Complications of Immunosuppression for Eye Diseases

描述(申请人提供)：眼部炎症性疾病是美国视力丧失的主要原因，在相对较早的年龄。免疫抑制是重症患者的主要治疗方法。在一项多中心回溯性队列研究中，我们将截至2005年的7957例眼部炎症患者与国家死亡指数(NDI)联系起来，发现在66,902人年的随访中有936人死亡。主要研究结果包括：1)建议大幅增加使用肿瘤坏死因子(TNF)抑制剂治疗的总死亡率和癌症死亡率；2)使用抗代谢药物、T细胞抑制剂或全身糖皮质激素治疗没有增加总死亡率和癌症死亡率；以及3)总体风险和癌症死亡率与普通人群非常相似(表明炎症性眼病患者可能是一组特殊人群，其治疗适应症不会影响对治疗应用与死亡率或癌症之间关系的研究)。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。我们建议将这项研究延长五年，以便：1)验证初步结果：使用肿瘤坏死因子抑制剂治疗的总体和癌症死亡率风险；2)评估所有四种主要免疫抑制剂类别的癌症发病率(致命和非致命)；3)推广统计方法，考虑成对器官设置的时间依赖性混淆，以便使用观察性眼科数据对治疗效果进行更有效的分析；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)效果。我们将把五个原始中心的队列规模增加~35%；后续时间和观察到的死亡人数将增加近一倍。辅助中心以肿瘤坏死因子抑制剂为重点的登记将增强AIM#1的统计能力。我们将把扩大的数据库与NDI和州癌症登记机构联系起来，并有一名新的合作调查员成功完成了一项类似的多种癌症登记研究。生物统计学方法学家将推广处理与器官配对有关的时间相关性混淆的方法，并与经验丰富的健康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有效性。 公共卫生相关性：所研究的药物有数百万人在使用；对其对死亡率和癌症影响的可靠估计将深刻影响风险-收益比，广泛影响眼科和系统性免疫疾病的管理。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临床合理治疗的证据的质量。

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.