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1. Reliability of a generative artificial intelligence tool for pediatric familial Mediterranean fever: insights from a multicentre expert survey

Author

Saverio La Bella, Marina Attanasi, Annamaria Porreca, Armando Di Ludovico, Maria Cristina Maggio, Romina Gallizzi, Francesco La Torre, Donato Rigante, Francesca Soscia, Francesca Ardenti Morini, Antonella Insalaco, Marco Francesco Natale, Francesco Chiarelli, Gabriele Simonini, Fabrizio De Benedetti, Marco Gattorno, and Luciana Breda

Subjects
Artificial intelligence, AI, Pediatric rheumatology, Familial mediterranean fever, Generative artificial intelligence, FMF, Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background Artificial intelligence (AI) has become a popular tool for clinical and research use in the medical field. The aim of this study was to evaluate the accuracy and reliability of a generative AI tool on pediatric familial Mediterranean fever (FMF). Methods Fifteen questions repeated thrice on pediatric FMF were prompted to the popular generative AI tool Microsoft Copilot with Chat-GPT 4.0. Nine pediatric rheumatology experts rated response accuracy with a blinded mechanism using a Likert-like scale with values from 1 to 5. Results Median values for overall responses at the initial assessment ranged from 2.00 to 5.00. During the second assessment, median values spanned from 2.00 to 4.00, while for the third assessment, they ranged from 3.00 to 4.00. Intra-rater variability showed poor to moderate agreement (intraclass correlation coefficient range: -0.151 to 0.534). A diminishing level of agreement among experts over time was documented, as highlighted by Krippendorff’s alpha coefficient values, ranging from 0.136 (at the first response) to 0.132 (at the second response) to 0.089 (at the third response). Lastly, experts displayed varying levels of trust in AI pre- and post-survey. Conclusions AI has promising implications in pediatric rheumatology, including early diagnosis and management optimization, but challenges persist due to uncertain information reliability and the lack of expert validation. Our survey revealed considerable inaccuracies and incompleteness in AI-generated responses regarding FMF, with poor intra- and extra-rater reliability. Human validation remains crucial in managing AI-generated medical information.

Published
2024
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2. Associations of C reactive protein to albumin ratio, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio with disease activity in patients with juvenile idiopathic arthritis

Author

Giulia Di Donato, Marina Attanasi, Debora Mariarita d’ Angelo, Saverio La Bella, Armando Di Ludovico, Francesco Chiarelli, and Luciana Breda

Subjects
Disease activity, C reactive protein to albumin ratio, Juvenile idiopathic arthritis, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Introduction Recent works in the scientific literature reported the role of C reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) as biomarkers of disease activity in rheumatic diseases. Objectives To investigate the role of CAR, PLR and NLR as potential markers of disease activity in children with non-systemic JIA (nsJIA) and their correlation with the risk of persistent disease activity of flare during follow up. Methods Our prospective, cross-sectional study involved 130 nsJIA patients (74 with active disease and 56 with inactive disease according to Wallace criteria) and 62 healthy controls. Demographic, clinical and laboratory data were collected at baseline (T0) and at 3 (T1), 6 (T2), 12 (T3) and 18 months (T4) during follow up. Disease activity was evaluated through Juvenile Arthritis Disease Activity Score (JADAS-27). Results At baseline, CRP and CAR were higher in patients than in controls (p = 0.046), while no differences were found for NLR and PLR. However, there was no positive correlation between CAR, NLR, PLR and JADAS-27 in JIA patients. To better investigate the role of CAR, NLR and PLR as markers of disease activity, we used a generalized estimating equation (GEE) model, applied to all patients either with or without active disease. According to this analysis, CAR and NLR baseline levels were predictive of higher risk of disease activity at 6 months follow up (p

Published
2024
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3. Effectiveness and Safety of Biosimilars in Pediatric Non-infectious Uveitis: Real-Life Data from the International AIDA Network Uveitis Registry

Author

Maria Tarsia, Antonio Vitale, Carla Gaggiano, Jurgen Sota, Anna Maselli, Chiara Bellantonio, Silvana Guerriero, Rosanna Dammacco, Francesco La Torre, Gaafar Ragab, Mohamed Tharwat Hegazy, Alex Fonollosa, Maria Pia Paroli, Emanuela Del Giudice, Maria Cristina Maggio, Marco Cattalini, Lampros Fotis, Giovanni Conti, Angela Mauro, Adele Civino, Federico Diomeda, Alejandra de-la-Torre, Carlos Cifuentes-González, Samar Tharwat, José Hernández-Rodríguez, Verónica Gómez-Caverzaschi, Laura Pelegrín, Kalpana Babu, Vishali Gupta, Francesca Minoia, Piero Ruscitti, Stefania Costi, Luciana Breda, Saverio La Bella, Alessandro Conforti, Maria Antonietta Mazzei, Ester Carreño, Rana Hussein Amin, Salvatore Grosso, Bruno Frediani, Gian Marco Tosi, Alberto Balistreri, Luca Cantarini, and Claudia Fabiani

Subjects
Adverse events, Biosimilars, Drug retention rate, Pediatric uveitis, Steroid-sparing effect, Tumor necrosis factor (TNF)-inhibitors, Ophthalmology, RE1-994
Abstract

Abstract Introduction Since many biological drug patents have expired, biosimilar agents (BIOs) have been developed; however, there are still some reservations in their use, especially in childhood. The aim of the current study is to evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibitors BIOs as treatment for pediatric non-infectious uveitis (NIU). Methods Data from pediatric patients with NIU treated with TNF inhibitors BIOs were drawn from the international AutoInflammatory Disease Alliance (AIDA) registries dedicated to uveitis and Behçet's disease. The effectiveness and safety of BIOs were assessed in terms of frequency of relapses, risk for developing ocular flares, best-corrected visual acuity (BCVA), glucocorticoids (GCs)-sparing effect, drug survival, frequency of ocular complications, and adverse drug event (AE). Results Forty-seven patients (77 affected eyes) were enrolled. The BIOs employed were adalimumab (ADA) (89.4%), etanercept (ETA) (5.3%), and infliximab (IFX) (5.3%). The number of relapses 12 months prior to BIOs and at last follow-up was 282.14 and 52.43 per 100 patients/year. The relative risk of developing ocular flares before BIOs introduction compared to the period following the start of BIOs was 4.49 (95% confidence interval [CI] 3.38–5.98, p = 0.004). The number needed to treat (NNT) for ocular flares was 3.53. Median BCVA was maintained during the whole BIOs treatment (p = 0.92). A significant GCs-sparing effect was observed throughout the treatment period (p = 0.002). The estimated drug retention rate (DRR) at 12-, 24-, and 36-month follow-up were 92.7, 83.3, and 70.8%, respectively. The risk rate for developing structural ocular complications was 89.9/100 patients/year before starting BIOs and 12.7/100 patients/year during BIOs treatment, with a risk ratio of new ocular complications without BIOs of 7.1 (CI 3.4–14.9, p = 0.0003). Three minor AEs were reported. Conclusions TNF inhibitors BIOs are effective in reducing the number of ocular uveitis relapses, preserving visual acuity, allowing a significant GCs-sparing effect, and preventing structural ocular complications. Trial Registration ClinicalTrials.gov ID NCT05200715.

Published
2024
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4. The Diagnostic Role of Skin Manifestations in Rheumatic Diseases in Children: A Critical Review of Paediatric Vasculitis

Author

Armando Di Ludovico, Marta Rinaldi, Federico Lauriola, Francesca Ciarelli, Saverio La Bella, Giulio Gualdi, Francesco Chiarelli, Kathryn Bailey, and Luciana Breda

Subjects
vasculitis, skin, paediatric, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Skin lesions are frequently observed in children with rheumatic diseases, particularly in conditions such as IgA vasculitis (IgAV) and Kawasaki disease (KD). In paediatric vasculitis, the presence of skin lesions serves as an early indicator, emphasising the importance of timely diagnosis to prevent complications, such as cardiac or renal involvement. Conversely, autoinflammatory disorders like juvenile systemic lupus erythematosus (SLE) and juvenile dermatomyositis (DM) may manifest with cutaneous manifestations either at the onset of disease or during its progression. Identifying these skin lesions prior to the appearance of systemic symptoms offers an opportunity for early diagnosis and treatment, which has a positive influence on the outcomes. Additionally, it is noteworthy that specific rheumatological conditions, such as acute rheumatic fever (ARF) or oligoarticular or polyarticular forms of juvenile idiopathic arthritis (JIA), may exhibit occasional, but significant skin involvement, which is strongly correlated with an unfavourable prognosis. The assessment of skin is important in the holist approach to assessing patients for potentially systemic/multisystem disorder and helps distinguish discrete conditions.

Published
2024
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5. The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases

Author

Saverio La Bella, Armando Di Ludovico, Giulia Di Donato, Ozge Basaran, Seza Ozen, Marco Gattorno, Francesco Chiarelli, and Luciana Breda

Subjects
pyrin, inflammasome, familial Mediterranean fever, FMF, autoinflammatory diseases, IL-1, Immunologic diseases. Allergy, RC581-607
Abstract

The activation of the pyrin inflammasome represents a highly intriguing mechanism employed by the innate immune system to effectively counteract pathogenic agents. Despite its key role in innate immunity, pyrin has also garnered significant attention due to its association with a range of autoinflammatory diseases (AIDs) including familial Mediterranean fever caused by disruption of the MEFV gene, or in other genes involved in its complex regulation mechanisms. Pyrin activation is strictly dependent on homeostasis-altering molecular processes, mostly consisting of the disruption of the small Ras Homolog Family Member A (RhoA) GTPases by pathogen toxins. The downstream pathways are regulated by the phosphorylation of specific pyrin residues by the kinases PKN1/2 and the binding of the chaperone 14-3-3. Furthermore, a key role in pyrin activation is played by the cytoskeleton and gasdermin D, which is responsible for membrane pores in the context of pyroptosis. In addition, recent evidence has highlighted the role of steroid hormone catabolites and alarmins S100A8/A9 and S100A12 in pyrin-dependent inflammation. The aim of this article is to offer a comprehensive overview of the most recent evidence on the pyrin inflammasome and its molecular pathways to better understand the pathogenesis behind the significant group of pyrin-related AIDs.

Published
2024
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6. Molecular Mechanisms of Fetal and Neonatal Lupus: A Narrative Review of an Autoimmune Disease Transferal across the Placenta

Author

Armando Di Ludovico, Marta Rinaldi, Francesca Mainieri, Stefano Di Michele, Virginia Girlando, Francesca Ciarelli, Saverio La Bella, Francesco Chiarelli, Marina Attanasi, Angela Mauro, Emanuele Bizzi, Antonio Brucato, and Luciana Breda

Subjects
neonatal lupus erythematosus, congenital heart block, autoantibodies, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

This study, conducted by searching keywords such as “maternal lupus”, “neonatal lupus”, and “congenital heart block” in databases including PubMed and Scopus, provides a detailed narrative review on fetal and neonatal lupus. Autoantibodies like anti-Ro/SSA and anti-La/SSB may cross the placenta and cause complications in neonates, such as congenital heart block (CHB). Management options involve hydroxychloroquine, which is able to counteract some of the adverse events, although the drug needs to be used carefully because of its impact on the QTc interval. Advanced pacing strategies for neonates with CHB, especially in severe forms like hydrops, are also assessed. This review emphasizes the need for interdisciplinary care by rheumatologists, obstetricians, and pediatricians in order to achieve the best maternal and neonatal health in lupus pregnancies. This multidisciplinary approach seeks to improve the outcomes and management of the disease, decreasing the burden on mothers and their infants.

Published
2024
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7. Clinical and Instrumental Temporomandibular Joint Evaluation in Children and Adolescents with Juvenile Idiopathic Arthritis: A Medium-Term Follow-Up

Author

Federica Maria Migliore, Luciana Breda, Erica Di Maria, Francesca Battestini, Beatrice Di Carlo, and Michele D’Attilio

Subjects
juvenile idiopathic arthritis, temporomandibular joint, electromyography, temporomandibular disorders, masticatory muscles, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

(1) Background: The aim of the study was to assess the potential effectiveness of clinical diagnostic examinations, such as muscle palpation, and instrumental examinations, such as electromyography, in the early detection of TMJ involvement in patients with juvenile idiopathic arthritis (JIA), as early diagnosis of these disorders can reduce the risk of developing facial growth anomalies and dento-skeletal malocclusions. (2) Methods: Evaluations were conducted on a cohort of 15 people with juvenile idiopathic arthritis (JIA) and a comparison group of 15 healthy participants at the start of the trial (T0) and after 18 ± 6 months (T1). Data were obtained through clinical examination, involving muscle palpation of the anterior temporalis, masseters, and sternocleidomastoids, and by instrumental analysis using electromyography. The parametric student’s t-test was used to evaluate group comparisons for data that were normally distributed, whereas the nonparametric Mann–Whitney U test was employed for parameters that did not follow a normal distribution. (3) Results: In the JIA group, higher levels of pain were recorded in the sternocleidomastoid muscles on both sides as compared to the control group (p < 0.05) at both T0 and T1. Electromyography revealed no statistically significant variances both in the JIA group and in the control group, except for the IMP index, characterized by a significant improvement over time for the JIA group. (4) Conclusions: According to the methodology employed in this study, all JIA patients had TMD symptoms, mainly muscle disorders. The existence of statistically significant parameters suggests the potential to regard muscle palpation and electromyography as predictive indicators of TMJ involvement in JIA subjects. Additional research is required to validate their reliability.

Published
2023
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8. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Syndrome: A 10-Year Retrospective Cohort Study in an Italian Centre of Pediatric Rheumatology

Author

Saverio La Bella, Marina Attanasi, Armando Di Ludovico, Giovanna Scorrano, Francesca Mainieri, Francesca Ciarelli, Federico Lauriola, Luisa Silvestrini, Virginia Girlando, Francesco Chiarelli, and Luciana Breda

Subjects
PANDAS, PANDAS syndrome, streptococcus, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, antibiotics, GAS, Biology (General), QH301-705.5
Abstract

Background. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is a rare pediatric disorder consisting of a sudden onset of obsessive–compulsive disorder (OCD) and/or tics after a group A Streptococcus (GAS) infection. Methods. In the period between 2013 and 2023, 61 children presented to our Pediatric Rheumatology unit with a suspicion of PANDAS syndrome. Among these, a retrospective analysis was conducted, and 19 fulfilled the current classification criteria and were included in this study. Results. The male-to-female ratio was 14:5, the median age at onset was 7.0 (2.0–9.5) years, and the median age at diagnosis was 8.0 (3.0–10.4) years. The median follow-up period was 16.0 (6.0–72.0) months. Family and personal history were relevant in 7/19 and 6/19 patients. Tics were present in all patients. Details for motor tics were retrospectively available in 18/19 patients, with the eyes (11/18) and neck/head (10/18) being most often involved. Vocal tics were documented in 8/19, behavioral changes in 10/19, and OCD in 2/19. Regarding the therapeutic response, all patients responded to amoxicillin, 12/13 to benzathine benzylpenicillin, and 7/9 to azithromycin. Conclusions. Our findings partially overlap with previous reports. Larger prospective studies are needed to improve treatment strategies and classification criteria.

Published
2023
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9. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Myth or Reality? The State of the Art on a Controversial Disease

Author

Saverio La Bella, Giovanna Scorrano, Marta Rinaldi, Armando Di Ludovico, Francesca Mainieri, Marina Attanasi, Alberto Spalice, Francesco Chiarelli, and Luciana Breda

Subjects
PANDAS, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections, PANDAS syndrome, neuropsychiatric disorder, streptococci, streptococcal infection, Biology (General), QH301-705.5
Abstract

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is one of the most controversial diseases in pediatric rheumatology. Despite first being described more than 25 years ago as the sudden and rapid onset of obsessive–compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine release in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations.

Published
2023
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10. Preliminary data revealing efficacy of Streptococcus salivarius K12 (SSK12) in Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome: A multicenter study from the AIDA Network PFAPA syndrome registry

Author

Francesco La Torre, Jurgen Sota, Antonella Insalaco, Giovanni Conti, Emanuela Del Giudice, Riccardo Lubrano, Luciana Breda, Maria Cristina Maggio, Adele Civino, Violetta Mastrorilli, Roberta Loconte, Marco Francesco Natale, Camilla Celani, Mery Romeo, Serena Patroniti, Cristina Gentile, Antonio Vitale, Valeria Caggiano, Carla Gaggiano, Federico Diomeda, Marco Cattalini, Giuseppe Lopalco, Giacomo Emmi, Paola Parronchi, Stefano Gentileschi, Fabio Cardinale, Emma Aragona, Farhad Shahram, Achille Marino, Patrizia Barone, Carla Moscheo, Burcugul Ozkiziltas, Francesco Carubbi, Ohoud Alahmed, Ludovica Iezzi, Benson Ogunjimi, Angela Mauro, Maria Tarsia, Ayman Abdel-Monem Ahmed Mahmoud, Henrique Ayres Mayrink Giardini, Petros P. Sfikakis, Katerina Laskari, Ewa Więsik-Szewczyk, José Hernández-Rodríguez, Bruno Frediani, Verónica Gómez-Caverzaschi, Abdurrahman Tufan, Ibrahim A. Almaghlouth, Alberto Balistreri, Gaafar Ragab, Claudia Fabiani, Luca Cantarini, and Donato Rigante

Subjects
PFAPA syndrome, autoinflammatory disease, International Registry, Streptococcus salivarius K12, probiotic, tonsillitis, Medicine (General), R5-920
Abstract

ObjectiveTo evaluate the potential role of Streptococcus salivarius K12 (SSK12) in controlling febrile flares in patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Further aims were to assess the impact of SSK12 on (i) flare duration, (ii) variation in the degree of the highest body temperature during flares, (iii) steroid-sparing effect, and (iv) change of PFAPA accompanying symptoms before and after SSK12 introduction.Patients and methodsThe medical charts from 85 pediatric patients with PFAPA syndrome (49 males and 36 females) enrolled in the AIDA registry and treated with SSK12 for a median period of 6.00 ± 7.00 months in the period between September 2017 and May 2022 were examined. Children recruited had a median time of disease duration of 19.00 ± 28.00 months.ResultsThe number of febrile flares significantly decreased comparing the 12 months before [median (IQR), 13.00 (6.00)] and after SSK12 initiation [median (IQR), 5.50 (8.00), p < 0.001]. The duration of fever was significantly reduced from 4.00 (2.00) days to 2.00 (2.00) days [p < 0.001]. Similarly, the highest temperature in°C was found significantly lower in the last follow-up assessment [median (IQR), 39.00 (1.00)] compared to the period prior to SSK12 start [median (IQR), 40.00 (1.00), p < 0.001]. Steroid load (mg/year) of betamethasone (or any equivalent steroid) significantly decreased between 12 months before treatment with SSK12 [median (IQR), 5.00 (8.00) mg/year] and the last follow-up visit [median (IQR), 2.00 (4.00) mg/year, p < 0.001]. The number of patients experiencing symptoms including pharyngitis/tonsillitis (p < 0.001), oral aphthae (p < 0.001) and cervical lymphadenopathy (p < 0.001) significantly decreased following SSK12.ConclusionSSK12 prophylaxis given for at least 6.00 months was found to reduce febrile flares of PFAPA syndrome: in particular, it halved the total number per year of fever flares, shortened the duration of the single febrile episode, lowered body temperature by 1°C in the febrile flare, provided a steroid-sparing effect, and significantly reduced the accompanying symptoms related to the syndrome.

Published
2023
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11. Pain Evaluation and Treatment in Children: A Practical Approach

Author

Lorenzo Sansone, Cristina Gentile, Eleonora Agata Grasso, Armando Di Ludovico, Saverio La Bella, Francesco Chiarelli, and Luciana Breda

Subjects
children, pain, pain management, assessment scales, analgesic agents, non-pharmacological techniques, Pediatrics, RJ1-570
Abstract

Pain is the most common complaint reported by children who access the emergency departments, but despite its frequency and the availability of many international guidelines, it often remains underreported and undertreated. Recently, the American Academy of Pediatrics and the American Pain Society have reiterated the importance of a multidisciplinary approach in order to eliminate pain in children. In all pediatric settings, an adequate assessment is the initial stage in a proper clinical approach to pain, especially in the emergency departments; therefore, an increasing number of age-related tools have been validated. A wide range of analgesic agents are currently available for pain management, and they should be tailored according to the patient’s age, the drug’s pharmacokinetics and the intensity of pain. In order to facilitate the choice of the appropriate drug, a treatment algorithm based on a ladder approach can be used. Moreover, non-pharmacological techniques should be considered to alleviate anxiety and distress in pediatric age. This review aims to offer a simple but intuitive description of the best strategies for pain relief in children, starting with the prompt recognition and quantification of pain through adequate assessment scales, and following with the identification of the most appropriate therapeutic choice among the ones available for pediatric age.

Published
2023
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12. Growth and puberty in children with juvenile idiopathic arthritis

Author

Debora Mariarita d’Angelo, Giulia Di Donato, Luciana Breda, and Francesco Chiarelli

Subjects
Juvenile idiopathic arthritis, Puberty, Growth, Bone, Hormone replacement therapy, Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Juvenile Idiopathic Arthritis is one of the most prevalent chronic diseases in children, with an annual incidence of 2–20 cases per 100,000 and a prevalence of 16–150 per 100,000. It is associated with several complications that can cause short-term or long-term disability and reduce the quality of life. Among these, growth and pubertal disorders play an important role. Chronic inflammatory conditions are often associated with growth failure ranging from slight decrease in height velocity to severe forms of short stature. The prevalence of short stature in JIA varies from 10.4% in children with polyarticular disease to 41% of patients with the systemic form, while oligoarthritis is mostly associated with localized excessive bone growth of the affected limb, leading to limb dissymmetry. The pathogenesis of growth disorders is multifactorial and includes the role of chronic inflammation, long-term use of corticosteroids, undernutrition, altered body composition, delay of pubertal onset or slow pubertal progression. These factors can exert a systemic effect on the GH/IGF-1 axis and on the GnRH-gonadotropin-gonadic axis, or a local influence on the growth plate homeostasis and function. Although new therapeutic options are available to control inflammation, there are still 10–20% of patients with severe forms of the disease who show continuous growth impairment, ending in a short final stature. Moreover, delayed puberty is associated with a reduction in the peak bone mass with the possibility of concomitant or future bone fragility. Monitoring of puberty and bone health is essential for a complete health assessment of adolescents with JIA. In these patients, an assessment of the pubertal stage every 6 months from the age of 9 years is recommended. Also, linear growth should be always evaluated considering the patient’s bone age. The impact of rhGH therapy in children with JIA is still unclear, but it has been shown that if rhGH is added at high dose in a low-inflammatory condition, post steroids and on biologic therapy, it is able to favor a prepubertal growth acceleration, comparable with the catch-up growth response in GH-deficient patients. Here we provide a comprehensive review of the pathogenesis of puberty and growth disorders in children with JIA, which can help the pediatrician to properly and timely assess the presence of growth and pubertal disorders in JIA patients.

Published
2021
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13. Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis

Author

Saverio La Bella, Marta Rinaldi, Armando Di Ludovico, Giulia Di Donato, Giulio Di Donato, Vincenzo Salpietro, Francesco Chiarelli, and Luciana Breda

Subjects
juvenile idiopathic arthritis, JIA, molecular mechanisms, paediatric rheumatology, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in the paediatric population. JIA comprises a heterogeneous group of disorders with different onset patterns and clinical presentations with the only element in common being chronic joint inflammation. This review sought to evaluate the most relevant and up-to-date evidence on current knowledge regarding the pathogenesis of JIA subtypes to provide a better understanding of these disorders. Despite significant improvements over the past decade, the aetiology and molecular mechanisms of JIA remain unclear. It has been suggested that the immunopathogenesis is characterised by complex interactions between genetic background and environmental factors that may differ between JIA subtypes. Human leukocyte antigen (HLA) haplotypes and non-HLA genes play a crucial role in the abnormal activation of both innate and adaptive immune cells that cooperate in causing the inflammatory process. This results in the involvement of proinflammatory cytokines, including tumour necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-10, IL-17, IL-21, IL-23, and others. These mediators, interacting with the surrounding tissue, cause cartilage stress and bone damage, including irreversible erosions. The purpose of this review is to provide a comprehensive overview of the genetic background and molecular mechanisms of JIA.

Published
2023
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14. The Role of Serum Calprotectin in Defining Disease Outcomes in Non-Systemic Juvenile Idiopathic Arthritis: A Pilot Study

Author

Debora Mariarita d’Angelo, Marina Attanasi, Giulia Di Donato, Giuseppe Lapergola, Mariarosaria Flacco, Francesco Chiarelli, Emma Altobelli, and Luciana Breda

Subjects
juvenile idiopathic arthritis, children, serum calprotectin, disease activity, S100 protein, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Serum calprotectin (MRP8/14) is currently being studied as a promising biomarker of disease activity and outcome in patients with juvenile idiopathic arthritis (JIA) but the data in the literature are conflicting. The aim of our study was to investigate the potential role of serum calprotectin as biomarker of disease activity and flare/remission in a group of nsJIA patients during a follow-up period of 18 months. In this prospective longitudinal study, two groups of patients with ns-JIA (55 active patients and 56 patients in remission according to Wallace’s criteria) and a control group (50 children) were recruited at baseline from January 2020 to September 2021. JIA patients were followed for up to 18 months at four timepoints: 3 months (T1), 6 months (T2), 12 months (T3) and 18 months (T4). At each timepoint, the following were recorded: JADAS27, blood counts, ESR, CRP, albumin, ferritin and serum calprotectin. To illustrate the performance of calprotectin, Kaplan–Meier curves were constructed from baseline to relapse/remission, dichotomizing patients at baseline in positive/negative on the basis progressive calprotectin cut-offs. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates. Comparing baseline clinical and laboratory data of the three groups (active vs. inactive JIA vs. controls), only serum calprotectin reached statistical significance (active patients vs. inactive (p = 0.0016) and vs. controls (p = 0.0012)). In the inactive group, during the 18 months of follow up, 31 patients (55.3%) had a relapse. Comparing the baseline data of relapsers vs. non-relapsers, serum calprotectin showed higher levels (p = 0.001) in relapsers. In survival analysis, a log rank test showed significant differences of up to 12 ng/mL (p = 0.045). Multivariate Cox regression confirmed that only baseline calprotectin levels were independently associated with disease recurrence. In the active group, in the 12 months of follow-up, 19 patients (38%) entered remission of the disease. In addition, in this group, the only statistical difference at the baseline was the value of MPR8/14 (p = 0.0001). Log rank test showed significant differences up to 10 ng/mL (p = 0.003). In the multivariate Cox regression, serum calprotectin levels at baseline were independently associated with remission. In conclusion, our study would suggest a dual role for calprotectin in predicting future relapse and treatment response in patients with nsJIA, thus influencing therapeutic decisions and management of these patients during follow up.

Published
2023
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15. Etanercept treatment for extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis: 6-year efficacy and safety data from an open-label trial

Author

Ivan Foeldvari, Tamàs Constantin, Jelena Vojinović, Gerd Horneff, Vyacheslav Chasnyk, Joke Dehoorne, Violeta Panaviene, Gordana Sušić, Valda Stanevicha, Katarzyna Kobusinska, Zbigniew Zuber, Bogna Dobrzyniecka, Irina Nikishina, Brigitte Bader-Meunier, Luciana Breda, Pavla Doležalová, Chantal Job-Deslandre, Ingrida Rumba-Rozenfelde, Nico Wulffraat, Ronald D. Pedersen, Jack F. Bukowski, Bonnie Vlahos, Alberto Martini, Nicolino Ruperto, and for the Paediatric Rheumatology International Trials Organisation (PRINTO)

Subjects
Etanercept, Juvenile idiopathic arthritis, Enthesitis-related arthritis, Extended oligoarticular juvenile idiopathic arthritis (eoJIA), Enthesitis-related arthritis (ERA), Psoriatic arthritis (PsA), Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) Methods Patients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). Results Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin’s lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. Conclusions Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. Trial registration ClinicalTrials.gov: CLIPPER, NCT00962741, registered 20 August, 2009, CLIPPER2, NCT01421069, registered 22 August, 2011.

Published
2019
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16. Type I Interferonopathies in Children: An Overview

Author

Debora M. d'Angelo, Paola Di Filippo, Luciana Breda, and Francesco Chiarelli

Subjects
autoinflammatory disease, type I interferon (IFN) signaling, Aicardi-Goutières syndrome, Janus kinase inhibitors, innate immunity, interferon, Pediatrics, RJ1-570
Abstract

Notable advances in gene sequencing methods in recent years have permitted enormous progress in the phenotypic and genotypic characterization of autoinflammatory syndromes. Interferonopathies are a recent group of inherited autoinflammatory diseases, characterized by a dysregulation of the interferon pathway, leading to constitutive upregulation of its activation mechanisms or downregulation of negative regulatory systems. They are clinically heterogeneous, but some peculiar clinical features may lead to suspicion: a familial “idiopathic” juvenile arthritis resistant to conventional treatments, an early necrotizing vasculitis, a non-infectious interstitial lung disease, and a panniculitis associated or not with a lipodystrophy may represent the “interferon alarm bells.” The awareness of this group of diseases represents a challenge for pediatricians because, despite being rare, a differential diagnosis with the most common childhood rheumatological and immunological disorders is mandatory. Furthermore, the characterization of interferonopathy molecular pathogenetic mechanisms is allowing important steps forward in other immune dysregulation diseases, such as systemic lupus erythematosus and inflammatory myositis, implementing the opportunity of a more effective target therapy.

Published
2021
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17. Bone Health in Children with Rheumatic Disorders: Focus on Molecular Mechanisms, Diagnosis, and Management

Author

Francesca Di Marcello, Giulia Di Donato, Debora Mariarita d’Angelo, Luciana Breda, and Francesco Chiarelli

Subjects
bone health, cartilage-bone interaction, secondary osteoporosis, rheumatic diseases, glucocorticoids, children, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Bone is an extremely dynamic and adaptive tissue, whose metabolism and homeostasis is influenced by many different hormonal, mechanical, nutritional, immunological and pharmacological stimuli. Genetic factors significantly affect bone health, through their influence on bone cells function, cartilage quality, calcium and vitamin D homeostasis, sex hormone metabolism and pubertal timing. In addition, optimal nutrition and physical activity contribute to bone mass acquisition in the growing age. All these factors influence the attainment of peak bone mass, a critical determinant of bone health and fracture risk in adulthood. Secondary osteoporosis is an important issue of clinical care in children with acute and chronic diseases. Systemic autoimmune disorders, like juvenile idiopathic arthritis, can affect the skeletal system, causing reduced bone mineral density and high risk of fragility fractures during childhood. In these patients, multiple factors contribute to reduce bone strength, including systemic inflammation with elevated cytokines, reduced physical activity, malabsorption and nutritional deficiency, inadequate daily calcium and vitamin D intake, use of glucocorticoids, poor growth and pubertal delay. In juvenile arthritis, osteoporosis is more prominent at the femoral neck and radius compared to the lumbar spine. Nevertheless, vertebral fractures are an important, often asymptomatic manifestation, especially in glucocorticoid-treated patients. A standardized diagnostic approach to the musculoskeletal system, including prophylaxis, therapy and follow up, is therefore mandatory in at risk children. Here we discuss the molecular mechanisms involved in skeletal homeostasis and the influence of inflammation and chronic disease on bone metabolism.

Published
2022
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18. Electromyographic Activity of Masticatory Muscles in Subjects with Juvenile Idiopathic Arthritis: A Case—Control Study

Author

Francesco Caroccia, Ludovica Passanello, Rossana Pipitone, Francesco Moscagiuri, Paolo Asperio, Alessandra Lucchese, Luciana Breda, and Michele D’Attilio

Subjects
juvenile idiopathic arthritis, temporomandibular joint, temporomandibular disorders, electromyography, masticatory muscles, Mathematics, QA1-939
Abstract

The aim of this study was to evaluate the effect of juvenile idiopathic arthritis (JIA) on the activity of masticatory muscles using surface electromyography (sEMG). Forty-one JIA subjects (ten males, thirty-one females; average age 13 years ± 3) and thirty-two healthy control subjects (twenty-seven females, five males; average age 14 years ± 2) were recruited. sEMG of anterior temporalis (TA), masseter (MM), and sternocleidomastoid (SCM) muscles was performed by using the occlusal contact analyzer software called Teethan (BTS S.p.A., Garbagnate Milanese, Milan, Italy). Comparisons between groups were assessed with unpaired t-tests for non-normally distributed data and with Mann–Whitney U tests for normally distributed parameters. The JIA group showed a significant increased percentage overlapping coefficient of TA (POC TA) (p = 0.01) and impact index (IMP) (p = 0.003). No significant differences were observed for the POC MM, POC SCM, percentage overlapping coefficient between posterior and anterior teeth contact (BAR), the torsion index (TORS), and the asymmetry index (ASIM). Masticatory muscles seemed to be slightly affected by JIA. sEMG could be an effective aid in the early clinical detection of TMJ involvement in JIA. Further research is needed to confirm its validity.

Published
2022
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20. Clinical and Instrumental TMJ Evaluation in Children and Adolescents with Juvenile Idiopathic Arthritis: A Case—Control Study

Author

Michele D’Attilio, Beatrice Di Carlo, Francesco Caroccia, Francesco Moscagiuri, Debora Mariarita d’Angelo, Francesco Chiarelli, Felice Festa, and Luciana Breda

Subjects
juvenile idiopathic arthritis, temporomandibular joint, electromyography, kinesiography, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

To investigate temporomandibular joint (TMJ) involvement signs such as muscle pain, the ratio of masseter and temporal muscle activity, mouth opening width and jaw deviation during mouth opening in children and adolescents with juvenile idiopathic arthritis (JIA), a group of 32 subjects with JIA and a control group of 32 healthy subjects were evaluated. Data were collected clinically by muscle palpation (masseters, anterior temporalis and sternocleidomastoids) and instrumental analysis (electromyography and kinesiography). Higher pain was registered in the masseter and sternocleidomastoid muscles on both sides and in the right anterior temporalis in the JIA group compared to the control group (p < 0.05). Electromyography showed no statistically significant difference in the frequency of the pathological ratio of masseter and temporal muscle activity (MM/TA < 1) both in the JIA group and in the control group. Kinesiography showed a statistically significant difference in mouth opening width and jaw deviation during mouth opening between the groups (p < 0.05): JIA subjects showed lower mouth opening values and wider deviation on mouth opening; 29 out of 32 JIA subjects showed jaw deviation towards the right side. JIA affects the TMJ, causing myalgia in the head and neck muscles, a reduction in mouth opening width and an increase in jaw deviation during mouth opening.

Published
2021
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21. Monogenic Autoinflammatory Diseases: State of the Art and Future Perspectives

Author

Giulia Di Donato, Debora Mariarita d’Angelo, Luciana Breda, and Francesco Chiarelli

Subjects
systemic autoinflammatory diseases, inflammasomopathies, interferonopathies, periodic fever, next generation sequencing, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways. In most cases, they have a strong genetic background, with mutations in single genes involved in inflammation. Therefore, they can derive from different pathogenic mechanisms at any level, such as dysregulated inflammasome-mediated production of cytokines, intracellular stress, defective regulatory pathways, altered protein folding, enhanced NF-kappaB signalling, ubiquitination disorders, interferon pathway upregulation and complement activation. Since the discover of pathogenic mutations of the pyrin-encoding gene MEFV in Familial Mediterranean Fever, more than 50 monogenic autoinflammatory diseases have been discovered thanks to the advances in genetic sequencing: the advent of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have allowed a better understanding of the underlying innate immunologic pathways and pathogenetic mechanisms, thus opening new perspectives in targeted therapies. Moreover, this field of research has become of great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently active or recently concluded, allowing us to hope for considerable acquisitions for the next few years. General paediatricians need to be aware of the importance of this group of diseases and they should consider autoinflammatory diseases in patients with clinical hallmarks, in order to guide further examinations and refer the patient to a specialist rheumatologist. Here we resume the pathogenesis, clinical aspects and diagnosis of the most important autoinflammatory diseases in children.

Published
2021
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22. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part one

Author

F. De Benedetti, J. Anton, M. Gattorno, H. Lachmann, I. Kone-Paut, S. Ozen, J. Frenkel, A. Simon, A. Zeft, E. Ben-Chetrit, H. M. Hoffman, Y. Joubert, K. Lheritier, A. Speziale, J. Guido, Roberta Caorsi, Federica Penco, Alice Grossi, Antonella Insalaco, Maria Alessio, Giovanni Conti, Federico Marchetti, Alberto Tommasini, Silvana Martino, Romina Gallizzi, Annalisa Salis, Francesca Schena, Francesco Caroli, Alberto Martini, Gianluca Damonte, Isabella Ceccherini, Marco Gattorno, Marie-Louise Frémond, Carolina Uggenti, Lien Van Eyck, Isabelle Melki, Darragh Duffy, Vincent Bondet, Yoann Rose, Bénédicte Neven, Yanick Crow, Mathieu P. Rodero, Yvonne Kusche, Johannes Roth, Katarzyna Barczyk-Kahlert, Giovanna Ferrara, Annalisa Chiocchetti, Silvio Polizzi, Josef Vuch, Diego Vozzi, Anna Mondino, Erica Valencic, Serena Pastore, Andrea Taddio, Flavio Faletra, Umberto Dianzani, Ugo Ramenghi, Qing Zhou, Xiaomin Yu, Erkan Demirkaya, Natalie Deuitch, Deborah Stone, Wanxia Tsai, Amanda Ombrello, Tina Romeo, Elaine F. Remmers, JaeJin Chae, Massimo Gadina, Steven Welch, Seza Ozen, Rezan Topaloglu, Mario Abinun, Daniel L. Kastner, Ivona Aksentijevich, Donatella Vairo, Rosalba Monica Ferraro, Giulia Zani, Jessica Galli, Micaela De Simone, Marco Cattalini, Elisa Fazzi, Silvia Giliani, Ebun Omoyinmi, Ariane Standing, Dorota Rowczenio, Annette Keylock, Sonia Melo Gomes, Fiona Price-Kuehne, Sira Nanthapisal, Claire Murphy, Thomas Cullup, Lucy Jenkins, Kimberly Gilmour, Despina Eleftheriou, Helen Lachmann, Philip Hawkins, Nigel Klein, Paul Brogan, Anita Dhanrajani, Mercedes Chan, Stephanie Pau, Janet Ellsworth, Jaime Guzman, Florence A. Aeschlimann, Marinka Twilt, Simon W. Eng, Shehla Sheikh, Ronald M. Laxer, Diane Hebert, Damien Noone, Christian Pagnoux, Susanne M. Benseler, Rae S. Yeung, Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Niklas Grün, Dirk Föll, Pieter Van Dijkhuizen, Federica Del Chierico, Clara Malattia, Alessandra Russo, Denise Pires Marafon, Nienke M. ter Haar, Silvia Magni-Manzoni, Sebastiaan J. Vastert, Bruno Dallapiccola, Berent Prakken, Fabrizio De Benedetti, Lorenza Putignani, Berna Eren Fidanci, Kenan Barut, Serap Arıcı, Dogan Simsek, Mustafa Cakan, Ezgi D. Batu, Sezgin Şahin, Ayşenur Kısaarslan, Ebru Yilmaz, Özge Basaran, Ferhat Demir, Kubra Ozturk, Zübeyde Gunduz, Betül Sozeri, Balahan Makay, Nuray Ayaz, Onder Yavascan, Ozlem Aydog, Yelda Bilginer, Zelal Ekinci, Dilek Yıldız, Faysal Gök, Muferret Erguven, Erbil Unsal, Ozgur Kasapcopur, For the FMF Arthritis Vasculitis and Orphan Disease Research in Paediatric Rheumatology (FAVOR), Hafize E. Sönmez, Betül Sözeri, Yonatan Butbul, Seza Özen, Claudia Bracaglia, Giusi Prencipe, Manuela Pardeo, Geneviève Lapeyre, Emiliano Marasco, Walter Ferlin, Robert Nelson, Cristina de Min, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, K. Marzan, N. Wulffraat, R. Schneider, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Stefano Volpi, Claudia Pastorino, Francesca Kalli, Alessia Omenetti, Sabrina Chiesa, Arinna Bertoni, Paolo Picco, Gilberto Filaci, Elisabetta Traggiai, Marie-Louise Fremond, Naoki Kitabayashi, Olivero Sacco, Isabelle Meyts, Marie-Anne Morren, Carine Wouters, Eric Legius, Isabelle Callebaut, Christine Bodemer, Frederic Rieux-Laucat, Mathieu Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Didier Bessis, Guilhem Cros, Gillian I. Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Frédéric Rieux-Laucat, K. Annink, N. ter Haar, S. Al-Mayouf, G. Amaryan, K. Barron, S. Benseler, P. Brogan, L. Cantarini, M. Cattalini, A. Cochino, F. Dedeoglu, A. De Jesus, O. Dellacasa, E. Demirkaya, P. Dolezalova, K. Durrant, G. Fabio, R. Gallizzi, R. Goldbach-Mansky, E. Hachulla, V. Hentgen, T. Herlin, M. Hofer, H. Hoffman, A. Insalaco, A. Jansson, I. Koné-Paut, A. Kozlova, J. Kuemmerle-Deschner, R. Laxer, S. Nielsen, I. Nikishina, A. Ombrello, E. Papadopoulou-Alataki, A. Ravelli, D. Rigante, R. Russo, Y. Uziel, Nienke ter Haar, Jerold Jeyaratnam, Anna Simon, Matteo Doglio, Jordi Anton, Consuelo Modesto, Pierre Quartier, Esther Hoppenreijs, Luca Cantarini, Loredana Lepore, Inmaculada Calvo Penades, Christina Boros, Rita Consolini, Donato Rigante, Ricardo Russo, Jana Pachlopnik Schmid, Thirusha Lane, Nicolino Ruperto, Joost Frenkel, Chiara Passarelli, Elisa Pisaneschi, Virginia Messia, Antonio Novelli, Fabrizio Debenedetti, P. A. Brogan, X. Wei, Martina Finetti, Francesca Orlando, Elisabetta Cortis, Angela Miniaci, Nicola Ruperto, Charlotte Eijkelboom, Pavla Dolezalova, Isabelle Koné-Paut, Marija Jelusic-Drazic, Liliana Bezrodnik, Mari Carmen Pinedo, Valda Stanevicha, Marielle van Gijn, Silvia Federici, Hermann Girschick, Gerd Ganser, Susan Nielsen, Troels Herlin, Sulaiman Mohammed Al-Mayouf, Michael Hofer, Jasmin Kuemmerle-Deschner, Susanne Schalm, Annette Jansson, on behalf of PRINTO and Eurofever registry, Marta Marchi, Chiara Marini, Angelo Ravelli, Alberto Garaventa, Sonia Carta, Enrica Balza, Patrizia Castellani, Caterina Pellecchia, Silvia Borghini, Maria Libera Trotta, Anna Rubartelli, Andrew Henrey, Thomas Loughin, Roberta Berard, Natalie Shiff, Roman Jurencak, Susanne Benseler, Lori Tucker, on behalf of ReACCh-Out Investigators, Charalampia Papadopoulou, Ying Hong, Petra Krol, Yiannis Ioannou, Clarissa Pilkington, Hema Chaplin, Stephania Simou, Marietta Charakida, Lucy Wedderburn, Lynn R. Spiegel, Sara Ahola Kohut, Jennifer Stinson, Paula Forgeron, Miriam Kaufman, Nadia Luca, Khush Amaria, Mary Bell, J Swart, F. Boris, E. Castagnola, A. Groll, G. Giancane, G. Horneff, H. I. Huppertz, T. Wolfs, E. Alekseeva, V. Panaviene, F. Uettwiller, V. Stanevicha, L. M. Ailioaie, E. Tsitami, S. Kamphuis, G. Susic, F. Sztajnbok, B. Flato, A. Pistorio, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Janet E. McDonagh, Wendy Thomson, Kimme L. Hyrich, CAPS, Maarit Tarkiainen, Pirjo Tynjala, Pekka Lahdenne, Janne Martikainen, Acute-JIA Study Group, Meredyth Wilkinson, Christopher Piper, Georg Otto, Claire T. Deakin, Stefanie Dowle, Stefania Simou, Daniel Kelberman, Claudia Mauri, Elizabeth Jury, David Isenberg, Lucy R. Wedderburn, Kiran Nistala, I. Foeldvari, D. J. Lovell, G. Simonini, M. Bereswill, J. Kalabic, Kiem Oen, Brian M. Feldman, Brenden Dufault, Jennifer Lee, Karen Watanabe Duffy, Ciaran Duffy, ReACCh-Out Investigators, N. Tzaribachev, G. Vega-Cornejo, I. Louw, A. Berman, I. Calvo, R. Cuttica, F. Avila-Zapata, R. Cimaz, E. Solau-Gervais, R. Joos, G. Espada, X. Li, M. Nys, R. Wong, S. Banerjee, For Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology Collaborative Study Group (PRCSG), Rebecca Nicolai, Margherita Verardo, Adele D’Amico, Luisa Bracci-Laudiero, Gian Marco Moneta, Gillian Rice, Anne-Laure Mathieu, Sulliman O. Omarjee, Tracy A. Briggs, James O’Sullivan, Simon Williams, Rolando Cimaz, Eve Smith, Michael W. Beresford, Yanick J. Crow, GENIAL Investigators, UK JSLE Study Group, Madeleine Rooney, Nick Bishop, joyce davidson, Clarissa pilkington, Michael Beresford, Jacqui Clinch, Rangaraj Satyapal, Helen Foster, Janet Gardner Medwin, Janet McDonagh, Sue Wyatt, On Behalf of the British Society for Paediatric and Adolescent Rheumatology, Valentina Litta Modignani, Francesco Baldo, Stefano Lanni, Alessandro Consolaro, Giovanni Filocamo, Helen J. Lachmann, on behalf of Eurofever Registry, Gianmarco Moneta, Camilla Celani, Bilade Cherqaoui, Linda Rossi-Semerano, Perrine Dusser, Véronique Hentgen, Claire Grimwood, Linda Rossi, Isabelle Kone Paut, Veronique Hentgen, Denise Lasigliè, Denise Ferrera, Giulia Amico, Marco Di Duca, Laura Obici, Roberto Ravazzolo, Ryuta Nishikomori, Juan Arostegui, Andrea Petretto, Chiara Lavarello, Elvira Inglese, Federica Vanoni, Michaël Hofer, on behalf of EUROFEVER PROJECT, P. N. Hawkins, T. van der Poll, U. A. Walker, H. H. Tilson, Pascal N. Tyrrell, Raphaela Goldbach-Mansky, Norbert Blank, Hal M. Hoffman, Elisabeth Weissbarth-Riedel, Boris Huegle, Tilmann Kallinich, Ahmet Gul, Marlen Oswald, Fatma Dedeoglu, Aki Hanaya, Takako Miyamae, Manabu Kawamoto, Yumi Tani, Takuma Hara, Yasushi Kawaguchi, Satoru Nagata, Hisashi Yamanaka, Almira Ćosićkić, Fahrija Skokić, Belkisa Čolić, Sanimir Suljendić, Anna Kozlova, Irina Mersiyanova, Mariya Panina, Lily Hachtryan, Vasiliy Burlakov, Elena Raikina, Alexey Maschan, Anna Shcherbina, Banu Acar, Meryem Albayrak, Betul Sozeri, Sezgin Sahin, Amra Adrovic, Nese Inan, Serhan Sevgi, Caroline M. Andreasen, Anne Grethe Jurik, Mia B. Glerup, Christian Høst, Birgitte T. Mahler, Ellen-Margrethe Hauge, Cecilia Lazea, Laura Damian, Calin Lazar, Rodica Manasia, Chloe M. Stephenson, Vimal Prajapati, Paivi M. Miettunen, Dilek Yılmaz, Yavuz Tokgöz, Yasin Bulut, Harun Çakmak, Ferah Sönmez, Elif Comak, Gülşah Kaya Aksoy, Mustafa Koyun, Sema Akman, Yunus Arıkan, Ender Terzioğlu, Osman Nidai Özdeş, İbrahim Keser, Hüseyin Koçak, Ayşen Bingöl, Aygen Yılmaz, Reha Artan, X. Xu, Fatemeh F. Mehregan, Vahid Ziaee, Mohammad H. Moradinejad, Francesco La Torre, Clotilde Alizzi, Pio D’Adamo, G. Junge, J. Gregson, Hasmik Sargsyan, Hulya Zengin, Berna E. Fidanci, Cagla Kaymakamgil, Dilek Konukbay, Dilek Yildiz, Faysal Gok, Iris Stoler, Judith Freytag, Banu Orak, Christine Seib, Lars Esmann, Eva Seipelt, Faekah Gohar, Dirk Foell, Ismail Dursun, Sebahat Tulpar, Sibel Yel, Demet Kartal, Murat Borlu, Funda Bastug, Hakan Poyrazoglu, Zubeyde Gunduz, Kader Kose, Mehmet E. Yuksel, Abdullah Calıskan, Ahmet B. Cekgeloglu, Ruhan Dusunsel, Katerina Bouchalova, Jana Franova, Marcel Schuller, Marie Macku, Katerina Theodoropoulou, Raffaella Carlomagno, Annette von Scheven-Gête, Claudia Poloni, Laura O. Damian, Dan Cosma, Amanda Radulescu, Dan Vasilescu, Liliana Rogojan, Simona Rednic, Mihaela Lupse, Lien De Somer, Pierre Moens, Rocio Galindo Zavala, Laura Martín Pedraz, Esmeralda Núñez Cuadros, Gisela Díaz-Cordovés Rego, Antonio L. Urda Cardona, Ilaria Dal Forno, Sara Pieropan, Ombretta Viapiana, Davide Gatti, Gloria Dallagiacoma, Paola Caramaschi, Domenico Biasi, Daniel Windschall, Ralf Trauzeddel, Hartwig Lehmann, Rainer Berendes, Maria Haller, Manuela Krumrey-Langkammerer, Antje Nimtz-Talaska, Philipp Schoof, Ralf Felix Trauzeddel, Christine Nirschl, Estefania Quesada-Masachs, Carla Aguilar Blancafort, Sara Marsal Barril, Francisca Aguiar, Rita Fonseca, Duarte Alves, Ana Vieira, Alberto Vieira, Jorge A. Dias, Iva Brito, Gordana Susic, Vera Milic, Goran Radunovic, Ivan Boricic, Pauline Marteau, Catherine Adamsbaum, Michel De Bandt, Irène Lemelle, Chantal Deslandre, Tu Anh Tran, Anne Lohse, Elisabeth Solau-Gervais, Pascal Pillet, Julien Wipff, Cécile Gaujoux-Viala, Sylvain Breton, Valérie Devauchelle-Pensec, Sandra Gran, Olesja Fehler, Stefanie Zenker, Michael Schäfers, Thomas Vogl, Severine Guillaume Czitrom, EH Pieter Van Dijkhuizen, Silvia Magni Manzoni, Francesca Magnaguagno, Laura Tanturri de Horatio, Nienke M. Ter Haar, Annemieke S. Littooij, Vitor A. Teixeira, Raquel Campanilho-Marques, Ana F. Mourão, Filipa O. Ramos, Manuela Costa, Wafa A. Madan, Orla G. Killeen, Adriana Rodriguez Vidal, Diana Sueiro Delgado, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Aleksey Kozhevnikov, Nina Pozdeeva, Mikhail Konev, Evgeniy Melchenko, Vladimir Kenis, Gennadiy Novik, Aysenur Pac Kısaarslan, Butsabong Lerkvaleekul, Suphaneewan Jaovisidha, Witaya Sungkarat, Niyata Chitrapazt, Praman Fuangfa, Thumanoon Ruangchaijatuporn, Soamarat Vilaiyuk, Dan Ø. Pradsgaard, Arne Hørlyck, Anne H. Spannow, Carsten W. Heuck, Talia Diaz, Fernando Garcia, Lorenia De La Cruz, Nadina Rubio, Joanna Świdrowska-Jaros, Elzbieta Smolewska, Mirta Lamot, Lovro Lamot, Mandica Vidovic, Edi Paleka Bosak, Ivana Rados, Miroslav Harjacek, Nikolay Tzaribachev, Polymnia Louka, Romiesa Hagoug, Chiara Trentin, Olga Kubassova, Mark Hinton, Mikael Boesen, Olena A. Oshlianska, Illya A. Chaikovsky, G. Mjasnikov, A. Kazmirchyk, Umberto Garagiola, Irene Borzani, Paolo Cressoni, Fabrizia Corona, Eszter Dzsida, Giampietro Farronato, Antonella Petaccia, Alenka Gagro, Agneza Marija Pasini, Goran Roic, Ozren Vrdoljak, Lucija Lujic, Matija Zutelija-Fattorini, Monika M. Esser, Deepthi R. Abraham, Craig Kinnear, Glenda Durrheim, Mike Urban, Eileen Hoal, Victoria B. Nikolayenko, Kubilay Şahin, Yasar Karaaslan, Adele Civino, Giovanni Alighieri, Sergio Davì, Roberto Rondelli, Andrea Magnolato, Francesca Ricci, Alma Olivieri, Valeria Gerloni, Bianca Lattanzi, Francesca Soscia, Alessandro De Fanti, Stefania Citiso, Lorenzo Quartulli, Maria Cristina Maggio, Manuela Marsili, Maria Antonietta Pelagatti, Valentino Conter, Franca Fagioli, Andrea Pession, Marco Garrone, Mariangela Rinaldi, Jaime De Inocencio, Stella Garay, Daniel J. Lovell, Berit Flato, EPOCA Study Group, Angela Aquilani, Simona Cascioli, Ivan Caiello, Denise Pires-Marafón, Rita Carsetti, Emily Robinson, Salvatore Albani, Wilco de Jager, Sytze de Roock, Trang Duong, Justine Ellis, Kimme Hyrich, Laetitia Jervis, Daniel Lovell, Lucy Marshall, Elizabeth D. Mellins, Kirsten Minden, Jane Munro, Peter A. Nigrovic, Jason Palman, Sunil Sampath, Laura E. Schanberg, Susan D. Thompson, Richard Vesely, Chris Wallace, Chris Williams, Qiong Wu, Nico Wulffraat, Rae S. M. Yeung, M. B. Seyger, D. Arikan, J. K. Anderson, A. Lazar, D. A. Williams, C. Wang, R. Tarzynski-Potempa, J. S. Hymans, Gabriele Simonini, Erika Scoccimarro, Irene Pontikaki, Teresa Giani, Alessandro Ventura, Pier Luigi Meroni, Gaetana Minnone, Marzia Soligo, Luigi Manni, Luisa Bracci Laudiero, Noortje Groot, I. Grein, N. M. Wulffraat, R. Schepp, G. Berbers, C. C. Barbosa Sandoval de Souza, V. Paes Leme Ferriani, G. Pileggi, S. de Roock, Ingrid H. R. Grein, Silvia Scala, Elisa Patrone, Casper Schoemaker, on behalf of Dutch JIA patient organization, Wendy Costello, on behalf of ENCA, Suzanne Parsons, Jean-David Cohen, Damien Bentayou, Marc-Antoine Bernard Brunel, Sonia Trope, Jens Klotsche, Miriam Listing, Martina Niewerth, Gerd Horneff, Angelika Thon, Hans-Iko Huppertz, Kirsten Mönkemöller, Ivan Foeldvari, ICON study group, Achille Marino, Stefano Stagi, Niccolò Carli, Federico Bertini, Adriana S. Díaz-Maldonado, Sally Pino, Pilar Guarnizo, Alfonso Ragnar Torres-Jimenez, Berenice Sanchez-Jara, Eunice Solis-Vallejo, Adriana Ivonne Cespedes-Cruz, Maritza Zeferino-Cruz, Julia Veronica Ramirez-Miramontes, Ankur Kumar, Anju Gupta, Deepti Suri, Amit Rawat, Nandita Kakkar, Surjit Singh, Özge A. Gücenmez, Erbil Ünsal, Bo Magnusson, Karina Mördrup, Anna Vermé, Christina Peterson, Board of the Swedish Pediatric Rheumatology Registry, Caroline Freychet, Jean Louis Stephan, Cathryn E. Harkness, Leanne Foster, Emma Henry, Pauline Taggart, Coskun F. Ozkececi, Esra Kurt, Gokalp Basbozkurt, Daiva Gorczyca, Jacek Postępski, Aleksandra Czajkowska, Bogumiła Szponar, Mariola Paściak, Anna Gruenpeter, Iwona Lachór-Motyka, Daria Augustyniak, Edyta Olesińska, Emediong S. Asuka, Tatyana Golovko, Samuel U. Aliejim, Emilio Inarejos Clemente, Estibaliz Iglesias Jimenez, Joan Calzada Hernandez, Sergi Borlan Fernandez, Clara Gimenez Roca, David Moreno Romo, Natalia Rodriguez Nieva, Juan Manuel Mosquera Angarita, Jordi Anton Lopez, Esmeralda Nuñez-Cuadros, Gisela Diaz-Cordovés, Rocío Galindo-Zavala, Antonio Urda-Cardona, Antonio Fernández-Nebro, Daniel Álvarez de la Sierra, Marina Garcia Prat, Mónica Martínez Gallo, Ricardo Pujol Borrell, Ana M. Marín Sánchez, Etienne Merlin, Sylvie Fraitag, Jean-Louis Stephan, Federico Annoni, Giancarla Di Landro, Sofia Torreggiani, Marta Torcoletti, Georgina Tiller, Jo Buckle, Angela Cox, Peter Gowdie, Roger C. Allen, Jonathan D. Akikusa, Hayde G. Hernández-Huirache, Edel R. Rodea-Montero, William Fahy, Christelle Sordet, Karin B. Berggren, Johanna T. Kembe, Joyce Bos, Wineke Armbrust, Marco van Brussel, Jeanette Cappon, Pieter Dijkstra, Jan Geertzen, Elizabeth Legger, Marion van Rossum, Pieter Sauer, Otto Lelieveld, Levent Buluc, Gur Akansel, Bahar Muezzinoglu, Ljubov Rychkova, Tatyana Knyazeva, Anna Pogodina, Tatyana Belova, Tamara Mandzyak, Ekaterina Kulesh, Alessandro Cafarotti, Cosimo Giannini, Roberta Salvatore, Giuseppe Lapergola, Caterina Di Battista, Maria Loredana Marcovecchio, Raffaella Basilico, Piernicola Pelliccia, Francesco Chiarelli, Luciana Breda, Beverley Almeida, Sarah Tansley, Harsha Gunawardena, Neil McHugh, Juvenile Dermatomyositis Research Group (JDRG), Jessie Aouizerate, Marie De Antonio, Christine Barnerias, Guillaume Bassez, Isabelle Desguerre, Romain Gherardi, Jean-Luc Charuel, François-Jérôme Authier, Cyril Gitiaux, C. H. Spencer, Rabheh Abdul Aziz, Chack-Yung Yu, Brent Adler, Sharon Bout-Tabaku, Katherine Lintner, Melissa Moore-Clingenpeel, Liza McCann, Nicola Ambrose, Mario Cortina-Borja, Juvenile Dermatomyositis Cohort and Biomarker Study (JCDBS), Prasad T. Oommen, Fabian Speth, Johannes-Peter Haas, Working Group “Juvenile Dermatomyositis” of the German Society for Paediatric and Adolescent Rheumatology (GKJR), Claudio Lavarello, Gabriella Giancane, Angela Pistorio, Lisa Rider, Rohit Aggarwal, Sheila K. Oliveira, Ruben Cuttica, Michel Fischbach, Gary Sterba, Karine Brochard, Frank Dressler, Patrizia Barone, Ruben Burgos-Vargas, Elizabeth Candell Chalom, Marine Desjonqueres, Graciela Espada, Anders Fasth, Stella Maris Garay, Rose-Marie Herbigneaux, Claire Hoyoux, Chantal Job Deslandre, Frederick W. Miller, Jiri Vencovsky, Erdal Sag, Gulsev Kale, Haluk Topaloglu, Beril Talim, Francesco Zulian, Tadej Avcin, Roberto Marini, Anne Pagnier, Michel Rodiere, Christine Soler, Rebecca Ten Cate, Yosef Uziel, Jelena Vojinovic, Ana V. Villarreal, Nydia Acevedo, Yuridiana Ramirez, Enrique Faugier, Rocio Maldonado, Bita Arabshahi, John H. Lee, Ian Leibowitz, Lawrence O. Okong’o, Jo Wilmshurst, Monika Esser, Christiaan Scott, Ezgi Deniz Batu, Nagehan Emiroglu, Hafize Emine Sonmez, Gokcen Dilsa Tugcu, Zehra Serap Arici, Ebru Yalcin, Deniz Dogru, Ugur Ozcelik, Mithat Haliloglu, Nural Kiper, Masato Yashiro, Mutsuko Yamada, Toshihiko Yabuuchi, Tomonobu Kikkawa, Nobuyuki Nosaka, Yosuke Fujii, Yukie Saito, Hirokazu Tsukahara, Sulaiman M. Al-Mayouf, Nora AlMutiari, Mohammed Muzaffer, Rawiah shehata, Adel Al-Wahadneh, Reem Abdwani, Safia Al-Abrawi, Mohammed Abu-shukair, Zeyad El-Habahbeh, Abdullah Alsonbul, Aleksandra Szabat, Monika Chęć, Violetta Opoka-Winiarska, Biman Saikia, Ranjana W. Minz, Christine Arango, Clara Malagon, Maria D. P. Gomez, Angela C. Mosquera, Ricardo Yepez, Tatiana Gonzalez, Camilo Vargas, GRIP study group, Marta Balzarin, Biagio Castaldi, Elena Reffo, Francesca Sperotto, Giorgia Martini, Alessandra Meneghel, Ornella Milanesi, Ozgur Kasapçopur, Maria Teresa Terreri, Ekaterina Alexeeva, Maria Katsicas, Mikhail Kostik, Thomas Lehman, W.-Alberto Sifuentes-Giraldo, Vanessa Smith, Flavio Sztajnbok, Tadey Avcin, Maria Jose Santos, Dana Nemcova, Cristina Battagliotti, Liora Harel, Mahesh Janarthanan, Kathryn Torok, Nicola Helmus, Eileen Baildem, Michael Blakley, Kim Fligelstone, Antonia Kienast, Clare Pain, Amanda Saracino, Gabriele Simoni, Lisa Weibel, Maria K. Osminina, Nathalia A. Geppe, Olga V. Niconorova, Olesya V. Karashtina, Oksana V. Abbyasova, Olga V. Shpitonkova, Sinem Durmus, Hafize Uzun, Angela Mauro, Eleonora Fanti, Fabio Voller, Franca Rusconi, Fernando Garcia-Rodriguez, Ana V. Villarreal-Treviño, Angel J. Flores-Pineda, Paola B. Lara-Herrea, Diego R. Salinas-Encinas, Talia Diaz-Prieto, Maria R. Maldonado-Velazquez, Sarbelio Moreno-Espinosa, Enrique Faugier-Fuentes, Mirella Crapanzano, Ilaria Parissenti, Man S. Parihar, Pandiarajan Vignesh, ManojKumar Rohit, Kavitha Gopalan, Savita V. Attri, Alan Salama, David Jayne, Mark Little, Yulia Kostina, Galina Lyskina, Olga Shpitonkova, Alena Torbyak, Olga Shirinsky, Maria Francesca Gicchino, Maria Cristina Smaldone, Mario Diplomatico, Alma Nunzia Olivieri, C H. Spencer, Richard McClead, Hiren Patel, Chung-Yung Yu, Dita Cebecauerová, Tomáš Dallos, Edita Kabíčková, Martin Kynčl, Daniela Chroustová, Jozef Hoza, Dana Němcová, Vladimír Tesař, Pavla Doležalová, Tuncay Hazirolan, Fatih Ozaltin, Fabiola Almeida, Isabela H. Faria de Paula, Maíra M. Sampaio, Fernando N. Arita, Andressa G. Alves, Maria Carolina Santos, Eunice M. Okuda, Silvana B. Sacchetti, Fernanda Falcini, Marini Francesca, Gemma Lepri, Marco Matucci-Cerinic, Maria Luisa Brandi, Hakan Kisaoglu, Sema Misir, Selim Demir, Yuksel Aliyazicioglu, Mukaddes Kalyoncu, Carlos Eduardo Ramalho, Fabiola D. Almeida, Joan Calzada-Hernández, Rosa Bou, Estíbaliz Iglesias, Judith Sánchez-Manubens, Fredy Hermógenes Prada Martínez, Clara Giménez Roca, Sergi Borlan Fernández, Marek Bohm, Kamran Mahmood, Valentina Leone, Mark Wood, Ken-Ichi Yamaguchi, Satoshi Fujikawa, Working Group of Behçet’s Disease, Pediatric Rheumatology Association of Japan (PRAJ), Kyu Yeun Kim, Do Young Kim, Dong Soo Kim, Maka Ioseliani, Ivane Chkhaidze, Maia Lekishvili, Nana Tskhakaia, Shorena Tvalabeishvili, Aleksandre Kajrishvili, Maiko Takakura, Masaki Shimizu, Natsumi Inoue, Mao Mizuta, Akihiro Yachie, Giovanni Corsello, Maryam Piram, Carla Maldini, Sandra Biscardi, Nathalie Desuremain, Catherine Orzechowski, Emilie Georget, Delphine Regnard, Isabelle Kone-Paut, Alfred Mahr, Mihaela Sparchez, Zeno Sparchez, Nydia Acevedo Silva, Ana V. Villarreal Treviño, Yuridiana Ramirez Loyola, Talia Diaz Prieto, Enrique Faugier Fuentes, Maria D. R. Maldonado Velazquez, Pilar Perez, Sagar Bhattad, Ranjana Minz, Jitendra Shandilya, Pediatric Allergy and Immunology Unit, PGIMER, Chandigarh, Ana Villarreal, Yuridiana Ramírez, Zeynep Birsin Özçakar, Suat Fitoz, Fatos Yalcinkaya, Annacarin Horne, Francesca Minoia, Francesca Bovis, Sergio Davi, Priyankar Pal, Kimo Stein, Sandra Enciso, Michael Jeng, Despoina Maritsi, Randy C. Cron, Anne Thorwarth, Sae Lim von Stuckrad, Angela Rösen-Wolff, Hella Luksch, Patrick Hundsdoerfer, Peter Krawitz, Nuray Aktay Ayaz, Doğan Simsek, Şebnem Sara Kılıc, Emine Sonmez, Aysenur Pac Kisaarslan, Ozge Altug Gucenmez, Z. Serap Arıcı, Fatih Kelesoglu, Zelal Ekinci Ekinci, Maria Miranda-Garcia, Carolin Pretzer, Michael Frosch, F. Gohar, Angela McArdle, Niamh Callan, Belinda Hernandez, Miha Lavric, Oliver FitzGerald, Stephen R. Pennington, Joachim Peitz, Joern Kekow, Ariane Klein, Anna C. Schulz, Frank Weller-Heinemann, Anton Hospach, J-Peter Haas, BIKER collaborative group, Karen Put, Jessica Vandenhaute, Anneleen Avau, Annemarie van Nieuwenhuijze, Ellen Brisse, Tim Dierckx, Omer Rutgeerts, Josselyn E. Garcia-Perez, Jaan Toelen, Mark Waer, Georges Leclercq, An Goris, Johan Van Weyenbergh, Adrian Liston, Patrick Matthys, Carine H. Wouters, Yasuo Nakagishi, Michael J. Ombrello, Victoria Arthur, Anne Hinks, Patricia Woo, International Childhood Arthritis Genetics (INCHARGE) Consortium, Barbara Stanimirovic, Biljana Djurdjevic-Banjac, Olivera Ljuboja, Boris Hugle, MArgarita Onoufriou, Olga Vougiouka, Kenza Bouayed, Sanae El Hani, Imane Hafid, Nabiha Mikou, Nunu Shelia, Mari Laan, Jaanika Ilisson, and Chris Pruunsild

Subjects
Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published
2017
Full Text
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23. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part three

Author

Riccardo Papa, Alessandro Consolaro, Francesca Minoia, Roberta Caorsi, Gianmichele Magnano, Marco Gattorno, Angelo Ravelli, Paolo Picco, Roberto Pillon, Denise Pires Marafon, Lidia Meli, Claudia Bracaglia, Andrea Taddio, Fabrizio De Benedetti, Enes Turan, Sara Sebnem Kilic, Yasuhiko Itoh, Tomoko Shigemori, Shingo Yamanishi, Hidehiko Nagasaki, Ela Tarakci, Nilay Arman, Devrim Tarakci, Yusuf S. Akgul, Ozgur Kasapcopur, Emily Wilson, Hanna Lythgoe, Eve Smith, Jenny Preston, Michael W. Beresford, Lynn R. Spiegel, Jennifer Stinson, Mark Connelly, Adam Huber, Nadia Luca, Argerie Tsimicalis, Stephanie Luca, Naweed Tajuddin, Roberta Berard, Julie Barsalou, Sarah Campillo, Brian Feldman, Shirley Tse, Paul Dancey, Ciaran Duffy, Nicole Johnson, Patrick McGrath, Natalie Shiff, Lori Tucker, Charles Victor, Chitra Lalloo, Lauren Harris, Joseph Cafazzo, Kristin Houghton, Ronald Laxer, Madeleine Rooney, Roisin Campbell, Catherine Wright, Wineke Armbrust, Otto Lelieveld, Jolanda Tuinstra, Nico Wulffraat, Joyce Bos, Jeanette Cappon, Marion van Rossum, Mariët Hagedoorn, Anna Vermé, Ylva Lampela, Ayse Huri Ozdogan, S. Ugurlu, K. Barut, A. Androvic, O. Kasapçopu, Jody Etheridge, Katie Dobson, Sue Kemp, AnnaCarin Horne, Karin Palmblad, Malin Höglund, Natalia Stepanenko, Svetlana Salugina, Evgeny Fedorov, Irina Nikishina, Maria Kaleda, Kenan Barut, Amra Adrovic, Sezgin Sahin, Laurence Toumoulin, Johnny Frossard, Stephanie Archimbaut, Anne Paitier, Rolande Guastalli, Severine Guillaume Czitrom, Sirirat Charuvanij, Chollada Chaiyadech, Takako Miyamae, Hisashi Yamanaka, Cecile Picard, Guillaume Thouvenin, Caroline Kannengiesser, Jean-Christophe Dubus, Nadia Jeremiah, Frédéric Rieux-Laucat, Bruno Crestani, Véronique Secq, Christelle Ménard, Martine Reynaud-Gaubert, Françoise Thivolet-Bejui, Philippe Reix, Alexandre Belot, Ezgi Deniz Batu, Hafize Emine Sonmez, Abdulsamet Erden, Ekim Z. Taskiran, Omer Karadag, Umut Kalyoncu, İbrahim Oncel, Berkan Kaplan, Zehra Serap Arici, Cagri Mesut Temucin, Haluk Topaloglu, Yelda Bilginer, Mehmet Alikasifoglu, Seza Ozen, Lien Van Eyck, Ellen De Langhe, Isabelle Jéru, Erika Van Nieuwenhove, Vasiliki Lagou, Paul J. Baker, Jocelyn Garcia-Perez, James Dooley, Lien De Somer, Raf Sciot, Pierre-Yves Jeandel, Julia Ruuth-Praz, Bruno Copin, Myrna Medley-Hashim, Andre Megarbane, Sinisa Savic, An Goris, Serge Amselem, Adrian Liston, Seth Masters, Carine Wouters, Nami Okamoto, Yuko Sugita, Kousuke Shabana, Takuji Murata, Hiroshi Tamai, Juliana Ferenczová, Erika Banóova, Pavol Mrážik, Veronika Vargova, Dubravko Bajramovic, Ksenija Stekic Novacki, Kristina Potocki, Marijan Frkovic, Marija Jelusic, Olga Kostareva, Svetlana Arsenyeva, Anna Shapovalenko, Lennart Jans, Nele Herregods, Jacob Jaremko, Rik Joos, Joke Dehoorne, Xenofon Baraliakos, Sofia Ramiro, Julio C. Casasola-Vargas, Désirée van der Heijde, Robert Landewé, Ruben Burgos-Vargas, Shirley M. Tse, Gerd Horneff, Kristina Unnebrink, Jaclyn K. Anderson, Aysenur Paç Kisaarslan, Betül Sözeri, Zübeyde Gündüz, Gökmen Zararsız, Hakan Poyrazoğlu, Ruhan Düşünsel, Kazutaka Ouchi, Shinji Akioka, Hiroshi Kubo, Norio Nakagawa, Hajime Hosoi, Lovro Lamot, Fran Borovecki, Sanja Kapitanovic, Kristina Gotovac, Mandica Vidovic, Mirta Lamot, Edi Paleka Bosak, Miroslav Harjacek, Ricardo A. Russo, María M. Katsicas, Ruben Burgos Vargas, Ana L. Ortiz-Peyegahud, Zhang Pingping, Mou Yikun, Qi Jun, Jiang Yutong, Gu Jieruo, Mikhail M. Kostik, Shilova Ekaterina, Ilia Avrusin, Yuriy Korin, Olga Kopchak, Eugenia Isupova, Irina Chikova, Panova Tatyana, Margarita Dubko, Vera Masalova, Ludmila Snegireva, Tatyana Kornishina, Olga Kalashnikova, Vyacheslav Chasnyk, Tatyana Likhacheva, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, R. Schneider, I. Kone-Paut, K. Schikler, K. Marzan, N. Wulffraat, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, A. Speziale, K. Lheritier, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Nienke Ter Haar, Rianne Scholman, Wilco de Jager, Tamar Tak, Pieter Leliefeld, Bas Vastert, Sytze de Roock, Ariane de Ganck, Nadia Ryter, Miha Lavric, Dirk Foell, Renee F. Modica, Kathleen G. Lomax, Pamela Batzel, Armelle Cassanas, Melissa E. Elder, Rina Denisova, Ekaterina Alexeeva, Saniya Valieva, Tatyana Bzarova, Kseniya Isayeva, Tatyana Sleptsova, Olga Lomakina, Alexandra Chomahidze, Margarita Soloshenko, Meyry Shingarova, Elena Kachshenko, Wilco De Jager, Sebastiaan J. Vastert, Gerdien Mijnheer, Berent J. Prakken, Nico M. Wulffraat, Hafize E. Sönmez, Asuman N. Karhan, Ezgi D. Batu, Zehra S. Arıcı, Ersin Gümüş, Hülya Demir, Aysel Yüce, Seza Özen, Jasmina Ahluwalia, Bhavneet Bharti, Sweta Rajpal, Varun Uppal, Alaknanda Walia, Surjit S. Samlok, Narender Kumar, Clarissa C. Valões, Beatriz C. Molinari, Ana Claudia G. Pitta, Natali W. Gormezano, Sylvia C. Farhat, Kátia Kozu, Adriana M. Sallum, Simone Appenzeller, Ana Paula Sakamoto, Maria T. Terreri, Rosa M. Pereira, Claudia S. Magalhães, Cássia Maria Barbosa, Francisco Hugo Gomes, Eloisa Bonfá, Clovis A. Silva, Kubra Ozturk, Zelal Ekinci, Maie Helal, Natalia Cabrera, Jean Christophe Lega, Jocelyne Drai, Rene Ecochard, O. V. Shpitonkova, N. S. Podchernyaeva, Y. O. Kostina, N. G. Dashkova, M. K. Osminina, Gozde Yucel, Ahmet Arvas, Nandini Moorthy, Paraskevi Dimou, Angela Midgley, Matthew Peak, Simon C. Satchell, Rachael D. Wright, Rachel Corkhill, Eve M. Smith, Sagar Bhattad, Amit Rawat, Surjit Singh, Anju Gupta, Deepti Suri, Martin de Boer, Taco Kuijpers, Vignesh Pandiarajan, Sapna Sandal, Sebastian Giraldo, Roy Sanguino, Adriana S. Diaz, Selcuk Uzuner, Gizem Durcan, Ali Guven Kilicoglu, Ayhan Bilgic, Kayhan Bahali, Sinem Durmus, Hafize Uzun, Nur Canpolat, Salim Caliskan, Lale Sever, Tomomi Sato, Fuminori Kimura, Wafaa Suwairi, Reem Abdwani, Abdulaziz Al Rowais, Jubran Al qanatish, Abdulrahman Al Asiri, Ekaterina Gaidar, Mikhail Kostik, Elena Serogodskaya, Tatyana Nikitina, Evgenia Isupova, Elham Sardar, Perrine Dusser, Antoine Rousseau, Marc Labetoulle, Emanuel Barreau, Bahram Bodaghi, Isabelle Kone-Paut, Ivan Foeldvari, Jordi Anton, Rosa Bou, Sheila Angeles-Han, Regitze Bangsgaard, Gabriele Brumm, Tamas Constantin, Clive Edelsten, Jens Klotsche, Kirsten Minden, Elisabetta Miserocchi, Susan Nielsen, Gabriele Simonini, Arnd Heiligenhaus, Juan Manuel Mosquera Angarita, Carmen Garcia de Vicuña, Maria Victoria Hernandez, Alfredo Adan, Victor Llorens, Rosa Alcobendas, Susana Noval, Juan Carlos Lopez Robledillo, Isabel Valls, Mari Carmen Pinedo, Alejandro Fonollosa, Jaime de Inocencio, Pilar Tejada, Beatriz Bravo, Manuel Torribio, María Jesús García de Yebenes, Jordi Antón, Uveitis Working Group of the Spanish Pediatric Rheumatology Society, Lorenza Maria Argolini, Irene Pontikaki, Maria Orietta Borghi, Laura Cesana, Barbara Castiglioni, Maurizio Gattinara, Pierluigi Meroni, Pierre Quartier, Veronique Despert, Sylvaine Poignant, Amandine Baptiste, Caroline Elie, Laurent Kodjikian, Dominique Monnet, Michel Weber, Laura Moal, LuuLy Pham, Emmanuel Barreau, Cherif Titah, Pascal Dureau, Vanessa Cecchin, Maria Elisabetta Zannin, Daniele Ferrari, Francesco Comacchio, Rolando Cimaz, Fernanda Falcini, Antonella Petaccia, Stefania Viola, Luciana Breda, Francesco La Torre, Fabio Vittadello, Giorgia Martini, Francesco Zulian, Caroline Galeotti, Guillaume Sarrabay, Olivier Fogel, Isabelle Touitou, Corinne Miceli-Richard, Isabelle Koné-Paut, Hala Etayari, Hashad Soad, Ihab El Kadry, Habibullah Eatamadi, Kais AlAlgawi, Mustafa Al Maini, Khulood Khawaja, Sophie Van den Berghe, Ilse de Schryver, Ann Raes, Lídia L. C. Teixeira, Ana Duarte, Sandra Sousa, Filipe Vinagre, Maria J. Santos, Nataly S. Shevchenko, Ludmila F. Bogmat, Marina V. Demyanenko, Navdha R. Ramchurn, Mark Friswell, Rebecca A. James, Lucy R. Wedderburn, Reshma Pattani, Clarissa A. Pilkington, Sandrine Compeyrot-Lacassagne, Ana V. Villarreal, Nydia Acevedo, Enrique Faugier, Rocio Maldonado, Dilek Yılmaz, Hilal Bektaş Uysal, Elena Kamenets, Ekaterina Zaharova, Stefka Radenska-Lopovok, Joao Nascimento, Helena Sofia, Carla Zilhão, Rui Almeida, Margarida Guedes, Murat Deveci, Svetlana Rodionovskaya, Vera Vinnikova, Irina Tsymbal, Edyta Olesińska, Jacek Postępski, Agnieszka Mroczkowska-Juchkiewicz, Agnieszka Pawłowska-Kamieniak, Beata Chrapko, Damjana Ključevšek, Nina Emeršič, Nataša Toplak, Tadej Avčin, Faina Rokhlina, Galina Glazyrina, Natalia Kolyadina, Kwangnam Kim, Sinae Eom, Daeyoung Kim, Jungwoo Rhim, Francesca Ricci, Paola Montesano, Barbara Bonafini, Veronica Medeghini, Ilaria Parissenti, Antonella Meini, Marco Cattalini, Paolo Airò, Nataliya Panko, Nataliya Shevchenko, Iryna Lebec, Yevgeniya Zajceva, Sara Rostlund, Marie André, Takuma Hara, Takayuki Kishi, Yumi Tani, Aki Hanaya, Satoru Nagata, Velma Selmanovic, Aida Omercahic-Dizdarevic, Adisa Cengic, Almira Cosickic, Aida Omerčahić Dizdarević, Gemma Lepri, Clara Malattia, Eleonora Bellucci, Marco Matucci-Cerinic, Anton Solovyev, Elena Fedotova, Ana Victoria Villarreal, Talia Diaz, Yuridiana Ramirez, Teresa Giani, Achille Marino, Daniel Hunt, Muthana Al Obaidi, Veli Veli, Charalampia Papadopoulou, Jochen Kammermeier, Anna Poluha, Gangadhara C. Bharmappanavara, Alison Kelly, Lindsay Shaw, Giovanna Ferrara, Michele Luzzati, Mattia Giovannini, Liliana Jurado, Juliana Chamorro, Lorena Sarmiento, Ester Conversano, Maria Francesca Gicchino, Giulia Macchini, Carmela Granato, Assunta Tirelli, Alma N. Olivieri, Marija Perica, Lana Tambić Bukovac, Reza Sinaei, Vadood Javadi Parvaneh, Reza Shiari, Khosro Rahmani, Fatemeh F. Mehregan, Mehrnoush Hassas Yeganeh, Inmaculada Calvo Penadés, Berta López Montesinos, Ma Isabel González Fernández, Adriana Rodríguez Vidal, Anand Prahalad Rao, Ayesha Romana, Jyothi Raghuram, Ankur Kumar, Vishali Gupta, Elif Comak, Gülşah Kaya Aksoy, Aygen Yılmaz, Atike Atalay, Mustafa Koyun, Reha Artan, Sema Akman, Maria I. Kaleda, Irina P. Nikishina, Sergei K. Soloviev, Victor A. Malievsky, Ekaterina V. Nikolaeva, Agnieszka Gazda, Beata Kołodziejczyk, Lidia Rutkowska-Sak, Angela Mauro, Pierluigi Marzuillo, Stefano Guarino, and Angela La Manna

Subjects
Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published
2017
Full Text
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28. Epilepsy in systemic lupus erythematosus

Author

Eleonora Agata, Grasso, Marta, Cacciatore, Cristina, Gentile, Luciana, Breda, Roberto, Giacomelli, and Alberto, Verrotti

Subjects
Epilepsy, Lupus Erythematosus, Rheumatology, Systemic, Immunology, Humans, Lupus Erythematosus, Systemic, Immunology and Allergy, Anticonvulsants, Atrophy, White Matter
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune systemic disease characterised by a broad spectrum of clinical manifestations that may also affect the central nervous system. Among the neurological symptoms, seizures were included in the criteria for the classification of SLE published by EULAR/ACR in 2019. Several studies have been undertaken to explore the role of SLE antibodies in the onset of seizures, however, their complex relation is still a matter of debate. The most common seizure type reported is generalised tonic-clonic. EEG and MRI findings are usually non-specific; background slowing, brain atrophy and hyper-intense lesions on the white matter are the most common finding. Prognosis is overall favourable, with a good response to antiepileptic drugs and immunosuppressive therapy. The purpose of this review is to summarise the most relevant literature contributions published over the years on the epidemiology, aetiopathogenesis, clinical aspects, diagnosis and treatment of seizures in the context of SLE.

Published
2021

29. Serum Calprotectin a Potential Biomarker in Juvenile Idiopathic Arthritis: A Meta-Analysis

Author

Emma Altobelli, Giovanni Farello, Giuseppe Lapergola, Giovanni Cannataro, Reimondo Petrocelli, Luciana Breda, and Paolo Matteo Angeletti

Subjects
Systemic disease, Funnel plot, medicine.medical_specialty, business.industry, Arthritis, biomarkers, General Medicine, Publication bias, Disease, Review, medicine.disease, meta-analysis, Study heterogeneity, serum calprotectin, systematic review, Meta-analysis, Internal medicine, Biomarkers, Juvenile idiopathic arthritis, Serum calprotectin, Systematic review, juvenile idiopathic arthritis, Medicine, Calprotectin, business
Abstract

Juvenile idiopathic arthritis (JIA) is the most common inflammatory chronic disease affecting children and adolescents. Today, there are no specific biomarkers of inflammation. Therefore, it is important to identify new markers as predictors of disease activity. Recently, some researchers have directed their interest toward a protein, calprotectin (CLP), as a potential biomarker. The primary objective of our systematic review and meta-analysis was to analyze the possible role of CLP in JIA. Method: A literature search was conducted using PubMed, EMBASE, Scopus, Science Direct on 10 August 2021. The selection of studies was made using the PRISMA 2020 guidelines. Cohen’s d with 95% CI and p-value were used as a measure of effect size. The random effects model was used to account for different sources of variation among studies. Heterogeneity was assessed using Q statistics and I2. The publication bias was analyzed and represented by a funnel plot, and funnel plot symmetry was assessed with Egger’s test. Results: Our results at follow-up showed a statistically significant difference between patients with active disease compared to patients with inactive disease: 0.39 (0.16; 0.62), p = 0.001; without statistical heterogeneity. Another important aspect that emerged were the differences between the systemic disease form and any form of inactive disease showing a different concentration of calprotectin: 0.74 (0.40; 1.08), p < 0.001; without statistical heterogeneity. On the other hand, meta-regression analyses performed on gender, age, duration of disease, percentage of patients with ANA+ or RF+, medium value of ESR or CRP were not statistically significant. A statistically significant difference in serum calprotectin concentration between patients with JIA and healthy controls were observed. In fact, it presented lower values in the control group. Conclusions: The use of serum CLP could represent, in the future, a useful tool in JIA in order to stratify disease activity more accurately and may aid a more tailored approach to drug of choice in children with JIA. Further studies are needed to evaluate CLP as a predictor of flare in combination with other potential biomarkers of subclinical disease activity.

Published
2021

30. Clinical and Instrumental TMJ Evaluation in Children and Adolescents with Juvenile Idiopathic Arthritis: A Case—Control Study

Author

Beatrice Di Carlo, Francesco Caroccia, Francesco Chiarelli, Francesco Moscagiuri, Michele D'Attilio, Felice Festa, Luciana Breda, and Debora Mariarita d’Angelo

Subjects
myalgia, musculoskeletal diseases, Technology, electromyography, QH301-705.5, QC1-999, Arthritis, Electromyography, Palpation, Temporal muscle, 03 medical and health sciences, 0302 clinical medicine, stomatognathic system, medicine, General Materials Science, temporomandibular joint, Biology (General), Instrumentation, Pathological, QD1-999, 030203 arthritis & rheumatology, Fluid Flow and Transfer Processes, Orthodontics, medicine.diagnostic_test, business.industry, Process Chemistry and Technology, Physics, General Engineering, Case-control study, kinesiography, 030206 dentistry, medicine.disease, Engineering (General). Civil engineering (General), Computer Science Applications, Temporomandibular joint, Chemistry, medicine.anatomical_structure, juvenile idiopathic arthritis, medicine.symptom, TA1-2040, business
Abstract

To investigate temporomandibular joint (TMJ) involvement signs such as muscle pain, the ratio of masseter and temporal muscle activity, mouth opening width and jaw deviation during mouth opening in children and adolescents with juvenile idiopathic arthritis (JIA), a group of 32 subjects with JIA and a control group of 32 healthy subjects were evaluated. Data were collected clinically by muscle palpation (masseters, anterior temporalis and sternocleidomastoids) and instrumental analysis (electromyography and kinesiography). Higher pain was registered in the masseter and sternocleidomastoid muscles on both sides and in the right anterior temporalis in the JIA group compared to the control group (p &lt, 0.05). Electromyography showed no statistically significant difference in the frequency of the pathological ratio of masseter and temporal muscle activity (MM/TA &lt, 1) both in the JIA group and in the control group. Kinesiography showed a statistically significant difference in mouth opening width and jaw deviation during mouth opening between the groups (p &lt, 0.05): JIA subjects showed lower mouth opening values and wider deviation on mouth opening, 29 out of 32 JIA subjects showed jaw deviation towards the right side. JIA affects the TMJ, causing myalgia in the head and neck muscles, a reduction in mouth opening width and an increase in jaw deviation during mouth opening.

Published
2021
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32. Intra-articular osteoid osteoma mimicking juvenile psoriatic dactylitis

Author

Luciana Breda, Giulia Sassano, Saverio La Bella, Cristina Gentile, Lorenzo Sansone, and Francesco Chiarelli

Subjects
Rheumatology, Immunology, Osteoma, Osteoid, Immunology and Allergy, Humans, Bone Neoplasms, Tomography, X-Ray Computed, Arthritis, Juvenile
Published
2021

33. Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study

Author

Giovanna Russo, Valentino Conter, M Caniglia, A Garaventa, Giulia Stabile, MF Gicchino, Elisa Rossi, Annalisa Arlotta, S Ladogana, C Atzeni, Rita Consolini, Luciana Vinti, Daniela Onofrillo, Roberto Rondelli, Nicola Santoro, Loredana Lepore, F Locatelli, Elisa Coassin, Monica Ficara, Micol Romano, S Martino, Roberta Burnelli, I Fontanili, Francesca Soscia, Eleonora Prete, Francesca Santarelli, Romina Gallizzi, Patrizia Barone, MG Cefalo, E Cortis, Giovanni Filocamo, M Amatruda, Angela Miniaci, Anna Maria Caroleo, Massimo Eraldo Abate, Maria Cristina Maggio, M Mascarin, Simone Cesaro, E Fabbri, F De Benedetti, Angelo Ravelli, Alma Nunzia Olivieri, C Micalizzi, A Magnolato, B Bigucci, Francesca Ricci, Elisa Tirtei, Antonella Colombini, Luciana Breda, Tamara Belotti, Raffaela De Santis, Roberta Pericoli, Serena Pastore, Silvia Magni-Manzoni, Rosa Anna Podda, Chiara Mainardi, Donato Rigante, Federico Verzegnassi, C Messina, Adele Civino, Cristina Pizzato, M Marsili, Chiara Gorio, Rossella Mura, M Cattalini, Andrea Pession, M Cappella, A Di Cataldo, Francesco La Torre, Assunta Tornesello, Andrea Roncadori, F Porta, Maria Antonietta Pelagatti, F Fagioli, P Bertolini, Ilaria Capolsini, C Rizzari, M Cellini, Bianca Lattanzi, Alessandro De Fanti, S Davì, Carmela De Fusco, Giovanni Alighieri, Andrea Biondi, Civino, Adele, Alighieri, Giovanni, Prete, Eleonora, Maria Caroleo, Anna, SilviaMagni-Manzoni, Vinti, Luciana, Romano, Micol, Santoro, Nicola, Filocamo, Giovanni, Belotti, Tamara, Santarelli, Francesca, Gorio, Chiara, Ricci, Francesca, Colombini, Antonella, Pastore, Serena, Cesaro, Simone, Barone, Patrizia, Verzegnassi, Federico, Olivieri, Alma Nunzia, Ficara, Monica, Miniaci, Angela, Russo, Giovanna, Gallizzi, Romina, Pericoli, Roberta, Breda, Luciana, Mura, Rossella, Annapodda, Rosa, Onofrillo, Daniela, Lattanzi, Bianca, Elisatirtei, Cristina Maggio, Maria, De Santis, Raffaela, Ritaconsolini, Arlotta, Annalisa, La Torre, Francesco, Mainardi, Chiara, Antonietta Pelagatti, Maria, Coassin, Elisa, Capolsini, Ilaria, Burnelli, Roberta, Tornesello, Assunta, Soscia, Francesca, De Fanti, Alessandro, Donatorigante, Pizzato, Cristina, De Fusco, Carmela, Eraldo Abate, Massimo, Roncadori, Andrea, Rossi, Elisa, Stabile, Giulia, Biondi, Andrea, Lepore, Loredana, Conter, Valentino, Rondelli, Roberto, Pession, Andrea, Ravelli, Angelo, Association of Paediatric Haematology and Oncology†and the Italian Paediatric Rheumatology Study Group†, Italian, Amatruda, M, Atzeni, C, Pbertolini, Bigucci, B, Caniglia, M, Cappella, M, Cattalini, M, Cefalo, Mg, Cellini, M, Cortis, E, Davì, S, De Benedetti, F, Di Cataldo, A, Fabbri, E, Fagioli, F, Fontanili, I, Garaventa, A, Gicchino, MARIA FRANCESCA, Ladogana, S, Locatelli, F, Magnolato, A, Marsili, M, Martino, S, Mascarin, M, Messina, C, Micalizzi, C, Porta, F, Rizzari, C, Civino A., Alighieri G., Prete E., Caroleo A.M., Magni-Manzoni S., Vinti L., Romano M., Santoro N., Filocamo G., Belotti T., Santarelli F., Gorio C., Ricci F., Colombini A., Pastore S., Cesaro S., Barone P., Verzegnassi F., Olivieri A.N., Ficara M., Miniaci A., Russo G., Gallizzi R., Pericoli R., Breda L., Mura R., Podda R.A., Onofrillo D., Lattanzi B., Tirtei E., Maggio M.C., De Santis R., Consolini R., Arlotta A., La Torre F., Mainardi C., Pelagatti M.A., Coassin E., Capolsini I., Burnelli R., Tornesello A., Soscia F., De Fanti A., Rigante D., Pizzato C., De Fusco C., Abate M.E., Roncadori A., Rossi E., Stabile G., Biondi A., Lepore L., Conter V., Rondelli R., Pession A., Ravelli A., Amatruda M., Atzeni C., Bertolini P., Bigucci B., Caniglia M., Cappella M., Cattalini M., Cefalo M.G., Cellini M., Cortis E., Davi S., De Benedetti F., Di Cataldo A., Fabbri E., Fagioli F., Fontanili I., Garaventa A., Gicchino M.F., Ladogana S., Locatelli F., Magnolato A., Marsili M., Martino S., Mascarin M., Messina C., Micalizzi C., Porta F., Rizzari C., Civino, A, Alighieri, G, Prete, E, Caroleo, A, Magni-Manzoni, S, Vinti, L, Romano, M, Santoro, N, Filocamo, G, Belotti, T, Santarelli, F, Gorio, C, Ricci, F, Colombini, A, Pastore, S, Cesaro, S, Barone, P, Verzegnassi, F, Olivieri, A, Ficara, M, Miniaci, A, Russo, G, Gallizzi, R, Pericoli, R, Breda, L, Mura, R, Podda, R, Onofrillo, D, Lattanzi, B, Tirtei, E, Maggio, M, De Santis, R, Consolini, R, Arlotta, A, La Torre, F, Mainardi, C, Pelagatti, M, Coassin, E, Capolsini, I, Burnelli, R, Tornesello, A, Soscia, F, De Fanti, A, Rigante, D, Pizzato, C, De Fusco, C, Abate, M, Roncadori, A, Rossi, E, Stabile, G, Biondi, A, Lepore, L, Conter, V, Rondelli, R, Pession, A, Ravelli, A, Bertolini, P, Cefalo, M, Davi, S, and Gicchino, M

Subjects
medicine.medical_specialty, business.industry, Immunology, Arthritis, Cancer, Odds ratio, Musculoskeletal manifestation, Juvenile idiopathic arthritis, medicine.disease, Histiocytosis, Rheumatology, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Prednisone, Internal medicine, Joint pain, Arthropathy, Musculoskeletal manifestations, childhood cancer, juvenile idiopathic arthritis, medicine, childhood cancer, Immunology and Allergy, Differential diagnosis, medicine.symptom, business, medicine.drug
Abstract

Summary Background Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. Methods We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. Findings Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0–27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2–4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89–408·12]), followed by weight loss (59·88 [6·34–565·53]), thrombocytopenia (12·67 [2·40–66·92]), monoarticular involvement (11·30 [4·09–31·19]), hip involvement (3·30 [1·13–9·61]), and male sex (2·40 [1·03–5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01–0·20]), joint swelling (0·03 [0·01–0·09]), and involvement of the small hand joints (0·02 [0–1·05]). Interpretation Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. Funding Associazione Lorenzo Risolo.

Published
2021

34. Persistence of disease flares is associated with an inadequate colchicine dose in familial Mediterranean fever: A national multicenter longitudinal study

Author

Angela Miniaci, Nicolino Ruperto, Maria Greca Magnolia, Alessandra Spagnolo, Giovanni Conti, Davide Montin, Maria Carrabba, Laura Obici, Giovanna Fabio, Edoardo Marrani, Giovanna Capozio, Marco Cattalini, Patrizia Barone, Maddalena Lancieri, Francesco Calzatini, Valentina Moressa, Maria Cristina Maggio, Gabriele Simonini, Camilla Celani, Luca Cantarini, Francesca Mazza, Diana Sutera, Roberta Mussinelli, Luciana Breda, Marta Bustaffa, Romina Gallizzi, Francesca Orlando, Maria Alessio, Antonella Insalaco, Alma Nunzia Olivieri, Donato Rigante, Carla Gaggiano, Francesca Ricci, Marco Gattorno, Bustaffa, M, Mazza, F, Sutera, D, Carrabba, Md, Alessio, M, Cantarini, L, Obici, L, Rigante, D, Maggio, Mc, Insalaco, A, Simonini, G, Cattalini, M, Conti, G, Olivieri, An, Barone, P, Miniaci, A, Moressa, V, Magnolia, Mg, Breda, L, Montin, D, Spagnolo, A, Fabio, G, Orlando, F, Gaggiano, C, Mussinelli, R, Capozio, G, Celani, C, Marrani, E, Ricci, F, Calzatini, F, Lancieri, M, Ruperto, N, Gattorno, M, Gallizzi, R, Bustaffa M., Mazza F., Sutera D., Carrabba M.D., Alessio M., Cantarini L., Obici L., Rigante D., Maggio M.C., Insalaco A., Simonini G., Cattalini M., Conti G., Olivieri A.N., Barone P., Miniaci A., Moressa V., Magnolia M.G., Breda L., Montin D., Spagnolo A., Fabio G., Orlando F., Gaggiano C., Mussinelli R., Capozio G., Celani C., Marrani E., Ricci F., Calzatini F., Lancieri M., Ruperto N., Gattorno M., and Gallizzi R.

Subjects
Longitudinal study, business.industry, Familial Mediterranean fever, Interleukin, Disease, Familial Mediterranea fever, medicine.disease, Symptom Flare Up, Colchicine, Humans, Interleukin 1 Receptor Antagonist Protein, Longitudinal Studies, Familial Mediterranean Fever, Persistence (computer science), chemistry.chemical_compound, Settore MED/38 - Pediatria Generale E Specialistica, chemistry, Colchicine, Humans, Interleukin 1 Receptor Antagonist Protein, Longitudinal Studies, Symptom Flare Up, Familial Mediterranean Fever, Immunology, COLCHICINE RESISTANCE, Immunology and Allergy, Medicine, business
Abstract

Familial Mediterranean fever (FMF) is characterized by self limited episodes of fever and polyserositis.1 MEFV gene en codes for a protein named Pyrin, which plays a pivotal role in the activation and secretion of IL-1.2 Daily colchicine is highly effective in preventing attacks in this disorder in a dose-related fashion.3 Many definitions of colchicine resistance are available in the literature. The European League Against Rheumatism (EULAR) guidelines defined resistance as one or more attacks per month in compliant patients who had been receiving the maxi mally tolerated dose for at least 6 months.4 A similar definition was confirmed by a recent consensus among experts.5 In the present national multicentric longitudinal study, we analyze the impact of colchicine treatment on disease activity and quality of life in real life in pediatric and adult patients with FMF.

Published
2021

35. Detection of Temporomandibular Joint Disfunction in Juvenile Idiopathic Arthritis Through Infrared Thermal Imaging and a Machine Learning Procedure

Author

Arcangelo Merla, Daniela Cardone, Luciana Breda, Michele D'Attilio, Nadia Trippetti, and David Perpetuini

Subjects
General linear model, Orthodontics, Thermal infrared, medicine.diagnostic_test, Receiver operating characteristic analysis, business.industry, Arthritis, Magnetic resonance imaging, Gold standard (test), medicine.disease, Temporomandibular joint, stomatognathic diseases, medicine.anatomical_structure, Infrared thermal imaging, Medicine, business
Abstract

Juvenile idiopathic arthritis (JIA) represents the most common rheumatologic disease in childhood, often characterized by temporomandibular joint (TMJ) disfunction (TMD). The gold standard to diagnose this pathology relies on magnetic resonance imaging. Alternatively, electromyographic (EMG) recordings could provide an early and immediate detection of TMD. Particularly, temporalis muscle is known to exhibit a greater EMG activity more frequently than the masseter in pathological subjects. Since muscular activity may influence the superficial circulation and, consequently, the skin temperature, the capabilities of functional thermal infrared imaging (fIRI) to detect TMD were also investigated. In this study, the feasibility of a multivariate data-driven approach based on General Linear Model to estimate the EMG ratio between masseter and temporalis (sEMG-M/T) from fIRI features was investigated. A leave-one-subject-out cross-validation was implemented to test the generalization capability of the model (r = 0.55; p = 1.72·10−6). Moreover, the output of the model was used to classify TMD and healthy controls. Since the two classes were unbalanced, a bootstrap procedure was applied. The performances of the classifier were investigated through Receiver Operating Characteristic analysis, which exhibited an area under the curve of 0.71. The results suggested that fIRI could be a relative cheap and simple to use tool for TMD assessment.

Published
2020

36. Pediatrician’s approach to diagnosis and management of group A streptococcal pharyngitis

Author

Caterina Di Battista, Emma Altobelli, Giuseppe Lapergola, Ilenia Di Muzio, Ilaria Zenobi, Debora Mariarita d’Angelo, Luciana Breda, and Valentina Marzetti

Subjects
0301 basic medicine, Microbiology (medical), Male, Pediatrics, medicine.medical_specialty, Streptococcus pyogenes, 030106 microbiology, Guidelines, Group A, 03 medical and health sciences, 0302 clinical medicine, Primary prevention, Surveys and Questionnaires, Sore throat, medicine, Humans, Rheumatic fever, 030212 general & internal medicine, Pediatricians, Aged, business.industry, Prophylaxis, Incidence (epidemiology), Group A streptococcus, Validated questionnaire, Pharyngitis, General Medicine, Guideline, Antibiotic Prophylaxis, Middle Aged, medicine.disease, Anti-Bacterial Agents, Infectious Diseases, Italy, Practice Guidelines as Topic, Female, Guideline Adherence, medicine.symptom, business
Abstract

Group A streptococcal (GAS) pharyngitis is responsible for 20–30% of pharyngitis cases in children (Shulman et al. Clin Infect Dis 55(10):e86–e102, 2012). Recommendations for the diagnosis and treatment of GAS pharyngitis have been published by the Italian National Institute of Health guidelines in 2012 (ESCMID Sore Throat Guideline Group et al. Clin Microbiol Infect 18(Suppl 1):1–28, 2012). Adherence to such guidance is relevant for primary prevention of complications of GAS pharyngitis, above all rheumatic fever (RF). The aim of our study was to evaluate the application of Italian guidelines by the family pediatricians from the Abruzzo region. A validated questionnaire was completed by the family pediatricians and used for data collection. The 154 family pediatricians from Abruzzo (88% of the total number of family pediatricians) participated in the study. Out of the 1232 answers, 455 (37%) were wrong. Only 8% of the participants answered correctly all the questions, whereas 0.6% missed all the questions. Through the Spearman’s correlation, our study found an inverse significant correlation between the questions regarding primary prophylaxis (Score B) and the work experience of pediatricians (Rho = − 0.276, p = 0.048). The majority of the family pediatricians from the Abruzzo region, in line with studies from other countries, have significant knowledge gaps about the diagnosis and treatment of GAS pharyngitis. Therefore, strategies to increase the pediatricians’ awareness of the guidelines are needed, in order to reduce the RF incidence.

Published
2020

37. Protein-losing enteropathy in an infant with rotavirus infection

Author

Adriana Parisi, Alessandro Cafarotti, Piernicola Pelliccia, Roberta Salvatore, Luciana Breda, and Francesco Chiarelli

Subjects
Rotavirus, Protein-Losing Enteropathies, 030204 cardiovascular system & hematology, medicine.disease_cause, Chromatography, Affinity, Rotavirus Infections, Feces, Plasma, 03 medical and health sciences, 0302 clinical medicine, Blood serum, Generalised oedema, Albumins, 030225 pediatrics, Abdomen, medicine, Humans, Enteropathy, Infusions, Intravenous, Antigens, Viral, Serum Albumin, Ultrasonography, business.industry, Protein losing enteropathy, Infant, medicine.disease, Rotavirus infection, Blood chemistry, Pediatrics, Perinatology and Child Health, Immunology, Female, Complication, business
Abstract

Protein-losing enteropathy (PLE) is a rare gastro-intestinal complication characterised by intestinal loss of proteins with consequent hypoproteinaemia and generalised oedema. Rotavirus infection associated with PLE in children has rarely been reported. A 6-month-old girl presented with diarrhoea, fever and generalised oedema. Total serum proteins were 34 g/L (61-79) and plasma albumin 16.8 g/L (40-50), serum sodium was 126 mmol/L and there was mild metabolic alkalosis (pH 7.46). Stool for alpha-1 antitrypsin was 1.2 mg/g (0.6) which supported the diagnosis of PLE. Stool examination demonstrated the presence of rotavirus antigen by the rapid immunochromatographic test. Abdominal ultrasound showed bowel distension and intestinal wall thickening with a small amount of ascites. Echocardiography excluded pericardial effusion. Two albumin infusions (1 g/kg) were required to sustain normal serum albumin levels. Over the next 2 weeks, there was gradual normalisation of stools and progressive reduction of oedema. In children with acute and symptomatic PLE, rotavirus should be considered in the differential diagnosis. The availability of the rapid immunochromatographic test facilitates the diagnosis. In most cases, supportive care alone is sufficient, but albumin infusions may be required in more severely affected children.

Published
2017

38. Etanercept treatment for extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis : 6-year efficacy and safety data from an open-label trial

Author

Gordana Susic, Valda Stanevicha, Ronald Pedersen, Joke Dehoorne, Katarzyna Kobusińska, Jelena Vojinovic, Vyacheslav Chasnyk, Jack F. Bukowski, Luciana Breda, Bogna Dobrzyniecka, Bonnie Vlahos, Irina Nikishina, Ivan Foeldvari, Nico M Wulffraat, Violeta Panaviene, Gerd Horneff, Pavla Doležalová, Zbigniew Zuber, Nicolino Ruperto, Ingrida Rumba-Rozenfelde, Chantal Job-Deslandre, Tamás Constantin, Alberto Martini, and Brigitte Bader-Meunier

Subjects
Male, lcsh:Diseases of the musculoskeletal system, Arthritis, CHILDREN, CATEGORIES, DISEASE-ACTIVITY, Etanercept, Enthesitis-related arthritis (ERA), Juvenile Arthritis Disease Activity Score, DOUBLE-BLIND, INITIATION, NECROSIS-FACTOR, DEFINING CRITERIA, Medicine and Health Sciences, Medicine, Child, Non-U.S. Gov't, Clinical trial, Efficacy, Enthesitis-related arthritis, Extended oligoarticular juvenile idiopathic arthritis (eoJIA), Juvenile idiopathic arthritis, Psoriatic arthritis (PsA), Safety, Oligoarthritis, Research Support, Non-U.S. Gov't, METHOTREXATE, Treatment Outcome, Antirheumatic Agents, Child, Preschool, Female, medicine.drug, Research Article, medicine.medical_specialty, Adolescent, Research Support, Psoriatic arthritis, Internal medicine, Adalimumab, Journal Article, Humans, etanercept, juvenile idiopathic arthritis, enthesitis-related arthritis, extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), psoriatic arthritis (PsA), efficacy, safety, clinical trial, PEDIATRIC-PATIENTS, business.industry, medicine.disease, Rheumatology, Arthritis, Juvenile, Oligoarticular Juvenile Idiopathic Arthritis, lcsh:RC925-935, business, ADALIMUMAB
Abstract

Background To describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA) Methods Patients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs). Results Out of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin’s lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported. Conclusions Open-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA. Trial registration ClinicalTrials.gov: CLIPPER, NCT00962741, registered 20 August, 2009, CLIPPER2, NCT01421069, registered 22 August, 2011. Electronic supplementary material The online version of this article (10.1186/s13075-019-1916-9) contains supplementary material, which is available to authorized users.

Published
2019

39. Lung function in children with juvenile idiopathic arthritis: A cross-sectional analysis

Author

Marianna Immacolata Petrosino, Manuela Marsili, Daniele Rapino, Giorgia Gasparroni, Francesco Chiarelli, Paola Di Filippo, Marina Attanasi, M. Lucantoni, Luciana Breda, and Sabrina Di Pillo

Subjects
musculoskeletal diseases, Pulmonary and Respiratory Medicine, Spirometry, Male, medicine.medical_specialty, Vital capacity, Adolescent, Gastroenterology, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, immune system diseases, DLCO, 030225 pediatrics, Internal medicine, medicine, Plethysmograph, Humans, Lung volumes, skin and connective tissue diseases, Child, Lung, Plethysmography, Whole Body, medicine.diagnostic_test, business.industry, Cumulative dose, respiratory system, Arthritis, Juvenile, Respiratory Function Tests, medicine.anatomical_structure, Cross-Sectional Studies, Methotrexate, 030228 respiratory system, Antirheumatic Agents, Pediatrics, Perinatology and Child Health, Female, business
Abstract

AIM We measured respiratory parameters in children with juvenile idiopathic arthritis (JIA) without clinical signs of respiratory involvement and assessed the influence of methotrexate (MTX) treatment and disease activity on lung function. METHODS In 49 JIA children and 70 controls lung volumes by spirometry and body plethysmography, and lung diffusion for carbon monoxide (DLCO) with single-breath technique were evaluated. RESULTS DLCO was significantly different between JIA children and controls (P = .01), whereas no differences were found in flow expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), forced expiratory flow at 25% to 75% of FVC (FEF 25-75 ), peak expiratory flow, total lung capacity, and residual volume. After dividing study JIA patients according to MTX treatment, a significant difference in DLCO was found among JIA patients treated with MTX and those treated with other drugs and controls (P

Published
2018

40. Asymptomatic Multiple Liver Granulomas in a Child

Author

Caterina Di Battista, Nadia Rossi, Giuseppe Lapergola, Paola Cipriano, Luciana Breda, and Piernicola Pelliccia

Subjects
medicine.medical_specialty, Text mining, business.industry, Pediatrics, Perinatology and Child Health, Medicine, medicine.symptom, business, Asymptomatic, Dermatology
Published
2019

41. TNF-α gene polymorphisms and juvenile idiopathic arthritis: Influence on disease outcome and therapeutic response

Author

Alessandra Scardapane, Michela Balsamo, Luciana Breda, Rossella Ferrante, Alessandra Savino, Manuela Nozzi, Liborio Stuppia, Ivana Antonucci, Francesco Chiarelli, and Vincenzo Dadorante

Subjects
Male, Adolescent, Genotype, Arthritis, Single-nucleotide polymorphism, Disease, Polymorphism, Single Nucleotide, Rheumatology, medicine, Humans, Juvenile, Genetic Predisposition to Disease, Child, Promoter Regions, Genetic, Gene, Tumor Necrosis Factor-alpha, business.industry, Infant, Promoter, Prognosis, medicine.disease, Arthritis, Juvenile, Treatment Outcome, Anesthesiology and Pain Medicine, Antirheumatic Agents, Child, Preschool, Immunology, Female, Tumor necrosis factor alpha, business
Abstract

To investigate the genetic contribution of TNF-α gene polymorphisms on the disease course and therapeutic response in patients with juvenile idiopathic arthritis (JIA).74 Caucasian patients with JIA were recruited with a control group of 77 healthy children. DNA was extracted for analysis of TNF-α gene promoter polymorphisms at positions -163, -244, -238, -376, and -308.No SNPs at position -163 were observed, while we observed only SNPs at positions -244 and -376 in the controls. No differences were observed in the prevalence of SNPs at -238 and -308 between JIA and controls. In JIA patients no significant differences were observed between the -238 and -308 G/A genotypes and different disease phenotypes. We observed a significant lower disease activity expressed in the carriers of -308 GG genotype with respect to GA and AA genotypes after 6 (p = 0.008 and p = 0.013, respectively) and 12 months of disease (p = 0.02 and p = 0.08, respectively). Also the -238 GG genotypes showed a better disease course after 12 months of disease. Moreover, the -238/-308 GG genotypes presented the higher reduction of disease activity both after 6 (p0.01 vs GA and p0.01 vs AA) and 12 months from baseline (p0.01 vs GA and p0.01 vs AA). After 12 months of biologic therapy, a significant higher disease activity was observed in patients with genotype -308 AA respect to both GA (p = 0.012) and GG (p = 0.016).JIA patients carrying the TNF-α -308 GA/AA and -238 GA genotypes are associated with a worse prognosis and with a lower response to anti-TNF-α drugs.

Published
2015

42. Dissecting the Heterogeneity of Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis

Author

Nicolino Ruperto, Antonella Buoncompagni, Bianca Lattanzi, Zane Davidsone, Maka Ioseliani, Jaime de Inocencio, Carmen De Cunto, Jeffrey M. Lipton, Angelo Ravelli, Claudia Saad Magalhães, Sandra Enciso, Thomas A. Griffin, Patrizia Barone, Hasan Tezer, Michael Jeng, Francesca Bovis, Paolo Picco, Sulaiman M. Al-Mayouf, Ageza M Kapovic, Nuray Aktay Ayaz, Jonathan D Akikusa, Erkan Demirkaya, Ingrida Rumba-Rozenfelde, Silvia Magni Manzoni, Olga Vougiouka, B. Bica, Alberto Martini, Randy Q. Cron, Romina Gallizzi, Francesca Minoia, Isabel Bolt, Wafaa Sewairi, Luciana Breda, AnnaCarin Horne, Sergio Davì, Teresa Hennon, G. Horneff, Lehn K. Weaver, and Kimo C. Stine

Subjects
Male, HEMOPHAGOCYTIC SYNDROMES, Internationality, Databases, Factual, Hepatosplenomegaly, Juvenile, Comorbidity, HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, Severity of Illness Index, MACROPHAGE ACTIVATION SYNDROME, SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS, Adolescent, Age Distribution, Arthritis, Juvenile, Child, Child, Preschool, Cohort Studies, Female, Humans, Macrophage Activation Syndrome, Multivariate Analysis, Prevalence, Prognosis, Retrospective Studies, Sex Distribution, Survival Analysis, Immunology and Allergy, Rheumatology, Immunology, Hemophagocytosis, medicine.symptom, medicine.medical_specialty, Hemophagocytic Lymphohistiocytosis, Hemophagocytic Syndromes, Macrophage activation syndromes, Systemic Juvenile Idiopathic Arthritis, Adolescent, Age Distribution, Arthritis, Juvenile, Child, Child, Preschool, Cohort Studies, Comorbidity, Databases, Factual, Female, Humans, Internationality, Macrophage Activation Syndrome, Male, Multivariate Analysis, Prevalence, Prognosis, Retrospective Studies, Severity of Illness Index, Sex Distribution, Survival Analysis, Immunology and Allergy, Rheumatology, Immunology, Databases, Internal medicine, Severity of illness, medicine, Preschool, Factual, Hemophagocytic lymphohistiocytosis, business.industry, Arthritis, Retrospective cohort study, medicine.disease, Macrophage activation syndrome, Macrophage activation syndromes, business
Abstract

Objective.To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey.Methods.International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course.Results.A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide.Conclusion.The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

Published
2015

43. Macrophage activation syndrome in Still's disease: analysis of clinical characteristics and survival in paediatric and adult patients

Author

Roberto Giacomelli, Caterina Di Battista, Paola Cipriani, Carmela Rago, Luciana Breda, Onorina Berardicurti, Alberto Verrotti, Francesco Carubbi, Vasiliki Liakouli, Piero Ruscitti, Ruscitti, Piero, Rago, Carmela, Breda, Luciana, Cipriani, Paola, Liakouli, Vasiliki, Berardicurti, Onorina, Carubbi, Francesco, Di Battista, Caterina, Verrotti, Alberto, and Giacomelli, Roberto.

Subjects
musculoskeletal diseases, 0301 basic medicine, Adult, Male, medicine.medical_specialty, Pediatrics, Adolescent, Disease, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Internal medicine, Medicine, Humans, Child, Survival rate, Retrospective Studies, 030203 arthritis & rheumatology, Hemophagocytic lymphohistiocytosis, biology, business.industry, Macrophage Activation Syndrome, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Prognosis, Arthritis, Juvenile, Ferritin, 030104 developmental biology, Macrophage activation syndrome, Child, Preschool, biology.protein, Female, business, Complication, Still's Disease, Adult-Onset
Abstract

Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, complicating Still's disease, both in paediatric and adult patients. In this work, we aimed to investigate clinical picture and outcome of Still's disease patients developing MAS. We performed a retrospective analysis of patients, both paediatrics and adults, affected by Still's disease attending our department. During the follow-up, each patient was investigated for MAS occurrence and possible predictors, clinical and laboratory factors, were analysed. We evaluated 50 patients affected by Still's disease, 21 paediatric and 29 adult patients. Ten patients experienced MAS (five adult and five paediatric patients) and its development significantly reduced the survival rate when compared with patients without this complication (p

Published
2017

44. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome

Author

Francesca Minoia, Francesca Bovis, Sergio Davì, Antonella Insalaco, Kai Lehmberg, Susan Shenoi, Sheila Weitzman, Graciela Espada, Yi-Jin Gao, Jordi Anton, Toshiyuki Kitoh, Ozgur Kasapcopur, Helga Sanner, Rosa Merino, Itziar Astigarraga, Maria Alessio, Michael Jeng, Vyacheslav Chasnyk, Kim E. Nichols, Zeng Huasong, Caifeng Li, Concetta Micalizzi, Nicolino Ruperto, Alberto Martini, Randy Q. Cron, Angelo Ravelli, AnnaCarin Horne, Mario Abinun, Amita Aggarwal, Jonathan Akikusa, Sulaiman Al-Mayouf, Maria Teresa Apaz, Tadej Avcin, Nuray Aktay Ayaz, Patrizia Barone, Bianca Bica, Isabel Bolt, Luciana Breda, Rolando Cimaz, Fabrizia Corona, Ruben Cuttica, Zane Davidsone, Carmen De Cunto, Jaime De Inocencio, Erkan Demirkaya, Eli M. Eisenstein, Sandra Enciso, Michel Fischbach, Michael Frosch, Romina Gallizzi, Maria Luz Gamir, Thomas Griffin, Alexei Grom, Soad Hashad, Teresa Hennon, Jan-Inge Henter, Gerd Horneff, Adam Huber, Norman Ilowite, Maka Ioseliani, Agneza Marija Kapović, Raju Khubchandani, Isabelle Koné-Paut, Sheila Knupp Feitosa de Oliveira, Bianca Lattanzi, Loredana Lepore, Jeffrey M. Lipton, Silvia Magni-Manzoni, Despoina Maritsi, Deborah McCurdy, Paivi Miettunen, Velma Mulaosmanovic, Susan Nielsen, Seza Ozen, Priyankar Pal, Sampath Prahalad, Donato Rigante, Ingrida Rumba-Rozenfelde, Ricardo Russo, Claudia Saad Magalhães, Wafaa Mohamed Saad Sewairi, Clovis Artur Silva, Valda Stanevicha, Gary Sterba, Kimo C. Stine, Gordana Susic, Flavio Sztajnbok, Syuji Takei, Ralf Trauzeddel, Elena Tsitsami, Erbil Unsal, Yosef Uziel, Olga Vougiouka, Carol A. Wallace, Lehn Weaver, Jennifer E. Weiss, Carine Wouters, Nico Wulffraat, Mabruka Zletni, Maurizio Arico, R. Maarten Egeler, Alexandra H. Filipovich, Helmut Gadner, Shinsaku Imashuku, Gritta Janka, Stephan Ladisch, Ken L. McClain, David Webb, Minoia, F., Bovis, F., Davi, S., Insalaco, A., Lehmberg, K., Shenoi, S., Weitzman, S., Espada, G., Gao, Y. -J., Anton, J., Kitoh, T., Kasapcopur, O., Sanner, H., Merino, R., Astigarraga, I., Alessio, M., Jeng, M., Chasnyk, V., Nichols, K. E., Huasong, Z., Li, C., Micalizzi, C., Ruperto, N., Martini, A., Cron, R. Q., Ravelli, A., Horne, A., Abinun, M., Aggarwal, A., Akikusa, J., Al-Mayouf, S., Apaz, M. T., Avcin, T., Ayaz, N. A., Barone, P., Bica, B., Bolt, I., Breda, L., Cimaz, R., Corona, F., Cuttica, R., Davidsone, Z., De Cunto, C., De Inocencio, J., Demirkaya, E., Eisenstein, E. M., Enciso, S., Fischbach, M., Frosch, M., Gallizzi, R., Gamir, M. L., Griffin, T., Grom, A., Hashad, S., Hennon, T., Henter, J. -I., Horneff, G., Huber, A., Ilowite, N., Ioseliani, M., Kapovic, A. M., Khubchandani, R., Kone-Paut, I., de Oliveira, S. K. F., Lattanzi, B., Lepore, L., Lipton, J. M., Magni-Manzoni, S., Maritsi, D., Mccurdy, D., Miettunen, P., Mulaosmanovic, V., Nielsen, S., Ozen, S., Pal, P., Prahalad, S., Rigante, D., Rumba-Rozenfelde, I., Russo, R., Magalhaes, C. S., Sewairi, W. M. S., Artur Silva, C., Stanevicha, V., Sterba, G., Stine, K. C., Susic, G., Sztajnbok, F., Takei, S., Trauzeddel, R., Tsitsami, E., Unsal, E., Uziel, Y., Vougiouka, O., Wallace, C. A., Weaver, L., E. Weiss, J., Wouters, C., Wulffraat, N., Zletni, M., Arico, M., Egeler, R. M., Filipovich, A. H., Gadner, H., Imashuku, S., Janka, G., Ladisch, S., Mcclain, K. L., and Webb, D.

Subjects
Male, 0301 basic medicine, Hemophagocytic, Logistic regression, Pediatrics, hemophagocytic syndrome, 0302 clinical medicine, diagnostic score, Diagnosis, Medicine, Cutoff, Child, primary hemophagocytic lymphohistiocytosi, Lymphohistiocytosis, education.field_of_study, primary hemophagocytic lymphohistiocytosis, Perinatology and Child Health, Quartile, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Macrophage activation syndrome, Child, Preschool, macrophage activation syndrome, Absolute neutrophil count, Female, Human, medicine.medical_specialty, Adolescent, Population, Lymphohistiocytosis, Hemophagocytic, Diagnosis, Differential, 03 medical and health sciences, Internal medicine, Humans, Preschool, education, 030203 arthritis & rheumatology, Receiver operating characteristic, business.industry, Infant, Reproducibility of Results, medicine.disease, Surgery, 030104 developmental biology, Macrophage Activation Syndrome, Pediatrics, Perinatology and Child Health, Differential, Differential diagnosis, business
Abstract

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of =123. A cutoff value of =60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

Published
2017

45. Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial

Author

Angelo Ravelli, Valeria Gerloni, Silvia Magni-Manzoni, Nicolino Ruperto, Serena Pastore, Franco Garofalo, Angela Pistorio, Sara Verazza, Marco Gattorno, Giovanni Filocamo, Adele Civino, Clara Malattia, Fabrizio De Benedetti, Maurizio Gattinara, Luciana Breda, Giulia Bracciolini, Valentina Marzetti, Alessandro Consolaro, Maria Cristina Maggio, Alberto Martini, Bianca Lattanzi, Stefania Viola, Sergio Davì, Donato Rigante, Giuseppe Presta, Stefano Lanni, Evert Hendrik Pieter van Dijkhuizen, Irene Pontikaki, Paolo Picco, Antonella Insalaco, Ravelli, A., Davì, S., Bracciolini, G., Pistorio, A., Consolaro, A., van Dijkhuizen, E., Lattanzi, B., Filocamo, G., Verazza, S., Gerloni, V., Gattinara, M., Pontikaki, I., Insalaco, A., De Benedetti, F., Civino, A., Presta, G., Breda, L., Marzetti, V., Pastore, S., Magni-Manzoni, S., Maggio, M., Garofalo, F., Rigante, D., Gattorno, M., Malattia, C., Picco, P., Viola, S., Lanni, S., Ruperto, N., and Martini, A.

Subjects
musculoskeletal diseases, medicine.medical_specialty, Population, Arthritis, Injections, Intra-Articular, 03 medical and health sciences, 0302 clinical medicine, Adrenal Cortex Hormones, Internal medicine, medicine, media_common.cataloged_instance, Humans, 030212 general & internal medicine, Prospective Studies, European union, Adverse effect, education, media_common, 030203 arthritis & rheumatology, education.field_of_study, business.industry, Medicine (all), General Medicine, Methylprednisolone acetate, Juvenile idiopathic arthritis, medicine.disease, Arthritis, Juvenile, Surgery, Clinical trial, Methotrexate, Treatment Outcome, Italy, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Oligoarticular Juvenile Idiopathic Arthritis, business, medicine.drug
Abstract

Summary Background Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. Methods We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m 2 ; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. Findings Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. Interpretation Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. Funding Italian Agency of Drug Evaluation.

Published
2017

46. MBL2 and FCN2 gene polymorphisms in a cohort of Italian children with rheumatic fever: A case-control study

Author

Liborio Stuppia, Rossella Ferrante, Caterina Di Battista, Leonardo Carlucci, Valentina Marzetti, Michela Balsamo, Ivana Antonucci, Francesco Chiarelli, Luciana Breda, and Giuseppe Lapergola

Subjects
0301 basic medicine, Male, Genotype, Single-nucleotide polymorphism, Mannose-Binding Lectin, Polymorphism, Single Nucleotide, Pathogenesis, Cohort Studies, 03 medical and health sciences, Rheumatology, Lectins, medicine, Humans, Allele, Risk factor, Child, Alleles, Retrospective Studies, business.industry, Case-control study, Carditis, medicine.disease, 030104 developmental biology, Anesthesiology and Pain Medicine, Italy, Case-Control Studies, Child, Preschool, Immunology, Rheumatic fever, Female, Rheumatic Fever, business
Abstract

Background Mannose-binding lectins and human ficolins are pattern-recognition proteins involved in innate immunity. A role for MBL2 and FCN2 gene polymorphisms in the pathogenesis of recurrent severe streptococcal infections and rheumatic carditis has been suggested. Objectives The aim of this study is to evaluate the presence of MBL2 and FCN2 gene polymorphisms (SNPs) in children with a history of rheumatic fever (RF) and to investigate their possible role in RF clinical presentation and disease course. Methods A total of 50 Caucasian patients with RF were recruited with a control group of 52 healthy children. DNA was extracted for analysis of MBL2 gene (exon 1, codons: 52, 54, and 57) and FCN2 gene (promoter region at position −986, −602, and −4). Results The FCN2 AG genotype at the −986 position was more frequently observed in patients, as compared to healthy subjects ( p = 0.006); furthermore, the A allele was identified as a possible risk factor for the development of RF (OR = 7.14, CI: 2.439–20.89). Conversely, the GG genotype at the same position was observed more frequently in the control group and can be considered a protective factor for the development of the disease ( p = 0.001, OR=8.37, 95% CI: 2.763–25.33). In addition, the FCN2 GG and AG genotypes in the −4 position were also found to be protective factors for the development of RF and for carditis respectively (OR = 3.32, CI: 1.066–10.364; OR=0.15, 95% CI: 0.037–0.566). Finally, the AA genotype in the −602 position was associated with a late onset of RF ( p = 0.006). The analysis of the MBL2 gene only resulted in a higher frequency of the AA genotype on position 57 in controls as compared to patients ( p = 0.025). Conclusions This is the first study evaluating the FCN2 gene polymorphisms in patients with RF and rheumatic carditis finding a protective effect of −986 GG and −4 GG genotypes in the development of RF and the −4 AG genotype for the development of carditis. Our data do not support a possible role for MBL2 polymorphisms in the pathogenesis and in the clinical manifestations of RF.

Published
2016

47. Neonatal-Onset Urticaria and Fever

Author

Francesco Chiarelli, Manuela Marsili, Caterina Di Battista, Luciana Breda, Marco Gattorno, and Isabella Ceccherini

Subjects
Male, Pediatrics, medicine.medical_specialty, Fever, Urticaria, business.industry, Infant, Newborn, Antibodies, Monoclonal, Neonatal onset, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Cryopyrin-Associated Periodic Syndromes, 03 medical and health sciences, 0302 clinical medicine, Text mining, Child, Preschool, Pediatrics, Perinatology and Child Health, NLR Family, Pyrin Domain-Containing 3 Protein, Medicine, Humans, 030212 general & internal medicine, business
Published
2016

48. 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis : A European league against Rheumatism/American college of Rheumatology/Paediatric rheumatology international trials organisation collaborative initiative

Author

Ravelli, Angelo, Minoia, Francesca, Davì, Sergio, Horne, Annacarin, Bovis, Francesca, Pistorio, Angela, Aricò, Maurizio, Avcin, Tadej, Behrens, Edward M., De Benedetti, Fabrizio, Filipovic, Lisa, Grom, Alexei A., Henter, Jan Inge, Ilowite, Norman T., Jordan, Michael B., Khubchandani, Raju, Kitoh, Toshiyuki, Lehmberg, Kai, Lovell, Daniel J., Miettunen, Paivi, Nichols, Kim E., Ozen, Seza, Pachlopnik Schmid, Jana, Ramanan, Athimalaipet V., Russo, Ricardo, Schneider, Rayfel, Sterba, Gary, Uziel, Yosef, Wallace, Carol, Wouters, Carine, Wulffraat, Nico, Demirkaya, Erkan, Brunner, Hermine I., Martini, Alberto, Ruperto, Nicolino, Cron, PARTICIPATING PHYSICIANS The following physicians contributed patient data for use in the study: Mario Abinun, Randy Q. APPENDIX A., Amita Aggarwal, Md, Jonathan Akikusa, Md, Sulaiman M. Al Mayouf, Md, Maria Alessio, Md, Jordi Anton, Md, Maria Teresa Apaz, Md, Itziar Astigarraga, Md, Nuray A. Ayaz, Md, Patrizia Barone, Md, Blanca Bica, Md, Isabel Bolt, Md, Luciana Breda, Md, Vyacheslav Chasnyk, Md, Rolando Cimaz, Md, Fabrizia Corona, Md, Ruben Cuttica, Md, Gianfranco D’Angelo, Md, Zane Davidsone, Md, Carmen De Cunto, Md, Jaime De Inocencio, Md, Eli Eisenstein, Md, Sandra Enciso, Md, Graciela Espada, Md, Michel Fischbach, Md, Michael Frosch, Md, Gallizzi, Romina, Maria Luz Gamir, Md, Yi Jin Gao, Md, Thomas Griffin, Md, Soad Hashad, Md, Teresa Hennon, Md, Gerd Horneff, Md, Zeng Huasong, Md, Adam Huber, Md, Norman Ilowite, Md, Antonella Insalaco, Md, Maka Ioseliani, Md, Marijia Jelusic Drazic, Md, Michael Jeng, Md, Agneza Kapovic, Md, Ozgur Kasapcopur, Md, Toshiyuki Kitoh, Md, Isabelle Kone Paut, Md, Sheila Knupp Feitosa de Oliveira, Md, Bianca Lattanzi, Md, Loredana Lepore, Md, Caifeng Li, Md, Jeffrey M. Lipton, Md, Silvia Magni Manzoni, Md, Despoina Maritsi, Md, Deborah McCurdy, Md, Rosa Merino, Md, Velma Mulaosmanovic, Md, Susan Nielsen, Md, Priyankar Pal, Md, Sampath Prahalad, Md, Donato Rigante, Md, Ingrida Rumba Rozenfelde, Md, Claudia Saad Magalhaes, Md, Helga Sanner, Md, Sujata Sawhney, Md, Wafaa M. Sewairi, Md, Bita Shakoory, Md, Susan Shenoi, Md, Artur Silva Clovis, Md, Valda Stanevicha, Md, Kimo C. Stine, Md, Gordana Susic, Md, Flavio Sztajnbok, Md, Syuji Takei, Md, Hasan Tezer, Md, Ralf Trauzeddel, Md, Elena Tsitsami, Md, Erbil Unsal, Md, Olga Vougiouka, Md, Lehn K. Weaver, Md, Jennifer Weiss, Md, Sheila Weitzman, Md, and Mabruka Zletni, M. D.

Subjects
Genetics and Molecular Biology (all), Delphi Technique, genetic structures, Ankylosing Spondylitis, Delphi method, Juvenile, Arthritis, Disease, Biochemistry, 0302 clinical medicine, Diagnosis, Medicine, Immunology and Allergy, 030212 general & internal medicine, Child, Non-U.S. Gov't, skin and connective tissue diseases, Societies, Medical, Medicine(all), Analgesics, Medicine (all), Macrophage Activation Syndrome, Research Support, Non-U.S. Gov't, Consensus conference, Amyloidosis, Europe, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, lipids (amino acids, peptides, and proteins), hormones, hormone substitutes, and hormone antagonists, musculoskeletal diseases, medicine.medical_specialty, Disease onset, Consensus, Immunology, MEDLINE, Classification Criteria, Systemic Juvenile Idiopathic Arthritis, European League Against Rheumatism/American College of Rheumatology, Paediatric Rheumatology International Trials Organisation Collaborative Initiative, Research Support, General Biochemistry, Genetics and Molecular Biology, Article, Diagnosis, Differential, 03 medical and health sciences, Arthritis, Juvenile, Humans, Internet, Logistic Models, Rheumatology, Medical, Internal medicine, Journal Article, In patient, Comparative Study, Intensive care medicine, 030203 arthritis & rheumatology, Ankylosing spondylitis, business.industry, Biochemistry, Genetics and Molecular Biology(all), fungi, Reproducibility of Results, Expert consensus, Consensus Development Conference, Patient data, medicine.disease, Adult Onset Still's Disease, United States, body regions, Ant-CCP, Macrophage activation syndrome, Differential, Physical therapy, Biochemistry, Genetics and Molecular Biology (all), Societies, business, Rheumatism, Genetics and Molecular Biology(all)
Abstract

Objective To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). Methods A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Results Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76). Conclusion We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.

Published
2016

49. Disease status, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept

Author

Marta Torcoletti, Achille Marino, Francesco La Torre, Giovanni Conti, Patrizia Barone, Donato Rigante, Francesco Zulian, Francesca Rovelli, Angelo Ravelli, Fabrizio De Benedetti, Gianfranco D'Angelo, Adele Civino, Alessandro De Fanti, Rebecca Nicolai, Valeria Gerloni, Irene Pontikaki, Silvia Magni-Manzoni, Francesca Bovis, Maria Cristina Maggio, Nicolino Ruperto, Serena Pastore, C Fede, Denise Pires Marafon, Alberto Martini, Chiara Sandrin, Fabrizia Corona, Romina Gallizzi, Sergio Davì, MG Alpigiani, Rita Consolini, Sara Verazza, Alessandro Consolaro, Giorgia Martini, Antonella Insalaco, Mauro Jorini, Alma Nunzia Olivieri, Rolando Cimaz, Rosanna Podda, Valentina Muratore, Luciana Breda, Marco Cattalini, Elisabetta Cortis, Verazza, Sara, Davì, Sergio, Consolaro, Alessandro, Bovis, Francesca, Insalaco, Antonella, Magni Manzoni, Silvia, Nicolai, Rebecca, Marafon, Denise Pire, De Benedetti, Fabrizio, Gerloni, Valeria, Pontikaki, Irene, Rovelli, Francesca, Cimaz, Rolando, Marino, Achille, Zulian, Francesco, Martini, Giorgia, Pastore, Serena, Sandrin, Chiara, Corona, Fabrizia, Torcoletti, Marta, Conti, Giovanni, Fede, Claudia, Barone, Patrizia, Cattalini, Marco, Cortis, Elisabetta, Breda, Luciana, Olivieri, Alma Nunzia, Civino, Adele, Podda, Rosanna, Rigante, Donato, La Torre, Francesco, D'Angelo, Gianfranco, Jorini, Mauro, Gallizzi, Romina, Maggio, Maria Cristina, Consolini, Rita, De Fanti, Alessandro, Muratore, Valentina, Alpigiani, Maria Giannina, Ruperto, Nicolino, Martini, Alberto, Ravelli, Angelo, Verazza, S., Davì, S., Consolaro, A., Bovis, F., Insalaco, A., Magni-Manzoni, S., Nicolai, R., Marafon, D., De Benedetti, F., Gerloni, V., Pontikaki, I., Rovelli, F., Cimaz, R., Marino, A., Zulian, F., Martini, G., Pastore, S., Sandrin, C., Corona, F., Torcoletti, M., Conti, G., Fede, C., Barone, P., Cattalini, M., Cortis, E., Breda, L., Olivieri, A., Civino, A., Podda, R., Rigante, D., La Torre, F., D'Angelo, G., Jorini, M., Gallizzi, R., Maggio, M., Consolini, R., De Fanti, A., Muratore, V., Alpigiani, M., Ruperto, N., Martini, A., and Ravelli, A.

Subjects
Male, Biologic therapie, Biologic therapies, Etanercept, Juvenile idiopathic arthritis, Pediatric rheumatology, TNF inhibitors, Adolescent, Antirheumatic Agents, Arthritis, Juvenile, Child, Child, Preschool, Cross-Sectional Studies, Drug Substitution, Female, Humans, Methotrexate, Patient Outcome Assessment, Retrospective Studies, Treatment Outcome, Pediatrics, Perinatology and Child Health, Rheumatology, Immunology and Allergy, Arthritis, Juvenile, Pediatrics, Inflammatory bowel disease, Settore MED/38 - Pediatria Generale E Specialistica, 0302 clinical medicine, Quality of life, Retrospective Studie, 030212 general & internal medicine, Antirheumatic Agent, Perinatology and Child Health, 3. Good health, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Research Article, Human, medicine.drug, medicine.medical_specialty, 03 medical and health sciences, Juvenile idiopathic arthriti, Internal medicine, medicine, Pediatrics, Perinatology, and Child Health, Adverse effect, Preschool, Cross-Sectional Studie, 030203 arthritis & rheumatology, business.industry, Retrospective cohort study, medicine.disease, Discontinuation, Physical therapy, business, TNF inhibitor
Abstract

Background: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). Methods: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. Results: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis. Conclusions: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.

Published
2016

50. Chronic nonbacterial osteomyelitis may be associated with renal disease and bisphosphonates are a good option for the majority of patients

Author

Loredana Lepore, Lorenzo Monasta, Valeria Gerloni, B Teruzzi, Marco Cattalini, Antonella Meini, Maria Alessio, Giovanna Ferrara, Serena Pastore, Francesco La Torre, Luciana Breda, Silvana Martino, Andrea Taddio, Pastore, Serena, Ferrara, Giovanna, Monasta, Lorenzo, Meini, Antonella, Cattalini, Marco, Martino, Silvana, Alessio, Maria, La Torre, Francesco, Teruzzi, Barbara, Gerloni, Valeria, Breda, Luciana, Taddio, Andrea, Lepore, Loredana, Pastore, S., Ferrara, G., Monasta, L., Meini, A., Cattalini, M., Martino, S., Alessio, M., La Torre, F., Teruzzi, B., Gerloni, V., Breda, L., Taddio, A., and Lepore, L.

Subjects
medicine.medical_specialty, Adolescent, Appendicular skeleton, Disease, Chronic nonbacterial osteomyelitis, Pediatrics, 03 medical and health sciences, Bone pain, 0302 clinical medicine, 030225 pediatrics, Internal medicine, medicine, Bisphosphonate, Humans, Risk factor, Preschool, Child, Children, Retrospective Studies, 030203 arthritis & rheumatology, Diphosphonates, Bisphosphonates, Chronic recurrent multifocal osteomyelitis, Pediatrics, Perinatology and Child Health, business.industry, Osteomyelitis, Chronic recurrent multifocal osteomyeliti, Child, Preschool, Chronic Disease, Kidney Diseases, Retrospective cohort study, General Medicine, Perinatology and Child Health, medicine.disease, Surgery, medicine.anatomical_structure, Chronic nonbacterial osteomyeliti, Cohort, medicine.symptom, business
Abstract

Aim The aim of this Italian study was to describe the clinical features, treatment options and outcomes of a cohort of patients with chronic nonbacterial osteomyelitis (CNO). Methods This was a retrospective cohort study. Laboratory data, diagnostic imaging, histological features and clinical course are reported. Results We enrolled 47 patients diagnosed with CNO. Bone pain was the leading symptom, and multifocal disease was present in 87% of the patients. The majority of the bone lesions were located in the appendicular skeleton (58%). Extraosseous manifestations were present in 34% of the patients, and renal involvement was detected in four patients. Inflammatory indices were increased in 80%, and bone x-rays were negative in 15% of the patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the first therapy for all patients, achieving clinical remission in 27%. A good response to NSAIDs was significantly associated with a better prognosis. Bisphosphonates were used in 26 patients, with remission in 73%. Only six patients (13%), all with spine involvement, developed sequelae. Conclusion We found a possible association between CNO and renal disease. Bisphosphonates were more likely to lead to clinical remission when NSAIDs and corticosteroids had failed. Vertebral localisation was the only risk factor for potential sequelae.

Published
2016

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