Rheumatoid Arthritis: Gerloni V

Gerloni V, Pontikaki I, Gattinara M, Fantini F. · UOS di Reumatologia Infantile, Istituto Ortopedico Gaetano Pini, Milano, Italia. · Reumatismo. · Pubmed #17898886 links to  free full text

Abstract: The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical benefit in active polyarticular refractory JIA: the rate and rapidity of response have exceeded those of all other studied DMARDs. Preliminary data show that they are efficacious also for other pediatric rheumatic disease (spondyloarthropathies, autoimmune uveitis, dermatomyositis, Kawasaki syndrome and some autoinflammatory diseases). TNF-inhibitors in JIA have demonstrated a favourable benefit-to-risk profile. However, as their use has increased worldwide, some unusual, usually not serious, adverse events have emerged. Severe infections, including TB, and deaths have been reported. Long-lasting active disease, systemic disease, concurrent and previous immunosuppressive therapies, all contribute to risk of infection and other serious AEs. Given the evidence that TNF has a primary role in the pathogenesis of JIA, particularly in joint destruction, neutralizing this cytokine early, within the window of opportunity, could halt or delay progression of joint damage and debilitating consequences of the disease. Thus, for JIA patients whose disease is not quickly controlled with MTX, TNF blockers may be considered as first-line treatment, although long-term safety data still need to be established.

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.

De Marco G, Gerloni V, Pontikaki I, Luriati A, Teruzzi B, Salmaso A, Valcamonica E, Gattinara M, Fantini F. · Ist. Ortopedico Gaetano Pini, U.O. di Reumatologia e U.O.S. Reumatologia Infantile, Cattedra di Reumatologia, Università di Milano. · Reumatismo. · Pubmed #17435842 links to  free full text

Abstract: OBJECTIVES: To evaluate, in long-term open label prospective study, infliximab as therapeutic choice for Juvenile Idiopathic Arthritis (JIA) non responsive to conventional therapy. METHODS: We enrolled to treat with infliximab 78 JIA patients (66 females, 12 males): the mean age was 20.7+/-7.1 years (median 20.9, range 5.4-34.9); mean JIA duration was 13.6+/-7.6 years (median 13.5, range 0.4-31.4). Infliximab, at dose of 3-10 mg/kg/infusion added to weekly subcutaneous Methotrexate or other previous DMARDs, was administered by intravenous infusions at weeks 0, 2, 6 and every 8 weeks thereafter. Chest X-ray, Mantoux's test, electrocardiogram were performed at baseline; laboratory tests and clinical evaluation were performed at each infusion. Response was evaluated according to ACR improvement criteria. RESULTS: Mean treatment period was 21.6 months+/-18.8 (median 14.7, range 1.4-72.4). Just after first infusion most of patients reported significant improvement in pain, fatigue, morning stiffness. Infliximab is still successfully administered to 23 patients (29.5%); 55 (70.5%) patients suspended because of: inefficacy (7), infusion reactions (17), adverse events (9), disease flare-up after a period of effectiveness on synovitis, pain, and morning stiffness (19), remission (2), lack of compliance to treatment (1). Infusion reactions, like dyspnea, flushing, chills, headache, hypotension, anxiety, throat oedema, were observed in 29 patients (34.5%). Anti-DNA antibodies were present in 7 patients (none developed Systemic Lupus Erythematous). CONCLUSIONS: Infliximab showed impressive effectiveness treating refractory JIA, although most of patients had to discontinue treatment because of disease flare-up or adverse events. Infliximab may represent a good therapeutic choice in patients non-responders to Methotrexate.

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.

Lurati A, Cimaz R, Gattinara M, Gerloni V, Teruzzi B, Salmaso A, Fantini F. · Ospedale Fornaroli, Unità di Reumatologia, Magenta, Milano. · Reumatismo. · Pubmed #18854886 links to  free full text

Abstract: BACKGROUND: Puberty is an essential step in bone mass accrual. Growth failure and impairment of sexual maturation are frequent manifestations of chronic illnesses in the paediatric population, and chronic rheumatologic disorders such as juvenile idiopathic arthritis (JIA) are no exception to this. METHODS: The aim of our study was to prospectively evaluate bone density in adolescent females with JIA, and to correlate the results with clinical variables, in particular with age at menarche. Lumbar spine (L2-L4) area bone mineral density (aBMD) (assessed by Dual X-ray Absorbiometry, DXA) was monitored every 6-12 months in a group of 38 girls with JIA. The evaluated bone density accrual during the peripubertal time as well as absolute and relative (Z-score) aBMD in relationship with age at menarche, JIA subset, disease activity (as evaluated by ESR and Hgb), corticosteroid and methotrexate treatment (mean pro kg daily dose, cumulative dose) was assessed. Height, body mass index (BMI), bone mass content (BMC) values were also collected. Volumetric BMD (vBMD) evaluated with a geometric correction formula has been calculated and compared to aBMD. RESULTS: Patients were divided into two groups: - group I included girls with menarche age within normal limits for Italian standards; - group II included girls with delayed menarche. The BMD values and Z scores in group I were not significantly different to normal population. The BMD values and Z scores in group II were significantly decreased when compared to the normal population (p<0.001). With a multivariate analysis only age at menarche seemed independently related to peripubertal mineralization (p=0.025, r between -0.65 and -0.75). With a binary logistic analysis only disease activity (ESR and Hgb values) seems independently related to a menarche delay (1.24+/-0.4 for each mm/h). CONCLUSION: Our data show a critical role for disease activity in determination of a regular pubertal onset and an optimal bone density achievement.

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.)

Gerloni V, Pontikaki I, Gattinara M, Fantini F. · Department of Rheumatology, Istituto Ortopedico Gaetano Pini, Milan, Italy. · Ann Rheum Dis. · Pubmed #17981916 No free full text.

Abstract: OBJECTIVE: To report adverse events (AEs) seen in a large cohort of patients with juvenile idiopathic arthritis (JIA) treated with tumour necrosis factor (TNF)alpha blockers (infliximab and etanercept). METHODS: All patients with JIA treated with infliximab or etanercept at the Paediatric Rheumatologic Centre of the G Pini Institute (Milan, Italy) from November 1999 to February 2006, were enrolled in an open, single-centre, long-term prospective study RESULTS: In all, 163 patients (68 infliximab, 95 etanercept) were enrolled. Mean (SD) age of onset was 6.4 (4.8) years, mean age 17.1 (9.2) years, mean therapy duration 22.9 (17.6) months. A total of 45 patients (32 infliximab, 13 etanercept) failed to respond to or did not tolerate the first therapy and switched to a second one. In all, 208 treatments (81 infliximab, 127 etanercept) were performed. A total of 71 AEs occurred in 51 (62.9%) patients on infliximab and led to discontinuation in 26 (32.1%); 133 AEs occurred in 69 (54.3%) patients on etanercept and led to discontinuation in 18 (14.2%). Some AEs, such as thrombocytopoenia, neuropsychiatric disorders, new onset of Crohn disease and new onset or flare-up of chronic iridocyclitis (CIC), are unusual and have rarely been described before, yet proved to be significant in frequency and/or clinically noteworthy in the large population we followed. CONCLUSIONS: In our 6-year study, anti-TNFalpha agents infliximab and etanercept were well tolerated and safe, and were associated with only few serious, but all reversible, AEs. However, such inhibitors are associated with various and numerous AEs. Children and young adults affected by JIA should be carefully monitored so as to limit the risk of AEs during anti-TNFalpha therapy as much as possible.

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.

Cimaz R, Cazalis MA, Reynaud C, Gerloni V, Zulian F, Biggioggero M, Martini G, Pontikaki I, Fantini F, Mougin B, Miossec P. · Unité Mixte Hospices Civils de Lyon-BioMérieux, Lyon, France. · Ann Rheum Dis. · Pubmed #17324969 No free full text.

Abstract: OBJECTIVE: To investigate the genetic contribution of cytokine gene polymorphisms (interleukin 1 (IL1) and tumour necrosis factor alpha (TNFalpha)) on disease phenotype and on response to TNF-blocking agents in a population of patients with juvenile idiopathic arthritis (JIA). METHODS: A cohort of 107 consecutive patients with JIA who were receiving treatment with anti-TNF agents was enrolled in this study. Analysis of genetic polymorphisms for IL1B +3954, IL1RA +2018, TNFalpha -238 and TNFalpha -308 was performed by enzyme-linked oligo sorbent assay, and compared with those obtained from 630 healthy Caucasians and 263 adult patients with rheumatoid arthritis. Relevant demographic, clinical and laboratory data were collected from clinical charts and entered into a customised database, and chi(2) analysis was performed to compare cytokine polymorphisms with disease type according to the International League of Associations for Rheumatology criteria, presence of uveitis, rheumatoid factor and anti-nuclear antibody positivity, erosive disease, frequency of adverse effects to anti-TNF and clinical response after 3 months. RESULTS: The T/T genotype of the IL1B +3954 polymorphism was absent in patients with JIA and present in 5% of controls (p = 0.015). No significant correlation was found between the studied polymorphisms and clinical or laboratory variables considered. Clinical response to TNF inhibitors at 3 months was not associated with the genetic polymorphisms considered. CONCLUSION: In our cohort, the absence of the rare IL1B +3954 gene polymorphism was associated with JIA, but without specificity to particular disease phenotypes. The TNF and IL1 gene polymorphism studied did not seem to be associated with response to anti-TNF treatment.

Gregorio A, Gambini C, Gerloni V, Parafioriti A, Sormani MP, Gregorio S, De Marco G, Rossi F, Martini A, Gattorno M. · 2nd Division of Pediatrics, G. Gaslini Institute, Genoa, Italy. · Rheumatology (Oxford). · Pubmed #16877460 links to  free full text

Abstract: OBJECTIVE: The aim of the study was to evaluate the pattern of the lymphoid organization in the synovial tissue of patients affected with juvenile idiopathic arthritis (JIA). METHODS: A total of 40 JIA patients who underwent synoviectomy or synovial biopsies were enrolled. The mean age at surgery was 15.1 yrs (range 6-30 yrs) and the mean disease duration was 6.7 yrs (range 3 months to 22.2 yrs). Tissue specimens were grouped according to the following criteria: (i) diffuse perivascular infiltrate without lymphoid organization, (ii) T cell-B cell aggregates with or without germinal centre reaction. RESULTS: Synovial tissues from 12 JIA patients did not show any sign of lymphoid organization, whereas 28 patients displayed a variable number of T-B cell aggregates. Typical features consistent with a germinal centre reaction were present in two JIA patients only. Lymphoid organization in JIA patients did not correlate with the duration and severity of the disease or with the degree of synovial inflammation, but did positively correlate with the presence of anti-nuclear antibodies. Moreover, a diffuse lymphocyte infiltration was significantly related to the presence of an acute phase of inflammation and the presence of lymphoid aggregates correlated with the degree of plasma cells infiltration. CONCLUSIONS: Lymphoid neogenesis in JIA represents a phase in the immunopathological process that characterize the development of inflammatory synovitis. It is not related to disease activity or severity, but appears to be more frequent in patients with circulating anti-nuclear antibodies.

Lurati A, Pontikaki I, Teruzzi B, Desiati F, Gerloni V, Gattinara M, Cimaz R, Fantini F. · Gaetano Pini Institute, Milan, Italy. · Arthritis Rheum. · Pubmed #16646003 links to  free full text

Abstract: OBJECTIVE: There are no validated criteria to evaluate clinical response in juvenile idiopathic arthritis (JIA). The purpose of this study was to compare 4 sets of criteria (2 from the American College of Rheumatology [ACR] and 2 from the European League Against Rheumatism [EULAR]) for clinical response evaluation in JIA patients treated with methotrexate and/or anti-tumor necrosis factor alpha drugs. METHODS: Seventy-five patients with JIA were evaluated at baseline and after 6 months of therapy with second-line drugs. Mean age at study onset was 12.8 years (range 2-32.9 years). Diagnoses were systemic JIA (n = 16), rheumatoid factor-positive JIA (n = 5), rheumatoid factor-negative JIA (n = 9), persistent oligoarticular JIA (n = 10), extended oligoarticular JIA (n = 33), and psoriatic arthritis (n = 2). Clinical response was evaluated with the ACR Pediatric 30 criteria and the ACR 20% response criteria (ACR20), and with the EULAR Disease Activity Score (DAS) and 28-joint DAS (DAS28). Patients with EULAR criteria responses of "good" or "moderate" were classified as responders. Responders and nonresponders according to the different criteria were then compared. RESULTS: For patients younger than 16 years, Cohen's kappa varied between 0.51 and 0.72, with a good-to-excellent reproducibility index for all comparisons, except for the DAS28/ACR20 comparison. The best agreement was obtained by comparing the DAS and the ACR Pediatric 30. For patients older than 16 years, the reproducibility index was good or excellent in only 2 cases, i.e., comparing the DAS and the ACR Pediatric 30 and comparing the DAS and the DAS28 (as expected). CONCLUSION: Our study shows a good agreement overall for the different criteria tested. The highest concordance was observed between the DAS and the ACR Pediatric 30, the lowest between the DAS28 and the ACR20. Our data suggest that the ACR Pediatric 30 criteria can be used also in adult patients affected by JIA, and that the original DAS can be an alternative to the ACR Pediatric 30 in both children and young adults with JIA.

Pontikaki I, Gerloni V, Gattinara M, Luriati A, Salmaso A, De Marco G, Teruzzi B, Valcamonica E, Fantini F. · Unità Semplice di Reumatologia Infantile, Dipartimento e Cattedra di Reumatologia dell'Università di Milano. · Reumatismo. · Pubmed #16639486 links to  free full text

Abstract: OBJECTIVES: To report adverse events registered in our population affected by JIA and treated with anti-TNFalpha blockers. METHODS: Ninety-five patients were enrolled to be treated with Etanercept, median age 14 years (range 4-34); median duration of therapy 12 months (range 1-40). 19 patients were also treated with MTX (median dose 12.5 mg/week). Fifty-six patients were enrolled to be treated with Infliximab associated with MTX (median dose of MTX 8.8 mg/week), median age 23.2 years (range 7.8-34.9); median duration of therapy 20.1 months (range 1.4-60.4). All adverse events were divided in definitely, probably and possibly related to the biologic agent. RESULTS: Side effects definitely related to Infliximab were the reactions to infusions and the Anti-dsDNA positivity. Side effects definitely related to Etanercept were severe headache and thrombocytopenia. Side effects probably correlated to both the biological agents were behavioural modifications and pain amplification syndrome. Probably correlated to the treatment with Etanercept was the onset of Crohn's disease in 3 patients. Possibly correlated to the biological agents were the new onset or flare-up of Chronic Iridocyclitis and single cases of thyroideal cancer, hypoglossal nerve paralysis and a severe Cytomegalovirus pulmonary infection. No case of tuberculosis infection was registered during this study. CONCLUSIONS: Treatment with a TNFalpha antagonist seems to be associated with various adverse events. Some of them, like onset of Crohn's disease, behavioural modifications are unusual and others, like pain amplification syndrome were never described before. Children and young adults affected by JIA should be monitored very carefully so as to limit as much as possible the risk of serious side effects on anti-TNFalpha therapy.

Bellintani C, Ghiringhelli P, Gerloni V, Gattinara M, Farronato G, Fantini F. · Cattedra e Reparto di Ortognatodonzia, Clinica Odontoiatrica, Università degli Studi di Milano. · Reumatismo. · Pubmed #16258606 links to  free full text

Abstract: OBJECTIVE: About 65% of children suffering from juvenile idiopathic arthritis (JIA) shows a more or less marked involvement of temporo-mandibular joint (TMJ) with altered mandibular growth, resorption of the condyles, occlusary instability, reduced chewing ability and facial dysmorphia. The purpose of our study is to prevent and to treat the progressive evolution of JIA on craniofacial growth and morphology with a functional appliance; surgery should be considered only in so far as the adequacy of TMJ movement is concerned. METHODS: From 1992 until now 72 children with proved JIA and TMJ involvement have been treated (50 females, 22 males, aged 6 to 16 years old). TMJ involvement was bilateral in 61% and unilateral in 39% of patients. A diagnostic workup was carried out involving tomograms of TMJ and cephalometric radiograph and analysis. The authors used a bimaxillary activator in the attempt to modify the unfavourable growth pattern and provide a gradual ante-rotation of the jaw. RESULTS: Almost all JIA patients showed satisfactory long term results, easing of pain, reduced skeletal discrepancy, increased function and good facial profile. CONCLUSIONS: The long term results of this study indicate that orthopaedic therapy might control the vicious circle of the malocclusion in children with JIA, preventing exacerbation of mandibular clockwise rotation. Surgical intervention for the improvement of TMJ function should be considered only if a severe restricted state is imminent.

Gerloni V, Pontikaki I, Gattinara M, Desiati F, Lupi E, Lurati A, Salmaso A, Fantini F. · Istituto G. Pini, Milan, Italy. <> · Arthritis Rheum. · Pubmed #15693004 links to  free full text

Abstract: OBJECTIVE: To evaluate the efficacy and safety of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (infliximab) with methotrexate (MTX) in juvenile idiopathic arthritis (JIA) with an active polyarticular course that is not responsive to MTX. METHODS: Twenty-four young adults with long-lasting, refractory JIA were enrolled in an open, prospective, 2-year pilot study. Patients received intravenous infliximab at 3 mg/kg of body weight at weeks 0, 2, and 6 and every 8 weeks thereafter, with weekly subcutaneous MTX. RESULTS: The median duration of therapy was 9.1 months. Significant improvements were observed in the number of joints (28-joint count) with active disease (median 6 at baseline, 2 at 2 weeks, 0 at 6 months, 0 at 1 year; P < 0.05). Pain as well as patient's and physician's global assessments of disease status were assessed on 0-100-mm (0 = best; 100 = worst) visual analog scales (VAS). There were significant improvements in VAS pain scores (45 at baseline, 25 at 2 weeks, 8.5 at 6 months, 10 at 1 year; P < 0.05), patient's global assessment of disease status (50 at baseline, 22 at 2 weeks, 11.5 at 6 months, 18 at 1 year; P < 0.05), and physician's global assessment of disease status (50.5 at baseline, 22.5 at 2 weeks, 6.5 at 6 months, 10 at 1 year; P < 0.01). In addition, there were significant improvements in the erythrocyte sedimentation rate (64 mm/hour at baseline, 36 mm/hour at 2 weeks, 23.5 mm/hour at 6 months, 35 mm/hour at 1 year; P < 0.01) and C-reactive protein level (4.9 mg/dl at baseline, 2.8 mg/dl at 2 weeks, 3.1 mg/dl at 6 months, 3.2 mg/dl at 1 year; P < 0.005). The percentage of patients meeting the American College of Rheumatology 20% improvement criteria at each assessment ranged from 54.2% to 86.7%. Of the responses on the Disease Activity Score in 28 joints, 37.5-63.6% were classified as "good," 14.3-33.3% were classified as "moderate," and 18-37.5% were classified as "no response." Twelve patients (50%) had adverse events, and 5 patients (20.8%) withdrew. CONCLUSION: Infliximab plus MTX showed high effectiveness and safety in short- and medium-term treatment of long-lasting refractory JIA. A controlled multicenter clinical trial is needed.

Ingegnoli F, Del Papa N, Comina DP, Maglione W, Lupi E, Gerloni V, Fantini F. · Department of Rheumatology, University of Milan, Istituto Ortopedico Gaetano Pini, Milan, Italy. · Clin Exp Rheumatol. · Pubmed #15301253 No free full text.

Abstract: OBJECTIVE: To determine the prevalence of anti-chromatin antibodies (Abs) in juvenile rheumatoid arthritis (JRA) and to assess any association between the presence of anti-chromatin Abs and clinical subsets of the disease. METHODS: IgG anti-chromatin Abs and anti-extractable nuclear antigens (ENA) Abs were detected by an enzyme-linked immunosorbent assay (ELISA), and antinuclear Abs (ANA) by indirect immunofluorescence in sera of 89 children with JRA. Ten children with systemic, 32 with polyarticular and 47 with pauciarticular disease onset (uveitis occurred in 17/47 children) were studied. As a control group, 12 sera of patients suffering from idiopathic uveitis and 31 age- and-sex-matched healthy children (HC) were examined. RESULTS: Abs to chromatin were detected in 14/47 (29.8%) of children suffering from pauciarticular onset JRA and in this group the higher prevalence of anti-chromatin Abs has been found in children with chronic uveitis (p = 0.002). Anti-chromatin positivity was observed in 2/10 (20%) of systemic and in 3/32 (9.3%) of polyarticular onset JRA. Furthermore, none of the patients with idiopathic uveitis and HC had Abs to chromatin. anti-chromatin Abs titers remained relatively stable over a 6-month control period. CONCLUSION: Our results confirm previous data about the presence of circulating anti-chromatin Abs in juvenile arthritis. Interestingly, anti-chromatin Abs were significantly higher in the group of patients with pauciarticular onset with past or present history of uveitis, than in patients without ocular involvement. A long-term follow-up study could be useful to demonstrate the potential utility of these autoantibodies in diagnosing, classifying and treating children affected.

Gattorno M, Gregorio A, Ferlito F, Gerloni V, Parafioriti A, Felici E, Sala E, Gambini C, Picco P, Martini A. · Second Division of Pediatrics, Rheumatology Unit, G. Gaslini Scientific Institute for Children, Largo G. Gaslini 5, 16147, Genoa, Italy. · Rheumatology (Oxford). · Pubmed #15199218 links to  free full text

Abstract: OBJECTIVE: To evaluate the synovial expression of osteopontin (OPN) and its possible correlation with the degree of synovial angiogenesis in human chronic idiopathic arthritis. METHODS: Forty-five patients with active juvenile idiopathic arthritis (JIA) were studied. All patients underwent SF aspiration before steroid injection. A paired plasma sample was collected from 22 JIA patients. Plasma from 15 age-matched healthy subjects was used as control. Plasma and SF were tested by ELISA for OPN and vascular endothelial growth factor (VEGF). Synovial tissue was obtained at synovectomy from 10 JIA patients. Immunohistochemistry was performed according to a standard technique with anti-OPN, anti-CD68, anti-CD31 anti-VEGF and anti-alpha(v)beta(3) antibodies. RESULTS: OPN levels were significantly higher in SF than in paired plasma samples (P<0.001). The same pattern was observed for VEGF (P<0.001). A positive correlation between OPN and VEGF concentrations was found in SF (r = 0.6, P = 0.001). In synovial tissue, OPN was expressed at the level of the lining and sublining layers with a distribution similar to that observed for VEGF. OPN expression in the lining layer correlated with the number of vessels present in the areas underlying the sublining layer. CONCLUSIONS: Synovial expression of OPN correlates with parameters of angiogenesis in JIA. These data support, in human disease, the possible role of OPN in the vascularization of inflamed synovial tissue, as previously shown in OPN-deficient animal models of arthritis.

Ingegnoli F, Del Papa N, Lupi E, Comina DP, Maglione W, Gerloni V, Fantini F. · Cattedra di Reumatologia, Istituto Gaetano Pini, Milano, Italia. · Reumatismo. · Pubmed #14872223 links to  free full text

Abstract: OBJECTIVE: to evaluate the prevalence and clinical significance of anti-chromatin antibodies (Abs) in juvenile rheumatoid arthritis (JRA). METHODS: IgG anti-chromatin Abs were detected by an enzyme-linked immunosorbent assay (ELISA), in sera of 94 children with JRA (10 children with systemic, 38 with polyarticular and 46 with oligoarticular disease onset). As control group, 33 age- and-sex-matched healthy children (HC) were also examined. RESULTS: Abs to chromatin were detected in 24/94 (25.5%) of children suffering from JRA. Particularly, the higher prevalence of anti-chromatin Abs has been found in children with oligoarticular (30,4%) and polyarticular (23.7%) onset JRA. In these groups Abs titers were significantly higher compared to systemic JRA and HC (p=0.003). Anti-chromatin Abs were observed more frequently in patients with oligoarticular disease and chronic uveitis (21.7%). Furthermore, higher levels of anti-chromatin Abs has been found in all the patients treated with anti-TNF-alpha therapy (p< 0.0001). CONCLUSIONS: our results confirm previous data about the prevalence of anti-chromatin Abs in JRA. These Abs were significantly higher in the group of patients with oligoarticular onset with past or present history of ocular involvement and in the group with polyarticular JRA treated with biologic therapy. A long-term follow-up study could be useful to evaluate the potential utility of these autoantibodies.

Fantini F, Gerloni V, Gattinara M, Cimaz R, Arnoldi C, Lupi E. · Institute of Rheumatology, Milano, Italy. · J Rheumatol. · Pubmed #12610820 No free full text.

Abstract: OBJECTIVE: As continuity of care in our institution allows longterm followup studies, we reviewed the files of all consecutive patients with juvenile chronic (idiopathic) arthritis (JCA) followed since 1970 to establish the frequency of remission. METHODS: Charts of all patients with JCA were reviewed. Relevant variables were entered into a customized database. The presence of remission (lack of signs of disease activity in the absence of antirheumatic therapy for at least 6 mo) during the disease course and at the last visit was assessed. RESULTS: The cohort included 683 patients, 463 females and 220 males. According to the disease onset, 420 had oligoarticular, 108 polyarticular (23 rheumatoid factor positive), and 88 systemic disease; 67 had a juvenile spondyloarthropathy (SpA). For all 4 categories the mean followup period was about 10 years. At the last visit 224 cases were in remission (32.8%). Remission rate was scarcely influenced by age at disease onset, but differed in the different disease categories. Of the total group of 683 patients, 153 (22.4%) were lost to followup (no control for at least 2 years). For all 4 categories the remission rate at the last visit was higher in patients who had been lost to followup: 42.3% versus 29.0% for systemic onset JCA, 20.8% versus 16.5% for polyarticular onset JCA, 44.7% versus 33.6% for pauciarticular onset JCA, and 66.7% versus 26.8% for juvenile SpA. The probability of attaining remission decreased in proportion to delay in entering the tertiary care center (from 35.7% to 22.8%). The rate of remission reached its peak after 5-10 years of followup, after which the trend reversed. CONCLUSION: Childhood arthritis achieved remission in only about one-third of our cases, with differences among disease categories based on the diagnosis.

Zulian F, Martini G, Falcini F, Gerloni V, Zannin ME, Pinello L, Fantini F, Facchin P. · Department of Pediatrics, University of Padua, Padua, Italy. · J Rheumatol. · Pubmed #12415607 No free full text.

Abstract: OBJECTIVE: To determine whether demographic, clinical, and laboratory variables at onset of arthritis can predict the development and the severity of anterior uveitis (AU) in oligoarticular juvenile idiopathic arthritis (JIA). METHODS: In a retrospective study, a cohort of 366 patients with oligoarticular onset JIA from 3 pediatric rheumatology centers were evaluated. Patients were classified in 3 groups: severe uveitis (SU) with a mean >/= 2 uveitis relapses/year with complications or need for immunosuppressive therapy; mild uveitis (MU) with a mean </= 1 uveitis relapse/year with no complications; and no uveitis. Variables that were significant with univariate tests or were clinically relevant for each outcome underwent multivariate logistic regression analysis. RESULTS: There were 316 patients available for analyses: 66 in the SU group, 64 in the MU group, and 186 in the no uveitis group. Multivariate analysis showed the following factors to be significant as predictors of AU onset: low age at onset (OR 0.96), a2-globulin plasma concentration (OR 1.34), and HLA-A19 (OR 2.87), B22 (OR 4.51) and DR9 (OR 2.33), while HLA-DR1 conferred protection (OR 0.13). This model was not good in predicting which patient would develop uveitis (sensitivity 55%, specificity 26%). Time interval between onset of arthritis and the first AU and elevated a2-globulin level in the serum were the best predictors of AU severity (OR 1.62 and 0.85, respectively). When applied prospectively, the model revealed good sensitivity (89.2%), specificity (76.1%), and efficiency (86.3%). CONCLUSION: Clinical and laboratory variables measurable at onset of arthritis can be used to predict severity of the course of AU in oligoarticular JIA, but not its onset. More accurate prediction can shorten or lengthen the intervals between ophthalmologic evaluations and can change the therapeutic approach undertaken on the basis of expected disease severity.

Gattorno M, Gerloni V, Morando A, Comanducci F, Buoncompagni A, Picco P, Fantini F, Pistoia V, Gambini C. · Department of Pathology, G. Gaslini Institute for Children, Genoa, Italy. · J Rheumatol. · Pubmed #12180743 No free full text.

Abstract: OBJECTIVE: Matrix metalloproteinases (MMP) are a large family of proteolytic enzymes involved in the remodeling of extracellular matrix during tissue resorption. We investigated synovial tissue expression of the main proteolytic enzymes (MMP-1, MMP-3, and MMP-13) and tissue inhibitor of metalloprotease 1 (TIMP-1) in juvenile idiopathic arthritides (JIA). METHODS: Expression of MMP-1, MMP-3, MMP-13, and TIMP-1 was studied by immunohistochemical analysis of synovial tissues, obtained at synoviectomy or arthroplasty from 9 patients with JIA, and was correlated with mononuclear cell infiltration into the lining layer. RESULTS: MMP-1 and MMP-3 were abundantly expressed in the lining layer, showing a high degree of correlation with macrophage infiltration (CD68+ cells). MMP-13 showed a lower degree of expression, with tissue distribution almost restricted to the sublining regions. TIMP-1 tissue distribution was similar to that observed for MMP-1 and -3, although with a definitely lower number of positive cells. CONCLUSION: The expression of MMP-1 and MMP-3 in the synovium of patients with IA was clearly correlated with the degree of inflammation. This indicates the possible role of MMP in the pathogenesis of synovitis in this group of pediatric idiopathic arthritides. Inadequate expression of tissue inhibitors may represent a crucial event for the development and perpetuation of tissue damage.