title: Methods for identifying long-term adverse effects of treatment in patients with eye diseases: the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study.
abstract: OBJECTIVE
  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 approximately 9,250 ocular inflammation patients at five tertiary centers over up to 30 years. Mortality and cause-specific mortality outcomes over approximately 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.
authors.affiliation: Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. john.kempen@uphs.upenn.edu
authors.forename: John H
authors.initials: JH
authors.lastname: Kempen
authors.forename: Ebenezer
authors.initials: E
authors.lastname: Daniel
authors.forename: Sapna
authors.initials: S
authors.lastname: Gangaputra
authors.forename: Kurt
authors.initials: K
authors.lastname: Dreger
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Jabs
authors.forename: R Oktay
authors.initials: RO
authors.lastname: Kaçmaz
authors.forename: Siddharth S
authors.initials: SS
authors.lastname: Pujari
authors.forename: Fahd
authors.initials: F
authors.lastname: Anzaar
authors.forename: C Stephen
authors.initials: CS
authors.lastname: Foster
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Helzlsouer
authors.forename: Grace A
authors.initials: GA
authors.lastname: Levy-Clarke
authors.forename: Robert B
authors.initials: RB
authors.lastname: Nussenblatt
authors.forename: Teresa
authors.initials: T
authors.lastname: Liesegang
authors.forename: James T
authors.initials: JT
authors.lastname: Rosenbaum
authors.forename: Eric B
authors.initials: EB
authors.lastname: Suhler
mesh_terms: D002423:Cause of Death; D004812:Epidemiologic Methods; D005128:Eye Diseases / Q000188:drug therapy* / Q000401:mortality*; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007249:Inflammation / Q000188:drug therapy / Q000401:mortality; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D007166:Immunosuppressive Agents