The Risk and Risk Factors of Incident Hydroxychloroquine Retinopathy Among Long-Term Users

尽管在抗风湿治疗方案的进展，羟氯喹（HCQ）仍然是几乎普遍的 推荐用于系统性红斑狼疮（SLE）患者。例如，在NEJM试验之后， 许多研究报告显示，HCQ停药导致SLE恶化的风险增加2.5倍， HCQ的广泛益处，包括提高生存率。此外，HCQ经常用于管理 类风湿性关节炎（RA）和其他风湿性疾病。三联疗法（包括HCQ）的疗效 在RA中的作用被证明与依那西普相似，同时更具成本效益。HCQ目前正在 在随机试验中研究作为高危人群中RA的预防措施。虽然HCQ是 通常耐受良好，但严重的长期不良事件是威胁视力的毒性视网膜病变。 从历史上看，风险被认为是低的（即，<2%）。然而，最近的一项大型研究（N= 2，361，服用HCQ ≥5 年）发现HCQ视网膜病变的患病率为7.5%， 2，361例光谱域光学相干断层扫描（SDOCT）或视野评估（VFA）检查 服用HCQ>5年的患者。患病率与HCQ剂量和使用时间相关，为10% 在使用HCQ（每日剂量> 5毫克/千克）的10年内，使用20年后上升到40%。这些流行病 这些数据重新引起了患者和处方医生的严重关注，甚至导致了修订 美国眼科学会（AAO）（2016）和英国皇家眼科学院指南 （2018年）。然而，在这种情况下，基于患病率（而不是发病率）的预测可能是错误的。 因为患病率取决于发病率和疾病持续时间， HCQ视网膜病变病例中的永久性。此外，基于幸存者的预测，如流行率研究， 不考虑死亡的竞争风险（例如，SLE死亡率增加>2倍），进一步导致风险 高估在临床指南中采用这种高估会产生错误的担忧， 使用HCQ。此外，增加患病率的因素可能不是通过增加 但通过增加条件的持续时间。因此，流行病例的相关因素可能不会 是HCQ视网膜病变的真正危险因素。从事故案例中得出的准确风险数据对于证据至关重要- 临床指南。在这项研究中，AAO指导视网膜专家，风湿病学家和流行病学家， 我们将共同努力，通过审查年度报告，确定HCQ视网膜病变事件的风险及其风险因素， VFA和SDOCT检查在> 6，000名HCQ长期使用者的队列中（即，≥ 5年），从 使用，通过集中盲读。这项发病率研究将直接建立在最近的流行率基础上， 研究经验和北方加州Kaiser Permanente的全系统HCQ视网膜病筛查数据。 凭借我们在药物流行病学、HCQ视网膜病变和风湿病学方面的集体专业知识， 由于我们拥有独特的数据存取功能，我们在及时解决这一关键问题方面处于无与伦比的地位。

Despite therapeutic advances in antirheumatic regimens, hydroxychloroquine (HCQ) is still near-universally recommended for systemic lupus erythematosus (SLE) patients. For example, following the NEJM trial, which showed that HCQ discontinuation led to a 2.5 times higher risk of SLE exacerbation, many studies have reported wide-ranging benefits of HCQ, including improved survival. Furthermore, HCQ is often used in the management of rheumatoid arthritis (RA) and other rheumatic conditions. The efficacy of triple therapy (which includes HCQ) in RA is proven to be similar to that of etanercept, while being much more cost-effective. HCQ is now being investigated in randomized trials as a preventive measure for RA among high-risk individuals. Although HCQ is generally well-tolerated, a critical long-term adverse event is vision-threatening toxic retinopathy. Historically, the risk was considered low (i.e., <2%). However, a recent large study (N=2,361 taking HCQ for ≥5 years) by our investigators found the prevalence of HCQ retinopathy to be 7.5% according to their review of spectral-domain optical coherence tomography (SDOCT) or visual field assessment (VFA) exams from 2,361 patients taking HCQ for >5 years. The prevalence correlated with HCQ dose and duration of use and was 10% within 10 years of HCQ use at a dose of >5mg/kg daily and rose to 40% after 20 years of use. These prevalence data have renewed serious concerns among patients and prescribing physicians alike and even led to a revision of the American Academy of Ophthalmology (AAO) (2016) and UK Royal College of Ophthalmology guidelines (2018). However, the prediction based on prevalence (as opposed to incidence) in this context can be substantially overestimating because prevalence depends on both incidence and disease duration, which is permanent in HCQ retinopathy cases. Furthermore, predictions based on survivors, as in prevalence studies, do not account for the competing risk of death (e.g., >2-fold increased mortality in SLE), further leading to risk overestimation. Adopting such overestimation in clinical guidelines creates false concerns, potentially worsening under-use of HCQ. Moreover, factors that increase prevalence may do so not by increasing the occurrence of the condition but by increasing the duration of the condition. Therefore, correlates of prevalent cases may not be true risk factors for HCQ retinopathy. Accurate risk data derived from incident cases is crucial for evidence- based clinical guidelines. In this study, AAO guideline retinal specialists, rheumatologists, and epidemiologists will work together to determine the risk of incident HCQ retinopathy and its risk factors by reviewing annual VFA and SDOCT exams in a cohort of > 6,000 HCQ long-term users (i.e., ≥ 5 years), starting from Year 5 of use, through centralized blinded readings. This incidence study will directly build upon the recent prevalence study experience and system-wide HCQ retinopathy screening data of Kaiser Permanente Northern California. With our collective expertise in pharmacoepidemiology, HCQ retinopathy, and rheumatology, combined with uniquely fitting data access, we are in an unparalleled position to address this key issue in a timely manner.