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

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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.