RESUMO
Background: Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred. Objective: To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo. Design: Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333). Setting: North America. Participants: Adults with known cardiovascular disease and diabetes or metabolic syndrome. Intervention: Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week. Measurements: Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication. Results: After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]). Limitation: The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period. Conclusion: Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased. Primary Funding Source: National Institutes of Health.
Assuntos
Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Estudos ProspectivosRESUMO
Osteoarthritis (OA) was once viewed originally as a mechanical disease of "wear and tear," but advances made during the past two decades suggest that abnormal biomechanics contribute to active dysregulation of chondrocyte biology, leading to catabolism of the cartilage matrix. A number of signaling and transcriptional mechanisms have been studied in relation to the regulation of this catabolic program, but how they specifically regulate the initiation or progression of the disease is poorly understood. Here, we demonstrate that cartilage-specific ablation of Nuclear factor of activated T cells c1 (Nfatc1) in Nfatc2(-/-) mice leads to early onset, aggressive OA affecting multiple joints. This model recapitulates features of human OA, including loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and eventual progression to cartilage effacement and joint instability. Consistent with the notion that NFATC1 is an OA-suppressor gene, NFATC1 expression was significantly down-regulated in paired lesional vs. macroscopically normal cartilage samples from OA patients. The highly penetrant, early onset, and severe nature of this model make it an attractive platform for the preclinical development of treatments to alter the course of OA. Furthermore, these findings indicate that NFATs are key suppressors of OA, and regulating NFATs or their transcriptional targets in chondrocytes may lead to novel disease-modifying OA therapies.
Assuntos
Cartilagem Articular/citologia , Condrócitos/metabolismo , Regulação da Expressão Gênica/fisiologia , Fatores de Transcrição NFATC/metabolismo , Osteoartrite/metabolismo , Animais , Cartilagem Articular/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Modelos Biológicos , Fatores de Transcrição NFATC/genética , Reação em Cadeia da Polimerase em Tempo Real , Microtomografia por Raio-XAssuntos
Dermatomiosite/diagnóstico , Músculo Esquelético/patologia , Biópsia , Transtornos de Deglutição/etiologia , Dermatomiosite/complicações , Dermatomiosite/tratamento farmacológico , Diagnóstico Diferencial , Edema/etiologia , Exantema/etiologia , Oftalmopatias/etiologia , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Debilidade Muscular/etiologiaAssuntos
Angioedema/diagnóstico , Dermatomiosite/patologia , Músculo Esquelético/patologia , Biópsia , Transtornos de Deglutição/etiologia , Dermatomiosite/complicações , Diagnóstico Diferencial , Edema/etiologia , Glucocorticoides/uso terapêutico , Humanos , Hipertensão/complicações , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pescoço/patologia , Tireotropina/sangueRESUMO
OBJECTIVE: The pathophysiology of the most common joint disease, osteoarthritis (OA), remains poorly understood. Since synovial fluid (SF) bathes joint cartilage and synovium, we reasoned that a comparative analysis of its protein constituents in health and OA could identify pathways involved in joint damage. We undertook this study to perform a proteomic analysis of knee SF from OA patients and control subjects and to compare the results to microarray expression data from cartilage and synovium. METHODS: Age-matched knee SF samples from 10 control subjects, 10 patients with early-stage OA, and 10 patients with late-stage OA were compared using 2-dimensional difference-in-gel electrophoresis and mass spectrometry (MS). MS with a multiplexed peptide selected reaction monitoring assay was used to confirm differential expression of a subset of proteins in an independent OA patient cohort. Proteomic results were analyzed by Ingenuity Pathways Analysis and compared to published synovial tissue and cartilage messenger RNA profiles. RESULTS: Sixty-six proteins were differentially present in healthy and OA SF. Three major pathways were identified among these proteins: the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway. Differential expression of 5 proteins was confirmed by selected reaction monitoring assay. A focused analysis of transcripts corresponding to the differentially present proteins indicated that both synovial and cartilage tissues may contribute to the OA SF proteome. CONCLUSION: Proteins involved in the acute-phase response signaling pathway, the complement pathway, and the coagulation pathway are differentially regulated in SF from OA patients, suggesting that they contribute to joint damage. Validation of these pathways and their utility as biomarkers or therapeutic targets in OA is warranted.
Assuntos
Cartilagem/metabolismo , Osteoartrite do Joelho/metabolismo , Proteoma/análise , RNA Mensageiro/análise , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/metabolismo , Reação de Fase Aguda/metabolismo , Idoso , Fatores de Coagulação Sanguínea/genética , Fatores de Coagulação Sanguínea/metabolismo , Estudos de Casos e Controles , Proteínas do Sistema Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Eletroforese em Gel Bidimensional , Feminino , Perfilação da Expressão Gênica , Humanos , Articulação do Joelho/metabolismo , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Osteoartrite do Joelho/genética , Líquido Sinovial/químicaRESUMO
OBJECTIVE: Systemic rheumatic conditions affect reproductive-aged patients and often require potentially teratogenic medications. We assessed the feasibility and impact of a standardized pregnancy intention screening question (One Key Question [OKQ]) in a large academic rheumatology practice. METHODS: This 6-month pilot quality improvement initiative prompted rheumatologists to ask female patients aged 18 to 49 years about their pregnancy intentions using OKQ. We administered surveys to assess rheumatologists' barriers to and comfort with reproductive health issues. We performed chart reviews to assess uptake and impact on documentation, comparing charts with OKQ documented with 100 randomly selected charts eligible for pregnancy intention screening but without OKQ documented. RESULTS: When we compared 32 of 43 preimplementation responses with 29 of 41 postimplementation responses, the proportion of rheumatologists who reported they were very comfortable with assessing their patients' reproductive goals increased (31%-38%) and the proportion reporting obstetrics and gynecology (OB/GYN) referral challenges as barriers to discussing reproductive goals decreased (41%-21%). During the implementation period, 83 of 957 (9%) eligible patients had OKQ documented in their chart. Female providers were more likely to screen than male providers (odds ratio 2.42, 95% confidence interval 1.21-4.85). Screened patients were more likely to have their contraceptive method documented (P < 0.001) and more likely to have been referred to OB/GYN for follow-up (P = 0.003) compared with patients who were not screened with OKQ. CONCLUSION: Although uptake was low, this tool improved provider comfort with assessing reproductive goals, the quality of documentation, and the likelihood of OB/GYN referral. Future studies should examine whether automated medical record alerts to prompt screening increase uptake.
RESUMO
OBJECTIVE: Renin-angiotensin system blockade is now standard in the management of the patient with type 2 diabetes mellitus. We aimed to investigate whether high doses of valsartan, an angiotensin receptor blocker, are superior to conventional doses to reduce urinary albumin excretion rates (UAER) in such patients. PATIENTS AND METHODS: Three hundred and ninety-one hypertensive patients with type 2 diabetes mellitus and UAER 20-700 microg/min were randomized to 160, 320 or 640 mg valsartan. All received valsartan 160 mg for the first 4 weeks. Valsartan dose was then increased in two of three groups for 30 weeks. Overnight urine collections at baseline, 4, 16, and 30 weeks in triplicate were used to assess proteinuria. RESULTS: Comparable albuminuria reductions occurred in all groups at week 4 (P<0.001). Subsequently, a highly significant albuminuria fall occurred with valsartan 320 and 640 mg (P<0.001) versus a modest additional change with 160 mg (P=0.03). At week 30, twice as many patients returned to normal albuminuria with valsartan 640 mg versus 160 mg (24 versus 12%; P<0.01). High doses were well tolerated, with no dose-related increases in adverse events, including hypotension and hyperkalemia. CONCLUSION: High doses of valsartan reduced albuminuria more than the more commonly used 160 mg dose, apparently independent of blood pressure. Thus, at least in type 2 diabetes mellitus, higher doses of valsartan are required to optimize tissue protection than for blood pressure control.
Assuntos
Albuminúria/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Tetrazóis/uso terapêutico , Valina/análogos & derivados , Idoso , Albuminúria/complicações , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos , Valina/administração & dosagem , Valina/efeitos adversos , Valina/uso terapêutico , ValsartanaRESUMO
BACKGROUND: The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. DESIGN: CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. SUMMARY: CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.
Assuntos
Antirreumáticos/efeitos adversos , Metotrexato/efeitos adversos , Antirreumáticos/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Ácido Fólico/uso terapêutico , Hematínicos/uso terapêutico , Humanos , Metotrexato/administração & dosagem , Metotrexato/sangue , Polimorfismo de Nucleotídeo Único/genética , Medicina de Precisão , Projetos de Pesquisa , Fatores de RiscoRESUMO
Evidence suggests that renin-angiotensin-aldosterone system inhibition ameliorates endothelial dysfunction. The authors examined the effect of amlodipine besylate/benazepril HCl combination treatment compared with amlodipine besylate monotherapy in modulating endothelial dysfunction. This multicenter, double-blind, 12-week study randomized 70 hypertensive subjects with at least one other endothelial dysfunction risk factor to amlodipine besylate/benazepril HCl (5/20 mg/d force-titrated to 5/40 mg/d) or amlodipine besylate monotherapy (5 mg/d force-titrated to 10 mg/d). Both the combination and monotherapy produced significant median increases from baseline in percentage flow-mediated vasodilation (2.0% and 1.2%, respectively) and percentage change in percent flow-mediated vasodilation (25% and 16%, respectively). These improvements were numerically larger with combination treatment, but between-group differences did not achieve statistical significance. Reductions in systolic and diastolic blood pressure were significantly greater (P=.0452/P=.0297) with combination treatment (-18.6/-12.3 mm Hg) than with monotherapy (-14.8/-9.1 mm Hg). A highly positive correlation between change in systolic blood pressure and change in percent of flow-mediated vasodilation was demonstrated only for combination treatment.
Assuntos
Anlodipino/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Benzazepinas/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Idoso , Anlodipino/efeitos adversos , Análise de Variância , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Benzazepinas/efeitos adversos , Biomarcadores/sangue , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Artéria Braquial/efeitos dos fármacos , Artéria Braquial/fisiopatologia , Bloqueadores dos Canais de Cálcio/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos/epidemiologia , Vasodilatação/efeitos dos fármacosRESUMO
Cartilage acidic protein 1 (CRTAC1) was recently identified as an elevated protein in the synovial fluid of patients with osteoarthritis (OA) by a proteomic analysis. This gene is also upregulated in both human and mouse OA by transcriptomic analysis. The objective of this study was to characterize the expression and function of CRTAC1 in OA. Here, we first confirm the increase of CRTAC1 in cartilage biopsies from OA patients undergoing joint replacement by real-time PCR and immunohistochemistry. Furthermore, we report that proinflammatory cytokines interleukin-1beta and tumor necrosis factor alpha upregulate CRTAC1 expression in primary human articular chondrocytes and synovial fibroblasts. Genetic deletion of Crtac1 in mice significantly inhibited cartilage degradation, osteophyte formation and gait abnormalities of post-traumatic OA in female, but not male, animals undergoing the destabilization of medial meniscus (DMM) surgery. Taken together, CRTAC1 is upregulated in the osteoarthritic joint and directly induced in chondrocytes and synovial fibroblasts by pro-inflammatory cytokines. This molecule is necessary for the progression of OA in female mice after DMM surgery and thus represents a potential therapy for this prevalent disease, especially for women who demonstrate higher rates and more severe OA.
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Artrite Experimental/genética , Artrite Experimental/prevenção & controle , Proteínas de Ligação ao Cálcio/genética , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/prevenção & controle , Animais , Artrite Experimental/fisiopatologia , Desenvolvimento Ósseo/genética , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/fisiologia , Células Cultivadas , Condrócitos/fisiologia , Condrogênese/genética , Citocinas/fisiologia , Feminino , Deleção de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Osteoartrite do Joelho/fisiopatologia , Caracteres Sexuais , Líquido Sinovial/fisiologia , Regulação para CimaRESUMO
INTRODUCTION: Biomarkers to identify osteoarthritis (OA) patients at risk for disease progression are needed. As part of a proteomic analysis of knee synovial fluid from normal and OA patients, differentially expressed proteins were identified that could represent potential biomarkers for OA. This study aimed to use mass spectrometry assays to identify representative peptides from several proteins in synovial fluid and peripheral blood, and assess their levels as biomarkers of OA progression. METHODS: Multiplexed high throughput selected reaction monitoring (SRM) assays were developed to measure tryptic peptides representative of 23 proteins in matched serum and synovial fluid samples from late OA subjects at the time of joint replacement. Subsequently plasma samples from the baseline visit of 173 subjects in an observational OA cohort were tested by SRM for peptides from nine of these proteins: afamin, clusterin, cartilage oligomeric matrix protein, hepatocyte growth factor, kallistatin, insulin-like growth factor binding protein, acid labile subunit, lubricin, lumican, and pigment epithelium-derived factor. Linear regression was used to determine the association between the peptide biomarker level at baseline and change in joint space width (ΔJSW) from baseline to 30 months, adjusting for age and sex. RESULTS: In the matched cohort, 17 proteins could be identified in synovial fluid and 16 proteins were detected in serum. For the progression cohort, the average age was 62 and average ΔJSW over 30 months was 0.68 mm. A high correlation between different peptides from individual proteins was observed, indicating our assays correctly measured their target proteins. Peptides representative of clusterin, lumican and lubricin showed statistically significant associations with joint space narrowing after adjustment for age and sex. Partial R2 values showed clusterin FMETVAEK and lubricin LVEVNPK peptide biomarkers explains about 2 to 3% of the variability of ΔJSW, similar to that explained by age. A biomarker score combining normalized data for both lubricin and clusterin peptides increased the model R2 to 0.079. CONCLUSIONS: Our results suggest that when combined, levels of peptides representative of clusterin and lubricin in plasma are as predictive of OA progression as age. Replication of these findings in other prospective OA cohorts is planned.
Assuntos
Biomarcadores/análise , Espectrometria de Massas/métodos , Osteoartrite do Joelho/diagnóstico por imagem , Proteoma/análise , Proteômica/métodos , Idoso , Sequência de Aminoácidos , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteoglicanas de Sulfatos de Condroitina/análise , Proteoglicanas de Sulfatos de Condroitina/sangue , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Clusterina/análise , Clusterina/sangue , Clusterina/metabolismo , Estudos de Coortes , Progressão da Doença , Feminino , Glicoproteínas/análise , Glicoproteínas/sangue , Glicoproteínas/metabolismo , Humanos , Sulfato de Queratano/análise , Sulfato de Queratano/sangue , Sulfato de Queratano/metabolismo , Modelos Lineares , Lumicana , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/metabolismo , Peptídeos/análise , Prognóstico , Proteoma/metabolismo , Radiografia , Líquido Sinovial/metabolismoRESUMO
Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.