Aesthetic Dermatology Update

The resurgence of Plaquenil (hydroxychloroquine)


 

Two of the most unusual dermatologic drugs have resurged as possible first-line therapy for rescue treatment of hospitalized patients with SARS-CoV-2, despite extremely limited clinical data supporting their efficacy, optimal dose, treatment duration, and potential adverse effects.

Dr. Lily Talakoub

Chloroquine and hydroxychloroquine were introduced as treatment and prophylaxis of malaria and approved by the Food and Drug Administration in 1949 and 1955, respectively. They belong to a class of drugs called 4-aminoquinolones and have a flat aromatic core and a basic side chain. The basic property of these drugs contribute to their ability to accumulate in lysosomes. They have a large volume of distribution in the blood and a half-life of 40-60 days. Important interactions include use with tamoxifen, proton pump inhibitors, and with smoking. Although both drugs cross the placenta, they don’t have any notable effects on the fetus.

Chloroquine and hydroxychloroquine enter the cell and accumulate in the lysosomes along a pH gradient. Within the lysosome, they increase the pH, thereby stabilizing lysosomes and inhibiting eosinophil and neutrophil chemotaxis and phagocytic activity. They also inhibit complement-mediated hemolysis, reduce acute phase reactants, and prevent MHC class II–mediated auto antigen presentation. Additionally, they decrease cell-mediated immunity by decreasing the production of interleukin-1 and plasma cell synthesis. Hydroxychloroquine can also accumulate in endosomes and inhibit toll-like receptor signaling, thereby reducing the production of proinflammatory cytokines.

One of the ways SARS-CoV-2 enters cells is by up-regulating and binding to ACE2. Chloroquine/hydroxychloroquine reduce glycosylation of ACE2 and thus inhibit viral entry. Additionally, by increasing the endosomal pH, they potentially inactivate enzymes that viruses require for replication. Their lifesaving benefits, however, are thought to involve blocking the proinflammatory cytokine IL-6 and suppressing the cytokine storm thought to induce acute respiratory distress syndrome. Interestingly, chloroquine has also been shown to allow zinc ions into the cell, and zinc is a potent inhibitor of coronavirus RNA polymerase.

Side effects of chloroquine and hydroxychloroquine include GI upset, retinal toxicity with long-term use, hypoglycemia, cardiomyopathy, QT prolongation, ventricular arrhythmias, and renal and liver toxicity. Adverse effects have been observed with long-term daily doses of more than 3.5 mg/kg of chloroquine or more than 6.5 mg/kg of hydroxychloroquine. Cutaneous effects include pruritus, morbilliform rashes (in an estimated 10% of those treated) and psoriasis flares, and blue-black hyperpigmentation (in about 25%) of the shins, face, oral palate, and nails.

Dr. Naissan O. Wesley, a dermatologist who practices in Beverly Hills, Calif.

Dr. Naissan O. Wesley

Initial in vitro studies first showed evidence of the ability of chloroquine and hydroxychloroquine to inhibit SARS-CoV-2 viral activity. In February 2020, the first clinical results of 100 patients treated with chloroquine were reported in a news briefing by the Chinese government. On March 20, the first clinical trial was published offering guidelines for the treatment of COVID-19 using hydroxychloroquine and azithromycin combination therapy – albeit with many limitations and reported biases in the study. Despite the poorly designed studies and inconclusive evidence, on March 28, the FDA issued an Emergency Use Authorization that allows providers to request a supply of hydroxychloroquine or chloroquine for hospitalized patients with COVID-19 who are unable to join a clinical trial.

On April 2, the first clinical trial to evaluate the safety and efficacy of hydroxychloroquine in adults hospitalized with COVID-19 began at Vanderbilt University Medical Center, Nashville, Tenn. The ORCHID trial (Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease), funded by the National Heart, Lung, and Blood Institute. This blinded, placebo-controlled study is evaluating hydroxychloroquine treatment of hospitalized patients with COVID-19 in hopes of treating the severe complications of acute respiratory distress syndrome. Participants are randomly assigned to receive 400 mg hydroxychloroquine twice daily as a loading dose and then 200 mg twice daily thereafter on days 2-5. As of this writing, this study is currently underway and outcomes are expected in the upcoming weeks.

There is now a shortage of chloroquine and hydroxychloroquine in patients who have severe dermatologic and rheumatologic diseases, which include some who been in remission for years because of these medications and are in grave danger of recurrence. During this crisis, we desperately need well-controlled, randomized studies to test the efficacy and prolonged safety profile of these drugs in COVID-19 patients, as well as appropriate funding to source these medications for hospitalized and nonhospitalized patients in need.

Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Talakoub. They had no relevant disclosures. Write to them at dermnews@mdedge.com.

Sources

Liu J et al. Cell Discov. 2020 Mar 18. doi: 10.1038/s41421-020-0156-0.

Vincent MJ et al. Virol J. 2005 Aug 22;2:69.

Gautret P et al. Int J Antimicrob Agents. 2020 Mar 20. doi: 10.1016/j.ijantimicag.2020.105949.

Devaux CA et al. Int J Antimicrob Agents. 2020 Mar 12:105938. doi: 10.1016/j.ijantimicag.2020.105938.

Aronson J et al. COVID-19 trials registered up to 8 March 2020 – an analysis of 382 studies. 2020. Centre for Evidence-Based Medicine. https://www.cebm.net/oxford-covid-19/covid-19-registered-trials-and-analysis/

Savarino A et al. Lancet Infect Dis. 2003 Nov;3(11):722-7.

Yazdany J, Kim AHJ. Ann Intern Med. 2020 Mar 31. doi: 10.7326/M20-1334.

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