Complications of Immunosuppression for Eye Diseases

描述（由申请人提供）：在美国，眼部炎症性疾病是导致视力丧失的主要原因，发病年龄相对较早。免疫抑制是严重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2005年之前发现的7,957例眼部炎症患者与国家死亡指数（NDI）联系起来，在66902人-年的死亡率随访中发现936例死亡。主要发现包括：1)肿瘤坏死因子（TNF）抑制剂治疗显著提高总体死亡率和癌症死亡率；2)抗代谢物、t细胞抑制剂或全身皮质类固醇治疗不会增加总体死亡率和癌症死亡率的风险；3)总体上与癌症死亡率风险非常相似（提示炎症性眼病患者可能是一个治疗适应症不会影响治疗使用与死亡率或癌症关系研究的群体）。在美国，数百万人使用肿瘤坏死因子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TNF抑制剂治疗的总体和癌症死亡率风险的初步发现；2)评估所有四种主要免疫抑制剂的癌症发生率（致死性和非致死性）；3)推广统计方法，考虑配对器官设置的时间相关混淆，以便使用观察性眼科数据对治疗效果进行更有效的分析；4)应用这些方法评价替代免疫抑制药物的相对（成本）效益。我们将在五个原始中心增加约35%的队列规模；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抑制剂为重点的入组将增强目标1的统计效力。我们将把扩大的数据库与NDI和州癌症登记处联系起来，并与一位成功完成了类似的多种癌症登记处研究的新合作研究者联系起来。生物统计方法学家将把处理时间依赖性混淆的方法推广到配对器官设置，并与经验丰富的卫生经济学家一起应用这些方法直接比较治疗眼部炎症的替代免疫抑制药物的成本和效果。

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.