Exposure to Immunosuppressive Drugs & Cancer Risk in SLE

描述（由申请人提供）： 在过去的20年里，对自身免疫和癌症之间联系的兴趣已经升级。系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，是育龄妇女中第二常见的自身免疫性疾病。以前的研究在评价SLE和癌症之间的潜在关系时没有定论;然而，我们的研究小组对7200多名SLE患者进行了一项队列研究，随访时间超过59，000年，结果证实所有癌症（标准化发病率比，[SIR] 1.2，95%置信区间，[CI] 1.1，1.4）和某些癌症，特别是血液系统癌症（SIR 3.0，95% CI 2.3，3.8），在SLE中的发生频率高于预期。此外，我们的队列研究显示最高点估计值或SIR发生在SLE的第1年，表明癌症风险不能完全由免疫抑制药物（ISD）暴露的累积剂量解释。因此，需要阐明ISDs在SLE中与癌症风险相关的作用，合乎逻辑的下一步是检验探索SLE中有或无ISDs暴露的癌症易感性的假设。我们建议在我们独特的国际多中心队列研究的背景下进行一项病例队列研究（经典巢式病例对照设计的灵活有效的变体），以确定ISD（硫唑嘌呤，环磷酰胺，甲氨蝶呤或环孢素）是否影响SLE患者的癌症风险，特别是针对血液系统恶性肿瘤。在主要分析中，将使用改良的考克斯比例风险回归，在控制其他药物使用、年龄、性别和SLE疾病持续时间和损害的模型中计算暴露于ISD后发生血液学癌症的风险比。在次要分析中，我们将研究其他临床因素的潜在作用，如继发性干燥综合征或效应调节剂，如吸烟。如果某些ISDs与癌症风险有关，处方模式可能会改变。这项研究还可能提供有关癌症和自身免疫之间潜在联系的新信息。

DESCRIPTION (provided by applicant): In the past 2 decades, interest in links between autoimmunity and cancer have escalated. Systemic lupus erythematosus (SLE), the prototype autoimmune disease, is the 2nd most common autoimmune disorder occurring in childbearing women. Previous studies were inconclusive when evaluating the potential relationship between SLE and cancer; however, our investigative team conducted a cohort study of 7200+ SLE patients with 59,000+ follow-up years, where results confirm that all cancers (Standardized Incidence Ratio, [SIR] 1.2, 95% Confidence Interval, [CI] 1.1, 1.4) and certain cancers, particularly hematologic (SIR 3.0, 95% CI 2.3, 3.8), occur more frequently than expected in SLE. Further, our cohort study shows the highest point estimates or SIRs occur in the 1st year of SLE, suggesting that cancer risk is not completely explained by the cumulative dose of immunosuppressive drug (ISD) exposure. Therefore, elucidation of the role of ISDs with respect to cancer risk in SLE is needed and the logical next step is to test hypotheses exploring susceptibility to cancer in SLE with and without exposures to ISDs. We are proposing to conduct a case-cohort study (a flexible and efficient varation of the classical nested case-control design), within the context of our unique international multi-center cohort study, to determine whether ISDs (azathiopdne, cyclophosphamide, methotrexate, or cyclosporin) influence cancer risk, specifically targeting hematologic malignancies, in SLE. In the primary analysis, modified Cox proportional hazards regression will be used to calculate the risk ratio for hematologic cancer development after exposure to ISDs in a model that controls for other medication use, age, sex, and SLE disease duration and damage. In secondary analyses, we will examine the potential role of other clinical factors, such as secondary Sjogren's syndrome or effect modifiers, such as smoking. If certain ISDs are linked to cancer risk, prescribing patterns may change. This study may also provide new information about potential links between cancer and autoimmunity.