Rheumatoid Arthritis: Buoncompagni A

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, 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.

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.

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.

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.

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

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

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

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

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

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

Felici E, Novarini C, Magni-Manzoni S, Pistorio A, Magnani A, Bozzola E, Buoncompagni A, Martini A, Ravelli A. · Dipartimento di Pediatria, Università di Genova, Unità Operativa Pediatria II, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genova, Italy. · J Rheumatol. · Pubmed #16142881 No free full text.

Abstract: OBJECTIVE: To describe the patterns and time course of arthritis in patients with antinuclear antibody (ANA)-positive juvenile idiopathic arthritis (JIA). METHODS: We identified patients followed during a 16-year period who had JIA by ILAR criteria, were ANA-positive (i.e., had >or= 2 positive ANA test results at titer >or= 1:160), and had a disease duration >or= 2 years. Demographic and clinical features, including ILAR category and cumulative number and type of joints affected over time, were recorded. RESULTS: A total of 195 patients were studied. The ILAR category was oligoarthritis in 159 patients and rheumatoid factor-negative polyarthritis in 36 patients. The cumulative rate of polyarticular extension in patients with oligoarticular onset was 26%, 38%, 45%, 49%, and 51% at 1, 2, 3, 4, and 5 years, respectively. At disease onset, most patients had monoarthritis and 95% had <or= 4 joints affected. The knee was the most frequently involved of all joints, followed by the ankle and proximal interphalangeal joints. Among patients with oligoarticular onset, the presence of ankle (in case of monoarticular disease) and/or wrist involvement in the first 6 months was more common in those who progressed to polyarthritis. CONCLUSION: The majority of our ANA-positive patients, including most of those who later developed polyarthritis, had monoarthritis at disease onset. Among patients with oligoarticular onset, polyarticular extension occurred in around 50% of cases within the first 3-4 years after disease onset, and tended to be less likely thereafter. The early occurrence of ankle and/or wrist disease may indicate a higher likelihood of arthritis progression.

Viola S, Felici E, Magni-Manzoni S, Pistorio A, Buoncompagni A, Ruperto N, Rossi F, Bartoli M, Martini A, Ravelli A. · Università di Genova, IRCCS G. Gaslini, Genoa, Italy. · Arthritis Rheum. · Pubmed #15986372 links to  free full text

Abstract: OBJECTIVE: To develop and validate a clinical measure of articular and extraarticular damage in patients with juvenile idiopathic arthritis (JIA). METHODS: The Juvenile Arthritis Damage Index (JADI), which is derived from physical examination and a brief review of the patient's clinical history, is composed of 2 parts: assessments of articular damage (JADI-A) and extraarticular damage (JADI-E). Instrument validation was accomplished by evaluating 158 JIA patients with disease duration of at least 5 years, seen consecutively over 21 months. The instrument's feasibility, face and content validity, construct and discriminative ability, internal consistency, and interrater reliability were examined. RESULTS: Among the 158 JIA patients, 47% and 37% had articular and extraarticular damage, respectively. The JADI was found to be feasible and to possess both face and content validity. The JADI-A score correlated highly with the number of joints with limited range of motion (Spearman's r [r(S)] = 0.72) and correlated moderately with the Childhood Health Assessment Questionnaire score (r(S) = 0.41), Steinbrocker functional classification (r(S) = 0.50), and Poznanski's score of radiographic damage (r(S) = -0.54), thereby demonstrating good construct validity. Correlations with the JADI-E score were lower, owing to the heterogeneity of its items. The JADI-A discriminated well among different levels of disability. The internal consistency (Chronbach's alpha) of the JADI-A and JADI-E was 0.93 and 0.59, respectively. The intraclass correlation coefficients between pairs of independent observers ranged from 0.85 to 0.97. CONCLUSION: The JADI exhibited good reliability, construct validity, and discriminative ability and is therefore a valid instrument for the assessment of long-term damage in patients with JIA, in the context of both clinical management and research settings.

Cassone R, Falcone A, Rossi F, Magni-Manzoni S, Felici E, Buoncompagni A, Martini A, Ravelli A. · Dipartimento di Pediatria, Università di Genova, Pediatria II, Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, Genova, Italy. · Clin Exp Rheumatol. · Pubmed #15485021 No free full text.

Abstract: OBJECTIVE: To describe the clinical and radiographic features of a group of juvenile idiopathic arthritis (JIA) patients who developed unilateral destructive wrist synovitis. METHODS: All wrist radiographs performed yearly between 1986 and 2002 in JIA patients who had wrist involvement were retrospectively reviewed to identify patients who had unilateral erosive wrist synovitis, defined as a difference of at least -3 units in the Poznanski score between the affected wrist and the unaffected wrist, with the Poznanski score in the unaffected wrist being > -2 units throughout the follow-up period. Clinical and radiographic data obtained during follow-up were recorded for all patients. RESULTS: Of a total of 250 patients for whom we had approximately 900 wrist radiographs, 6 patients were found to have unilateral erosive wrist synovitis. The JIA onset subtype was oligoarticular in 5 patients and polyarticular in 1 patient and the disease duration from presentation to the last follow-up visit ranged from 2 to 16 years. The arthritis course was polyarticular in all patients. Five patients had positive antinuclear antibodies (ANA) and 1 had positive rheumatoid factor (RF). At the last follow-up visit, all patients had some impairment of wrist function and 2 patients had wrist subluxation. There was a marked radiographic damage in all affected wrist, with the Poznanski ranging from -8.0 to -8.50 units in 3 patients and being -5.5, -3.1 and -2.4 units, respectively, in 3 patients. The severity of radiographic damage in the ANA-positive patients with the longest disease duration was comparable to that observed in the RF-positive patient. CONCLUSION: Unilateral erosive wrist synovitis seems to be uncommon in JIA. Patients with unilateral wrist synovitis may be at risk of a destructive course irrespective of the JIA onset subtype.

Chiesa S, Prigione I, Morandi F, Buoncompagni A, Picco P, Bocca P, Martini A, Pistoia V, Gattorno M. · 2nd Division of Pediatrics, "G. Gaslini" Scientific Institute for Children, Genoa, Italy. · J Rheumatol. · Pubmed #15468374 No free full text.

Abstract: OBJECTIVE: It has been suggested that CD45RO+CD27+ T cells represent recently activated memory cells, whereas CD45RO+CD27- T cells are activated memory T cells in the process of differentiating into effector cells. We investigated (1) CCR7 and CCR5 expression and (2) modulation of cytokine expression in "early" (CD27+) and "differentiated" (CD27-) memory CD4+ T cells from peripheral blood and synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA). METHODS: SF CD4+CD45RO+CD27+ and CD27- memory T cells from 6 patients with JIA were tested by flow cytometry for intracellular interferon-gamma (IFN-gamma) and interleukin 4 (IL-4) after in vitro priming with CD3 and CD28 mAb in the presence of IL-4, and subsequent culture with IL-2. RESULTS: SF CD4+CD45RO+CD27+ cells contained higher proportions of CCR7+ (median 46% vs 23%) and lower proportions of CCR5+ (73% vs 90%) cells than paired CD27- T cells. Both CD27+ and CD27- memory T helper cells from SF displayed a higher IFN-gamma/IL-4 ratio than their peripheral blood counterparts. No significant difference was observed in the percentage of IFN-gamma-expressing cells between CD27+ (32%, range 4-47%) and CD27- (29.4%, range 5-52%) memory T helper cells from SF. CONCLUSION: Irrespective of their differentiation stage, both CD27+ and CD27- SF memory T helper cells were found to switch from a proinflammatory to an antiinflammatory pattern of cytokine production.

Gattorno M, Prigione I, Vignola S, Falcini F, Chiesa S, Morandi F, Picco P, Buoncompagni A, Martini A, Pistoia V. · 2nd Department of Pediatrics, G. Gaslini Scientific Institute for Children and University of Genoa, Largo G. Gaslini 5, 16147, Genoa, Italy. · Clin Exp Rheumatol. · Pubmed #12508783 No free full text.

Abstract: OBJECTIVE: CD27 is a member of tumour necrosis factor receptor family. Its expression is predominantly confined to mature lymphocytes and is strongly enhanced after cell activation. Shedding of the CD27 from the surface of activated cells is related to their effector phase. The aim of the present study was to evaluate the levels of soluble CD27 in sera and synovial fluids, together with its expression on circulating and synovial fluid (SF) memory T cells, in children with JIA. METHODS: Sera from 40 patients with active JIA were studied for soluble CD27. Paired SF samples were available in 20 patients. Sera from 12 age-matched patients affected with various acute infectious diseases and 12 age-matched healthy subjects were used as controls. In 8 JIA patients freshly isolated circulating and SF lymphocytes were stained for CD27 in CD4+CD45 RO+ T cell subpopulation and analyzed by cytometry. RESULTS: Soluble CD27 serum levels were significantly higher in patients with polyarticular JIA and acute systemic infectious diseases than in patients with active oligoarticular or healthy controls. Both polyarticular and oligoarticular JIA patients showed increased levels of soluble CD27 in SF when compared with paired serum samples (p = 0.01). In all the patients tested a significant enrichment of CD27- T cells was seen in the SF (median 39.5%, range 18-56%) when compared to paired CD4+CD45RO+ peripheral lymphocytes (median 19.5%, range 5-43%; p = 0.01). CONCLUSIONS: A clear enrichment of CD4+ memory SF T cells with a CD27-phenotype is observed when compared to correspondent circulating T lymphocytes. This issue is conceivably related to re-activation and recruitment of memory T cells to the site of inflammation, and to the subsequent expansion of a subpopulation of "effector" memory T cells.

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.

Picco P, Gattorno M, Sormani MP, Vignola S, Buoncompagni A, Battilana N, Pistoia V, Ravazzolo R. · Department of Pediatric Rheumatology, G. Gaslini Institute, Genova, Italy. · Ann N Y Acad Sci. · Pubmed #12114294 No free full text.

Abstract: Adult patients with rheumatic arthritis and other rheumatic disorders show inappropriate cortisol secretion and peculiar CRH promoter gene polymorphisms. So far, no data are available about this topic in children with juvenile idiopathic arthritis (JIA). We have studied a series of 13 prepubertal patients (10 female, 3 male) affected with oligoarticular JIA (o-JIA) without clinical and biological signs of disease activity (ESR and IL-6). ACTH plasma concentrations were significantly increased at 8 a.m. in o-JIA patients, whereas no differences were found in cortisol plasma concentrations. The ACTH/cortisol ratio was significantly increased in o-JIA patients with respect to the normal population both at 8 a.m. and at noon. DHEAS and testosterone plasma concentration did not statistically differ in the two populations. The genetic study was aimed at defining the prevalence of polymorphisms A1 and A2 in o-JIA patients, but we failed to find allelic or genotypic differences. Our study suggests the presence of a partial resistance to ACTH with a dysregulated pattern of secretion also in inactive o-JIA patients. These preliminary data need further confirmation in larger pediatric studies.

Vignola S, Picco P, Falcini F, Sabatini F, Buoncompagni A, Gattorno M. · Second Division of Paediatrics (Rheumatology Unit), G. Gaslini Scientific Institute for Children, Genoa, Italy. · Rheumatology (Oxford). · Pubmed #12048298 links to  free full text

Abstract: OBJECTIVE: To evaluate the role of vascular endothelial growth factor (VEGF) in the pathogenesis of local joint inflammation in juvenile idiopathic arthritis (JIA). METHODS: Sera from 50 patients affected with JIA and 10 age-matched healthy controls were tested with a commercial ELISA for VEGF. Corresponding synovial fluid (SF) concentrations of VEGF and p75 soluble tumour necrosis factor receptor (sTNFR) were evaluated in 20 active JIA patients. RESULTS: Serum concentrations of VEGF were significantly higher in patients with active polyarticular disease than in patients with active and inactive oligoarticular disease and healthy controls. In JIA patients, serum concentrations of VEGF displayed a significant correlation with a number of clinical and laboratory parameters of disease activity. VEGF concentrations in SF were significantly higher than those detected in corresponding sera. Moreover, a clear correlation was found between corresponding SF and serum VEGF concentrations. In SF, VEGF showed a strong positive correlation with p75 sTNFR. CONCLUSIONS: Concentrations of VEGF in SF in patients with JIA are higher than corresponding serum concentrations, suggesting that this pro-angiogenic factor may have a major role in the outgrowth of hyperplastic pannus and tissue damage at the site of tissue inflammation.

Gattorno M, Vignola S, Falcini F, Sabatini F, Buoncompagni A, Simonini G, Picco P, Pistoia V. · 2nd Division of Pediatrics, G. Gaslini Institute for Children, Genoa, Italy. · J Rheumatol. · Pubmed #11950028 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 in idiopathic arthritides. We investigated serum and synovial fluid (SF) concentrations of MMP-3 and its tissue inhibitor (TIMP-1) in juvenile idiopathic arthritides (JIA). METHODS: Sera from 45 patients with active, 15 patients with inactive JIA, and 15 healthy controls were evaluated by ELISA for MMP-3 (stromelysin-1), TIMP-1, and soluble p75 tumor necrosis factor receptor (sTNFR). Paired SF concentrations were evaluated in 19 patients with JIA. RESULTS: MMP-3 serum concentrations were significantly higher in patients with active poly- and oligoarticular JIA versus inactive patients (p = 0.04 and p = 0.02, respectively) and healthy controls (p < 0.001 for both). Serum MMP-3, but not TIMP-1, concentration displayed a variable degree of correlation with clinical and laboratory variables of disease activity and with p75 sTNFR concentrations (r = 0.37, p = 0.005). SF MMP-3 concentrations were 30-300 times higher than those found in paired sera (p < 0.001, Wilcoxon rank test). A clear inversion of MMP-3/TIMP-1 ratio was observed when sera (median 0.31. range 0.02-1.5) were compared with the corresponding SF samples (5.3, range 4.9-5.5; p < 0.001). CONCLUSION: MMP-3 (stromelysin-1) is clearly overexpressed in SF of patients with JIA. An inadequate counter-expression of TIMP-1 may represent a crucial event for the development and perpetuation of tissue damage.

Ruperto N, Ravelli A, Pistorio A, Malattia C, Viola S, Cavuto S, Alessio M, Alpigiani MG, Buoncompagni A, Corona F, Cortis E, Falcini F, Gerloni V, Lepore L, Sardella ML, Strano CG, Zulian F, Gado-West L, Tortorelli A, Fantini F, Martini A, Anonymous00072. · Laboratorio di Informatica Medica, IRCCS S. Matteo, Università di Pavia, Italy. · Clin Exp Rheumatol. · Pubmed #11510339 No free full text.

Abstract: We report herein the results of the cross-cultural adaptation and validation into the Italian language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Italian CHAQ was already published in the literature and was therefore revalidated while the Italian CHQ was fully cross culturally adapted with 3 forward and 3 backward translations, and than validated. A total of 1,192 subjects were enrolled: 404 patients with JIA (16% systemic onset, 31% polyarticular onset, 21% extended oligoarticular subtype, and 32% persistent oligoarticular subtype) and 788 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Italian version of the CHAQ-CHQ are reliable, and valid tools for the functional, physical and psychosocial assessment of children with JIA.

Picco P, Gattorno M, Marchese N, Vignola S, Sormani MP, Barabino A, Buoncompagni A. · 2nd Division of Pediatrics, National Institute for Cancer, Genoa, Italy. · Clin Exp Rheumatol. · Pubmed #11138347 No free full text.

Abstract: OBJECTIVE: This study was aimed at evaluating intestinal permeability (IP) in patients with oligoarticular juvenile idiopathic arthritis (o-JIA), spondyloarthropathy (SpA) associated with inflammatory bowel disease (IBD) and other forms of juvenile-onset chronic arthritiis (OIA) using the lactulose/mannitol (L/M) test in comparison with other non-invasive parameters of gut involvement. METHODS: A series of 26 children affected with o-JIA and 14 with either SpA/IBD or OIA were assessed for IP. The urinary L/M ratio was measured by gas chromatography. The erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and faecal alpha 1 antitrypsin concentrations were also evaluated. Ten o-JIA patients displayed active arthritis while in 16 the disease was under control. Among the OIA patients, 11 were affected with psoriatic arthritis and the remaining 3 with chronic reactive arthritis. 14 patients with SpA-IBD had active synovitis or spine inflammation. 14 eo-pJCA and 22 OIA and SpA-IBD patients, respectively, were receiving NSAID therapy. RESULTS: The mean L/M ratios for the Spa-IBD (0.07 +/- 0.02, mean +/- SD), OIA (0.05 +/- 0.02) and o-JIA (0.04 +/- 0.02) patients were significantly higher (p < 0.001, p = 0.022 and p = 0.01, respectively) than those found in controls (0.02 +/- 0.01). Logistic regression analysis disclosed a positive correlation between the L/M ratio and the presence of gastrointestinal manifestations (p = 0.011). The type of disease (p = 0.28), the disease activity in the JCA patient group (p = 0.24) and NSAID administration (p = 0.210) did not seem to significantly influence the L/M ratio. CONCLUSIONS: All of the subtypes of juvenile chronic arthritides that we studied displayed an increased IP. Hence, gut wall inflammation (albeit asymptomatic) may also be present in o-JIA patients. The SpA-IBD patients with gastrointestinal symptoms displayed the highest mean L/M ratio values. The L/M test seemed to correlate with histopathological features of the gut mucosa. The L/M ratio was shown to be a highly sensitive but poorly specific test for predicting gut inflammatory disease compared to other non-invasive screening tests.

Picco P, Gattorno M, Buoncompagni A, Vignola S, Maggiani M, Rossi G, Pistoia V, Borrone C. · 2nd Pediatric Division, G. Gaslini Scientific Institute, Genoa, Italy. · Ann N Y Acad Sci. · Pubmed #10415619 No free full text.

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