Hydroxychloroquine and COVID-19: a Rheumatologist's Take on the Lessons Learned

Abstract

Purpose of review: Told from the viewpoint of rheumatologists, this review tells the story of hydroxychloroquine and its swift ascent to become a household name as a therapeutic strategy against the novel SARS-CoV-2 virus. This review describes the history, mechanisms, pharmacokinetics, therapeutic applications, and safety profile of hydroxychloroquine as an immunomodulatory and antiviral agent. It also summarizes the major studies that launched and assessed the use of hydroxychloroquine against COVID-19 infection.

Recent findings: More recent literature calls into question the long-held dogma that endolysosomal alkalinization is the primary mode of action of hydroxychloroquine. Ongoing uncertainty about the multiple potential mechanisms contributing to the therapeutic effect of hydroxychloroquine in rheumatic and viral disease led to a natural avenue for exploration in the treatment of COVID-19. Taken as a whole, the literature does not support utilizing hydroxychloroquine to treat or prevent infection from the SARS-CoV-2 virus. This is, at least in part, due to the wide variability in hydroxychloroquine pharmacokinetics between patients and difficulty achieving adequate target tissue concentrations of hydroxychloroquine without encountering unacceptable toxicities. Hydroxychloroquine continues to be a routinely prescribed, well-tolerated, effective, and low-cost treatment for rheumatic disease. Its therapeutic versatility has led to frequent repurposing for other conditions, most recently as an investigative treatment against the SARS-CoV-2 virus. Despite overall negative findings, the intense study of hydroxychloroquine against COVID-19 infection has enhanced our overall understanding of how hydroxychloroquine operates in autoimmune disease and beyond.

Keywords: COVID-19; Hydroxychloroquine; Immunomodulation; SARS-CoV-2.

Fig. 1

Major proposed mechanisms of HCQ in autoimmune disease. Figure adapted from Schrezenmeier et al. [14], Wallace et al. [23], and Nirk et al. [24]. (Clockwise from bottom left) HCQ raises the pH of the lysosomal compartment, inhibiting hydrolytic enzymatic processing of extracellular autoantigen endocytosed by the cell. HCQ raises the pH of the autophagosomal compartment, inhibiting degradation of intracellular debris and autophagic flux. HCQ hinders fusion of lysosomes with autophagosomes, diminishing successful MHC class II-mediated autoantigen presentation by antigen-presenting cells. HCQ thwarts naïve T cell and B cell activation, subsequently decreasing production of autoreactive antibodies. HCQ limits Toll-like receptor signaling and cGAS-STING pathways, lessening production of proinflammatory cytokines. HCQ, hydroxychloroquine; TCR, T cell receptor; cGAS-STING, cyclic GMP-AMP stimulator of interferon genes; TLR, Toll-like receptor