Assessing Safety Biologic Disease Modifying Drugs Rheumatoid Arthritis Patients

类风湿性关节炎患者服用生物修饰抗风湿药物的安全性评价 与普通人群相比，类风湿性关节炎(RA)患者的预期寿命较短，他们患严重感染、早期心血管疾病、胰岛素抵抗和淋巴增殖性肿瘤的风险增加。目前对RA的治疗主要基于抗风湿药物(DMARDS)，包括新型生物拮抗剂肿瘤坏死因子α(TNFa)和白介素1(IL-1)。通过阻断关键的炎症介质，这些药物控制RA的活动；然而，这些相同的机制也可能损害免疫反应，使患者更容易受到感染性因素或异常细胞增殖的影响。生物DMARDS治疗是否会增加RA患者发生严重感染和肿瘤的风险仍然存在争议。 已经对TNFa拮抗剂用于治疗非风湿性疾病患者的充血性心力衰竭进行了评估。没有显示出益处，矛盾的是，高剂量的这些DMARDS对一些患者是有害的。然而，生物性DMARDS对无充血性心力衰竭的RA患者的心脏影响仍不清楚。 RA增加了冠心病的风险，而传统的风险因素并不能完全解释这一点。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心血管疾病的风险，但特定的DMARD对心肌梗死风险的影响尚不清楚。 慢性炎症还与代谢综合征和胰岛素抵抗有关，后者是动脉粥样硬化的已知危险因素，在RA患者中高度流行。糖皮质激素治疗矛盾地改善了RA患者的胰岛素敏感性，提示炎症和胰岛素抵抗可能是密切相关的。此外，IL-1受体拮抗剂Anakinra的效果也有所改善 糖尿病患者的血糖控制和英夫利昔单抗改善了RA患者的胰岛素抵抗。 这一益处是否延伸到其他DMARD，或者DMARD治疗是否可以延缓RA患者的糖尿病发作，目前尚不清楚。 为了评估生物DMARDS在RA患者中的安全性，我们提出了一系列有三个特定目标的研究：1)检验与传统DMARD相比，使用生物DMARDS会增加严重感染风险的假设。2)验证使用生物DMARDS较传统DMARDS增加淋巴增生性肿瘤风险的假设。3)验证与传统DMARDS相比，使用生物DMARDS会增加充血性心力衰竭的风险，降低心肌梗死和糖尿病的风险的假设。

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.