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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZEY1-VSN (06))
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Wideroff, Louise
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University of Pennsylvania
Schools of Medicine
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