This U01 application SHIELD (Stopping Hydroxychloroquine (HCQ) In Elderly Lupus Disease) follows completion of an R34 and is driven by the exigency to establish evidence-based protocols for the management of aging lupus patients, a topic that has received minimal attention. Data are needed to accurately weigh the balance between accumulating ocular exposure of HCQ versus the risk of disease flare in a population that may have more inactive disease than younger patients. Despite a track record of safety with regard to infection compared to traditional immunosuppressive agents, the risk of HCQ retinal toxicity escalates with continued use. Evaluation using sensitive standard of care approaches suggests nearly a third of patients accrue retinal damage. The decision to discontinue HCQ is difficult; however clinical equipoise should guide this consideration especially in patients who have been stable and on the medication for years. As the longevity of lupus patients improves, which may increase comorbidities that affect HCQ clearance (e.g., renal insufficiency), the ratio of efficacy to toxicity is expected to decrease. That disease activity may wane in the aging population drives the ratio down even further. The purpose of this U01 is to conduct a Phase III, randomized, double-blind placebo controlled, multi-center, non-inferiority clinical trial to address the safety of withdrawal of HCQ in SLE patients ≥60 years old. The central hypothesis is that HCQ can be safely discontinued in stable/quiescent patients assessed by validated disease activity and flare instruments in the context of serologic, cytokine and transcriptomic profiling. The population under study will be 330 patients who fulfill at least one of the classification criteria (ACR, SLICC, EULAR/SLICC) for SLE, are ≥60yrs, are currently taking at least 200 mg HCQ daily for at least 7yrs and have stable disease. Patients will be randomized to either the placebo or active arm and followed every 2 months for one year to assess disease activity and flares. Subjects will be recruited from NYU (Peter Izmirly, Jill Buyon), Albert Einstein (Anna Broder), HSS (Jane Salmon), Columbia (Anca Askanase), OMRF (Joan Merrill), Penn State (Nancy Olsen), and UCLA (Maureen McMahon). The primary outcome will be the occurrence of a moderate/severe flare during follow-up. Sample size is based on the projection of a 13% moderate/severe flare rate in patients remaining on HCQ and a non-inferiority margin equal to a 10% absolute difference in rates between groups. The trial infrastructure has been established in compliance with NIH guidelines and completion of the following deliverables from the awarded R34: model recruitment supported by an sIRB with all sites; study protocol with inclusion of biomarker studies and comprehensive statistical analysis plan; manual of operating procedures; electronic data capture system; data management plan; acquisition of study drugs; and training of support staff. It is anticipated that this trial will significantly impact the care of our aging lupus population and provide a molecular landscape of autoimmune parameters that may identify patients appropriate for medication adjustments.

PROJECT NARRATIVE While HCQ is effective in reducing lupus disease activity and maintaining stability, over long periods, HCQ can result in ocular damage. This grant will support a phase III, randomized, double-blind, placebo-controlled, non- inferiority, multi-center clinical trial to evaluate the safety of withdrawing hydroxychloroquine (HCQ) from lupus patients 60 years and older. It is anticipated that this trial will significantly impact the care of our aging lupus population and provide a molecular landscape of autoimmune parameters which may identify patients appropriate for medication adjustments.