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

John H. Kempen, Department of Ophthalmology and Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary; and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA; Sight for Souls, Bellevue, Washington, USA; MCM Eye Unit; MyungSung Christian Medical Center (MCM) General Hospital and MyungSung Medical School, Addis Ababa, Ethiopia; Department of Ophthalmology, Addis Ababa University School of Medicine, Addis Ababa, Ethiopia. Electronic address: John_Kempen@meei.harvard.edu.
Craig W. Newcomb, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Terri L. Washington, Center for Occupational Biostatistics and Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA.
C Stephen Foster, Massachusetts Eye Research and Surgery Institution, Waltham, Massachusetts, USA.
Lucia Sobrin, Department of Ophthalmology and Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary; and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Jennifer E. Thorne, Wilmer Eye Institute, Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Douglas A. Jabs, Wilmer Eye Institute, Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Eric B. Suhler, Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon, USA; Portland Veteran's Affairs Medical Center, Portland, Oregon, USA.
James T. Rosenbaum, Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon, USA; Department of Medicine, Oregon Health and Science University, Portland, Oregon, USA; Legacy Devers Eye Institute, Portland, Oregon, USA.
H Nida Sen, Department of Ophthalmology, George Washington University, Washington, District of Columbia, USA; Janssen Retina Global Clinical Development, Princeton, New Jersey, USA.
Grace A. Levy-Clarke, Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, West Virginia, USA.
Robert B. Nussenblatt, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
Nirali P. Bhatt, Department of Ophthalmology, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Careen Y. Lowder, Cole Eye Institute, Department of Ophthalmology, Cleveland Clinic, Cleveland, Ohio, USA.
Debra A. Goldstein, Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Yannek I. Leiderman, Illinois Eye & Ear Infirmary, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
Nisha R. Acharya, F.I. Proctor Foundation, Department of Ophthalmology, University of California San Francisco School of Medicine, San Francisco, California, USA.
Gary N. Holland, Ocular Inflammatory Disease Center, Jules Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Russell W. Read, Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA.
James P. Dunn, Mid-Atlantic Retina, Wills Eye Hospital, Philadelphia, Pennsylvania, USA.
Kurt A. Dreger, Department of Ophthalmology, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Population, Family, and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Pichaporn Artornsombudh, Department of Ophthalmology, Somdech Phra Pinkloa Hospital, Royal Thai Navy, Bangkok, Thailand; Department of Ophthalmology, Chulalongkorn University, Bangkok, Thailand.
Hosne A. Begum, Wilmer Eye Institute, Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Tonetta D. Fitzgerald, Department of Ophthalmology, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Srishti Kothari, Massachusetts Eye Research and Surgery Institution, Waltham, Massachusetts, USA; Department of Ophthalmology, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abhishek R. Payal, Mahatme Eye Bank Eye Hospital, Nagpur, Maharashtra, India.
Ebenezer Daniel, Department of Ophthalmology, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Sapna S. Gangaputra, Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
R Oktay Kaçmaz, Santen Inc. Emeryville, California, USA.
Teresa L. Liesegang, Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon, USA.
Siddharth S. Pujari, Siddharth Netralaya Superspecialty Eye Hospital, Belgaum, Karnataka, India.
Naira Khachatryan, Department of Ophthalmology, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Document Type

Journal Article

Publication Date

7-25-2023

Journal

Ophthalmology

DOI

10.1016/j.ophtha.2023.07.023

Abstract

OBJECTIVE: To determine the incidence of all-cause and cancer mortality 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 cancer mortality for each class of immunosuppressant and for each individual immunosuppressant compared with person-time unexposed to any immunosuppression. PARTICIPANTS: Patients with non-infectious OID, excluding those with HIV infection or pre-existing cancer. INTERVENTIONS: 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 non-interventional cohort study. MAIN OUTCOMES AND MEASURES: Overall and cancer mortality. RESULTS: Over 187,151 person-years (median follow-up 10.0 years), during which 15,938 patients were at risk for mortality-we observed 1,970 deaths, 435 attributed 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 (SID) (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 versus 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 cancer mortality (aHR=1.25, 0.89, 0.89, 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 cancer mortality over a median cohort follow-up of 10.0 years. These results suggest safety of these agents with respect to overall and cancer mortality for patients treated with immunosuppression for a wide range of inflammatory diseases.

Department

Ophthalmology

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