Hydroxychloroquine, Chloroquine, and Arrhythmic Risk in Systemic Autoimmune Diseases: Focus More on the Patient and You Will Keep the Rhythm!

Abstract

S ystemic autoimmune rheumatic diseases (SARDs), such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, are a group of chronic inflammatory diseases characterized by an interaction between genetic predisposition, environmental triggers, and immune responses, resulting in immune system dysfunction and systemic inflammation. 1,2 Although acute treatment is dominated by glucocorticoids, hydroxychloroquine (HCQ) and chloroquine (CQ) represent a cornerstone of chronic therapies. 1,3 HCQ and CQ are considered Disease-Modifying Antirheumatic Drugs (DMARDs) that are able to slow rheumatological disease progression. At the molecular level, they interfere with lysosomal activity and autophagy, affect membrane stability, and alter signaling pathways and transcriptional activities. 4 At the cellular level, they exert their immunomodulatory effects through several direct and indirect mechanisms, reducing Toll-Like Receptor signaling, cytokine production, and CD154 expression in T cells. 4 However, despite their wide use and benefits, some cardiac concerns arose with their administration as potential treatments for patients with Coronavirus disease-2019 (COVID-19), in particular, druginduced heart rate-corrected QT interval (QTc) prolongation and Torsades de Pointes ventricular tachycardia (TdP) onset. 5,6 The direct cardiotoxicity of COVID-19 itself, the specific dosage used, the duration of the treatment, and the combination with another QTcprolonging medication (azithromycin) make direct comparisons to patients with SARDs impossible. 3,7 In 2021, the American College of Rheumatology highlighted the possible severe cardiac side effects of HCQ and CQ, such as QTc prolongation, cardiac conduction abnormalities, sudden cardiac death, and cardiomyopathy. 3 These side effects were thought to result from direct drug-induced hERG (human ether-a-go-go-related gene) potassium channel blockade and/or drug accumulation in cardiac lysosomes with consequent lysosomal enzymatic inhibition and cardiac myocyte vacuolization. 3 However, prospective data are currently lacking to accurately determine the risk of QTc prolongation and the actual incidence of cardiac toxicity among patients with SARDs treated with HCQ and CQ.In the present issue of the Journal of Cardiovascular Pharmacology, Dr. Nikolic and colleagues 8 present a study aiming at assessing the prevalence of arrhythmias and cardiac conduction abnormalities associated with the use of HCQ (at a dosage #400 mg/day) and CQ (at a dosage #250 mg/day) in patients with SARDs, and at comparing the QTc length and the risk of prolonged QTc between those taking these drugs and those not. To this purpose, the authors systematically reviewed the literature, including 34 studies for qualitative synthesis (19 retrospective, 6 prospective, 5 case controlled, and 3 retrospective observational-including pharmacovigilance) and 11 studies for quantitative synthesis (meta-analysis). Most studies (n = 26) reported outcomes among HCQ users, 6 in both HCQ and CQ users, and 2 in CQ users alone...