21 research outputs found
Efficacy and safety of adrenocorticotropic hormone gel in refractory dermatomyositis and polymyositis
No full text© 2018 author(s). Aim To evaluate the efficacy, safety, tolerability and steroid-sparing effect of repository corticotropin injection (RCI), in an open-label clinical trial, in refractory adult polymyositis (PM) and dermatomyositis (DM). Methods Adults with refractory PM and DM were enrolled by two centres. Inclusion criteria included refractory disease defined as failing glucocorticoid and/or ≥1 immunosuppressive agent, as well as active disease defined as significant muscle weakness and \u3e2 additional abnormal core set measures (CSMs) or a cutaneous 10 cm Visual Analogue Scale score of ≥3 cm and at least three other abnormal CSMs. All patients received RCI of 80 units subcutaneously twice weekly for 24 weeks. The primary end point for the trial was the International Myositis Assessment and Clinical Studies definition of improvement. Secondary end points included safety, tolerability, steroid-sparing as well as the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism myositis response criteria (EULAR) Results Ten of the 11 enrolled subjects (6 DM, 4 PM) completed the study. Seven of 10 met the primary end point of efficacy at a median of 8 weeks. There was a significant decrease in prednisone dose from baseline to conclusion (18.5 (15.7) vs 2.3 (3.2); P10% and the physician global by \u3e40%. RCI was considered safe and tolerable. No patient developed significant weight gain or an increase of haemoglobin A1c or cushingoid features. Conclusion Treatment with RCI was effective in 70% of patients, safe and tolerable, and led to a steroid dose reduction in patients with adult myositis refractory to glucocorticoid and traditional immunosuppressive drugs. Trial registration number NCT01906372; Results
Successful treatment of cardiac involvement in dermatomyositis with rituximab
No full textPolymyositis and dermatomyositis are autoimmune inflammatory myopathies characterized by muscle weakness and inflammation. Current recommended therapy includes corticosteroids as mainstay treatment in addition to immunosuppressant. We present herein a 25 year-old female with dermatomyositis and cardiac involvement resistant to disease modifying anti-rheumatic drugs and anti-tumor necrosis factor-α. She was treated with anti-CD20 monoclonal antibody, rituximab. The patient demonstrated a remarkable clinical and laboratory response. B-cell depletion therapy with rituximab may be a viable option in patients with dermatomyositis and heart disease. © 2007 Elsevier Masson SAS. All rights reserved.Allanore Y, 2006, ANN RHEUM DIS, V65, P249, DOI 10.1136-ard.2005.038679; Chiappetta N, 2005, JCR-J CLIN RHEUMATOL, V11, P264, DOI 10.1097-01.rhu.0000182155.08982.60; Efthimiou P, 2006, ANN RHEUM DIS, V65, P1233, DOI 10.1136-ard.2005.048744; Erlacher P, 2001, CLIN CHIM ACTA, V306, P27, DOI 10.1016-S0009-8981(01)00392-8; HELMERS SB, 2007, ANN RHEUM DIS, P8; Hengstman GJD, 2003, EUR NEUROL, V50, P10, DOI 10.1159-000070852; HOCHBERG MC, 1986, SEMIN ARTHRITIS RHEU, V15, P168, DOI 10.1016-0049-0172(86)90014-4; Itoh K, 2006, ARTHRITIS RHEUM, V54, P1020, DOI 10.1002-art.21721; Kiely PDW, 2000, ANN RHEUM DIS, V59, P750, DOI 10.1136-ard.59.9.750; Lambotte O, 2005, J RHEUMATOL, V32, P1369; Levine TD, 2005, ARTHRITIS RHEUM, V52, P601, DOI 10.1002-art.20849; Lundberg IE, 2005, LUPUS, V14, P708, DOI 10.1191-0961203305lu2205oa; Noss EH, 2006, J RHEUMATOL, V33, P1021; Oddis CV, 2003, RHEUMATOLOGY, P1537; Targoff IN, 2002, RHEUM DIS CLIN N AM, V28, P859, DOI 10.1016-S0889-857X(02)00032-7; Touma Z, 2006, SCAND J RHEUMATOL, V35, P323, DOI 10.1080-03009740500484056; Wortmann RL, 2005, KELLEYS TXB RHEUMATO, P130922191
Follow-up results of myositis patients treated with H. P. Acthar gel
No full text© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: [email protected]. OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by proximal muscle weakness. H. P. Acthar gel [repository corticotropin injection (RCI)] is a formulation of adrenocorticotropic hormone and has been approved by Food and Drug Administration for use in IIM; however, literature is limited. In this study, we report longitudinal follow-up of myositis patients treated with RCI. METHODS: Patients with refractory IIM who were enrolled in the prospective, open-label RCI trial were included in this study. The post-trial follow-up period was 6 months with assessments every 2 months, which included myositis core set measures including extra-muscular global, muscle and patient global disease activities, HAQ, and manual muscle testing. RESULTS: Two patients were lost to follow-up after finalization of the trial, and the remaining eight patients were enrolled in the follow-up study. One patient remained on RCI after the trial. In the follow-up period, four of eight patients had flare at on average 4.1 months after the RCI trial. Among the patients who flared, three required an increase in prednisone. One patient was restarted on RCI at 5.5 months, but had minimal improvement after 3 months. Four patients who remained stable continued to satisfy criteria for the definition of improvement through the 6-month follow-up. However, none showed any further improvement in the primary or secondary efficacy outcomes after the initial RCI trial. CONCLUSION: To our knowledge, this is the first study reporting the follow-up results of patients treated with standard dose and duration of Acthar. We believe that our study will provide the basis for the development of future randomized RCI trials in IIM
Tumour necrosis factor-α single nucleotide polymorphisms are not independent of HLA class I in UK Caucasians with adult onset idiopathic inflammatory myopathies
No full textObjective. To investigate haplotype tagging single nucleotide polymorphisms (SNPs) in the tumour necrosis factor α (TNF-α) gene, in UK Caucasian idiopathic inflammatory myopathy (IIM) patients. Methods. A cross-sectional, case-control study of four TNF-α SNPs was undertaken, comparing cases of polymyositis (PM) (n = 121), dermatomyositis (DM) (n = 109) and myositis overlapping with other connective tissue diseases (CTD-overlap) (n = 73) with normal subjects (n = 177). Subgroup analyses were undertaken after stratifying for myositis specific/associated antibodies. Results. The TNF-308A allele demonstrated a strong association with each myositis disease subgroup vs controls [PM, odds ratio (OR) 2.8, 95% confidence interval 1.9-4.3; DM, OR 2.5, 1.6-3.8; CTD-overlap, OR 3.3, 2.1-5.1]. The TNF-308GA/AA genotype frequency was significantly increased vs controls (PM, OR 3.7, 2.1-6.3; DM, OR 3.2, 1.8-5.5; CTD-overlap, OR 5.0, 2.6-9.6) suggesting a dominant model. The association was strongest in patients possessing anti-aminoacyl transfer RNA synthetase (anti-synthetase) (OR 5.1, 3.3-8.0) or -PM-Scl (OR 5.0, 2.7-8.9) antibodies. The -1031T allele was also a significant risk factor in DM (OR 2.2, 1.4-3.6), anti-synthetase (OR 2.9, 1.6-5.3) and -PM-Scl (OR 5.6, 1.9-6.4) antibody positive patients. The TNF-308A association was lost after adjusting for HLA-B*08, but remained independent of HLA-DQB1*02 (both are alleles forming part of the common ancestral haplotype). The HLA-B*08/TNF-308A/DRB1*03/ DQA1*05/DQB1*02 haplotype was a risk factor in all myositis subgroups vs controls (OR 3.0, 1.8-5.3). Conclusions. TNF-308A and -1031T alleles are significant risk factors in the IIMs. In the IIMs, the TNF-308A allele is part of the common ancestral haplotype, but is not independent of HLA-B*08. © 2007 The Author(s)
Disfunção cardíaca na sepse experimental avaliada em coração isolado e perfundido de camundongo
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2010A síndrome da resposta inflamatória sistêmica (SIRS), quando associada a uma infecção pode evoluir para sepse e choque séptico, que são importantes causas de morte nas UTIs. Em geral, a morte é causada por um colapso cardiovascular e hipotensão refratária, que aparecem logo no início da sepse. A disfunção vascular é mais estudada e compreendida que a disfunção cardíaca, contudo a última é reconhecida como um importante mediador da disfunção de múltiplos órgãos na sepse. O objetivo do presente trabalho foi caracterizar a disfunção cardíaca na sepse experimental induzida pela ligadura e perfuração do ceco (CLP) em camundongos, utilizando a metodologia de coração isolado e perfundido (preparação de Langendorff), e também, avaliar a participação do óxido nítrico nesse processo. Os parâmetros cardíacos avaliados foram: Tensão sistólica e diastólica, +dT/dt (velocidade de contração), -dT/dt (velocidade de relaxamento), AUC (área sob a curva), pressão de perfusão das coronárias e frequência cardíaca. Observamos que durante a sepse severa (índice de mortalidade de 100% quarenta e oito horas após a CLP) o perfil de atividade apresentado pelos corações sépticos, apesar de variado, mostra que a sepse causa importantes alterações na funcionalidade cardíaca. O parâmetro tensão sistólica, três horas após os animais serem submetidos à CLP, mostrou que 38% dos corações apresentaram valores superiores aos apresentados pelos corações controle (e por isso denominados de suprafuncionais), 12% apresentaram valores inferiores (subfuncionais) e 50% apresentaram valores semelhantes aos apresentados pelos corações controle (normofuncionais). Seis horas após a CLP o subgrupo suprafuncional correspondeu a apenas 21% do total de corações avaliados, enquanto o subgrupo subfuncional correspondeu a 29%. Doze horas após a CLP o subgrupo normofuncional foi o mais numeroso, correspondendo a 77% do total de corações avaliados. Por fim, vinte e quatro horas após a CLP houve um aumento substancial no número de corações subfuncionais, representando 40% dos corações avaliados. Perfil semelhante foi encontrado em relação aos parâmetros velocidade de contração, velocidade de relaxamento e AUC. Quando estimulados com isoprenalina para avaliação da capacidade contrátil e capacidade cronotrópica positiva, os corações dos animais submetidos à CLP vinte e quatro horas antes apresentaram importante redução no funcionamento das células auto-rítmicas do nodo sino-atrial, alterações no sistema de condução dos estímulos e ainda, o sistema contrátil destes corações encontrou-se parcialmente reduzido. Tanto os corações suprafuncionais avaliados três horas após a CLP quanto os corações suprafuncionais avaliados vinte e quatro horas após, apresentaram tensão sistólica superior à apresentada pelos corações controle em resposta à isoprenalina. A resposta cronotrópica e inotrópica positiva dos demais corações avaliados (subfuncionais três horas após a CLP, normofuncionais três e vinte e quatro horas após a CLP) foi semelhante à resposta apresentada pelos corações controle, sugerindo que a atividade beta-adrenérgica, atividade contrátil e o aspecto elétrico da frequência cardíaca estão preservados nestes corações. Observamos ainda que os níveis plasmáticos de NOx encontram-se elevados a partir de três horas após o procedimento cirúrgico, permanecendo assim até pelo menos quarenta e oito horas após a CLP. A infusão de um inibidor não-seletivo das enzimas NOS (L-NAME) não alterou a atividade basal dos corações controle e dos corações sépticos avaliados vinte e quatro horas após a CLP. Por outro lado, quando estimulados com isoprenalina, os corações controle infundidos com L-NAME apresentaram resposta cronotrópica e inotrópica positiva inferior à apresentada pelos corações controle que receberam apenas Krebs. Os corações sépticos que receberam L-NAME quando estimulados com isoprenalina apresentaram resposta concentração-dependente à isoprenalina, tanto no parâmetro tensão sistólica quanto no parâmetro frequência cardíaca, efeito este que não foi observado nos corações sépticos que receberam apenas Krebs. O substrato L-arginina não é um fator limitante para a produção de óxido nítrico, visto que não foram observadas diferenças em corações controle e corações sépticos avaliados vinte e quatro horas após a CLP e que tiveram arginina adicionada à solução de perfusão. Assim, nosso trabalho mostra que ocorrem importantes alterações cardíacas durante a sepse, as quais acometem tanto a maquinaria contrátil quanto as células auto-rítmicas, tendo início logo nas primeiras horas de instalação do quadro e perdurando até horários mais tardios. Demonstramos ainda, que o óxido nítrico parece estar envolvido nas alterações observadas
Genetic association study of NF-κB genes in UK caucasian adult and juvenile onset idiopathic inflammatory myopathy
No full textObjective: Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-κB). Several genes share homology with the NF-κB family of proteins. This study investigated the role of NF-κB-related genes in disease susceptibility in UK Caucasian IIM. Methods: Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-κB-related genes. Data were stratified by IIM subgroup/serotype. Results: A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P = 0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D' = 1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08. Conclusion: An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-κB genes therefore do not independently confer susceptibility in IIM. © The Author(s) 2011. Published by Oxford University Press on behalf of The British Society for Rheumatology
Inflamação das vias aéreas e envolvimento pulmonar intersticial na esclerose sistêmica: associação com alterações esofágicas e microaspiração
No full textTese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Ciências Médicas, Florianópolis, 2012INTRODUCAO: O envolvimento pulmonar na Esclerose Sistemica (ES) tem sido associado com refluxo gastroesofagico (RGE) causado por dismotilidade esofagica e microaspiracao. Entretanto, a microaspiracao ainda nao foi objetivamente demonstrada. Nos objetivamos demonstrar, em pacientes com ES, a ocorrencia de microaspiracao e investigar sua associacao com o envolvimento intersticial pulmonar e das vias aereas e as anormalidades esofagicas. METODOS: Quarenta e sete pacientes com ES e 38 controles pareados por idade foram incluidos no estudo. Todos foram submetidos a inducao do escarro, espirometria e teste de broncoprovocacao com metacolina. Os pacientes tambem realizaram pletismografia e tomografia de torax de alta resolucao (TCAR), a qual foi analisada de acordo com um escore tomografico (Indice Tomografico, IT), monitoramento do pH esofagico de 24 horas e esofagomanometria. O indice lipidico de macrofagos (ILM) no escarro induzido foi usado como metodo para aferir a microaspiracao. RESULTADOS: O grupo dos pacientes constituiu-se de 91,5% de mulheres, com idade media (DP) de 49,3 (11,8) anos e media (DP) de duracao de doenca de 8,1(7,4) anos, 68,1% deles com a forma limitada da doenca. Anormalidades manometricas esofagicas foram encontradas em 78,7% dos pacientes e 70,2% deles tinha RGE patologico. Cinquenta e um por cento dos casos apresentava envolvimento pulmonar intersticial (IT . 3) e alteracoes a espirometria ocorreram em 48,9% deles (23,4% com defeito restritivo e 21,3% com defeito obstrutivo leve). Os niveis de DLCO (corrigidos pelo volume alveolar, DLCO/VA) estavam reduzidos em 44,6% dos casos. Microaspiracao (ILM . 7) foi encontrada em 93,6% dos pacientes, sendo que 42,6% deles tinham microaspiracao considerada significativa (ILM . 50). Os pacientes apresentaram contagem celular total (CT) (p=0,007), contagem de neutrofilos (pAbstract : INTRODUCTION: Pulmonary involvement has been associated with gastroesophageal reflux (GER) caused by esophageal dysmotility and probably microaspiration in patients with systemic sclerosis (SSc). However, microaspiration was not objectively demonstrated. We aimed to demonstrate the occurrence of microaspiration and to investigate its association with airways and pulmonary interstitial involvement and with esophageal abnormalities in SSc patients. METHODS: We enrolled 47 SSc patients and 38 controls matched by age. They performed sputum induction, spirometry and methacholine bronchial provocation test. Patients also performed plethysmography, chest high resolution computed tomography (HRCT), scored according to a tomographic index (TIx), esophageal 24 hour pH monitoring and esophageal manometry. Lipid laden alveolar macrophage index (LLAM) in induced sputum was used to measure microaspiration. RESULTS: Patients were 91,5% women, with mean (SD) age of 49,3 (11,8) years and mean disease duration of 8,1(7,4) years, 61,8% of them with limited disease subset. Esophageal manometry abnormalities were found in 78,7% of the patients and 70,2% of them had pathological GER. Fifty one percent of the cases presented with interstitial lesions on HRCT (TIx . 3) and 44,6% of them had spirometric abnormalities (23,4% with restrictive defect and 21,3% with mild obstructive defect). DLCO (corrected by alveolar volume, DLCO/VA) levels were reduced in 48,9 % of the patients. Microaspiration (LLAM . 7) was found in 93,6% of the patients and in 42,6% % of them it was considered severe (LLAM . 50). Patients had higher sputum total cell (TCC) (p=0,007), neutrophil (p< 0,001) and eosinophil counts (p=0,008) than controls. There was a positive correlation between LLAM and neutrophil count (r=0,30, p=0,04) and between LLAM and TCC (r=0,37, p=0,006). Mean DLCO/VA was was negatively correlated with LLAM (r=0,33, p=0,02) and tended to be lower in patients with manometry abnormalities and/or moderate to severe GER (severe esophageal involvement, p=0,05). Those patients with severe esophageal involvement had higher TIx (p=0,03). Neutrophils were higher in patients with HRCT lesions (p=0,04), but no association was found between LLAM and TIx. About one third (27,7%)of the patients had airway hyperresponsiveness, compared with none of the controls (p<0,0001), which was not associated with any other clinical or functional characteristics. CONCLUSION: In SSc patients, microaspiration and airways inflammation were both frequent and were associated with each other. Microaspiration was also associated with esophageal abnormalities and abnormal pulmonary function. Patients with HRCT lesions had more frequently an airways inflammatory pattern. These results demonstrate an association between microaspiration and lung involvement in SSc
2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative
No full textEULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: A methodology report
No full textObjective T o describe the methodology used to develop new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIMs) and their major subgroups. Methods A n international, multidisciplinary group of myositis experts produced a set of 93 potentially relevant variables to be tested for inclusion in the criteria. Rheumatology, dermatology, neurology and paediatric clinics worldwide collected data on 976 IIM cases (74% adults, 26% children) and 624 non-IIM comparator cases with mimicking conditions (82% adults, 18% children). The participating clinicians classified each case as IIM or non-IIM. Generally, the classification of any given patient was based on few variables, leaving remaining variables unmeasured. We investigated the strength of the association between all variables and between these and the disease status as determined by the physician. We considered three approaches: (1) a probability-score approach, (2) a sum-ofitems approach criteria and (3) a classification-tree approach. Results T he approaches yielded several candidate models that were scrutinised with respect to statistical performance and clinical relevance. The probabilityscore approach showed superior statistical performance and clinical practicability and was therefore preferred over the others. We developed a classification tree for subclassification of patients with IIM. A calculator for electronic devices, such as computers and smartphones, facilitates the use of the European League Against Rheumatism/American College of Rheumatology (EULAR/ ACR) classification criteria. Conclusions The new EULAR/ACR classification criteria provide a patient's probability of having IIM for use in clinical and research settings. The probability is based on a score obtained by summing the weights associated with a set of criteria items. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted
