Characteristics of 1555 childhood-onset lupus in three groups based on distinct time intervals to disease diagnosis: a Brazilian multicenter study.

Objective The objective of this study was to compare demographic data, clinical/laboratorial features and disease activity at diagnosis in three different groups with distinct time intervals between onset of signs/symptoms and disease diagnosis. Methods A multicenter study was performed in 1555 childhood-onset systemic lupus erythematosus (American College of Rheumatology criteria) patients from 27 pediatric rheumatology services. Patients were divided into three childhood-onset systemic lupus erythematosus groups: A: short time interval to diagnosis (<1 month); B: intermediate time interval (≥1 and <3 months); and C: long time interval (≥3 months). An investigator meeting was held to define the protocol. Demographic data, SLICC classification criteria and SLEDAI-2 K were evaluated. Results The number of patients in each group was: A = 60 (4%); B = 522 (33.5%); and C = 973 (62.5%). The median age at diagnosis (11.1 (4.2-17) vs. 12 (1.9-17.7) vs. 12.5 (3-18) years, P = 0.025) was significantly lower in group A compared with groups B and C. The median number of diagnostic criteria according to SLICC (7 (4-12) vs. 6 (4-13) vs. 6 (4-12), P < 0.0001) and SLEDAI-2 K (18 (6-57) vs. 16 (2-63) vs. 13 (1-49), P < 0.0001) were significantly higher in group A than the other two groups. The frequency of oral ulcers in the palate (25% vs. 15% vs. 11%, P = 0.003), pleuritis (25% vs. 24% vs. 14%, P < 0.0001), nephritis (52% vs. 47% vs. 40%, P = 0.009), neuropsychiatric manifestations (22% vs. 13% vs. 10%, P = 0.008), thrombocytopenia (32% vs. 18% vs. 19%, P = 0.037), leucopenia/lymphopenia (65% vs. 46% vs. 40%, P < 0.0001) and anti-dsDNA antibodies (79% vs. 66% vs. 61%, P = 0.01) were significantly higher in group A compared with the other groups. In contrast, group C had a less severe disease characterized by higher frequencies of synovitis (61% vs. 66% vs. 71%, P = 0.032) and lower frequencies of serositis (37% vs. 33% vs. 25%, P = 0.002), proteinuria >500 mg/day (48% vs. 45% vs. 36%, P = 0.002) and low complement levels (81% vs. 81% vs. 71%, P < 0.0001) compared with groups A or B. Conclusions Our large Brazilian multicenter study demonstrated that for most childhood-onset systemic lupus erythematosus patients, diagnosis is delayed probably due to mild disease onset. Conversely, the minority has a very short time interval to diagnosis and a presentation with a more severe and active multisystemic condition.

Validation of the Portuguese Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY) in Brazil.

BACKGROUND AND OBJECTIVE: Simple Measure of the Impact of Lupus Erythematosus in Youngsters (SMILEY) is a health-related quality of life (HRQOL) assessment tool for pediatric systemic lupus erythematosus (SLE), which has been translated into Portuguese for Brazil. We are reporting preliminary data on cross-cultural validation and reliability of SMILEY in Portuguese (Brazil). METHODS: In this multi-center cross-sectional study, Brazilian children and adolescents 5-18 years of age with SLE and parents participated. Children and parents completed child and parent reports of Portuguese SMILEY and Portuguese Pediatric Quality of Life Inventory (PedsQL™) Generic and Rheumatology modules. Parents also completed the Childhood Health Assessment Questionnaire (CHAQ). Physicians completed the SLE disease activity index (SLEDAI), Physician's Global Assessment of disease activity (PGA) and Systemic Lupus Erythematosus International Collaborating Clinics ACR Damage Index (SDI). RESULTS: 99 subjects (84 girls) were enrolled; 93 children and 97 parents filled out the SMILEY scale. Subjects found SMILEY relevant and easy to understand and completed SMILEY in 5-15 minutes. Brazilian SMILEY was found to have good psychometric properties (validity and reliability), and the child-parent agreement was moderate. CONCLUSION: SMILEY may eventually be used routinely as a research/clinical tool in Brazil. It may be also adapted for other Portuguese-speaking nations offering critical information regarding the effect of SLE on HRQOL for children with SLE.

Non-clinical studies required for new drug development - Part I: early in silico and in vitro studies, new target discovery and validation, proof of principles and robustness of animal studies.

This review presents a historical overview of drug discovery and the non-clinical stages of the drug development process, from initial target identification and validation, through in silico assays and high throughput screening (HTS), identification of leader molecules and their optimization, the selection of a candidate substance for clinical development, and the use of animal models during the early studies of proof-of-concept (or principle). This report also discusses the relevance of validated and predictive animal models selection, as well as the correct use of animal tests concerning the experimental design, execution and interpretation, which affect the reproducibility, quality and reliability of non-clinical studies necessary to translate to and support clinical studies. Collectively, improving these aspects will certainly contribute to the robustness of both scientific publications and the translation of new substances to clinical development.

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

Tecnologías en la enseñanza en enfermería, innovación y uso de TICs: revisión integrativa / Innovation and use of information and communication technologies in nursing teaching: An integrative review / Tecnologias no ensino em enfermagem, inovação e uso de TICs: revisão integrativa

Resumen Introducción: La utilización de los recursos digitales modernos para la enseñanza constituye una estrategia para atender las nuevas necesidades de aprendizaje. En el ámbito de enfermería puede facilitar la inserción de los estudiantes en la práctica clínica en modo virtual para que desarrollen sus habilidades y competencias. Objetivo: Analizar las evidencias sobre la utilización de tecnologías en la enseñanza de enfermería. Métodos: Revisión integrativa realizada en el portal de revistas SciELO y en las bases de datos IBECS, LILACS, BDENF, Web of Science, PubMed y CINAHL. Resultados: Se realizó la identificación inicial de 62 artículos, se aplicaron los criterios de exclusión hasta el establecimiento de la muestra de 26 artículos. Después de la lectura y análisis de los estudios, se constató que las tecnologías son más utilizadas junto con las clases teóricas en las aulas, o como plataformas online de enseñanza, o también como herramientas auxiliares para la práctica de simulaciones realísticas. Discusión: El uso de internet fue predominante en los estudios, pues favorece la actualización, la comunicación y la cualificación académica. En cuanto a las plataformas digitales de enseñanza, el espacio virtual permite reunir e integrar diversos medios con finalidades diferentes posibilitando la creación de actividades variadas. Para la enseñanza a través de simulaciones se presentaron diversos beneficios de inmersión a un ambiente profesional desde la universidad. Conclusiones: El estudio presenta una visión general de las tecnologías educativas utilizadas para la enseñanza de enfermería y provee conocimiento de nuevas metodologías, lo que beneficia a profesores y estudiantes.

Abstract Introduction: The utilization of modern digital resources in teaching constitutes a strategy to address the new learning needs. In the area of nursing, the use of digital resources can facilitate the insertion of students into the clinical practice by providing a virtual environment in which students can develop their skills and competencies. Objective: To analyze the evidence regarding the utilization of technologies in nursing teaching. Methods: This is an integrative review based on the SciELO publications and IBECS, LILACS, BDENF, Web of Science, PubMed and CINAHL databases. Results: 62 relevant articles were identified. After considering the exclusion criteria, a final sample with 26 articles was constituted. The studies were read and analyzed, and it was found that the diverse technologies are more frequently utilized in conjunction with theory classes in classrooms, as online teaching platforms, or as auxiliary tools to support realistic simulations. Discussion: The use of the Internet was prevalent in the analyzed studies. Regarding some teaching digital platforms, virtual spaces showed being useful to create diverse teaching-learning activities; with simulations being helpful to prepare students to enter the professional practice. Conclusions: This study presents a general view of the educational technologies utilized in nursing teaching, while displaying some specific methodologies which can be of benefit for both students and teachers.

Resumo Introdução: A utilização de recursos digitais modernos para o ensino constitui uma estratégia para atender as novas necessidades de aprendizagem. No âmbito de enfermagem pode facilitar a inserção dos estudantes na prática clínica em modalidade virtual para que desenvolvam suas habilidades e competências. Objetivo: Analisar as evidências sobre a utilização de tecnologias no ensino de enfermagem. Métodos: Revisão integrativa realizada no portal de periódicos SciELO e nas bases de dados IBECS, LILACS, BDENF, Web of Science, PubMed e CINAHL. Resultados: Foi realizada a identificação inicial de 62 artigos, aplicaram-se os critérios de exclusão até o estabelecimento da amostra de 26 artigos. Após a leitura e a análi-se dos estudos, foi constatado que as tecnologias são mais utilizadas em conjunto com as aulas teóricas nas salas de aula, ou como plataformas de ensino online, ou também como ferramentas auxiliares para a prática de simulações realísticas. Discussão: O uso da internet foi predominante nos estudos, dado que favorece a atualização, a comunicação e a qualificação acadêmica. Sobre as plataformas digitais de ensino, o espa-ço virtual permite reunir e integrar diversos médios com finalidades diferentes possibilitando a criação de atividades variadas. Apresentaram-se diversos benefícios de imersão para o ensino através de simulações em um ambiente profissional desde a universidade. Conclusões: O estudo apresenta uma visão geral das tecnologias educacionais utilizadas no ensino de enfermagem e provê conhecimento de novas metodologias, o qual beneficia professores e estudantes.

Evaluation of the 1982 ARA lupus criteria data set in pediatric patients. Committees of Pediatric Rheumatology of the Brazilian Society of Pediatrics and the Brazilian Society of Rheumatology.

OBJECTIVE: Although commonly used, the 1982 revised criteria for the classification of Systemic Lupus Erythematosus (SLE) have not been completely evaluated in pediatric patients. This study was aimed at evaluating the sensitivity and specificity of the 1982 revised criteria when applied to pediatric patients. METHODS: One hundred and three children with SLE and 101 children with other rheumatic diseases were selected from 5 rheumatology centers in Brazil. Diagnosis of SLE by the 1982 criteria were compared with our clinical diagnosis. The diagnosis of other diseases was made according to internationally accepted classification criteria or, when these were not available, according to the physician's own experienced judgement. RESULTS: The median number of criteria fulfilled by the patients with SLE and the controls were 6 and 1, respectively. The most common criteria observed in children with SLE were: abnormal antinuclear antibody titers (94%), arthritis (83%), immunologic disorder (83%), hematologic disorder (70%), malar rash (67%), and photosensitivity (58%). When the immunologic disorder was broken down into its constituent elements, antibodies to dsDNA and Sm were observed in 73.0% (65/89) and 31.4% (15/48), respectively. The sensitivity and specificity observed were 96% and 100%, respectively. CONCLUSION: The 1982 classification criteria can be successfully applied to children with SLE. These criteria may serve as a basis for multi-center collaborative studies on children with SLE.

The Brazilian version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report the cross-cultural adaptation and validation into Brazilian-Portuguese of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children regardless the underlying disease. The Brazilian CHAQ was revalidated, while the CHQ has been derived from the Portuguese version. A total of 471 subjects were enrolled: 157 patients with JIA (27% systemic onset, 38% polyarticular onset, 9% extended oligoarticular subtype, and 26% persistent oligoarticular subtype) and 314 healthy children. The CHAQ discriminated clinically healthy subjects from JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and lower overall well-being scores when compared to their healthy peers. Also the CHQ discriminated clinically healthy subjects from JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being score when compared to their healthy peers. In conclusion the Brazilian versions of the CHAQ-CHQ are reliable and valid tools for the combined physical and psychosocial assessment of children with JIA.

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

Risk factors for amenorrhea in juvenile systemic lupus erythematosus (JSLE): a Brazilian multicentre cohort study.

We evaluated the prevalence and clinical associations of amenorrhea in 298 female juvenile systemic lupus erythematosus (JSLE) patients (ACR criteria) followed in 12 Brazilian Paediatric Rheumatology centres. Amenorrhea was observed in 35 patients (11.7%) with a mean duration of 7.2 +/- 3.6 months. The hormones were performed in 32/35 patients and none of them had FSH and LH levels above and estradiol below the normal range according to pubertal changes. JSLE patients with amenorrhea were younger (15.04 +/- 2.5 versus 17.8 +/- 3.1 years; P = 0.001), and had a shorter period of time between menarche and current age (3.4 +/- 2.9 versus 6.7 +/- 5.4 years; P = 0.001). Interestingly, the frequency, cumulative dose, number of pulses and duration of intravenous cyclophosphamide treatment were alike in patients with and without amenorrhea (P > 0.05). In contrast, patients with amenorrhea had significantly higher SLEDAI (P = 0.01) and SLICC/ACR-DI (P = 0.024) scores compared to those without this condition. Independent risk factors identified by multivariate analysis were higher SLEDAI (OR = 1.059; CI = 1.004-1.116; P = 0.034) and SLICC/ACR-DI (OR = 2.125; IC = 1.373-3.291; P = 0.001) scores. Our data suggest that in spite of immunosuppressive therapy, JSLE patients have an adequate ovarian follicular reserve and amenorrhea is particularly associated with disease activity and damage.

Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study.

OBJECTIVE: Juvenile localized scleroderma (JLS) includes a number of conditions often grouped together. With the long-term goal of developing uniform classification criteria, we studied the epidemiological, clinical and immunological features of children with JLS followed by paediatric rheumatology and dermatology centres. METHODS: A large, multicentre, multinational study was conducted by collecting information on the demographics, family history, triggering environmental factors, clinical and laboratory features, and treatment of patients with JLS. RESULTS: Seven hundred and fifty patients with JLS from 70 centres were enrolled into the study. The disease duration at diagnosis was 18 months. Linear scleroderma (LS) was the most frequent subtype (65%), followed by plaque morphea (PM) (26%), generalized morphea (GM) (7%) and deep morphea (DM) (2%). As many as 15% of patients had a mixed subtype. Ninety-one patients (12%) had a positive family history for rheumatic or autoimmune diseases; 100 (13.3%) reported environmental events as possible trigger. ANA was positive in 42.3% of the patients, with a higher prevalence in the LS-DM subtype than in the PM-GM subtype. Scl70 was detected in the sera of 3% of the patients, anticentromere antibody in 2%, anti-double-stranded DNA in 4%, anti-cardiolipin antibody in 13% and rheumatoid factor in 16%. Methotrexate was the drug most frequently used, especially during the last 5 yr. CONCLUSION: This study represents the largest collection of patients with JLS ever reported. The insidious onset of the disease, the delay in diagnosis, the recognition of mixed subtype and the better definition of the other subtypes should influence our efforts in educating trainees and practitioners and help in developing a comprehensive classification system for this syndrome.

[Enthesopathy: a symptom seldom recognized by pediatricians] / Entesopatia: um sintoma pouco reconhecido pelo pediatra.

OBJECTIVE: The disease in the entheses, which are sites of attachment of tendons, ligaments, fascias or joint capsules to bone, may be noted clinically by the onset of tenderness or pain associated to digitopression in certain points. This revision article aims to draw the attention of pediatricians to the enthesopathies or enthesitis (inflammatory disease of these structures) in childhood and adolescence. METHODS: The study reviews concepts about the structure of the enthesis and the clinical, laboratorial and radiological features concerning enthesopathy, as well as differential diagnosis and therapeutic measures. Articles and texts concerning the theme were obtained based on a research in Medline (available data since 1966) and Lilacs (available data since 1981) database, as well as in Pediatric Rheumatology textbooks published after 1990. RESULTS: Enthesopathy in children and adolescents appears more often in the limbs and seems to be associated to the development of spondyloarthropathies, occurring less commonly in other inflammatory diseases or even noninflammatory conditions. CONCLUSIONS: The identification of enthesopathies is important to the early diagnosis of children and adolescents in risk of developing spondyloarthropathies, so that they may be included early in an adequate program of physical and drug therapies.

Estudo clínico multicêntrico de naproxeno suspensäo vs ácido acetilsalicílico no tratamento da artrite reumatóide juvenil / Multicenter clinical trial with naproxen suspension vs acetylcalicylic acid in the treatment of juvenile rheumatoid arthritis

Os autores relatam os resultados obtidos num ensaio clínico multicêntrico, simples-cego, de naproxeno suspensäo vs. ácido acetilsalicílico no tratamento de 52 crianças com artrite reumatóide juvenil. Os pacientes foram divididos em dois grupos de 26 cada um, aos quais foram administrados naproxeno suspensäo (25 mg/ml, na dose de 10 mg/Kg/dia, divididos em duas administraçöes diárias, ou ácido acetilsalicílico, em comprimidos de 500 mg, na dose de 100 mg/Kg/dia divididos em quatro administraçöes diárias. A duraçäo do estudo foi de 60 dias, para ambos os grupos, e a idade das crianças variou de dois a 14 anos. A avaliaçäo final feita pelos investigadores apresentou os seguintes resultados: no grupo naproxeno (69,2%), regular em 5(19,2%) e má em 3(11,5%). No grupo ácido acetilsalicílico os resultados foram bons em 16 pacientes (61,4%), regulares em 5(19,2%) e maus em 5(19,2%). Ao final, 80,7% dos pais, 57,6% das crianças e 69,2% dos investigadores consideraram os resultados do uso do naproxeno entre muito bons ou bons, comparados respectivamente, a 61,4%, 49,9% e 61,4% com o uso do ASS. Quanto aos efeitos colaterais apesar de mais freqüentes no grupo com AAS (vômitos, náuseas, dor epigástrica, cefaléia) do que no grupo com naproxeno (náuseas, diarréia, epistaxe), em geral foram leves e transitórios, com exceçäo de uma criança do grupo naproxeno, que apresentou hematúria macroscópica e foi retirada do estudo, observando-se regressäo completa da lateraçäo em 15 dias. A colaboraçäo das crianças ao esquema terapêutico com o naproxeno suspensäo foi mais facilmente obtida, näo só por necessitar de apenas duas administraçöes diárias, comparadas as quatro do ácido acetilsalicílico, como pelo fato de ser formulaçäo líquida e ter sabor agradável. Teve influência, também, o aspecto cultural negativo que grande parte dos pais tem quanto ao ácido acetilsalicílico, por considerarem-no uma medicaçäo de uso comum, pouco adequada a uma doença täo séria como a artrite reumatóide juvenil e, eventualmente, por ter sido usada anteriormente em algumas crianças...