur with those of previous surveys in showing that only a few patients with JIA have a chance of remaining in long-term remission status without medications. These findings highlight the critical need for therapies that have the capacity to induce sustained complete disease control of JIA.

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.

Ravelli A, Martini A. · Dipartimento di Pediatria, Università di Genova, U.O. Pediatria II, IRCCS G. Gaslini, Genova, Italy. · Clin Exp Rheumatol. · Pubmed #14969057 No free full text.

Abstract: The definition and management of "early arthritis" in children differ from those in adults because juvenile idiopathic arthritis (JIA) is markedly different from adult rheumatoid arthritis. Since a significant proportion of patients with JIA develop articular damage and enter adult life with persistently active disease, it is important to predict early in the disease course the long-term outcome in order to tailor treatment to the risk of disability. Over the past 3 decades a number of studies have evaluated the long-term outcome of cohorts of patients with JIA and some of them have also attempted to identify early prognostic factors. In summary, greater severity/extension of arthritis at onset, symmetric disease, precocious hip/wrist involvement, the presence of rheumatoid factor, and prolonged active disease were the best predictors of a poor outcome. Specific correlates for systemic JIA were persistent systemic features and thrombocytosis at 6 months following presentation, whereas joint symmetry and a higher erythrocyte sedimentation rate at onset were associated with a more severe course in oligoarticular JIA. However, although data is accumulating on prognostic factors in JIA, prediction of long-term outcome in the first few months remains difficult. To better define prognostic factors in future analyses, a considerable effort should be made to increase standardization among studies. Furthermore, a radiographic scoring system and a set of remission criteria specific for JIA should be developed.

Ravelli A. · Pediatria II, Istituto G. Gaslini, Università di Genova, Italy. · Curr Opin Rheumatol. · Pubmed #12192253 No free full text.

Abstract: Macrophage activation syndrome (MAS) is a serious complication of childhood systemic inflammatory disorders that is thought to be caused by excessive activation and proliferation of T lymphocytes and macrophages. Recent findings in hemophagocytic lymphohistiocytosis, a disease that is clinically similar to MAS, highlight the possible pathogenetic role of a defective function of perforin, a protein involved in the cytolytic processes and control of lymphocyte proliferation. Although the clinical features of MAS have been well documented, early diagnosis can be difficult. Measurement of the serum ferritin level may assist in the diagnosis and may be a useful indicator of disease activity, therapy response, and prognosis. The recognition that MAS belongs to the secondary or reactive hemophagocytic syndromes has led to the proposal to rename it according to the contemporary classification of histiocytic disorders. Cyclosporin A has been found effective in patients with corticosteroid-resistant MAS. A recent report has suggested that etanercept may be a useful adjunctive therapeutic agent.

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.

Bartoli M, Tarò M, Magni-Manzoni S, Pistorio A, Traverso F, Viola S, Magnani A, Gasparini C, Martini A, Ravelli A. · Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy. · Ann Rheum Dis. · Pubmed #17660217 No free full text.

Abstract: OBJECTIVE: To investigate the relationship between the magnitude of clinical response in the first 6 months of methotrexate (MTX) therapy and long-term outcome in children with juvenile idiopathic arthritis (JIA). METHODS: The clinical charts of 125 JIA patients who were started with MTX and then followed for at least 5 years were reviewed. Based on the level of American College of Rheumatology (ACR) Pediatric response at 6 months, patients were divided in four mutually exclusive groups: (1) non-responders, (2) responders at 30%, (3) responders at 50%, and (4) responders at 70%. The long-term outcome in each response group was evaluated by calculating the percentage change in active and restricted joint counts from baseline to 1, 2 and 5 years and the frequency of inactive disease at 5 years. RESULTS: At 6 months, 42 patients were classified as non-responders, 24 as 30% responders, 26 as 50% responders, and 33 as 70% responders. Patients who had achieved a 70% response showed a significantly greater percentage improvement in active joint count between baseline to 5 years compared with non-responders and 30% responders, and a significantly greater percentage improvement in restricted joint count between baseline to 5 years compared with 30% responders. The 70% responders also had a greater frequency of inactive disease at 5 years compared with 30% responders, CONCLUSIONS: Our results show that the achievement of an ACR Pediatric 70 response at 6 months after start of MTX therapy predicts a more favorable long-term outcome of patients with JIA.

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.

Ravelli A, Moretti C, Temporini F, Rossi F, Magni-Manzoni S, Pistorio A, Martini A. · Pediatria II, IRCCS G. Gaslini, Università di Genova, Italy. · Clin Exp Rheumatol. · Pubmed #12175118 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy and safety of a combination therapy with methotrexate (MTX) and cyclosporine A (CyA) in patients with juvenile idiopathic arthritis (JIA) who were refractory to MTX as a single second-line agent. METHODS: Seventeen consecutive patients with JIA who had refractory polyarthritis despite a minimum of 6 months of MTX as a single second-line agent at the dose of 15 to 25 mg/m2/week were continued with MTX with the addition of CyA (4 mg/kg/day) for 6 to 30 months (median 10 months) were analyzed. The clinical response to therapy was assessed through the preliminary definition of improvement in JIA. RESULTS: At the end of the treatment, as compared to the time when CyA was added to MTX, 8 patients (47%) met the 30% definition of improvement; among them 5 (29%) met the 70% definition of improvement, and 2 (12%) achieved complete disease control. Seven patients (41%) experienced side effects: 4 gastrointestinal discomfort, 1 liver transaminase elevation, and 2 increase > or = 30% in the serum creatinine concentration. No patients was discontinued from combination therapy due to adverse events. CONCLUSION: In our JIA patients who were refractory to MTX as a single second-line agent, the addition of CyA was associated with a significant clinical improvement in roughly half of the patients.

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.

Magnani A, Pistorio A, Magni-Manzoni S, Falcone A, Lombardini G, Bandeira M, Rossi F, Sala I, Martini A, Ravelli A. · Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genova, Italy. · J Rheumatol. · Pubmed #19208600 No free full text.

Abstract: OBJECTIVE: To investigate whether the achievement of inactive disease in the first 5 years predicts a more favorable outcome of children with juvenile idiopathic arthritis (JIA). METHODS: We reviewed clinical charts of 123 patients who started taking methotrexate, were followed for at least 5 years, and received a yearly assessment in the first 5 years. At each yearly visit, the presence of inactive disease was assessed. Patients were divided into 3 groups: (1) patients who never reached inactive disease; (2) patients who reached inactive disease in only 1 visit; and (3) patients who reached inactive disease in > or = 2 visits. Outcome was evaluated after 6 to 18 years (median 7.1 yrs) by assessing the following clinical measures: restricted joint count, Childhood Health Assessment Questionnaire (CHAQ), Juvenile Arthritis Damage Index (JADI), and Poznanski score of radiographic damage. RESULTS: In the first 5 years, 62 patients (50.4%) were noted to have active disease at their yearly visit, 40 patients (32.5%) were noted to have inactive disease only once, and 21 patients (17.1%) were noted to have inactive disease in > or = 2 visits. Patients who achieved inactive disease 1 or more times had lower restricted joint count (p = 0.007) and JADI-Articular score (p = 0.004) at last followup visit than those who never reached such a state. A similar trend, although not significant, was observed for CHAQ and Poznanski score of radiographic damage. CONCLUSION: Attainment of the state of inactive disease at least once in the first 5 years was found to be associated with less longterm joint damage and with a trend toward less functional impairment.

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.

Malattia C, Damasio MB, Magnaguagno F, Pistorio A, Valle M, Martinoli C, Viola S, Buoncompagni A, Loy A, Ravelli A, Tomà P, Martini A. · Istituto G. Gaslini, Genoa, Italy. · Arthritis Rheum. · Pubmed #19035414 No free full text.

Abstract: OBJECTIVE: To compare magnetic resonance imaging (MRI), conventional radiography, and ultrasonography in identifying bone erosions in patients with juvenile idiopathic arthritis (JIA), and to determine the validity and reliability of an MRI scale in detecting and grading joint damage. METHODS: In 26 JIA patients, the clinically more affected wrist was studied with MRI, radiography, and ultrasonography, coupled with standard clinical assessment and biochemical analysis. MR images were assessed independently by 2 readers according to an apposite devised scoring system. RESULTS: Of 26 patients, 25 (96.1%) had 1 or more erosions as detected by MRI, whereas conventional radiography and ultrasonography revealed erosions in 13 (50%) of 26 and 12 (50%) of 24 patients, respectively. The ability of MRI to detect erosive changes was significantly higher with respect to conventional radiography (P = 0.002 with Bonferroni correction [P(B)]) and ultrasonography (P(B) = 0.0002) in the group of patients with <3 years' disease duration. Ultrasonography and conventional radiography were of equivalent value for the detection of destructive changes. Wrist MRI score correlated highly with radiographic erosion score (r(s) = 0.82) and with wrist limited range of motion score (r(s) = 0.69). The interreader intraclass correlation coefficient (ICC) for MRI score was excellent (0.97); intrareader ICCs were good for both investigators (0.97 and 0.79). CONCLUSION: MRI seems to be a powerful tool to detect early structural damage in JIA. The proposed MRI scale for bone erosions appears promising in terms of reliability and construct validity. The pathophysiologic meaning and the prognostic value of bone erosions revealed only by MRI remain to be established in longitudinal studies.

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.

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.

Gattorno M, Piccini A, Lasigliè D, Tassi S, Brisca G, Carta S, Delfino L, Ferlito F, Pelagatti MA, Caroli F, Buoncompagni A, Viola S, Loy A, Sironi M, Vecchi A, Ravelli A, Martini A, Rubartelli A. · G. Gaslini Institute, Genoa, Italy. · Arthritis Rheum. · Pubmed #18438814 links to  free full text

Abstract: OBJECTIVE: To assess the clinical response to interleukin-1 (IL-1) blockade and in vitro IL-1beta and IL-18 secretion in patients with systemic-onset juvenile idiopathic arthritis (JIA). METHODS: Twenty-two patients with systemic-onset JIA were treated with the IL-1 receptor antagonist (IL-1Ra) anakinra. Monocytes from 18 patients and 20 healthy donors were activated by different Toll-like receptor ligands. Intracellular and secreted IL-1beta and IL-18 were analyzed by Western blotting and enzyme-linked immunosorbent assay. RESULTS: Ten patients with systemic-onset JIA exhibited a dramatic response to anakinra and were classified as complete responders. Eleven patients had an incomplete response or no response, and 1 patient could not be classified in terms of response. Compared with patients who had an incomplete response or no response, complete responders had a lower number of active joints (P = 0.02) and an increased absolute neutrophil count (P = 0.02). In vitro IL-1beta and IL-18 secretion in response to various stimuli was not increased and was independent of treatment efficacy. Likewise, secretion of IL-1Ra by monocytes from patients with systemic-onset JIA was not impaired. An overall low level of IL-1beta secretion upon exposure to exogenous ATP was observed, unrelated to treatment responsiveness or disease activity. CONCLUSION: Two subsets of systemic-onset JIA can be identified according to patient response to IL-1 blockade. The 2 subsets appear to be characterized by some distinct clinical features. In vitro secretion of IL-1beta and IL-18 by monocytes from patients with systemic-onset JIA is not increased and is independent of both treatment outcome and disease activity.

Vivarelli M, D'Urbano LE, Insalaco A, Lunt M, Jury F, Tozzi AE, Ravelli A, Martini A, Donn R, De Benedetti F. · Direzione Scientifica, Pediatria II Reumatologia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy. · Clin Exp Rheumatol. · Pubmed #18078632 No free full text.

Abstract: OBJECTIVES: To address the clinical relevance of macrophage migration inhibitory factor (MIF) promoter polymorphisms in oligoarticular juvenile idiopathic arthritis (o-JIA) by evaluating their associations with serum and SF MIF levels, with response to intra-articular glucocorticoid injections and with outcome of the disease. METHODS: Seventy-five Caucasian patients with o-JIA were studied. Alleles of the -794 CATT variable number of tandem repeats (VNTR) and of the -173 G/C single nucleotide polymorphism (SNP) were identified by capillary electrophoresis following fluorescently labelled PCR and by allelic discrimination assay, respectively. MIF levels were measured by ELISA. The association of MIF promoter polymorphisms with polyarticular extension, Childhood Health Assessment Questionnaire (CHAQ) score at the last follow-up visit and occurrence of chronic anterior uveitis was evaluated only in patients with a follow up > 5 years. RESULTS: Neither of the MIF promoter polymorphisms was associated with serum MIF levels, nor with the long-term outcome of o-JIA. The -173 G/C SNP was significantly associated with both SF MIF levels and duration of response to intra-articular glucocorticoid injection. Carriers of a MIF -173 C allele were 4 times more likely to relapse within 3 months. No association was found between the different MIF CATT alleles and both SF MIF levels and duration of response to intra-articular glucocorticoids. CONCLUSION: Our study shows the clinical relevance of the MIF -173 G/C SNP in o-JIA and suggests that the -173 C allele may represent a predictor of poor response to intra-articular glucocorticoid treatment.

De Benedetti F, Ravelli A. · Dipartimento di Scienze Pediatriche, Università degli Studi di Pavia, IRCCS Policlinico San Matteo, Pavia, Italy. · BioDrugs. · Pubmed #18034561 No free full text.

Abstract: Overexpression of cytokines in inflamed joints plays an important role in joint inflammation and in damage to articular tissue. Biological agents aimed at specifically antagonising tumour necrosis factor (TNF) are effective in the treatment of adult rheumatoid arthritis. A recent trial of etanercept, a genetically engineered fusion protein consisting of the Fc domain of human IgG1 and the TNF receptor p75, has demonstrated that this agent is also well tolerated and effective in patients with juvenile idiopathic arthritis (JIA). Etanercept offers a promising new alternative for patients with JIA who have persistently active arthritis despite treatment with methotrexate. Further studies are needed to clarify whether etanercept is equally effective in the various onset types of JIA (oligoarthritis, polyarthritis and systemic arthritis), whether it can modify disease progression and whether it can be administered safely for long periods of time to children.

Magni-Manzoni S, Pistorio A, Labò E, Viola S, Garcia-Munitis P, Panigada S, Visconti C, Buoncompagni A, Martini A, Ravelli A. · Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico S. Matteo, Pavia, Italy. · Ann Rheum Dis. · Pubmed #17965116 No free full text.

Abstract: OBJECTIVE: To describe the longitudinal course of physical functioning in children with juvenile idiopathic arthritis (JIA) and identify predictors of long-term functional impairment. METHODS: Between January 1987 and December 2002, 227 patients had two or more functional ability questionnaires completed by a parent. The total number of questionnaires was 1356 and the follow-up between first and last questionnaire administration was 949.7 patient years. At each questionnaire administration, patients were assigned to one of three functional disability states (1 = no disability; 2 = mild to moderate disability; 3 = severe disability), based on their functional ability score. Predictor variables included sex, onset age, JIA category, age at visit, disease duration, presence of antinuclear antibodies, joint counts, acute phase reactants and initial disability state. RESULTS: Despite patient variability in the course of physical functioning, the following three longitudinal patterns were observed: (1) a stable state of disability throughout the entire study period, with continued absence of disability in 27.8% of patients and persistently moderate disability in 3.5% of patients; (2) a steady improvement (22.9% of patients) or deterioration (5.7% of patients) in disability over time; (3) a fluctuating course of disability, with deterioration and improvement (40.1% of patients). Younger age at disease onset and a greater restricted joint count were the strongest predictors of long-term functional impairment. CONCLUSION: A wide within-patient and between-patient variability in the longitudinal course of functional disability was found. Children with early disease onset and a greater number of restricted joints had the highest risk of developing long-term physical disability.