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Abstract：
OBJECTIVE: To determine the incidence of all-cause and cancer mortality (CM) in association with immunosuppression.
METHODS: 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.
METHODS: 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.
METHODS: 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.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
METHODS: 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.
METHODS: 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.
METHODS: 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.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
摘要：
目的：确定与免疫抑制相关的全因和癌症死亡率（CM）的发生率。
方法：眼部炎性疾病（OID）亚专科中心的回顾性队列研究。我们收集了从临床开始（最早于1979年）到2010年的暴露和协变量数据。然后，我们通过国家死亡指数链接确定总体死亡率和癌症特异性死亡率。我们构建了单独的Cox模型，以评估每种类型的免疫抑制剂以及每种单独的免疫抑制剂的总体和CM，与未暴露于任何免疫抑制的人时间相比。
方法：非感染性OID患者，不包括人类免疫缺陷感染或先前存在的癌症。
方法：肿瘤坏死因子（TNF）抑制剂（主要是英夫利昔单抗，阿达木单抗,和依那西普)；抗代谢物(甲氨蝶呤，霉酚酸酯，硫唑嘌呤）；钙调神经磷酸酶抑制剂（环孢菌素）；和烷化剂（环磷酰胺）在这项非干预性队列研究中有临床指征时给予。
方法：总死亡率和CM。
结果：超过187151人年（中位随访10.0年），在此期间，有15938名患者面临死亡风险，我们观察了1970年的死亡,因为癌症435。两名患者均未接触免疫抑制剂（标准化死亡率[SMR]=0.95，95%置信区间[CI]，0.90-1.01）和那些暴露于免疫抑制剂但没有全身性炎症性疾病（SID）（SMR=1.04，95％CI，0.95-1.14）的死亡风险与美国人群相似。比较暴露于TNF抑制剂的患者，抗代谢物，钙调磷酸酶抑制剂，和烷化剂，患者没有接触任何这些，我们发现总死亡率(校正风险比[aHR]=0.88,0.89,0.90,1.11)和CM(aHR=1.25,0.89,0.86,1.23)没有显著增加.这些结果在敏感性分析中是稳定的，无论是排除还是包括SID患者，跨越0-，3-,或5年的滞后和跨四分位数的免疫抑制剂的剂量和持续时间。
结论：我们的结果，在一个队列中，治疗适应症被证明与死亡风险无关，发现常用的免疫抑制剂，尤其是抗代谢物甲氨蝶呤，霉酚酸酯，和硫唑嘌呤；TNF抑制剂阿达木单抗和英夫利昔单抗，和环孢素-在10.0年的中位队列随访中,与总体和CM升高无关.这些结果表明，对于广泛的炎性疾病，这些药物在总体和CM方面的安全性。
背景：专有或商业披露可以在本文末尾的脚注和披露中找到。
方法：眼部炎性疾病（OID）亚专科中心的回顾性队列研究。我们收集了从临床开始（最早于1979年）到2010年的暴露和协变量数据。然后，我们通过国家死亡指数链接确定总体死亡率和癌症特异性死亡率。我们构建了单独的Cox模型，以评估每种类型的免疫抑制剂以及每种单独的免疫抑制剂的总体和CM，与未暴露于任何免疫抑制的人时间相比。
方法：非感染性OID患者，不包括人类免疫缺陷感染或先前存在的癌症。
方法：肿瘤坏死因子（TNF）抑制剂（主要是英夫利昔单抗，阿达木单抗,和依那西普)；抗代谢物(甲氨蝶呤，霉酚酸酯，硫唑嘌呤）；钙调神经磷酸酶抑制剂（环孢菌素）；和烷化剂（环磷酰胺）在这项非干预性队列研究中有临床指征时给予。
方法：总死亡率和CM。
结果：超过187151人年（中位随访10.0年），在此期间，有15938名患者面临死亡风险，我们观察了1970年的死亡,因为癌症435。两名患者均未接触免疫抑制剂（标准化死亡率[SMR]=0.95，95%置信区间[CI]，0.90-1.01）和那些暴露于免疫抑制剂但没有全身性炎症性疾病（SID）（SMR=1.04，95％CI，0.95-1.14）的死亡风险与美国人群相似。比较暴露于TNF抑制剂的患者，抗代谢物，钙调磷酸酶抑制剂，和烷化剂，患者没有接触任何这些，我们发现总死亡率(校正风险比[aHR]=0.88,0.89,0.90,1.11)和CM(aHR=1.25,0.89,0.86,1.23)没有显著增加.这些结果在敏感性分析中是稳定的，无论是排除还是包括SID患者，跨越0-，3-,或5年的滞后和跨四分位数的免疫抑制剂的剂量和持续时间。
结论：我们的结果，在一个队列中，治疗适应症被证明与死亡风险无关，发现常用的免疫抑制剂，尤其是抗代谢物甲氨蝶呤，霉酚酸酯，和硫唑嘌呤；TNF抑制剂阿达木单抗和英夫利昔单抗，和环孢素-在10.0年的中位队列随访中,与总体和CM升高无关.这些结果表明，对于广泛的炎性疾病，这些药物在总体和CM方面的安全性。
背景：专有或商业披露可以在本文末尾的脚注和披露中找到。
