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BACKGROUND: Hydroxychloroquine (HCQ) is the first-line treatment for systemic lupus erythematosus (SLE); however, there is heterogeneity in its clinical use. This consensus aims to bridge the gap in SLE treatment by providing practical and valuable recommendations for health professionals. METHODS: The methodology used is based on a systematic literature review and a nominal group technique (NGT). A ten-member scientific committee formulated eight clinically relevant questions. First, a systematic review was conducted to identify the available evidence, which the scientific committee evaluated to developed recommendations based on their expertise, achieving consensus through NGT. RESULTS: 1673 titles and abstracts were screened, and 43 studies were included for meeting the inclusion criteria. The scientific committee established 11 recommendations for HCQ use in initiation, maintenance, and monitoring, considering benefits and potential adverse effects of HCQ. Unanimous agreement was achieved on all recommendations. CONCLUSIONS: The available evidence supports HCQ's effectiveness and safety for SLE. Individualized assessment of the initial HCQ dose is important, especially in situations requiring dose reduction or discontinuation. This risk-benefit assessment, specifically focusing on the balance between retinal toxicity and the risk of SLE relapse, should guide decisions regarding medication withdrawal, considering disease activity, risk factors, and HCQ potential benefits. Close monitoring is essential for optimal disease management and minimize potential risks, such as QT prolongation or retinal toxicity.
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Antirreumáticos , Hidroxicloroquina , Lúpus Eritematoso Sistêmico , Humanos , Antirreumáticos/uso terapêutico , Hidroxicloroquina/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , ConsensoRESUMO
OBJECTIVE: To characterize and describe clinical experience with childhood-onset non-infectious uveitis. STUDY DESIGN: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared. RESULTS: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated (p < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use. CONCLUSION: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.
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OBJECTIVE: To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA, sJIA). METHODS: Patients with pJIA or sJIA from two open-label, 52-week phase 1 b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight-based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years and safety for up to 5 years in the LTE. RESULTS: Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, â¼10 µg/ml; sJIA, â¼75 µg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 kg and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection). CONCLUSION: Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile.
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OBJECTIVE: To investigate the frequency and trajectories of individual patients with polyarticular-course juvenile idiopathic arthritis (JIA) achieving novel composite end points on abatacept. METHODS: Data from a clinical trial of subcutaneous abatacept (NCT01844518) and a post hoc analysis of intravenous abatacept (NCT00095173) in patients with polyarticular-course JIA were included. Three end points were defined and evaluated: combined occurrence of low disease activity (LDA) measured by the Juvenile Arthritis Disease Activity Score; 50% improvement in American College of Rheumatology criteria for JIA (ACR50); and patient-reported outcomes. Patient-reported outcomes included visual analog scale score of minimal pain (pain-min) and Childhood Health Assessment Questionnaire disability index score of 0 (C-HAQ DI0). In this post hoc analysis, maintenance of month 13 and 21 end points (LDA+pain-min, LDA+C-HAQ DI0, and ACR50+pain-min) in those who achieved them at month 4 was determined. RESULTS: Composite end points (LDA+pain-min, LDA+C-HAQ DI0, and ACR50+pain-min) were achieved at month 4 (44.7%, 19.6%, and 58.9% of the 219 patients treated with subcutaneous abatacept, respectively). Of those who achieved LDA+pain-min at month 4, 84.7% (83 of 98) and 65.3% (64 of 98) maintained LDA+pain-min at months 13 and 21, respectively. The proportions of patients meeting LDA+pain-min outcomes increased from 44.7% (98 of 219) at month 4 to 54.8% (120 of 219) at month 21. The frequency of patients who met an LDA+C-HAQ DI score of 0 increased from 19.6% (43 of 219) at month 4 to 28.8% (63 of 219) at month 21. CONCLUSION: Among individual patients with polyarticular-course JIA treated with abatacept who achieved 1 of the combined clinical and patient-reported outcomes composite end points, many maintained them over 21 months of abatacept treatment.
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Antirreumáticos , Artrite Juvenil , Humanos , Criança , Abatacepte/efeitos adversos , Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Antirreumáticos/efeitos adversos , Resultado do Tratamento , DorRESUMO
BACKGROUND: Treatment options in patients with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are currently limited. This trial aimed to demonstrate the efficacy and safety of secukinumab in patients with active ERA and JPsA with inadequate response to conventional therapy. METHODS: In this randomised, double-blind, placebo-controlled, treatment-withdrawal, phase 3 trial, biologic-naïve patients (aged 2 to <18 years) with active disease were treated with open-label subcutaneous secukinumab (75/150 mg in patients <50/≥50 kg) in treatment period (TP) 1 up to week 12, and juvenile idiopathic arthritis (JIA) American College of Rheumatology 30 responders at week 12 were randomised 1:1 to secukinumab or placebo up to 100 weeks. Patients who flared in TP2 immediately entered open-label secukinumab TP3 that lasted up to week 104. Primary endpoint was time to disease flare in TP2. RESULTS: A total of 86 patients (median age, 14 years) entered open-label secukinumab in TP1. In TP2, responders (ERA, 44/52; JPsA, 31/34) received secukinumab or placebo. The study met its primary end point and demonstrated a statistically significant longer time to disease flare in TP2 for ERA and JPsA with secukinumab versus placebo (27% vs 55%, HR, 0.28; 95% CI 0.13 to 0.63; p<0.001). Exposure-adjusted incidence rates (per 100 patient-years (PY), 95% CI) for total patients were 290.7/100 PY (230.2 to 362.3) for adverse events and 8.2/100 PY (4.1 to 14.6) for serious adverse events in the overall JIA population. CONCLUSIONS: Secukinumab demonstrated significantly longer time to disease flare than placebo in children with ERA and JPsA with a consistent safety profile with the adult indications of psoriatic arthritis and axial spondyloarthritis. TRIAL REGISTRATION NUMBER: NCT03031782.
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Antirreumáticos , Artrite Juvenil , Artrite Psoriásica , Adulto , Criança , Humanos , Adolescente , Artrite Juvenil/tratamento farmacológico , Antirreumáticos/efeitos adversos , Exacerbação dos Sintomas , Resultado do Tratamento , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/induzido quimicamente , Método Duplo-CegoRESUMO
Se ha descrito un nuevo síndrome inflamatorio multisistémico pediátrico vinculado a SARS-CoV-2. Este cuadro presenta una expresividad clínica variable y se asocia a infección activa o reciente por SARS-CoV-2. En este documento se revisa la literatura existente por parte de un grupo multidisciplinar de especialistas pediátricos. Posteriormente, se realizan recomendaciones sobre estabilización, diagnóstico y tratamiento de este síndrome
A new paediatric multisystem inflammatory syndrome, linked to SARS-CoV-2, has been described. The clinical picture is variable and is associated with an active or recent infection due to SARS-CoV-2. A review of the existing literature by a multidisciplinary group of paediatric specialists is presented in this document. Later, they make recommendations on the stabilisation, diagnosis, and treatment of this síndrome
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Humanos , Criança , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/complicações , Consenso , Diagnóstico Diferencial , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controle , Hospitalização , BetacoronavirusRESUMO
A new paediatric multisystem inflammatory syndrome, linked to SARS-CoV-2, has been described. The clinical picture is variable and is associated with an active or recent infection due to SARS-CoV-2. A review of the existing literature by a multidisciplinary group of paediatric specialists is presented in this document. Later, they make recommendations on the stabilisation, diagnosis, and treatment of this syndrome.
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COVID-19/diagnóstico , COVID-19/terapia , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/terapia , Algoritmos , Criança , HumanosRESUMO
OBJECTIVES: This ongoing Phase-2, randomised, placebo-controlled, double-blind study evaluated the efficacy, safety and pharmacokinetics of intravenous belimumab in childhood-onset systemic lupus erythematosus (cSLE). METHODS: Patients (5 to 17 years) were randomised to belimumab 10 mg/kg intravenous or placebo every 4 weeks, plus standard SLE therapy. Primary endpoint: SLE Responder Index (SRI4) response rate (Week 52). Key major secondary endpoints: proportion of patients achieving the Paediatric Rheumatology International Trials Organisation/American College of Rheumatology (PRINTO/ACR) response using 50 and '30 alternative' definitions (Week 52), and sustained response (Weeks 44 to 52) by SRI4 and Parent Global Assessment of well-being (Parent-global). Safety and pharmacokinetics were assessed. Study not powered for statistical testing. RESULTS: Ninety-three patients were randomised (belimumab, n=53; placebo, n=40). At Week 52, there were numerically more SRI4 responders with belimumab versus placebo (52.8% vs 43.6%; OR 1.49 (95% CI 0.64 to 3.46)). PRINTO/ACR 30 alternative (52.8% vs 27.5%; OR 2.92 (95% CI 1.19 to 7.17)) and PRINTO/ACR 50 (60.4% vs 35.0%; OR 2.74 (95% CI 1.15 to 6.54)) responses were more frequent with belimumab than placebo, as were sustained responses for SRI4 (belimumab, 43.4%; placebo, 41.0%; OR 1.08 (95% CI 0.46 to 2.52)) and Parent-global (belimumab, 59.1%; placebo, 33.3%; OR 3.49 (95% CI 1.23 to 9.91)). Serious adverse events were reported in 17.0% of belimumab patients and 35.0% of placebo patients; one death occurred (placebo). Week-52, geometric mean (95% CI) belimumab trough concentration was 56.2 (45.2 to 69.8) µg/mL. CONCLUSION: The belimumab intravenous pharmacokinetics and benefit-risk profile in cSLE are consistent with adult belimumab studies and the 10 mg/kg every 4 weeks dose is appropriate. TRIAL REGISTRATION NUMBER: NCT01649765.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Administração Intravenosa , Adolescente , Fator Ativador de Células B/antagonistas & inibidores , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
No disponible
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Humanos , Atenção Primária à Saúde/estatística & dados numéricos , Pediatria/estatística & dados numéricos , Congressos como Assunto/estatística & dados numéricosRESUMO
BACKGROUND: Patients with polyarticular-course juvenile idiopathic arthritis (pJIA), receiving disease-modifying anti-rheumatic drugs with immunosuppressive effects, may be at increased risk of vaccine-preventable infections. This substudy assessed protective antibody responses to diphtheria and tetanus vaccination given prior to study enrolment in patients with pJIA. FINDINGS: This was a substudy of a 24-month, single-arm, open-label, multicenter, Phase III trial (NCT01844518) of subcutaneous abatacept in children with active pJIA (N = 219). Patients aged 2-5 years, with ≥2 continuous months of weekly weight-tiered (10-< 25 kg [50 mg], 25-< 50 kg [87.5 mg]) subcutaneous abatacept treatment (with/without methotrexate and/or low-dose corticosteroids), who received diphtheria/tetanus vaccine prior to enrolment, were eligible. Protective antibody levels to diphtheria/tetanus (> 0.1 IU/mL), and safety, were assessed. Overall, 29 patients were analyzed: 19 (65.5%), 1 (3.4%) and 9 (31.0%) patients had > 12, 6-12 and 2-< 6 months of abatacept exposure, respectively. All patients had protective antibody levels to tetanus and 26 (89.7%) patients had protective antibody levels to diphtheria. Of the 3 patients without protective antibody levels to diphtheria, each had an antibody level of 0.1 IU/mL, bordering the lower threshold of protection. Concomitant use of methotrexate and/or low-dose corticosteroids had no evident effect on antibody levels. No unexpected adverse events, including cases of diphtheria or tetanus, were reported during the 24-month period. CONCLUSIONS: Patients aged 2-5 years with pJIA who received 2-24 months of weekly subcutaneous abatacept, with or without concomitant methotrexate and/or low-dose corticosteroids, maintained effective diphtheria and tetanus vaccination protection without new safety signals. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01844518); registered May 1, 2013; https://clinicaltrials.gov/ct2/show/NCT01844518?term=NCT01844518&rank=1.
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Abatacepte/uso terapêutico , Anticorpos Antibacterianos/sangue , Artrite Juvenil/tratamento farmacológico , Vacina contra Difteria e Tétano/uso terapêutico , Difteria/prevenção & controle , Imunossupressores/uso terapêutico , Tétano/prevenção & controle , Pré-Escolar , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
OBJECTIVE: To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS). METHODS: CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. RESULTS: Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy. CONCLUSION: Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Formação de Anticorpos/imunologia , Proteína C-Reativa/metabolismo , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/imunologia , Síndromes Periódicas Associadas à Criopirina/metabolismo , Diarreia/induzido quimicamente , Feminino , Febre/induzido quimicamente , Humanos , Lactente , Recém-Nascido , Masculino , Nasofaringite/induzido quimicamente , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Proteína Amiloide A Sérica/metabolismo , Resultado do Tratamento , Vacinas/uso terapêuticoRESUMO
OBJECTIVE: Evaluate growth in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ) for up to 2 years in a phase III trial. METHODS: Patients with pcJIA lasting at least 6 months and inadequate response to methotrexate received open-label TCZ intravenously every 4 weeks (randomly assigned to 8 or 10 mg/kg if they weighed < 30 kg; received 8 mg/kg if they weighed ≥ 30 kg) for 16 weeks. Patients with JIA American College of Rheumatology 30 response at Week 16 were randomly assigned to TCZ or placebo for 24 weeks, with an open-label extension through Week 104. Mean ± SD height velocity (cm/yr) and World Health Organization (WHO) height SD score (SDS) were measured in patients receiving ≥ 1 dose of TCZ who did not receive growth hormone and in patients whose baseline Tanner stage was ≤ 3. RESULTS: The study included 187 of 188 patients (99.5%) with mean WHO height SDS -0.5 ± 1.2, which was unrelated to age or disease duration (Spearman rank correlations r = 0.08 and r = -0.12, respectively). There were 123 patients at Tanner stage ≤ 3 at baseline, among whom 103 completed the study with 2 years of height SDS data. Mean height SDS increased from baseline to year 2 (+0.40, p < 0.0001). In 74 of 103 patients (72%), height SDS was greater than at baseline, and mean height velocity was 6.7 ± 2.0 cm/year. CONCLUSION: Among patients with pcJIA at Tanner stage ≤ 3 at baseline, 72% (74/103) had increased height SDS at the end of the study.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Estatura/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Adolescente , Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Juvenil/fisiopatologia , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).
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Anticorpos Monoclonais/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Deficiência de Mevalonato Quinase/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Adulto JovemRESUMO
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 Castilian 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 526 JIA patients (8.6% systemic, 49.4% oligoarticular, 18.2% RF negative polyarthritis, 23.8% other categories) and 78 healthy children, were enrolled in six centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Castilian 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 practise and clinical research.
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Artrite Juvenil/diagnóstico , Avaliação da Deficiência , Medidas de Resultados Relatados pelo Paciente , Reumatologia/métodos , Adolescente , Idade de Início , Artrite Juvenil/fisiopatologia , Artrite Juvenil/psicologia , Artrite Juvenil/terapia , Estudos de Casos e Controles , Criança , Pré-Escolar , Características Culturais , Feminino , Nível de Saúde , Humanos , Masculino , Pais/psicologia , Pacientes/psicologia , Valor Preditivo dos Testes , Prognóstico , Psicometria , Qualidade de Vida , Reprodutibilidade dos Testes , TraduçãoRESUMO
OBJECTIVE: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), ≥50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (Cminss ) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity. RESULTS: The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 µg/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects. CONCLUSION: Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.
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Abatacepte/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Imunossupressores/administração & dosagem , Adolescente , Artrite Juvenil/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Injeções Subcutâneas , Masculino , Resultado do TratamentoRESUMO
OBJECTIVE: Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response to treatment in an international cohort of MKD patients. METHODS: All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases. RESULTS: The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10-20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD. CONCLUSION: We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected.
Assuntos
Deficiência de Mevalonato Quinase/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Sistema de Registros , Dor Abdominal/etiologia , Dor Abdominal/genética , Dor Abdominal/fisiopatologia , Adolescente , Idade de Início , Amiloidose/etiologia , Amiloidose/genética , Amiloidose/fisiopatologia , Artralgia/etiologia , Artralgia/genética , Artralgia/fisiopatologia , Artrite/etiologia , Artrite/genética , Artrite/fisiopatologia , Doenças Cerebelares/etiologia , Doenças Cerebelares/genética , Doenças Cerebelares/fisiopatologia , Criança , Pré-Escolar , Conjuntivite/etiologia , Conjuntivite/genética , Conjuntivite/fisiopatologia , Diarreia/etiologia , Diarreia/genética , Diarreia/fisiopatologia , Feminino , Genótipo , Cefaleia/etiologia , Cefaleia/genética , Cefaleia/fisiopatologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Linfadenopatia/etiologia , Linfadenopatia/genética , Linfadenopatia/fisiopatologia , Masculino , Deficiência de Mevalonato Quinase/complicações , Deficiência de Mevalonato Quinase/fisiopatologia , Mialgia/etiologia , Mialgia/genética , Mialgia/fisiopatologia , Faringite/etiologia , Faringite/genética , Faringite/fisiopatologia , Fenótipo , Estudos RetrospectivosRESUMO
OBJECTIVE: The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). METHODS: CLIPPER was a 96-week, phase IIIb, open-label, multicenter study. Patients with eoJIA, ERA, or PsA received ETN 0.8 mg/kg once weekly (50 mg max) for up to 96 weeks. The proportions of patients reaching the JIA American College of Rheumatology (ACR) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated. Adverse events (AE) were collected throughout the study (intention-to-treat sample). RESULTS: There were 127 patients (eoJIA n = 60, ERA n = 38, PsA n = 29) who received ≥ 1 dose of ETN. The mean disease duration was 31.6 (eoJIA), 23.0 (ERA), and 21.8 (PsA) months. At Week 96, JIA ACR 30/50/70/90/100/inactive disease responses (95% CI) were achieved by 84.3% (76.7, 90.1), 83.5% (75.8, 89.5), 78.7% (70.6, 85.5), 55.1% (46.0, 63.9), 45.7% (36.8, 54.7), and 27.6% (20.0, 36.2) of patients, respectively. The most common AE (no. events, events per 100 patient-yrs) overall were headache (23, 10.7), pyrexia (12, 5.6), and diarrhea (10, 4.6). The most common infections were upper respiratory tract infection (83, 38.6), pharyngitis (50, 23.2), gastroenteritis (22, 10.2), bronchitis (19, 8.8), and rhinitis (17, 7.9). No cases of malignancy, active tuberculosis, demyelinating disorders, or death were reported. CONCLUSION: Over 96 weeks of therapy, ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories, with no major safety issues.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Psoriásica/tratamento farmacológico , Etanercepte/uso terapêutico , Adolescente , Antirreumáticos/efeitos adversos , Criança , Pré-Escolar , Etanercepte/efeitos adversos , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
Familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS) belong to the cryopyrin-associated periodic syndromes (CAPS) with CIAS1 gene mutations as a common molecular basis. Patients with FCAS have the least severe clinical phenotype but are characterized by the development of symptoms induced by a generalized exposure to cold appearing during the first months of childhood. It is important to make differential diagnosis between FCAS and acquired cold urticaria (ACU) and familial atypical cold urticaria (FACU). Muckle-Wells syndrome is characterized by recurrent fever and urticarial rash, progressive sensorineural deafness and the development of secondary amyloidosis, but it is not considered the most severe disease of this group. Sensorineural deafness and amyloidosis are the two major complications of MWS and determine poor prognosis of the disease.
Assuntos
Temperatura Baixa/efeitos adversos , Síndromes Periódicas Associadas à Criopirina , Doenças Hereditárias Autoinflamatórias/etiologia , Idade de Início , Amiloidose/etiologia , Artralgia/etiologia , Proteínas de Transporte/genética , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/etiologia , Síndromes Periódicas Associadas à Criopirina/genética , Diagnóstico Diferencial , Perda Auditiva Neurossensorial/etiologia , Doenças Hereditárias Autoinflamatórias/classificação , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fenótipo , Prognóstico , Urticária/diagnóstico , Urticária/etiologiaRESUMO
El síndrome autoinflamatorio familiar inducido por frío (FCAS) y el síndrome de Muckle-Wells forman parte del grupo de criopirinopatías o síndromes asociados a criopirina (CAPS) que presentan en común la presencia de mutaciones en el gen CIAS1. Los pacientes con diagnóstico de FCAS, aunque constituyen las formas clínicas más leves de este grupo, debutan en los primeros meses de vida y los síntomas se presentan tras la inducción por frío. El diagnóstico diferencial se plantea con los síndromes de urticarias adquiridas (ACU) y los síndromes familiares por frío atípicos (FACUS). Respecto al síndrome de Muckle-Wells (MWS) presenta, además de la fiebre y el exantema urticarial como síntomas recurrentes, la sordera neurosensorial progresiva que afectará al 60% de los pacientes, que junto con la amiloidosis secundaria ensombrecerá el pronóstico de este síndrome (AU)
Familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS) belong to the cryopyrin-associated periodic syndromes (CAPS) with CIAS1 gene mutations as a common molecular basis. Patients with FCAS have the least severe clinical phenotype but are characterized by the development of symptoms induced by a generalized exposure to cold appearing during the first months of childhood. It is important to make differential diagnosis between FCAS and acquired cold urticaria (ACU) and familial atypical cold urticaria (FACU). Muckle-Wells syndrome is characterized by recurrent fever and urticarial rash, progressive sensorineural deafness and the development of secondary amyloidosis, but it is not considered the most severe disease of this group. Sensorineural deafness and amyloidosis are the two major complications of MWS and determine poor prognosis of the disease (AU)