Assessing Safety Biologic Disease Modifying Drugs Rheumatoid Arthritis Patients

评估类风湿性关节炎患者生物疾病修饰药物的安全性

• 批准号: 8327308
• 负责人: MARIE R. GRIFFIN
• 金额: $ 19.79万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327308
• 关键词: Abnormal Cell; Address; Affect; Antirheumatic Agents; Atherosclerosis; Benefits and Risks; Cardiac; Cardiovascular Diseases; Caring; Cell Proliferation; Chronic; Clinical Research; Clinical Trials; Congestive Heart Failure; Coronary heart disease; Data; Databases; Diabetes Mellitus; Disease; Disease-Modifying Second-Line Drugs; Dose; Drug Controls; Drug Kinetics; Effectiveness; Epidemiologic Studies; Evaluation; General Population; Glucocorticoids; Health Personnel; Immune response; Infection; Infectious Agent; Inflammation; Inflammation Mediators; Insulin Resistance; Interleukin-1; Life Expectancy; Metabolic syndrome; Myocardial Infarction; Neoplasms; Observational Study; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Pilot Projects; Play; Population; Property; Rheumatism; Rheumatoid Arthritis; Risk; Risk Factors; Role; Safety; Selection Bias; Testing; Therapeutic; Tumor Necrosis Factor-alpha; Veterans; anakinra; base; blood glucose regulation; cardiovascular disorder risk; improved; infliximab; insulin sensitivity; multidisciplinary; novel

Assessing the Safety of Biologic Disease Modifying Anti-Rheumatic Drugs in Patients with Rheumatoid Arthritis Patients with rheumatoid arthritis (RA) have shorter life expectancy compared to the general population and they are at increased risk for serious infections, early cardiovascular disease, insulin resistance and lymphoproliferative neoplasias. Current treatment of RA is based on disease modifying antirheumatic drugs (DMARDs), including novel biologic antagonists of tumor necrosis factor alpha (TNFa) and interleukin 1 (IL-1). Through the blockade of key inflammatory mediators, these drugs control RA activity; however, these same mechanisms could also impair immune responses, rendering patients more susceptible to infectious agents or abnormal cell proliferation. Whether or not therapy with biologic DMARDs increases the risk of serious infections and neoplasias among patients with RA remains controversial. TNFa antagonists have been evaluated for the treatment of congestive heart failure in patients without rheumatic diseases. No benefits were shown and paradoxically, high doses of these DMARDs were deleterious in some patients. Nevertheless, the cardiac effects of biologic DMARDs in patients with RA but without preexisting congestive heart failure remain unclear. RA imparts an increased risk for coronary heart disease that is not fully explained by traditional risk factors. Chronic inflammation is postulated to play an integral role in the pathogenesis of this accelerated atherosclerosis. Although previous studies suggested that DMARD therapy could reduce the risk of cardiovascular disease in RA, the effect of specific DMARDs on the risk of myocardial infarction is unknown. Chronic inflammation is also associated with the metabolic syndrome and insulin resistance, known risk factors for atherosclerosis and highly prevalent conditions among patients with RA. Glucocorticoid therapy paradoxically improved insulin sensitivity in patients with RA, suggesting that inflammation and insulin resistance may be closely related. Furthermore, anakinra, the IL-1 receptor antagonist, improved glucose control in patients with diabetes, and infliximab improved insulin resistance in patients with RA. Whether this benefit extends to other DMARDs or whether DMARD therapy can delay the onset of diabetes in patients with RA is currently unknown. To evaluate the safety of biologic DMARDs in patients with RA, we propose a sequence of studies with three specific aims: 1) To test the hypothesis that use of biologic DMARDs increases the risk of serious infections compared with traditional DMARDs. 2) To test the hypothesis that use of biologic DMARDs increases the risk of developing lymphoproliferative neoplasias compared with traditional DMARDs. 3) To test the hypothesis that use of biologic DMARDs increases the risk of congestive heart failure and decreases the risk of myocardial infarction and diabetes compared with traditional DMARDs.

类风湿性关节炎患者应用生物性疾病缓解类风湿药物的安全性评价 类风湿性关节炎（RA）患者的预期寿命较短，与一般人群相比，他们的严重感染，早期心血管疾病，胰岛素抵抗和淋巴增生性肿瘤的风险增加。目前RA的治疗是基于疾病缓解抗风湿药物（DMARD），包括肿瘤坏死因子α（TNF α）和白细胞介素1（IL-1）的新型生物拮抗剂。通过阻断关键炎症介质，这些药物控制RA活性;然而，这些相同的机制也可能损害免疫反应，使患者更容易感染病原体或异常细胞增殖。生物DMARD治疗是否会增加RA患者发生严重感染和肿瘤的风险仍存在争议。 已经评估了TNF α拮抗剂用于治疗无风湿性疾病的患者的充血性心力衰竭。没有显示出任何益处，矛盾的是，高剂量的这些DMARD对某些患者是有害的。然而，生物DMARD对RA患者心脏的影响，但没有预先存在的充血性心力衰竭仍不清楚。 RA增加了患冠心病的风险，传统危险因素无法完全解释这一点。慢性炎症被认为在这种加速的动脉粥样硬化的发病机制中起着不可或缺的作用。尽管先前的研究表明DMARD治疗可以降低RA患者心血管疾病的风险，但特定DMARD对心肌梗死风险的影响尚不清楚。 慢性炎症也与代谢综合征和胰岛素抵抗相关，这是动脉粥样硬化的已知危险因素，也是RA患者中非常普遍的疾病。糖皮质激素治疗反而改善了类风湿关节炎患者的胰岛素敏感性，提示炎症和胰岛素抵抗可能密切相关。此外，阿那白滞素，IL-1受体拮抗剂，改善 糖尿病患者的血糖控制，英夫利西单抗改善RA患者的胰岛素抵抗。 这种益处是否扩展到其他DMARD或DMARD治疗是否可以延迟RA患者的糖尿病发作目前尚不清楚。 为了评价生物制剂DMARDs在RA患者中的安全性，我们提出了一系列具有三个特定目的的研究：1）检验与传统DMARDs相比，使用生物制剂DMARDs会增加严重感染风险的假设。2)检验与传统DMARD相比，使用生物DMARD会增加淋巴增生性肿瘤发生风险的假设。3)检验与传统DMARD相比，使用生物DMARD会增加充血性心力衰竭的风险并降低心肌梗死和糖尿病的风险的假设。