Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis.

OBJECTIVE: To develop a composite disease activity score for systemic JIA (sJIA) and to provide preliminary evidence of its validity. METHODS: The systemic Juvenile Arthritis Disease Activity Score (sJADAS) was constructed by adding to the four items of the original JADAS a fifth item that aimed to quantify the activity of systemic features. Validation analyses were conducted on patients with definite or probable/possible sJIA enrolled at first visit or at the time of a flare, who had active systemic manifestations, which should include fever. Patients were reassessed 2 weeks to 3 months after baseline. Three versions were examined, including ESR, CRP or no acute-phase reactant. RESULTS: A total of 163 patients were included at 30 centres in 10 countries. The sJADAS was found to be feasible and to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha 0.64-0.65), fair ability to discriminate between patients with different disease activity states and between those whose parents were satisfied or not satisfied with illness outcome (P < 0.0001 for both), and strong responsiveness to change over time (standardized response mean 2.04-2.58). Overall, these properties were found to be better than those of the original JADAS and of DAS for RA and of Puchot score for adult-onset Still's disease. CONCLUSION: The sJADAS showed good measurement properties and is therefore a valid instrument for the assessment of disease activity in children with sJIA. The performance of the new tool should be further examined in other patient cohorts that are evaluated prospectively.

Development and validation of a composite disease activity score for measurement of muscle and skin involvement in juvenile dermatomyositis.

OBJECTIVE: To develop a composite DAS for JDM and provide preliminary evidence of its validity. METHODS: The Juvenile DermatoMyositis Activity Index (JDMAI) is composed of four items: physician's global assessment of overall disease activity; parent's/child's global assessment of child's wellbeing; measurement of muscle strength; and assessment of skin disease activity. The score of the JDMAI is the arithmetic sum of the scores of each individual component. Six versions of the JDMAI were tested, which differed in the tools used to assess the third and fourth items. Validation procedures were conducted using three large multinational patient samples including a total of 627 patients. RESULTS: The JDMAI was found to possess face and content validity, good construct validity, satisfactory internal consistency (Cronbach's alpha = 0.58-0.89), fair responsiveness to clinically important change (standardized response mean = 0.82-3.12 among patients improved) and strong capacity to discriminate patients judged as being in the state of inactive disease or low, moderate or high disease activity by the physician (P < 0.001) or whose parents were satisfied or not satisfied with the course of their child's illness (P < 0.001). Overall, the six versions of the JDMAI showed similar metrological performances in validation analyses. CONCLUSION: The JDMAI was found to possess good measurement properties in a large population of patients with a wide range of disease activity, and is, therefore, suitable for use in both clinical and research settings. The final version of the JDMAI will be selected after its prospective validation.

The Argentinian Spanish version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Argentinian Spanish language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 373 JIA patients (23.1% systemic, 30.8% oligoarticular, 28.1% RF negative polyarthritis, 18% other categories) and 100 healthy children were enrolled in five centres. The JAMAR components discriminated well healthy subjects from JIA patients. Notably, there was no significant difference between healthy subjects and their affected peers in the school-related item. All JAMAR components revealed good psychometric performances. In conclusion, the Argentinian Spanish version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

The interplay between serine proteases and caspase-1 regulates the autophagy-mediated secretion of Interleukin-1 beta in human neutrophils.

Neutrophils play major roles against bacteria and fungi infections not only due to their microbicide properties but also because they release mediators like Interleukin-1 beta (IL-1ß) that contribute to orchestrate the inflammatory response. This cytokine is a leaderless protein synthesized in the cytoplasm as a precursor (pro-IL-1ß) that is proteolytically processed to its active isoform and released from human neutrophils by secretory autophagy. In most myeloid cells, pro-IL-1ß is processed by caspase-1 upon inflammasome activation. Here we employed neutrophils from both healthy donors and patients with a gain-of-function (GOF) NLRP3-mutation to dissect IL-1ß processing in these cells. We found that although caspase-1 is required for IL-1ß secretion, it undergoes rapid inactivation, and instead, neutrophil serine proteases play a key role in pro-IL-1ß processing. Our findings bring to light distinctive features of the regulation of caspase-1 activity in human neutrophils and reveal new molecular mechanisms that control human neutrophil IL-1ß secretion.

Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience.

CARD11-associated diseases are monogenic inborn errors of immunity involving immunodeficiency, predisposition to malignancy and immune dysregulation such as lymphoproliferation, inflammation, atopic and autoimmune manifestations. Defects in CARD11 can present as mutations that confer a complete or a partial loss of function (LOF) or contrarily, a gain of function (GOF) of the affected gene product. We report clinical characteristics, immunophenotypes and genotypes of 15 patients from our center presenting with CARD11-associated diseases. Index cases are pediatric patients followed in our immunology division who had access to next generation sequencing studies. Variant significance was defined by functional analysis in cultured cells transfected with a wild type and/or with mutated hCARD11 constructs. Cytoplasmic aggregation of CARD11 products was evaluated by immunofluorescence. Nine index patients with 9 unique heterozygous CARD11 variants were identified. At the time of the identification, 7 variants previously unreported required functional validation. Altogether, four variants showed a GOF effect as well a spontaneous aggregation in the cytoplasm, leading to B cell expansion with NF-κB and T cell anergy (BENTA) diagnosis. Additional four variants showing a LOF activity were considered as causative of CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS). The remaining variant exhibited a neutral functional assay excluding its carrier from further analysis. Family segregation studies expanded to 15 individuals the number of patients presenting CARD11-associated disease. A thorough clinical, immunophenotypical, and therapeutic management evaluation was performed on these patients (5 BENTA and 10 CADINS). A remarkable variability of disease expression was clearly noted among BENTA as well as in CADINS patients, even within multiplex families. Identification of novel CARD11 variants required functional studies to validate their pathogenic activity. In our cohort BENTA phenotype exhibited a more severe and expanded clinical spectrum than previously reported, e.g., severe hematological and extra hematological autoimmunity and 3 fatal outcomes. The growing number of patients with dysmorphic facial features strengthen the inclusion of extra-immune characteristics as part of the CADINS spectrum. CARD11-associated diseases represent a challenging group of disorders from the diagnostic and therapeutic standpoint, especially BENTA cases that can undergo a more severe progression than previously described.

Comparison of clinical features and drug therapies among European and Latin American patients with juvenile dermatomyositis.

OBJECTIVES: To compare the demographic features, presenting manifestations, diagnostic investigations, disease course, and drug therapies of children with juvenile dermatomyositis (JDM) followed in Europe and Latin America. METHODS: Patients were inception cohorts seen between 1980 and 2004 in 27 paediatric rheumatology centres. The following information was collected through the review of patient charts: sex; age at disease onset; date of disease onset and diagnosis; onset type; presenting clinical features; diagnostic investigations; course type; and medications received during disease course. RESULTS: Four hundred and ninety patients (65.5% females, mean onset age 7.0 years, mean disease duration 7.7 years) were included. Disease presentation was acute or insidious in 57.1% and 42.9% of the patients, respectively. The course type was monophasic in 41.3% of patients and chronic polycyclic or continuous in 58.6% of patients. The more common presenting manifestations were muscle weakness (84.9%), Gottron's papules (72.9%), heliotrope rash (62%), and malar rash (56.7%). Overall, the demographic and clinical features of the 2 continental cohorts were comparable. European patients received more frequently high-dose intravenous methylprednisolone, cyclosporine, cyclophosphamide, and azathioprine, while methotrexate and antimalarials medications were used more commonly by Latin American physicians. CONCLUSIONS: The demographic and clinical characteristics of JDM are similar in European and Latin American patients. We found, however, several differences in the use of medications between European and Latin American paediatric rheumatologists.

Pediatric Inflammatory Multisystem Syndrome Associated With SARS-CoV-2: A Retrospective Cohort Study From Argentina.

OBJECTIVE: To evaluate the differential characteristics of SARS-COV-2 associated inflammatory multisystem syndrome (MIS-C) in children. METHODS: A retrospective cohort study was conducted.  The definition of MIS- C was based on WHO criteria. Temporally related COVID-19 patients were included as controls. RESULTS: 25 patients with MIS-C and 75 controls were included. Multivariate multiple logistic regression model of variables that showed to be significant in univariate analysis revealed that age ≥2 years (OR 24.7; 95% CI 1.03 -592.4; P=0.048), lymphopenia (OR 9.03, 95%CI 2.05-39.7; P=0.004), and platelet count <150x109/L (OR 11.7; 95% CI 1.88-75.22; P=0.009) were significantly associated with MIS-C. Presence of underlying disease seemed to reduce the risk of MIS-C (OR 0.06; 95% CI 0.01-0.3). CONCLUSIONS: MIS-C was more common in patients older than 2 years and in those with lymphopenia or thrombocytopenia. Underlying disease appears to reduce the risk of MIS-C.

Juvenile arthritis management in less resourced countries (JAMLess): consensus recommendations from the Cradle of Humankind.

Juvenile idiopathic arthritis (JIA) is the most prevalent chronic rheumatic disease in children and young people (CYP) and a major cause of pain and disability. The vast majority of the world's children and their families live in less resourced countries (LRCs) and face significant socioeconomic and healthcare challenges. Current recommendations for standards of care and treatment for children with JIA do not consider children living in less resourced countries. In order to develop appropriate recommendations for the care of CYP with JIA in less resourced countries a meeting of experienced pediatric rheumatologists from less resourced countries was convened with additional input from a steering group of international pediatric rheumatologists with experience in developing recommendations and standards of care for JIA. Following a needs assessment survey of healthcare workers caring for CYP with JIA in LRC, a literature review was carried out and management recommendations formulated using Delphi technique and a final consensus conference. Responses from the needs assessment were received from 121/483 (25%) practitioners from 25/49 (51%) less resourced countries. From these responses, the initial 84 recommendations were refined and expanded through a series of 3 online Delphi rounds. A final list of 90 recommendations was proposed for evaluation. Evidence for each statement was reviewed, graded, and presented to the consensus group. The degree of consensus, level of agreement, and level of evidence for these recommendations are reported. Recommendations arrived at by consensus for CYP with JIA in less resourced countries cover 5 themes: (1) diagnosis, (2) referral and monitoring, (3) education and training, (4) advocacy and networks, and (5) research. Thirty-five statements were drafted. All but one statement achieved 100% consensus. The body of published evidence was small and the quality of evidence available for critical appraisal was low. Our recommendations offer novel insights and present consensus-based strategies for the management of JIA in less resourced countries. The emphasis on communicable and endemic diseases influencing the diagnosis and treatment of JIA serves as a valuable addition to existing JIA guidelines. With increasing globalization, these recommendations as a whole provide educational and clinical utility for clinicians worldwide. The low evidence base for our recommendations reflects a shortage of research specific to less resourced countries and serves as an impetus for further inquiry towards optimizing care for children with JIA around the world.

Autoinflammatory diseases: a Latin American multicenter study according to age and sex / Doenças autoinflamatórias: um estudo multicêntrico latino-americano de acordo com o sexo e a idade

ABSTRACT Objective: To evaluate autoinflammatory diseases (AID) according to age at diagnosis and sex, and response to therapy in a large population. Methods: This is a cross-sectional observational study of a Latin American registry using a designed web system for data storage, collected between 2015 and 2018. Any altered findings during follow-up were recorded. The forms were translated into Portuguese and Spanish, including demographic, clinical, laboratory, genetic and treatment characteristics. Results: We included 152 patients, 51.3% male and 75% Caucasian. The median age at disease onset was 2.1 years (0-15.6 years) and median age at diagnosis 6.9 years (0-21.9 years); 111 (73%) were children (0-9 years old), and 41 (27%) were adolescents and young adults (AYA) (10-21 years old). Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA) occurred in 46/152 (30%), chronic non-bacterial osteomyelitis (CNO) in 32/152 (21%), and familial Mediterranean fever (FMF) in 24/152 (15.7%). PFAPA was significantly higher in young children than in AYA (38.7% vs. 7.3%, p<0.001), while CNO were lower (13.5% vs. 41.5%, p<0.001). The frequency of females was significantly higher in CNO (28.4% vs. 14.1%, p=0.031) and lower in FMF (8.1% vs. 23.1%, p=0.011). The most used drugs were glucocorticoids, non-steroidal anti-inflammatory drugs (NSAID), and colchicine. Glucocorticoids and colchicine treatment were used in all AID with good to moderate response. However, cryopyrin-associated periodic syndromes (CAPS) seemed unresponsive to glucocorticoids. NSAIDs and methotrexate were the main medications used to treat CNO. Conclusions: Differences among AID patients were observed in the LA population regarding sex and age at disease diagnosis.

RESUMO Objetivo: Avaliar as doenças autoinflamatórias (DAI) de acordo com sexo e idade no momento do diagnóstico e a resposta terapêutica em uma grande população. Métodos: Este é um estudo observacional transversal de um registro latino-americano que usou um sistema de dados coletados entre 2015 e 2018. Quaisquer achados alterados ao longo do acompanhamento foram registrados. Os formulários foram traduzidos para os idiomas português e espanhol, incluindo características demográficas, clínicas, laboratoriais, genéticas e de tratamento. Resultados: Incluímos 152 pacientes, sendo 51,3% do sexo masculino e 75% da raça branca. A média de idade de início da doença foi de 2,1 anos (0-15,6 anos) e a média de idade de diagnóstico 6,9 anos (0-21,9 anos); 111 (73%) eram crianças (0-9 anos) e 41 (27%) adolescentes/adultos jovens (10-21 anos). A síndrome de febre periódica, estomatite aftosa, faringite e adenite (PFAPA) ocorreu em 46/152 (30%), osteomielite não bacteriana crônica (CNO) em 32/152 (21%) e febre familiar do Mediterrâneo (FMF) em 24/152 (15,7%). A PFAPA foi significativamente maior em crianças pequenas (38,7 vs. 7,3%, p<0,001), e a CNO, em adolescentes/adultos jovens (13,5 vs. 41,5%, p<0,001). A frequência do sexo feminino foi significativamente maior na CNO (28,4 vs. 14,1%, p=0,031) e menor na FMF (8,1 vs. 23,1%, p=0,011). Os medicamentos mais utilizados foram glicocorticoides, anti-inflamatórios não esteroidais (AINE) e colchicina. O tratamento com glicocorticoides e colchicina foi usado em todas as DAI com resposta boa a moderada. No entanto, as síndromes periódicas associadas à criopirina (CAPS) pareciam não responder aos glicocorticoides. AINE e metotrexato foram os principais medicamentos utilizados no tratamento da CNO. Conclusões: Diferenças de pacientes com DAI foram observadas na população latino-americana em pacientes agrupados por sexo e idade ao diagnóstico da doença.

Development and Testing of a Hybrid Measure of Muscle Strength in Juvenile Dermatomyositis for Use in Routine Care.

OBJECTIVE: To develop and test a hybrid measure of muscle strength for juvenile dermatomyositis (JDM), which is based on the combination of the Manual Muscle Testing in 8 muscles (MMT-8) and the Childhood Myositis Assessment Scale (CMAS) but is more comprehensive than the former and more feasible than the latter. METHODS: The hybrid MMT-8/CMAS (hMC) is composed of all 8 items of the MMT-8 and 3 items of the CMAS: time of head lift, assessment of abdominal muscles, and floor rise. The score ranges 0-100, with 100 indicating normal muscle strength. Validation procedures were conducted using 3 large multinational patient samples, including a total of 810 JDM patients. RESULTS: The hMC revealed face and content validity, good construct validity, excellent test-retest reliability (intraclass correlation coefficient = 0.99), and internal consistency (Cronbach's α = 0.94), strong responsiveness to clinical change over time (standardized response mean = 0.8 among patients judged as improved by the caring physician), and satisfactory capacity to discriminate patients judged as being in the states of inactive disease or low, moderate, or high disease activity by the physician (P < 0.001) or patients whose parents were satisfied or not satisfied with the illness course (P < 0.001). CONCLUSION: The hMC was found to possess good measurement properties in a large population of patients with a wide range of disease activity and severity. The new tool, which is primarily intended for use in routine clinical care, should be further tested in other populations of patients evaluated prospectively.

Biologic agents in juvenile spondyloarthropathies.

The juvenile spondyloarthropathies (JSpA) are a group of related rheumatic diseases characterized by involvement of peripheral large joints, axial joints, and entheses (enthesitis) that begin in the early years of life (prior to 16(th) birthday).The nomenclature and concept of spondyloarthropathies has changed during the last few decades. Although there is not any specific classification of JSpA, diseases under the spondyloarthropathy nomenclature umbrella in the younger patients include: the seronegative enthesitis and arthropathy (SEA) syndrome, juvenile ankylosing spondylitis, reactive arthritis, and inflammatory bowel disease-associated arthritis. Moreover, the ILAR criteria for Juvenile Idiopathic Arthritis includes two categories closely related to spondyloarthritis: Enthesitis-related arthritis and psoriatic arthritis.We review the pathophysiology and the use of biological agents in JSpA. JSpA are idiopathic inflammatory diseases driven by an altered balance in the proinflammatory cytokines. There is ample evidence on the role of tumor necrosis factor (TNF) and interleukin-17 in the physiopathology of these entities. Several non-biologic and biologic agents have been used with conflicting results in the treatment of these complex diseases. The efficacy and safety of anti-TNF agents, such as etanercept, infliximab and adalimumab, have been analysed in controlled and uncontrolled trials, usually showing satisfactory outcomes. Other biologic agents, such as abatacept, tocilizumab and rituximab, have been insufficiently studied and their role in the therapy of SpA is uncertain. Interleukin-17-blocking agents are promising alternatives for the treatment of JSpA patients in the near future. Recommendations for the treatment of patients with JSpA have recently been proposed and are discussed in the present review.

[Takayasu arteritis in pediatric patients]. / Arteritis de Takayasu en pediatría.

Takayasu's arteritis is a chronic inflammatory disease that primarily affects the large vessels, such as the aorta and its branches. It represents the third most frequent vasculitis during pediatric age. Our objective was to describe clinical and complementary exams features as well as treatment modalities of a case series of pediatric patients. We present 11 patients (10 girls) with median age at onset of 8 years (range: 2-15). The median diagnosis delay was 16 months (range: 2-96). Clinical presentations were lower limb claudication, arterial hypertension, CNS involvement, presence of murmurs, systemic symptoms, lymphadenopathy, chest pain, abdominal pain and arthritis. Laboratory tests showed: elevated ESR, anemia and trombocytosis. Vascular imaging studies exhibited stenosis, dilatation, occlussion and aneurysms. The outcome of the disease was persistent active condition (1 patient), relapse (4 patients), remission (3 patients), motor sequelae (1 patient) and death (2 patients). All patients were treated with steroids and immunosuppressants. Takayasu 's arteritis is a condition that can potentially be life-threatening. The diagnosis should be suspected in a variety of clinical manifestations during childhood.

Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients.

OBJECTIVE: To investigate the long-term outcome and prognostic factors of juvenile dermatomyositis (DM) through a multinational, multicenter study. METHODS: Patients consisted of inception cohorts seen between 1980 and 2004 in 27 centers in Europe and Latin America. Predictor variables were sex, continent, ethnicity, onset year, onset age, onset type, onset manifestations, course type, disease duration, and active disease duration. Outcomes were muscle strength/endurance, continued disease activity, cumulative damage, muscle damage, cutaneous damage, calcinosis, lipodystrophy, physical function, and health-related quality of life (HRQOL). RESULTS: A total of 490 patients with a mean disease duration of 7.7 years were included. At the cross-sectional visit, 41.2-52.8% of patients, depending on the instrument used, had reduced muscle strength/endurance, but less than 10% had severe impairment. Persistently active disease was recorded in 41.2-60.5% of the patients, depending on the activity measure used. Sixty-nine percent of the patients had cumulative damage. The frequency of calcinosis and lipodystrophy was 23.6% and 9.7%, respectively. A total of 40.7% of the patients had decreased functional ability, but only 6.5% had major impairment. Only a small fraction had decreased HRQOL. A chronic course, either polycyclic or continuous, consistently predicted a poorer outcome. Mortality rate was 3.1%. CONCLUSION: This study confirms the marked improvement in functional outcome of juvenile DM when compared with earlier literature. However, many patients had continued disease activity and cumulative damage at followup. A chronic course was the strongest predictor of poor prognosis. These findings highlight the need for treatment strategies that enable a better control of disease activity over time and the reduction of nonreversible damage.

Osteoartropatía hipertrófica hepática en un niño con enfermedad colestática / Hepatic hipertrophic osteoarthropathy in a child with cholestatic disease

La osteoartropatía hipertrófica hepática es una rara entidad que se asocia con enfermedades hepáticas graves, en especial relacionadas con colestasis crónica.Se define por la presencia de hipocratismo digital, reacción perióstica y artritis. Describimos el caso de un paciente con osteoartropatía hipertróficahepática que se desarrolló después de un cuadro de enfermedad hepática con colestasis persistente,quien presentó poliartritis que imposibilitaba ladeambulación. Los signos clínicos y radiológicos desaparecieron después del trasplante hepático.Palabras clave: osteoartropatía hipertrófica, colestasis,niños.