How Do We Dose Hydroxychloroquine? : Two Fascinating Cases of Hydroxychloroquine Toxicity  *Cristine Kuzhuppilly Arcilla (Main Author/Presenter; Rheumatology Fellow); *Kaur,Ikwinder; **Adams, Maria; *Thway, Myint, M.D. *University of Florida Jacksonville Rheumatology Fellowship Program **University of Florida Jacksonville Ophthalmology

Summary: Hydroxychloroquine( HCQ) is one of the most well-tolerated and safest drugs central to many rheumatologic conditions. After FDA approval in 1955, HCQ has been used with dosage recommendations starting from an initial loading dose, followed by a fixed dose of 200-400mg/day. Over time, dosing was changed to a dose based on the ideal body weight, not exceeding 6.5 mg/kg daily. In 2016, the American Academy of Ophthalmology recommended using less than 5.0 mg/kg using an actual body weight. New guidelines for its ocular toxicity screening required baseline screening within one year of starting HCQ, followed by annual screening after 5 years. However, the occurrence of rare but detrimental side effects from chronic HCQ use, including retinopathy and cardiotoxicity, were reported even within adequate actual weight-based dosing. Major risk factors of toxicity include use of more than 5 years,dose of more than 5 mg/kg of actual body weight, renal disease,and concomitant tamoxifen use. On the other hand, screening of QTc prolongation is not employed in routine monitoring of its toxicity. Here, we describe two cases with detrimental adverse events of retinopathy and pro-block from chronic HCQ use within the recommended actual body weight dosing. A 53-year-old female with discoid lupus on HCQ for more than 20 years presented for routine HCQ eye examination. She reported seeing circles with flashing lights inside and complained that her vertical blinds appeared wavy for past 6 months. She was taking HCQ 200 mg twice daily for more than 20 years at 4.6 mg/kg dose. She was recently reduced to 200 mg twice daily, 5 days a week due to the absence of active discoid lesions. She reported receiving yearly eye examinations. She was unsure if an optometrist or an ophthalmologist was seeing her. Laboratory showed positive ANA 1:160 titer with normal complement and creatinine levels. Her visual acuity was correctable to 20/20- OU and her color vision testing was 6/8 OU. Funduscopy showed bilateral bull's eye maculopathy. Optical coherence tomography revealed classic disruption of the parafoveal ellipsoid zone. Humphrey's visual field testing revealed pericentral ring scotomas.HCQ was discontinued immediately.   A 49-year-old female with seronegative erosive rheumatoid arthritis on HCQ of 3.6 mg/kg dose consistently for more than 10 years presented for syncope. She was driving home when she experienced lightheadedness, palpitations, and blurry vision before blacking out, causing her to hit her car into a tree.  She denies any syncope or seizures in the past and is not on other QTc prolonging medications. She has no family history of arrhythmia or sudden deaths. Examination showed left periorbital hematoma with no focal neurologic deficits.CT did not reveal evidence of acute fracture of the head and cervical spine but showed displaced left naso-orbital ethmoid fracture.CTA showed no evidence of stenosis. EKG revealed sinus tachycardia of 119 bpm, no ischemic changes, and newly prolonged QTc of 618ms.Laboratory showed potassium of 3.1mmol/l, magnesium of 1.8mg/dl, calcium 9.4mg/dl, creatinine of 0.69mg/dl, TSH of 2.3 MIU/l.Troponins were normal (7ng/l), and pro-BNP was elevated (304 pg/ml). EP study recorded an episode of polymorphic VT.HCQ was discontinued;electrolytes were corrected. Echocardiography showed a reduced ejection fraction of 45-50%.Left cardiac catheterization demonstrated normal coronaries. Cardiac MRI did not show delayed enhancement to suggest infiltrative disease. QTc prolongation improved to 561ms, and loop recorder was placed before discharge.  We presented two cases with catastrophic adverse events from HCQ within adequate weight-based dosing of less than 5 mg/kg daily. Abrupt discontinuation of HCQ should be done at the earliest signs of toxicity; however, the damage from its toxicity could be irreversible. Traditionally, HCQ monitoring has primarily involved periodic ophthalmologic examinations and adherence to weight-based dosing guidelines. Weight-based dosing fails to account for individual variations in drug metabolism and clearance, potentially leading to suboptimal dosing or increased risk of toxicity.   Call for Consensus: Achieving widespread adoption of HCQ-level monitoring necessitates consensus among rheumatologists regarding its utility and implementation. Collaborative efforts are needed to establish standardized protocols for HCQ level monitoring, including frequency of testing, interpretation of results, and adjustment of dosing regimens. Professional societies and regulatory bodies are pivotal in endorsing these guidelines and promoting their integration into clinical practice.