title: Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: a critical assessment of the evidence.
abstract: OBJECTIVE
  To critically assess potentially carcinogenic effects of immunosuppressive therapy in the ocular inflammation setting.
  
  
  METHODS
  Focused evidence assessment.
  
  
  METHODS
  Relevant publications were identified by MEDLINE and EMBASE queries and reference list searches.
  
  
  RESULTS
  Extrapolation from transplant, rheumatology, skin disease, and inflammatory bowel disease cohorts to the ocular inflammation setting suggest that: 1) alkylating agents increase hematologic malignancy risk and cyclophosphamide increases bladder cancer risk, but less so with < or =18 months' duration of therapy and hydration, respectively; 2) calcineurin inhibitors and azathioprine probably do not increase total cancer risk to a detectable degree, except perhaps some other risk factors (uncommon in ocular inflammation patients) might interact with the former to raise risk; 3) tumor necrosis factor (TNF) inhibitors may accelerate diagnosis of cancer in the first six to 12 months, but probably do not increase long-term cancer risk; and 4) changes in risk with methotrexate, mycophenolate mofetil, and daclizumab appear negligible, although nontransplant data are limited for the latter agents. Immunosuppression in general may increase skin cancer risk in a sun exposure-dependent manner.
  
  
  CONCLUSIONS
  Use of alkylating agents for a limited duration seems justifiable for severe, vision-threatening disease, but otherwise cancer risk may be a relevant constraint on use of this approach. Antimetabolites, daclizumab, TNF inhibitors, and calcineurin inhibitors probably do not increase cancer risk to a degree that outweighs the expected benefits of therapy. Monitoring for skin cancer may be useful for highly sun-exposed patients. Data from ocular inflammation patients are needed to confirm the conclusions made in this analysis by extrapolation.
authors.affiliation: Ocular Inflammation Service, Scheie Eye Institute, The University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. john.kempen@uphs.upenn.edu
authors.forename: John H
authors.initials: JH
authors.lastname: Kempen
authors.forename: Sapna
authors.initials: S
authors.lastname: Gangaputra
authors.forename: Ebenezer
authors.initials: E
authors.lastname: Daniel
authors.forename: Grace A
authors.initials: GA
authors.lastname: Levy-Clarke
authors.forename: Robert B
authors.initials: RB
authors.lastname: Nussenblatt
authors.forename: James T
authors.initials: JT
authors.lastname: Rosenbaum
authors.forename: Eric B
authors.initials: EB
authors.lastname: Suhler
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Thorne
authors.forename: C Stephen
authors.initials: CS
authors.lastname: Foster
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Jabs
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Helzlsouer
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000963:Antimetabolites / Q000009:adverse effects; D001379:Azathioprine / Q000009:adverse effects; D000077561:Daclizumab; D016208:Databases, Factual; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007249:Inflammation / Q000188:drug therapy; D008137:Longitudinal Studies; D008727:Methotrexate / Q000009:adverse effects; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives; D009369:Neoplasms / Q000139:chemically induced*; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014605:Uveitis / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000963:Antimetabolites; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D000077561:Daclizumab; D009173:Mycophenolic Acid; D001379:Azathioprine; D008727:Methotrexate