Methods for identifying long-term adverse effects of treatment in patients with eye diseases: The Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study

John H. Kempen, Ebenezer Daniel, Sapna Gangaputra, Kurt Dreger, Douglas A. Jabs, R. Oktay Kaçmaz, Siddharth S. Pujari, Fahd Anzaar, C. Stephen Foster, Kathy J. Helzlsouer, Grace A. Levy-Clarke, Robert B. Nussenblatt, Teresa Liesegang, James T. Rosenbaum, Eric B. Suhler

Research output: Contribution to journalReview articlepeer-review

95 Scopus citations


Purpose: To evaluate potential epidemiologic methods for studying long-term effects of immunosuppression on the risk of mortality and fatal malignancy, and present the methodological details of the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study. Methods: Advantages and disadvantages of potential study designs for evaluating rare, late-occurring events are reviewed, and the SITE Cohort Study approach is presented. Results: The randomized, controlled trial is the most robust method for evaluating treatment effects, but long study duration, high costs, and ethical concerns when studying toxicity limit its use in this setting. Retrospective cohort studies are potentially more cost-effective and timely, if records exist providing the desired information over sufficient follow-up time in the past. Case-control methods require extremely large sample sizes to evaluate risk associated with rare exposures, and recall bias is problematic when studying mortality. The SITE Cohort Study is a retrospective cohort study. Past use of antimetabolites, T-cell inhibitors, alkylating agents, and other immunosuppressives is ascertained from medical records of ∼9,250 ocular inflammation patients at five tertiary centers over up to 30 years. Mortality and cause-specific mortality outcomes over ∼100,000 person-years are ascertained using the National Death Index. Immunosuppressed and non-immunosuppressed groups of patients are compared with each other and general population mortality rates from US vital statistics. Calculated detectable differences for mortality/fatal malignancy with respect to the general population are 22%/49% for antimetabolites, 28%/62% for T-cell inhibitors, and 36%/81% for alkylating agents. Conclusions: Information from the SITE Cohort Study should clarify whether use of these immunosuppressive drugs for ocular inflammation increases the risk of mortality and fatal cancer. This epidemiologic approach may be useful for evaluating long-term risks of systemic therapies for other ocular diseases.

Original languageEnglish (US)
Pages (from-to)47-55
Number of pages9
JournalOphthalmic Epidemiology
Issue number1
StatePublished - Jan 2008


  • Cancer
  • Cohort study
  • Immunosuppression
  • Mortality
  • Ocular inflammation

ASJC Scopus subject areas

  • Epidemiology
  • Ophthalmology


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