Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Dec;130(12):1258-1268.
doi: 10.1016/j.ophtha.2023.07.023. Epub 2023 Jul 26.

Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality

John H Kempen  1 , Craig W Newcomb  2 , Terri L Washington  3 , C Stephen Foster  4 , Lucia Sobrin  5 , Jennifer E Thorne  6 , Douglas A Jabs  6 , Eric B Suhler  7 , James T Rosenbaum  8 , H Nida Sen  9 , Grace A Levy-Clarke  10 , Robert B Nussenblatt  11 , Nirali P Bhatt  12 , Careen Y Lowder  13 , Debra A Goldstein  14 , Yannek I Leiderman  15 , Nisha R Acharya  16 , Gary N Holland  17 , Russell W Read  18 , James P Dunn  19 , Kurt A Dreger  20 , Pichaporn Artornsombudh  21 , Hosne A Begum  22 , Tonetta D Fitzgerald  12 , Srishti Kothari  23 , Abhishek R Payal  24 , Ebenezer Daniel  12 , Sapna S Gangaputra  25 , R Oktay Kaçmaz  26 , Teresa L Liesegang  27 , Siddharth S Pujari  28 , Naira Khachatryan  12 , Armin Maghsoudlou  29 , Hilkiah K Suga  30 , Clara M Pak  31 , Kathy J Helzlsouer  32 , Jeanine M Buchanich  3 ; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study Research Group
Affiliations

Use of Immunosuppression and the Risk of Subsequent Overall or Cancer Mortality

John H Kempen et al. Ophthalmology. 2023 Dec.

Abstract

Purpose: To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression.

Design: Retrospective cohort study at ocular inflammatory disease (OID) subspecialty centers. We harvested exposure and covariate data retrospectively from clinic inception (earliest in 1979) through 2010 inclusive. Then we ascertained overall and cancer-specific mortalities by National Death Index linkage. We constructed separate Cox models to evaluate overall and CM for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression.

Participants: Patients with noninfectious OID, excluding those with human immunodeficiency infection or preexisting cancer.

Methods: Tumor necrosis factor (TNF) inhibitors (mostly infliximab, adalimumab, and etanercept); antimetabolites (methotrexate, mycophenolate mofetil, azathioprine); calcineurin inhibitors (cyclosporine); and alkylating agents (cyclophosphamide) were given when clinically indicated in this noninterventional cohort study.

Main outcome measures: Overall mortality and CM.

Results: Over 187 151 person-years (median follow-up 10.0 years), during which 15 938 patients were at risk for mortality, we observed 1970 deaths, 435 due to cancer. Both patients unexposed to immunosuppressants (standardized mortality ratio [SMR] = 0.95, 95% confidence interval [CI], 0.90-1.01) and those exposed to immunosuppressants but free of systemic inflammatory diseases (SIDs) (SMR = 1.04, 95% CI, 0.95-1.14) had similar mortality risk to the US population. Comparing patients exposed to TNF inhibitors, antimetabolites, calcineurin inhibitors, and alkylating agents with patients not exposed to any of these, we found that overall mortality (adjusted hazard ratio [aHR] = 0.88, 0.89, 0.90, 1.11) and CM (aHR = 1.25, 0.89, 0.86, 1.23) were not significantly increased. These results were stable in sensitivity analyses whether excluding or including patients with SID, across 0-, 3-, or 5-year lags and across quartiles of immunosuppressant dose and duration.

Conclusions: Our results, in a cohort where the indication for treatment was proven unassociated with mortality risk, found that commonly used immunosuppressants-especially the antimetabolites methotrexate, mycophenolate mofetil, and azathioprine; the TNF inhibitors adalimumab and infliximab, and cyclosporine-were not associated with increased overall and CM over a median cohort follow-up of 10.0 years. These results suggest the safety of these agents with respect to overall and CM for patients treated with immunosuppression for a wide range of inflammatory diseases.

Financial disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Cancer mortality; Immunosuppression; Mortality; Tumor necrosis factor inhibitor; antimetabolite.

PubMed Disclaimer

Conflict of interest statement

Potential Conflicts of Interest:

  1. John H. Kempen: Betaliq (Equity Owner); Tarsier Pharma (Equity Owner); Gilead (Consultant)

  2. C. Stephen Foster: Aldeyra (Consultant, Grant Support), Allakos (Consultant), Bausch & Lomb (Consultant, Grant Support), Eyegate (Consultant, Grant Support, Stock), Genentech (Consultant), Novartis (Consultant, Grant Support), pSivida (Consultant, Grant Support), Aciont (Grant Support), Alcon (Grant Support, Lecture Fees), Clearside (Grant Support), Dompé (Grant Support), Mallinckrodt (Grant Support, Lecture Fees), Allergan (Lecture Fees), Ocular Therapeutix (Food and Beverage), SUN Pharmaceutical Industries (Food and Beverage), Aerie Pharmaceuticals (Food and Beverage), Horizon Therapeutics (Food and Beverage), Eyepoint Pharmaceuticals (Food and Beverage), Eyevance Pharmaceuticals (Food and Beverage), Alimera Sciences (Food and Beverage).

  3. Lucia Sobrin: Genentech (Food and Beverage).

  4. Jennifer E. Thorne: Abbvie (Consultant); Canfield (Consultant); Clearside (Consultant); Gilead (Consultant); Guidepoint (Consultant); Roche (Consultant); Tarsier Pharma (Scientific Advisory Board; Equity Owner); UptoDate (Consultant)’ F. Hoffmann-La Roche AG (consultant)

  5. Douglas A. Jabs: Abbvie (Research Funding)

  6. Eric B. Suhler: Eyevensys (Consultant); Santen (Consultant); EyeGate (Consultant, Financial Support); Abbvie (Consultant, Financial Support); Clearside (Consultant, Financial Support); EyePoint (Consultant, Financial Support); Gilead (Food and Beverage)

  7. James T. Rosenbaum: Corvus Pharmaceuticals (Employment); Abbvie (Consultant); Gilead (Consultant); Janssen (Consultant); Eyevensys (Consultant); UpToDate (Consultant); Pfizer (Financial Support); Novartis (Consultant); Roche (Consultant); Alcon Research Institute (Financial Support); UCB (consultant); Horizon (Consultant and finanicial support); Santen (consultant); Celgene (Consultant); Pfizer (Education); UCB (Consultant).

  8. H. Nida Sen: Janssen (Employee)

  9. Grace A. Levy-Clarke: Abbvie (Consultant, Lecture Fees); Allergan (Grant Support); Mallinckrodt (Consultant, Grant Support); Sanofi (Grant Support; Lecture Fees)

  10. Nirali P. Bhatt: Allergan (Food and Beverage).

  11. Debra A. Goldstein Bausch & Lomb (Consultant).

  12. Yannek I. Leiderman: Research to Prevent Blindness (Grant); Alcon (Consultant); Microsurgical Guidance Solutions (Equity Owner); Regeneron Healthcare Solutions (Compensation); Genentech (Consultant) patents pending: WO2020163845 and USSN: 63/183424

  13. Nisha R. Acharya: Abbvie (Research Funding); Roche (Consultant)

  14. Russell W. Read: Johnson & Johnson (Food and Beverage)

  15. Sapna S. Gangaputra: Alimera (Food and Beverage)

  16. R. Oktay Kaçmaz: Santen (Employee)

  17. Armin Maghsoudlou: E.R. Squibb & Sons (Food and Beverage).

  18. James P. Dunn: Bionic Site (Data and Safety Monitoring Committee)

  19. The other authors indicate no potential conflicts of interest.

Figures

Figure 1:
Figure 1:
Forest plot indicating the relative hazard of overall mortality in association with classes of drugs and specific drugs, patients with ocular inflammatory diseases participating in the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study.
Figure 2:
Figure 2:
Forest plot indicating the relative hazard of cancer mortality in association with classes of drugs and specific drugs, patients with ocular inflammatory diseases participating in the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study.
See this image and copyright information in PMC

References

    1. Kempen JH, Daniel E, Dunn JP, et al. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs: retrospective cohort study. BMJ. 2009;339:b2480. - PMC - PubMed
    1. Kempen JH, Gangaputra S, Daniel E, et al. Long-term risk of malignancy among patients treated with immunosuppressive agents for ocular inflammation: A critical assessment of the evidence. Am J Ophthalmol. 2008;146(6):802–812. - PMC - PubMed
    1. Writing Committee for the Multicenter Uveitis Steroid Treatment T, Follow-up Study Research Group, Kempen JH, et al. Association Between Long-Lasting Intravitreous Fluocinolone Acetonide Implant vs Systemic Anti-inflammatory Therapy and Visual Acuity at 7 Years Among Patients With Intermediate, Posterior, or Panuveitis. JAMA. 2017;317(19):1993–2005. - PMC - PubMed
    1. Jabs DA. Immunosuppression for the Uveitides. Ophthalmology. 2018;125(2):193–202. - PMC - PubMed
    1. Cancer; IAfRo. Agents Classified by the IARC Monographs, Volumes 1–130. (https://monographs.iarc.fr/agents-classified-by-the-iarc/.) Accessed July 27, 2022.