Complications of Immunosuppression for Eye Diseases

描述（由申请人提供）：在美国，眼部炎症性疾病是视力丧失的主要原因，发生在相对较早的年龄。免疫抑制是重症病例的主要治疗方法。在一项多中心回顾性队列研究中，我们将截至2005年（含）的7，957例眼部炎症患者与国家死亡指数（NDI）联系起来，在66，902人-年的死亡率随访中发现936例死亡。主要发现包括：1）提示肿瘤坏死因子（TNF）抑制剂治疗显著增加总体和癌症死亡率; 2）抗代谢药、T细胞抑制剂或全身皮质类固醇治疗没有增加总体和癌症死亡率的风险;和3）总体和癌症死亡风险与一般人群非常相似（提示炎症性眼病患者可能是一个治疗适应症不会使治疗使用与死亡率或癌症之间关系的研究产生偏倚的群体）。在美国，数百万人使用TNF抑制剂治疗一系列炎症性疾病。我们建议将研究延长5年，以便：1）验证初步结果：TNF抑制剂治疗的总体和癌症死亡风险; 2）评估癌症发病率（致死性和非致死性）所有四种主要类别的免疫抑制剂; 3）将解释时间依赖性混杂的统计方法推广到配对器官设置，允许使用观察性眼科数据进行更有效的治疗效果分析;以及，4）应用这些方法来评估替代免疫抑制药物的相对（成本）有效性。我们将在最初的五个中心将队列规模增加约35%;随访时间和观察到的死亡人数将增加近一倍。在辅助中心以TNF-α为重点的入组将提高目标1的统计学把握度。我们将把扩大后的数据库与NDI和国家癌症登记处联系起来，由一名新的合作研究者成功完成了一项类似的多癌症登记研究。生物统计学方法学家将把处理时间依赖性混杂的方法推广到配对器官环境，沿着经验丰富的健康经济学家应用这些方法，直接比较眼部炎症替代免疫抑制药物的成本和有效性。 公共卫生相关性：研究的药物被数百万人使用;对它们对死亡率和癌症影响的有力估计将深刻影响风险效益比，广泛影响眼部和全身免疫性疾病的管理。评估替代免疫抑制剂治疗眼部炎症的相对（成本）效果将大大提高可用于指导合理临床管理的证据质量。

DESCRIPTION (provided by applicant): Ocular inflammatory diseases are major causes of vision loss in the United States, at a relatively early age. Immunosuppression is a primary therapeutic approach for severe cases. In a, a multicenter retrospective cohort study, we linked 7,957 ocular inflammation patients seen by 2005 inclusive to the National Death Index (NDI), finding 936 deaths over 66,902 person-years of follow-up for mortality. Primary findings included: 1) a suggestion of substantially increased overall and cancer mortality with Tumor Necrosis Factor (TNF) inhibitor therapy; 2) no increased risk of overall and cancer mortality with antimetabolite, T-cell inhibitor, or systemic corticosteroid therapy; and 3) overall and cancer mortality risk very similar the general population (suggesting that inflammatory eye diseases patients may be a group in which the indications-for- treatment will not bias study of the relationship between treatment use and mortality or cancer). Millions of individuals in the United States use TNF inhibitors for a range of inflammatory diseases. We propose to extend the study for five years in order to: 1) validate preliminary findings re: overall and cancer mortality risk with TNF inhibitor therapy; 2) evaluate cancer incidence (fatal and non-fatal) for all four major classes of immunosuppressive agents; 3) generalize statistical methodology accounting for time- dependent confounding to the paired organ setting, to allow more valid analyses of treatment effects using observational ophthalmic data; and, 4) apply these methods to evaluate the relative (cost-) effectiveness of alternative immunosuppressive drugs. We will increase the cohort size by ~35% at the five original centers; the follow-up time and number of deaths observed will nearly double. TNF inhibitor-focused enrollment at ancillary centers will enhance statistical power for aim #1. We will link the enlarged database to the NDI and state cancer registries, with a new co-investigator who successfully completed a similar multiple cancer registry study. A biostatistical methodologist will generalize methods for dealing with time-dependent confounding to the paired organ setting, applying these methods along with a seasoned health economist to directly compare the costs and effectiveness of alternative immunosuppresive drugs for ocular inflammation. PUBLIC HEALTH RELEVANCE: The drugs studied are used by millions; well-powered estimates of their impact on mortality and cancer will affect risk-benefit ratios profoundly, widely influencing management of eye and systemic diseases of immunity. Estimation of the relative (cost-) effectiveness of alternative immunosuppressants for ocular inflammation will greatly increase the quality of evidence available to guide rational clinical management.