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1.
Life Sci ; 240: 116857, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31521691

RESUMO

AIMS: Daphnetin (DAP) is a traditional Chinese drug usually used to treat cardiovascular diseases. Studies have confirmed the anti-inflammatory, antioxidant, anti-bacterial and insecticidal, anti-tumor and neuro-protective effects of DAP. However, its anti-arthritic potential remains unexplored. The aim of this study is to investigate the in vitro and in vivo chondroprotective effects of DAP. MAIN METHODS: The effect of DAP on primary rabbit chondrocytes was examined using recombinant human IL-1ß for 24 h. For the in vivo studies, rabbits were randomly divided into groups: a normal control group and osteoarthritis (OA) groups. The OA groups received three different doses of DAP for 4 or 8 weeks. The anti-arthritic effect of DAP was assessed using histopathological examinations, qRT-PCR, western blotting and immunohistochemical analysis. KEY FINDINGS: Both in vitro and in vivo results indicate that DAP exerts a protective effect against IL-1ß in chondrocytes. In vitro, DAP inhibits the expression of IL-6, IL-12, MMP-3, MMP-9 and MMP-13, induced by IL-1ß in rabbit chondrocytes, and stimulates the production of IL-10. The inhibitory effect of DAP on the MMPs is partially regulated by the inhibition of the PI3K/AKT, MAPK and NF-κB signaling pathways. The effect of DAP on OA may be attributed to the suppression of inflammatory factor secretion, chondrocyte apoptosis observed by the decrease in pro-apoptotic Caspase-3 and BAX, and the activation of anti-apoptotic BCL-2. SIGNIFICANCE: DAP has a broad range of prospects in the treatment of OA, which provides a novel therapeutic strategy for OA.


Assuntos
Antirreumáticos/uso terapêutico , Condrócitos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Umbeliferonas/uso terapêutico , Animais , Antirreumáticos/efeitos adversos , Apoptose/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Sobrevivência Celular , Condrócitos/patologia , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Interleucina-1beta/farmacologia , Masculino , Osteoartrite/patologia , Cultura Primária de Células , Coelhos , Transdução de Sinais/efeitos dos fármacos , Umbeliferonas/efeitos adversos
2.
Expert Opin Investig Drugs ; 28(12): 1113-1123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31738612

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic, refractory disorder caused by autoimmunity in the synovial joints. Disease-modifying anti-rheumatic drugs (DMARDs) and biologicals offer remission in only two-thirds of RA patients within 3 months, hence new therapeutic approaches are necessary. Tyrosine kinase inhibitors (TKIs) are newly developed small molecule drugs which have demonstrated encouraging results in this disease.Areas covered: The key findings from phase I and II clinical trials that have investigated the use of novel TKIs in the treatment of RA are discussed. We examined the literature published between January 2014 to January 2019 using electronic databases including PubMed, Web of Science, Medline, Embase, and Google Scholar. Additional information about phase I and II trials on the ClinicalTrial.gov website up to January 2019 was also retrieved.Expert opinion: JAK inhibitors are promising drugs with sound efficacy and acceptable safety and may be beneficial to patients who do not respond to DMARDs and biologicals. The response rates among RA patients to TKIs are diverse; genetic and environmental factors may be involved in the varying responses which are closely related to the pathogenesis of RA. Future studies may reveal the underlying mechanisms of resistance and non-response.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antirreumáticos/efeitos adversos , Artrite Reumatoide/patologia , Desenvolvimento de Medicamentos , Humanos , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos
3.
Expert Opin Drug Metab Toxicol ; 15(12): 1021-1032, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31709838

RESUMO

Introduction: Osteoarthritis (OA) is the leading cause of disability in the elderly, usually presenting with mono-or oligo-arthritis where local drug delivery by intra-articular (IA) injection may be more effective in terms of increased bioavailability, less systemic exposure and reduced adverse events. Several intra-articular medications for symptomatic are available on the market while the new disease-modifying drugs (DMOADs) are progressing into phase 3 pipeline of drug development.Areas covered: This narrative review covered the pharmacokinetic and pharmacodynamics of clinically available IA drugs which include corticosteroids, hyaluronic acid as well as injection techniques, efficacy, adverse effects and contraindications. In addition, the authors briefly describe the newer disease-modifying OA drugs (DMOAD) which are undergoing phase 3 pipeline of development such as Fibroblast growth factor (FGF-18) and Wnt inhibitor.Expert opinion: This is a rapidly evolving area with both new products and new trials regularly emerging. It is also a critically important area in a disease field that lacks for safe and effective treatments, where intra-articular delivery may enhance both local efficacy and reduce systemic toxicity.


Assuntos
Antirreumáticos/administração & dosagem , Desenvolvimento de Medicamentos , Osteoartrite do Joelho/tratamento farmacológico , Idoso , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Glucocorticoides/administração & dosagem , Humanos , Ácido Hialurônico/administração & dosagem , Injeções Intra-Articulares , Osteoartrite do Joelho/patologia
4.
Expert Opin Drug Metab Toxicol ; 15(11): 913-925, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31623470

RESUMO

Introduction: The treatment of psoriasis with conventional topical therapies and disease-modifying anti-rheumatic drugs (DMARDs) is often linked to unsatisfactory outcomes and the risk of serious adverse events. Over the last decades, research advances in understanding the role of tumor necrosis factor alpha (TNF α) and other cytokines in the pathogenesis of psoriasis have driven the introduction of biologic agents targeting specific immune mediators in everyday clinical practice. TNF α inhibitors are a consolidated treatment option for patients with moderate-to-severe disease with remarkable efficacy and a reassuring safety profile.Areas covered: The PubMed database was searched using combinations of the following keywords: psoriasis, TNF α inhibitors, biologic therapy, pharmacodynamics, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, adverse effects. The aim of this review is to describe the pharmacodynamic profile of anti-TNF α inhibitors, currently approved by the European Medicines Agency (EMA) for the treatment of psoriasis, focusing on related clinical implications, also in comparison to the new generation biological therapies targeting the interleukin 23/interleukin 17 axis.Expert opinion: Pharmacodynamics of TNF α inhibitors should be fully considered in planning patient's therapy strategies, especially in case of secondary failures, poor adherence to treatment, instable psoriasis, high risk of infection, pregnant or lactating women, metabolic comorbidities, coexistence of other immune-mediated inflammatory diseases.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Desenvolvimento de Medicamentos , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Adesão à Medicação , Psoríase/imunologia , Psoríase/patologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/metabolismo
5.
Intern Med ; 58(18): 2703-2709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31527369

RESUMO

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the JC virus under an immunosuppressed state. This condition carries a high risk of cryptococcal meningitis. We herein report a 65-year-old woman who simultaneously developed PML and cryptococcal meningitis and presented with bilateral sixth nerve palsy. She had been treated with methotrexate and infliximab for rheumatoid arthritis. Her symptoms improved with antifungal drug treatment and discontinuation of immunosuppression therapy. Although concurrent PML and cryptococcal meningitis is rare, it should be considered in immunosuppressed patients.


Assuntos
Antifúngicos/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Imunossupressão/efeitos adversos , Infliximab/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Meningite Criptocócica/tratamento farmacológico , Metotrexato/efeitos adversos , Idoso , Antirreumáticos/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/etiologia , Meningite Criptocócica/etiologia , Metotrexato/uso terapêutico , Resultado do Tratamento
6.
Reumatol. clín. (Barc.) ; 15(4): 229-236, jul.-ago. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-184416

RESUMO

Objetivo: Describir los objetivos, la metodología y los resultados del primer año de la nueva versión del registro español de acontecimientos adversos de terapias biológicas y fármacos sintéticos con diana identificable en enfermedades reumáticas (BIOBADASER III). Metodología: Registro prospectivo multicéntrico de pacientes con enfermedades inflamatorias reumáticas en tratamiento con terapia biológica o fármacos sintéticos con diana identificable y atendidos en servicios de Reumatología en España. El objetivo principal de BIOBADASER Fase III es la recogida y análisis de acontecimientos adversos al que se ha añadido como objetivo secundario la evaluación de la efectividad mediante la recogida de índices de actividad. Los pacientes que entran en el registro son evaluados al menos una vez cada año y cada vez que presenten un acontecimiento adverso o se produzcan modificaciones en el tratamiento. La recogida de datos de la fase iii se inició el 17 de diciembre del 2015. Resultados: Durante el primer año han participado 35 centros. El número de pacientes incluidos en esta nueva fase en diciembre del 2016 era de 2.664. La edad media era de 53,7 años, con una mediana de duración de la enfermedad hasta el inicio de tratamiento de 8,1 años. Un 40,4% de los pacientes estaban diagnosticados de artritis reumatoide. Los acontecimientos adversos más frecuentes eran las infecciones e infestaciones. Conclusiones: La fase iii de BIOBADASER se ha puesto en marcha para responder a un entorno farmacológico cambiante con la aparición de los biosimilares y las pequeñas moléculas en el tratamiento de la patología reumática. Esta nueva etapa se adapta a los cambios normativos en la comunicación de acontecimientos adversos y amplía la información recogida incluyendo los índices de actividad


Objective: Describe the objectives, methods and results of the first year of the new version of the Spanish registry of adverse events involving biological therapies and synthetic drugs with an identifiable target in rheumatic diseases (BIOBADASER III). Methodology: Multicenter prospective registry of patients with rheumatic inflammatory diseases being treated with biological drugs or synthetic drugs with an identifiable target in rheumatology departments in Spain. The main objective of BIOBADASER Phase III is the registry and analysis of adverse events; moreover, a secondary objective was added consisting of assessing the effectiveness by means of the registry of activity indexes. Patients in the registry are evaluated at least once every year and whenever they experience an adverse event or a change in treatment. The collection of data for phase iii began on 17 December 2015. Results: During the first year, 35 centers participated. The number of patients included in this new phase in December 2016 was 2,664. The mean age was 53.7 years and the median duration of treatment was 8.1 years. In all, 40.4% of the patients were diagnosed with rheumatoid arthritis. The most frequent adverse events were infections and infestations. Conclusions: BIOBADASER Phase III has been launched to adapt to a changing pharmacological environment, with the introduction of biosimilars and small molecules in the treatment of rheumatic diseases. This new stage is adapted to the changes in the reporting of adverse events and now includes information related to activity scores


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Sistemas de Notificação de Reações Adversas a Medicamentos/organização & administração , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Terapia Biológica/efeitos adversos , Doenças Reumáticas/tratamento farmacológico , Antirreumáticos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Medicamentos Sintéticos/efeitos adversos
7.
Gastroenterology ; 157(5): 1279-1292.e11, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31326413

RESUMO

BACKGROUND & AIMS: Altered interactions between the mucosal immune system and intestinal microbiota contribute to pathogenesis of inflammatory bowel diseases (IBD). It is not clear how inhibitors of cytokines, such as antagonists of tumor necrosis factor (anti-TNF), affect the intestinal microbiome. We investigated the effects of anti-TNF agents on gut microbe community structure and function in a longitudinal 2-step study of patients with IBD. We correlated our findings with outcomes of treatment and investigated patterns of metabolites in fecal samples before and after anti-TNF therapy. METHODS: We performed a prospective study of 2 cohorts of patients in Germany; the discovery cohort comprised 12 patients with IBD, 17 patients with rheumatic disease, and 19 healthy individuals (controls); fecal samples were collected at baseline and 2, 6, and 30 weeks after induction of anti-TNF therapy. The validation cohort comprised 23 patients with IBD treated with anti-TNF or vedolizumab (anti-α4ß7 integrin) and 99 healthy controls; fecal samples were collected at baseline and at weeks 2, 6, and 14. Fecal microbiota were analyzed by V3-V4 16S ribosomal RNA gene amplicon sequencing. Clinical response and remission were determined by clinical disease activity scores. Metabolic network reconstruction and associated fecal metabolite level inference was performed in silico using the AGORA (Assembly of Gut Organisms through Reconstruction and Analysis) resource. Metabolomic analyses of fecal samples from a subset of patients were performed to validate metabolites associated with treatment outcomes. RESULTS: Anti-TNF therapy shifted the diversity of fecal microbiota in patients with IBD, but not with rheumatic disease, toward that of controls. Across timepoints, diversity indices did not vary significantly between patients with IBD who did or did not achieve clinical remission after therapy. In contrast, in silico modeling of metabolic interactions between gut microbes found metabolite exchange to be significantly reduced at baseline in fecal samples from patients with IBD and to be associated with later clinical remission. Predicted levels of butyrate and substrates involved in butyrate synthesis (ethanol or acetaldehyde) were significantly associated with clinical remission following anti-TNF therapy, verified by fecal metabolomic analyses. CONCLUSIONS: Metabolic network reconstruction and assessment of metabolic profiles of fecal samples might be used to identify patients with IBD likely to achieve clinical remission following anti-TNF therapy and increase our understanding of the heterogeneity of IBD.


Assuntos
Antirreumáticos/uso terapêutico , Bactérias/metabolismo , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/tratamento farmacológico , Intestinos/efeitos dos fármacos , Doenças Reumáticas/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antirreumáticos/efeitos adversos , Bactérias/genética , Estudos de Casos e Controles , Fezes/microbiologia , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Intestinos/imunologia , Intestinos/microbiologia , Metabolômica , Seleção de Pacientes , Valor Preditivo dos Testes , Estudos Prospectivos , Indução de Remissão , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/imunologia , Doenças Reumáticas/microbiologia , Ribotipagem , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
8.
JAMA ; 322(4): 315-325, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31334793

RESUMO

Importance: Patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy need treatment options. Objective: To evaluate the effects of filgotinib vs placebo on the signs and symptoms of RA in a treatment-refractory population. Design, Setting, and Participants: A 24-week, randomized, placebo-controlled, multinational phase 3 trial conducted from July 2016 to June 2018 at 114 sites internationally, randomizing 449 adult patients (and treating 448) with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs. Interventions: Filgotinib, 200 mg (n = 148); filgotinib, 100 mg (n = 153); or placebo (n = 148) once daily; patients continued concomitant stable conventional synthetic DMARDs (csDMARDs). Main Outcomes and Measures: The primary end point was the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary outcomes included week 12 assessments of low disease activity (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] ≤3.2) and change in Health Assessment Questionnaire-Disability Index, 36-Item Short-Form Health Survey Physical Component, and Functional Assessment of Chronic Illness Therapy-Fatigue scores, as well as week 24 assessment of remission (DAS28-CRP <2.6) and adverse events. Results: Among 448 patients who were treated (mean [SD] age, 56 [12] years; 360 women [80.4%]; mean [SD] DAS28-CRP score, 5.9 [0.96]; 105 [23.4%] with ≥3 prior bDMARDs), 381 (85%) completed the study. At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P < .001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%-65.0%] for filgotinib, 100 mg; both P < .001). The most common adverse events were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths. Conclusions and Relevance: Among patients with active RA who had an inadequate response or intolerance to 1 or more bDMARDs, filgotinib, 100 mg daily or 200 mg daily, compared with placebo resulted in a significantly greater proportion achieving a clinical response at week 12. However, further research is needed to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02873936.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Idoso , Antirreumáticos/efeitos adversos , Biomarcadores/sangue , Proteína C-Reativa/análise , Relação Dose-Resposta a Droga , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Testes Hematológicos , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Indução de Remissão , Índice de Gravidade de Doença , Triazóis/administração & dosagem , Triazóis/efeitos adversos
9.
Drugs Aging ; 36(9): 853-862, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31292906

RESUMO

BACKGROUND: Elderly individuals are disproportionately affected by rheumatoid arthritis (RA), but few studies have addressed the efficacy and safety of treatments in this population. OBJECTIVE: Our objective was to assess the efficacy and safety of etanercept in elderly patients (aged ≥ 65 years) with RA. METHODS: The efficacy analysis was a post hoc analysis of data from the open-label period of three phase IV clinical trials of etanercept for RA. Least squares (LS) change from baseline (cfb) in 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and modified Total Sharp Scores (mTSS) were analyzed by age (< 65 vs. ≥ 65 years) for each study. The safety analyses were of data pooled from the double-blind, placebo-controlled periods of 19 phase I-IV randomized studies of etanercept in patients with RA. The percentage occurrence of adverse events (AEs) in placebo- and etanercept-treated patients was analyzed by age (< 65 vs. ≥ 65 years). RESULTS: There were no significant differences in LS mean cfb in DAS28 or mTSS between the two age groups. LS mean cfb in HAQ-DI scores was consistently lower in elderly than in non-elderly patients, although significant differences were not observed in all trials. Overall, AE occurrence was higher in elderly than non-elderly patients, regardless of treatment. In etanercept-treated patients, there were small yet statistically significant increases in the occurrence of congestive heart failure, serious infections, and non-melanoma skin cancers in elderly versus non-elderly patients. For most AEs, occurrence did not significantly differ between elderly and non-elderly patients. CONCLUSION: Overall, there were no substantial differences in the efficacy or safety of etanercept between elderly and non-elderly patients with RA.


Assuntos
Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Etanercepte/efeitos adversos , Etanercepte/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Resultado do Tratamento
10.
Reumatismo ; 71(2): 99-102, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31309782

RESUMO

Anti-tumor necrosis factor drugs are used routinely according to treatment guidelines for several chronic rheumatologic problems. However, a rare and usually unpredictable adverse drug reaction namely peripheral nervous system demyelination is being increasingly recognized. Biosimilars are gaining momentum especially in countries like India. Hence, we report a case of Guillain-Barré syndrome secondary to an etanercept biosimilar, probably the first case reported so far.


Assuntos
Antirreumáticos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Etanercepte/efeitos adversos , Síndrome de Guillain-Barré/induzido quimicamente , Humanos , Masculino , Adulto Jovem
12.
Expert Opin Investig Drugs ; 28(7): 573-581, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31208237

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease, which affects joints and extra-articular structures. Nowadays, the armamentarium of therapeutic options is progressively expanding and embraces several mechanisms of action: TNF inhibition, B-cell depletion, T-cell co-stimulation inhibition, IL-6 blockade, and JAK-inhibition. Granulocyte-Monocyte-Colony-Stimulating-Factor (GM-CSF) is a mediator acting as a cytokine with a proven pathogenetic role in RA, providing a potential alternative target for the management of the disease. Mavrilimumab is a monoclonal antibody against GM-CSF receptor, which has been successfully tested in RA patients. Areas covered: Beginning with a description of the preclinical evidence and the rationale for GM-CSF blockade in RA, this review will provide a wide overview of mavrilimumab efficacy and safety profile by analyzing phase I/II RCTs conducted in patients with moderate to severe RA. Expert opinion: According to the promising results from phase I-II RCTs, mavrilimumab could be considered as an additional therapeutic option for RA patients multi-resistant to the available targeted drugs. However, the optimal dose and the profile of this new drug should be confirmed in phase III RCTs before the marketing.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Artrite Reumatoide/fisiopatologia , Resistência a Medicamentos , Humanos , Terapia de Alvo Molecular , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Índice de Gravidade de Doença
13.
Lupus ; 28(8): 1017-1020, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31166865

RESUMO

Hydroxychloroquine (HCQ) has been used to treat systemic lupus erythematosus (SLE) in Japan since 2015. We herein report a case of SLE that developed generalized pustular psoriasis (GPP) following the administration of HCQ. Twenty-one days after the HCQ treatment, a pustular rash with itching appeared on the auricle, scalp, and forearm, and spread rapidly to the face and body trunk with a high fever and arthralgia. Skin biopsy showed pustule formation under the cornified layer, neutrophil infiltration, the destruction of keratinocytes, and spongiform pustules of Kogoj. The patient was diagnosed with GPP. HCQ was immediately discontinued, the dose of prednisolone (PSL) was increased, and granulocyte and monocyte adsorption apheresis was performed. Her symptoms subsequently disappeared. Since arthralgia relapsed after the tapering of PSL, cyclosporine was added. Although single nucleotide polymorphisms (c.28C>T and c.115+6T>C) in the interleukin (IL)-36RN gene, which encodes the IL-36 receptor antagonist, have frequently been reported in GPP, these mutations were not observed in the present case. The potential development of GPP needs to be considered when administering HCQ to patients with SLE.


Assuntos
Antirreumáticos/efeitos adversos , Hidroxicloroquina/efeitos adversos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Psoríase/induzido quimicamente , Adulto , Antirreumáticos/uso terapêutico , Artralgia/tratamento farmacológico , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Japão , Leucaférese
14.
BMJ Case Rep ; 12(5)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31154348

RESUMO

Methotrexate (MTX) was originally formulated as one of the first antitumour drugs due to its ability to alter folate metabolism, which renders it to be an antiproliferative agent. Classically, the higher dosage is administered via parenteral route, in a cyclical fashion, to achieve antitumour effects. Patients on high doses of MTX are prone to develop rare complications of myelosuppression and pancytopenia, in a dose-dependent fashion, secondary to altered folate metabolism. 1 Herein, we present a unique case of rheumatoid arthritis presented with pancytopenia due to low-dose MTX and doxycycline drug interaction. We also report the successful management of pancytopenia and oral ulcers with combination therapy of leucovorin and granulocyte colony-stimulating factor.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico , Doxiciclina/uso terapêutico , Metotrexato/uso terapêutico , Pancitopenia/diagnóstico , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Diagnóstico Diferencial , Doxiciclina/administração & dosagem , Doxiciclina/efeitos adversos , Quimioterapia Combinada , Humanos , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Pancitopenia/induzido quimicamente
15.
Int Immunopharmacol ; 73: 389-394, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31151076

RESUMO

BACKGROUND: There is no mainstay protocol for management of Methotrexate-induced oral ulcers; commonly used protocols are cessation of Methotrexate, folic acid treatment, corticosteroids or combination. A new era of oral ulcers management is represented by platelet concentrates. The current study assessed the effect of topical human platelet lysate compared to topical Clobetasol Propionate in management of methotrexate-induced oral ulceration in rheumatoid arthritis patients. METHODS: This randomized controlled clinical trial include 30 patients in two parallel groups (intervention - human platelet lysate, control - Clobetasol Propionate), with allocation ratio 1:1. Outcome measures were pain intensity using numerical rating scale, WHO scale for oral mucositis, measuring size of the largest ulcer and total number of oral ulcers. RESULTS: A statistically significant difference was detected between HPL and Clobetasol groups on comparing numerical rating scale, WHO mucositis scale, size and total number of oral ulcers throughout all visits. A considerable quick pain reduction and clinical improvement were noticed in HPL group compared to Clobetasol. CONCLUSION: Human platelet lysate has superior effect when compared to one of the most potent topical corticosteroids, Clobetasol Propionate, in reducing pain and clinical signs of Methotrexate-induced oral ulcers in patients with rheumatoid arthritis.


Assuntos
Antirreumáticos/efeitos adversos , Plaquetas , Metotrexato/efeitos adversos , Úlceras Orais/induzido quimicamente , Úlceras Orais/terapia , Administração Tópica , Adulto , Artrite Reumatoide/tratamento farmacológico , Clobetasol/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Pessoa de Meia-Idade
16.
Clin Exp Rheumatol ; 37(6): 1003-1009, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31172925

RESUMO

OBJECTIVES: The MARI study investigated the prescription patterns of methotrexate (MTX) in patients presenting with rheumatoid arthritis (RA) in Italy. The primary aims of this cross-sectional analysis from the MARI study were to investigate the effect of gender on the prescription patterns and safety of MTX therapy. METHODS: The study enrolled 1336 patients with RA. Retrospective data included patients' clinical history, previous treatment with MTX and other DMARDs, and MTX modifications in the previous 12-month period. Cross-sectional data included information about current treatment with MTX (dose and route of administration, and adverse events), concomitant medications, disease activity, and modifications of MTX treatment at study entry. The prescription patterns of MTX, rates and causes of MTX modifications were analysed according to gender. RESULTS: There were no significant differences related to gender in the prescription patterns of MTX, either at 6 months after starting MTX or at the time of study entry. In the 12 months prior to study entry, women (4%) were more likely to undergo MTX modifications (dose or route of administration) compared to men (2%, p=0.032), due to subjective intolerance, but this difference was no longer significant after controlling for confounders. At study entry, a higher proportion of women (27%) reported tolerability issues (nausea and weakness) related to MTX compared to men (14%, p=0.001). Although a similar percentage of males and females changed dose or route of administration of MTX at the time of study entry, the reasons for such modifications were dissimilar between genders. Particularly, a higher proportion of women underwent MTX modification due to intolerance (women 6% vs. men 1%, p=0.002). CONCLUSIONS: In Italy, prescription patterns of MTX do not differ between genders. However, women seem to be at higher risk of adverse events leading to MTX modifications.


Assuntos
Antirreumáticos , Artrite Reumatoide , Metotrexato/administração & dosagem , Padrões de Prática Médica , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Atitude , Estudos Transversais , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Feminino , Humanos , Itália , Masculino , Metotrexato/efeitos adversos , Estudos Retrospectivos , Fatores Sexuais , Resultado do Tratamento
17.
J Med Case Rep ; 13(1): 196, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31242930

RESUMO

BACKGROUND: Methotrexate, an immunosuppressant, is widely used as the standard therapeutic drug for rheumatoid arthritis. With the increasing frequency of use of methotrexate, adverse effects of methotrexate have been reported, one of which is known as methotrexate-associated lymphoproliferative disorders. The etiology of hepatic methotrexate-associated lymphoproliferative disorders remains largely unknown. To date, there have only been ten cases of hepatic methotrexate-associated lymphoproliferative disorders reported in the English literature and a case report is very rare. CASE PRESENTATION: An 82-year-old Japanese man with rheumatoid arthritis treated with methotrexate presented with fever. Contrast-enhanced computed tomography showed multiple hypovascular nodules in his liver, spleen, and lung, and para-aortic lesions. Endoscopic ultrasound-guided fine-needle aspiration biopsy for liver tumors was performed, and pathological results identified cluster of differentiation 20-positive lymphocytes. Discontinuance of methotrexate led to regression of the nodules and a final definitive diagnosis of methotrexate-associated lymphoproliferative disorders was made. CONCLUSIONS: We review 11 reported cases of hepatic methotrexate-associated lymphoproliferative disorders including the present case. Physicians should discontinue methotrexate in patients with rheumatoid arthritis treated with methotrexate when elevated soluble interleukin-2 receptor and hypovascular lesions in contrast-enhanced computed tomography are confirmed considering the possibility of methotrexate-associated lymphoproliferative disorders.


Assuntos
Antirreumáticos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Transtornos Linfoproliferativos/induzido quimicamente , Transtornos Linfoproliferativos/diagnóstico , Metotrexato/efeitos adversos , Idoso de 80 Anos ou mais , Artrite Reumatoide/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico por imagem , Humanos , Masculino
18.
Behav Processes ; 165: 66-77, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181266

RESUMO

Behavioral economics has been consistently useful in describing a wide range of clinical phenomena, particularly in reference to behavioral excesses such as substance abuse, problematic gambling and obesity/overeating. Given an opportunity to explore these processes as they relate to treatment adherence in patients with multiple sclerosis (MS), our central thesis was that behavioral economic tools/processes that have been helpful in other areas of application (e.g., substance abuse, obesity) could be leveraged to help understand treatment non-adherence and hopefully lead to efforts to combat it. The current paper tells a story of how an interdisciplinary set of researchers came to combine their separate expertise in MS and behavioral economics to yield novel insights into the failures of treatment adherence often experienced in this clinical population.


Assuntos
Antirreumáticos/uso terapêutico , Comportamento de Escolha , Economia Comportamental , Adesão à Medicação , Esclerose Múltipla/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto , Antirreumáticos/efeitos adversos , Aconselhamento , Feminino , Humanos , Comunicação Interdisciplinar , Colaboração Intersetorial , Masculino , Esclerose Múltipla/psicologia , Pesquisa , Telefone , Resultado do Tratamento
19.
Int J Rheum Dis ; 22(8): 1572-1577, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31245906

RESUMO

AIM: Methotrexate (MTX) is the anchor drug for the treatment of rheumatoid arthritis (RA). MTX is associated with adverse events that limit its use. The MTX intolerance severity score (MISS) was developed to identify symptoms related to MTX use in juvenile idiopathic arthritis and RA patients. The aim of this study is to translate and validate the MISS in the Arabic language. METHODS: Forward and backward translation of the MISS were performed by two fluent Arabic translators and reviewed by three rheumatologists. Consecutive patients with RA who used MTX for ≥3 months were recruited from two tertiary care centers in Riyadh, Saudi Arabia. A test was considered positive if the patient scored ≥6 points. The internal consistency and stability of the items were evaluated using Cronbach's alpha and the test-retest method. RESULTS: A total of 185 patients were recruited. Of those patients, 158 (85.4%) were female. The mean (±SD) age and disease duration were 49.7 (±12.67) and 8.67 (±7.1) years, respectively. The mean Disease Activity Score of 28 joints was 3.2 (±1.3). Fifty-five (30%) patients were illiterate. Seventy-three (39.5%) patients had a positive MISS. Of those patients, 55 (75.3%) and 18 (24.7%) were using the oral and subcutaneous forms of MTX, respectively. The Arabic MISS had good internal consistency (Cronbach's alpha = 0.792) and a factorable study size for test-retest and factor analysis (Kaiser-Meyer-Olkin = 0.745). CONCLUSION: The Arabic MISS showed validity and good reliability in detecting MTX intolerance in RA patients. MTX intolerance is prevalent among RA patients. Larger studies are needed to confirm these findings.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Metotrexato/efeitos adversos , Inquéritos e Questionários , Tradução , Adulto , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/epidemiologia , Estudos Transversais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Reprodutibilidade dos Testes , Arábia Saudita/epidemiologia
20.
Turk J Ophthalmol ; 49(3): 149-153, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31245977

RESUMO

Objectives: To determine length of hydroxychloroquine use and cumulative dose and evaluate the ocular effects by 10-2 central visual field test, microperimetry (MP), color fundus photography, optical coherence tomography (OCT), and fundus autofluorescence (FAF) in hydroxychloroquine users. Materials and Methods: Patients who used hydroxychloroquine continuously for at least 2 years for various connective tissue diseases were included in the study. A total of 300 eyes of 150 patients aged 19-78 years who were followed due to risk of developing hydroxychloroquine maculopathy in the Istanbul University Istanbul Faculty of Medicine Ophthalmology Department between the years 1995-2017 were evaluated. Best corrected visual acuity (BCVA), biomicroscopic, and fundoscopic examination were performed at all visits. MP, FAF, OCT, fundus photography, and central 10-2 visual field examinations were performed 3 times at 6-month intervals. Results: The mean age of patients was 48.9±10.8 years; 141 (94%) patients were female and 9 (6%) were male. The mean duration of hydroxychloroquine use was 10.5±6.4 (2-30) years. Fifty-six patients had been using the drug for 5 years or less. The mean cumulative drug dose was 754.7±447.2 (146-1825) g. Mean BCVA was 0.02±0.08 LogMAR at all follow-up visits (p=0.999). Mean MP values at the first, second, and third examinations were 14.07±3.24 dB, 14.18±3.35 dB, and 14.54±2.79 dB, respectively (p>0.05). Mean central macular thickness was 221.9±19.8 µm at initial examination, 221.8±19.9 µm at the second visit, and 221.8±19.8 µm at the final visit (p=0.113). There was a weak negative correlation between age and MP values at all three visits (visit 1: p=0.003, r=- 0.170; visit 2: p=0.001, r=-0.185, visit 3: p=0.011, r=-0.146). There was statistically significant relationship between MP values and hydroxychloroquine length of use and cumulative dose (p=0.027 and p=0.049, respectively). Duration of use was not associated with changes in 10/2 visual field (p=0.124). There were significant relationships between alterations in FAF and hydroxychloroquine length of use and cumulative dose (p=0.027 and p=0.049, respectively). Conclusion: FAF alterations were significantly associated with duration of hydroxychloroquine use and cumulative dose. As objective methods are more reliable, examinations such as FAF can be recommended as auxiliary methods in the follow-up and early detection of toxic maculopathy.


Assuntos
Hidroxicloroquina/efeitos adversos , Macula Lutea/patologia , Doenças Retinianas/induzido quimicamente , Acuidade Visual , Adulto , Idoso , Antirreumáticos/efeitos adversos , Doenças do Tecido Conjuntivo/tratamento farmacológico , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Incidência , Macula Lutea/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/diagnóstico , Doenças Retinianas/epidemiologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Turquia/epidemiologia , Campos Visuais/fisiologia , Adulto Jovem
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