TY - JOUR
T1 - Long-term Risk of Malignancy Among Patients Treated With Immunosuppressive Agents for Ocular Inflammation
T2 - A Critical Assessment of the Evidence
AU - Kempen, John H.
AU - Gangaputra, Sapna
AU - Daniel, Ebenezer
AU - Levy-Clarke, Grace A.
AU - Nussenblatt, Robert B.
AU - Rosenbaum, James T.
AU - Suhler, Eric B.
AU - Thorne, Jennifer E.
AU - Foster, C. Stephen
AU - Jabs, Douglas A.
AU - Helzlsouer, Kathy J.
N1 - Funding Information:
This study is supported by the National Eye Institute, Bethesda, Maryland Grant EY014943 (Dr Kempen) and by the Paul and Evanina Mackall Foundation, New York, New York, and Research to Prevent Blindness, New York, New York. Dr Kempen is Bethesda, Maryland, Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Dr Thorne is a Research to Prevent Blindness Harrington Special Scholar Award recipient. Drs Jabs and Rosenbaum are Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr Levy-Clarke was previously and Dr Nussenblatt continues to be supported by intramural funds of the National Eye Institute. Cyclophosphamide; Bristol-Myers Squibb, generics: No disclosures. Chlorambucil; GlaxoSmithKline, generics: No disclosures. Cyclosporine; Novartis, Abbott, generics: Dr Rosenbaum reports having received ≤$10,000 for consulting fees or paid advisory boards for both Novartis and Abbott Laboratories, and having a research grant pending from Abbott Laboratories; Dr Suhler reports having received a research grant from Abbott Laboratories; Dr Jabs reports having received ≤$10,000 for consulting fees or paid advisory boards for Novartis. Tacrolimus; Astellus Pharma US: No disclosures. Sirolimus; Wyeth Pharmaceuticals: No disclosures. Azathioprine; aalPharma, Inc, Prometheus Laboratories, generics: No disclosures. Methotrexate; DAVA Pharmaceuticals; Barr Laboratories, generics: No disclosures. Mycophenolate; Roche Laboratories: No disclosures. Adalimumab; Abbott Laboratories: Dr Rosenbaum reports having received ≤$10,000 for consulting fees or paid advisory boards for, and having a research grant pending from, Abbott Laboratories; Dr Suhler reports having received a research grant from Abbott. Infliximab; Centocor, Inc: Drs Rosenbaum and Suhler report having received a research grant from Centocor. Dr Foster reports having received fees of ≤$10,000 for speaking at the invitation of Centocor. Etancercept; Amgen, Inc; Wyeth Pharmaceuticals: Dr Rosenbaum reports equity ownership/stock options >$10,000 in Amgen. Daclizumab; Roche Laboratories: No disclosures. Involved in conception and design (J.H.K., S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., C.S.F., D.A.J., K.J.H.); analysis and interpretation and writing of the article (J.H.K.); critical review of the article (J.H.K, S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., C.S.F., D.A.J., K.J.H.); final approval of the article (J.H.K., S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., C.S.F., D.A.J., K.J.H.); data collection (J.H.K., S.G., E.D.); provision of resources (J.H.K., S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., C.S.F., D.A.J., K.J.H.); statistical expertise (J.H.K.); obtaining funding (J.H.K.); literature search (J.H.K., S.G., E.D.); and administrative, technical, or logistic support (J.H.K, S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., C.S.F., D.A.J., K.J.H.).
PY - 2008/12
Y1 - 2008/12
N2 - Purpose: To critically assess potentially carcinogenic effects of immunosuppressive therapy in the ocular inflammation setting. Design: 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 ≤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. Conclusion: 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.
AB - Purpose: To critically assess potentially carcinogenic effects of immunosuppressive therapy in the ocular inflammation setting. Design: 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 ≤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. Conclusion: 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.
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U2 - 10.1016/j.ajo.2008.04.035
DO - 10.1016/j.ajo.2008.04.035
M3 - Article
C2 - 18579112
AN - SCOPUS:56249109045
SN - 0002-9394
VL - 146
SP - 802-812.e1
JO - American journal of ophthalmology
JF - American journal of ophthalmology
IS - 6
ER -