Clinical characteristics and cardiac outcome of acute rheumatic fever in Italy in the last 15 years.

OBJECTIVE: To analyze clinical characteristics, cardiac outcome and response to therapy of an Italian pediatric population affected with acute rheumatic fever (ARF) in the last 15 years. METHODS: 135 patients with ARF (aged 2-14.9 years, mean 8.4+/-2.5 years) diagnosed from 1992 to 2006 at the Pediatric Rheumatology Centre of the University of Milan (Italy) were retrospectively reviewed. All patients underwent physical examination, laboratory evaluation, electrocardiogram and echocardiography. Patients were divided into 2 groups: group 1 - patients with complete adherence to updated Jones criteria (107 patients), and group 2 - exceptions (28 patients). Echocardiographic criteria were used to confirm the presence of carditis and to evaluate severity of mitral (MR) and aortic regurgitation (AR) at diagnosis and after treatment with steroids or acetylsalicylic acid (ASA)/non-steroidal anti-inflammatory drugs (NSAIDs). RESULTS: We observed a persistence of ARF in the last 15 years (mean 9 new cases/year with a peak of 19 cases in 2000). Carditis and arthritis were the main major criteria observed (102/135 and 71/135 patients respectively), then chorea (29/135), erythema marginatum (8/135) and subcutaneous nodules (1/135). Arthritis and chorea resolved completely with various therapies. At the last follow-up (> or =5 years) in group 1, loss of MR was observed in 46% steroid-treated (26/56 cases) and in 39% ASA/NSAID-treated (7/18 cases) patients and loss of AR in 59% steroid-treated (22/38) and 2/7 ASA/NSAID-treated patients (p>0.05). CONCLUSION: Incidence of ARF is clinically important currently in the area of northern Italy. Non-suppurative complications of streptococcal pharyngitis should be considered when deciding therapy in a pediatric patient that presents with sore throat.

Evidence of clonotypic pattern of T-cell repertoire in synovial fluid of children with juvenile rheumatoid arthritis at the onset of the disease.

Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are characterized by chronic inflammation, synovial cell proliferation and progressive joint damage. It has been speculated that T cells play an important role in the pathogenesis of RA and JRA in the early stage of the disease. Previous studies have demonstrated discrepant results regarding the significance of T-cell clonality in RA or JRA lesions. It can be postulated that the heterogeneity of these data may be linked to the stage of the disease, as the relative importance of selective immunological events is different during the time from onset to established disease. To avoid this problem, we conducted the present study in nine children affected by JRA at the onset of the disease and before treatment. We analysed the T-cell receptor beta chain variable (TCRBV) of CD4+ and CD8+ lymphocytes in peripheral blood (PBL) and synovial fluid (SFL), by a panel of monoclonal antibodies (MoAbs). Furthermore, to assess the clonotypic pattern of T-cell repertoire, the CDR3 length distribution was evaluated by spectratyping analysis. Our results showed no significant expansion of distinct TCRBV subset in either synovial or peripheral compartments. Conversely, when we studied the CDR3 length distribution, an oligoclonal pattern was found in the SFL of six patients, suggesting the presence of a clonotypic restriction of T cells in SFL, which is not detectable in PBL. These findings are consistent with an antigen driven T-cell expansion sequestered at the inflammatory site.

Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children: a prospective multicenter study.

OBJECTIVE: Osteopenia/osteoporosis is being increasingly reported as a complication of many chronic diseases, even in children. In this preliminary study, we evaluated the effect of an oral bisphosphonate (alendronate) on bone mass in children with diffuse connective tissue diseases. METHODS: Thirty-eight children with low bone mass were treated with alendronate for 1 year; 38 children who had the same primary disorders as the study patients but in a less severe form served as untreated control patients. We were also able to evaluate changes in bone mass (before and after alendronate) in 16 of the treated patients whose bone mineral density (BMD) had been routinely measured before the present study was initiated. RESULTS: BMD increased by a mean +/- SD of 14.9 +/- 9.8% (P < 0.002 versus baseline) in the treated patients (reaching the normal range in 13 patients), while the BMD was 2.6 +/- 5% (not significant versus baseline) in the control group (15 had a decrease). Most interestingly, there was a large increase in BMD (15.3 +/-9.9%) after alendronate therapy in the 16 children who had their BMD followed up in the year before the study, during which time they had shown little increase in BMD (1.03 +/- 6.3%), and often a decrease. Considering their condition, increases in the height of all patients was satisfactory. No new fractures were observed after alendronate therapy was initiated. CONCLUSION: Bisphosphonates can be considered essential components of the treatment of secondary osteoporosis, not only in adults, but also in pediatric patients. Alendronate has a positive effect on secondary osteopenia/osteoporosis in children with connective tissue diseases.

Bone mass change during methotrexate treatment in patients with juvenile rheumatoid arthritis.

Thirty-two children affected by juvenile rheumatoid arthritis (JRA) were studied with serial measurements of bone mass for an average of 18 months, to evaluate the effects of long-term methotrexate (MTX) treatment on bone. Bone mineral density (BMD) was measured on lumbar spine and total body. During MTX therapy some increase in BMD was observed, though this was smaller than in a control group of healthy children. Axial (spine and trunk) and appendicular (upper and lower limbs) BMD showed similar increases. BMD, either as an absolute value or as a percent variation from baseline, did not correlate with either MTX dose or length of therapy. In children treated also with corticosteroids, these drugs negatively influenced bone mass increase. The main determinant of absolute spine BMD value appeared to be weight, while height and lean mass seemed to be the determinants of total body BMD. Pubertal stage and disease activity significantly influenced the yearly change in BMD. In conclusion, our data suggest that long-term, low-dose therapy with MTX does not induce osteopenia in children with JRA.

Responsiveness of outcome measures in juvenile chronic arthritis. Italian Pediatric Rheumatology Study Group.

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.

Arthritis as a presenting feature of non-Hodgkin's lymphoma.

Leukaemia can present with joint swelling in the absence of abnormal haematological findings. Arthritis as a presenting sign of lymphoma, however, is extremely rare. Three children with non-Hodgkin's lymphoma who had joint swelling at the onset of their disease are reported. Two cases showed histological features of anaplastic large cell lymphoma (Ki-1/CD30 positive), and one of angioimmunoblastic T cell lymphoma. In all patients the unusual presentation delayed correct diagnosis.

Oral versus intramuscular methotrexate in juvenile chronic arthritis. Italian Pediatric Rheumatology Study Group.

OBJECTIVE: To compare the efficacy and safety of methotrexate (MTX) after oral and intramuscular administration in children with juvenile chronic arthritis (JCA). METHODS: Pediatric rheumatology centers in Italy participated in this short-term, prospective, open trial. Each investigator was allowed to choose the oral or intramuscular route of administration according to his personal preference in everyday clinical practice. Patients enrolled by each center were given MTX through the same method of administration. All patients received 10 mg/m2 of MTX each week for six months. RESULTS: A total of 257 patients with JCA (127 treated orally and 130 intramuscularly) were enrolled in the trial by 11 Italian centers. The response rate after 6 months of MTX therapy was 58% in the oral and 61% in the intramuscular cohort. The frequency of adverse side effects did not differ significantly between the two treatment groups. CONCLUSION: The results of this study suggest that MTX at the conventional dose regimen is equally effective and has a similar safety profile in children with JCA when administered orally or by intramuscular injections.

Idiopathic limb edema in children with chronic arthritis: a multicenter report of 12 cases.

Lymphedema, a well known extraarticular manifestation of rheumatoid arthritis, has been rarely described in children with idiopathic chronic arthritis. We describe 12 cases of lymphedema and idiopathic arthritis of childhood seen at 4 different pediatric rheumatology centers. Eight patients were girls, 4 boys; the age at appearance of lymphedema ranged from 2.3 to 17 years. In all patients except one, lymphedema was localized to the lower limbs. The outcome of lymphedema was variable, but not always related to the arthritis course, and was mostly independent of any specific therapy. Lymphography was performed in only one patient, and revealed lack of lymphatic drainage in the affected leg. We conclude that the association of lymphedema and idiopathic arthritis of childhood is not rare; this association is unlikely to be coincidental, even though the pathogenetic mechanisms are currently not well understood.

A multicenter study on insulin-like growth factor-I serum levels in children with chronic inflammatory diseases.

OBJECTIVE: To study insulin-like factor-I (IGF-I) levels in children and adolescents with connective tissue diseases (CTDs), compare them with values obtained in normal controls, and correlate them with age, sex, steroid treatment, and inflammatory parameters. METHODS: A multicenter, cross-sectional study was performed in 3 Italian pediatric rheumatology centers. The subjects studied comprised 117 patients with juvenile arthritis (53 systemic, 25 pauciarticular and 17 polyarticular) and other CTDs (22), and 78 children without inflammatory conditions. IGF-I levels were measured by radioimmunoassay after acid-ethanol extraction. RESULTS: Mean IGF-I serum levels were 167.6 ng/ml (+/- 132.5) in patients and 214.4 (+/- 142.8) in controls. A significant correlation was found between IGF-I levels and age in the controls (P = 0.001), but not in the patients. Covariance analysis with age as the covariate showed significantly lower IGF-I levels in the patient group (P = 0.001). No significant correlation was found between IGF-I levels and the total quantity of steroid taken. Multiple regression analysis showed that IGF-I levels were inversely correlated with the ESR (P = 0.0001) and positively correlated with age (P = 0.0002) and sex (P = 0.021) in the patient group. CONCLUSION: IGF-I serum levels are decreased in patients with CTDs; inflammation could play a major role.

Local nasal immunotherapy with a powder extract for grass pollen induced rhinitis in pediatric ages: a controlled study.

Forty pediatric patients, ranging from 5-13 years of age and suffering from grass pollen rhinoconjunctivitis, were submitted to local nasal preseasonal (12 weeks) immunotherapy, either with a grass pollen extract or with placebo. After 1 year, 15 of these patients (5 previously treated with active product and 10 with placebo) were treated with the grass pollen extract preseasonally for 2 consecutive years. Before and after treatment, serum total IgA and IgE, and specific IgG and IgE were assayed as well as carrying out nasal provocation tests (NPT) with extracts at different concentrations, endpoint evaluations by rhinomanometry and prick tests with different concentrations of extract. After only 1 year, the actively treated patients showed a significant decrease of daily nasal and conjunctival signs and symptoms-as judged by a 1 to 3 score-in comparison with the control group. The placebo group showed the same results after the 3rd year. The improvement was confirmed by a significant increase of the dose threshold in NPT. No immunological alterations were evident.

Soy allergy in atopic children.

BACKGROUND: Although soy is considered a major food allergen (along with milk, egg, peanut, fish, and wheat), the prevalence of soy allergy in the pediatric population is not well defined. OBJECTIVE: To determine the prevalence of soy allergy in atopic children attending the Allergy Clinic at the Pediatric Department of Milan University. METHODS: Seven hundred four patients with allergic signs and symptoms, aged 1 month to 18 years, were recruited between December, 1991 and April, 1992. The subjects with positive skin prick tests to soy were tested using a DBPCFC with powdered soy formula in fruit juice, and rice or corn flour as placebo. In children who refused the liquid challenge, capsules containing dehydrated soy flour or talcum powder as placebo were administered. An age-matched and sex-matched group of subjects with negative skin prick tests to soy were tested using an open challenge with soy formula. RESULTS: A positive skin prick test to soy was found in 148/704 patients (21%); 131 out of 148 children with positive skin prick test (group A) and 131 out of 556 children with negative skin prick test to soy (group B) were challenged with soy: 8/131 (6%) in group A had a positive soy challenge while no clinical reactions were observed in children in group B. A younger median age, a positive past and current personal history of cow milk allergy, and a previous history of soy allergy were found most often in children with positive soy skin prick test and positive soy challenge than in children with positive skin prick test and negative soy challenge. The eight soy-allergic children reacted to the soy challenge mostly with cutaneous and gastrointestinal symptoms; symptoms were immediate in six and late in two children. The eliciting dose of soy was very small in the immediate reaction; higher and repeated doses were necessary for the onset of late reactions. CONCLUSION: The prevalence of clinical soy allergy in our children with positive skin prick tests to soy is 6.1% (8/131), while none of 131 children with negative skin prick test to soy reacted to the challenge.

Levels of circulating intercellular adhesion molecule 1 and E-selectin in serum and synovial fluid of juvenile chronic arthritis patients.

OBJECTIVE: To measure the levels of two adhesion molecules (AM), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble E-selectin (sE-selectin), in serum and synovial fluid (SF) of patients with juvenile chronic arthritis (JCA). METHODS: Both soluble AM levels were tested, in serum and synovial fluid (SF) samples, with an enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Serum levels of sICAM-1 and sE-selectin in JCA patients were not significantly different from those of a control group. Synovial fluid levels of sICAM-1, but not of sE-selectin, assayed significantly higher (p < 0.05) in JCA patients than in controls. Moreover SF levels of both molecules correlated negatively with disease duration, being higher in the earliest phases. No significant correlations were found between JCA sICAM-1 and sE-selectin levels and leukocyte count or ESR. CONCLUSIONS: These observations may signify a more important role of ICAM-1 than E-selectin in the migration of inflammatory cells into JCA SF. The negative correlation of both AMSF levels in JCA patients with disease duration could reflect a higher expression of ICAM-1 and E-selectin during the earliest phases of the disease.

A three-year double-blind placebo-controlled study with specific oral immunotherapy to Dermatophagoides: evidence of safety and efficacy in paediatric patients.

Very few double-blind trials of oral immunotherapy have been reported. The majority of these have been performed with pollen extracts and the results have often been equivocal. The major weaknesses of these studies have been the short periods of the trials, the low doses of allergen employed and inadequate evaluation of efficacy. The present study has involved a placebo-controlled double-blind trial of oral immunotherapy for three years with Dermatophagoides pteronyssinus at relatively high doses in 18 paediatric patients. Throughout the trial clinical parameters (symptom and medication scores) and immunological parameters (specific IgE, IgG1 and IgG4 levels) were monitored in order to assess the safety and efficacy of the treatment. The treatment was well tolerated by all patients and no side-effects were experienced. Clinical improvement was evident after the second year of therapy and this was confirmed by a significant reduction in conjunctival reactivity assessed by a specific conjunctival provocation test. In addition, there were significant changes in the immunological parameters with a reduction in specific IgE and increased levels of IgG4 and IgG1, results in keeping with previous studies of oral and subcutaneous immunotherapy. Although the results do not provide an explanation of the basis of successful oral immunotherapy, they clearly demonstrate the efficacy and safety of the treatment and suggest that it may be a useful and more acceptable alternative for patients than the traditional subcutaneous immunotherapy.

[The use of thymopentin in the prevention of recurrent infections of the respiratory system. Multicenter study]. / Impiego della timopentina nella prevenzione delle infezioni ricorrenti dell'apparato respiratorio. Ricerca multicentrica.

Eighty children, between 1-12 years, suffering from recurrent respiratory infections were admitted to a multicentre study and treated with thymopentin, an immunomodulating compound that represents the active site of the natural thymic hormone thymopoietin. Thymopentin efficacy, measured as reduction in the number of infective episodes, and tolerability were assessed and, at the end of the study a global evaluation was made by each investigator. Moreover, the following factors were recorded: clinical course, duration of symptoms/signs, frequency of administration of antipyretic, antibiotic, anti-inflammatory and mucolytic therapy, school attendance and hospitalization. Thymopentin treatment resulted in a statistically significant decrease of infective recurrences. The use of symptomatic and antibiotic drugs was also reduced. Side effects were few and mild. The investigators' overall evaluation of thymopentin's efficacy and tolerability was favourable. In conclusion, thymopentin, administered subcutaneous for 5 weeks in winter, may be useful in the treatment of children with recurrent infections of the respiratory tract.

Influence of dietary manipulation on incidence of atopic disease in infants at risk.

Of 5,500 newborn infants whose family histories were screened, 900 were found to have anamnestic risk. Cord-blood IgE was evaluable in 4,677 of these newborns, of which 394 had levels > or = 1 IU/mL; 84 infants had both anamnestic risk and elevated cord-blood IgE levels. Parents of infants with anamnestic risk were informed of their child's risk of atopy. Additionally, for 391 infants at two of the three participating hospitals, a preventive diet was prescribed that recommended breastfeeding for the first 6 months of life, with maternal diet restricted to no more than 200 dL of cow milk per day, no more than one egg per week, and no tomato, fish, shellfish, nuts, or foods allergenic to the mother. Only soy formula was recommended, and introduction of solid foods was also carefully prescribed. Furthermore, doctors recommended against exposure to tobacco smoke, animal allergens, and early entrance into daycare. Evaluable infants whose parents complied with the prescribed diet were found to have a lower incidence of atopy during the first year of life (13.3%, n = 158) than infants whose parents had ignored the prescribed diet (54.7%, n = 86) or infants whose parents were offered no dietary recommendations (28.9%, n = 218). Differences between the compliant group and the two groups with unrestricted diets were significant, indicating that this prescribed diet may protect against or delay onset of food allergies during the first year of life.