Value of antimalarial drugs in the treatment of lupus

Introduction

Antimalarial agents are now used as the standard of care for the treatment of systemic lupus erythematosus (SLE). The first documented use of antimalarial medications dates back to the sixteenth century, when powder from the cinchona bark tree, which grows in the Andes, was used successfully to treat malaria and was distributed through Europe by the Jesuits. In the nineteenth century, chemical analysis showed that Cinchona bark contained 25 different alkaloids. Payne reported the first evidence-based successful use of quinine for cutaneous lupus in 1894. However, quinacrine (atabrine) was patented only 35 years after.

Quinacrine was used as antimalarial prophylactic drug by millions of US soldiers during the Second World War—the biggest unplanned safety trial for a single medication in history. During these years, the beneficial effects of quinacrine on inflammatory arthritis and skin rash were recognized. These observations led to the development of new drugs, including chloroquine, looking for more favorable safety profile and better effectivity against inflammatory conditions. There were early European reports on the use of antimalarial agents for the treatment of SLE. However, it was not until 1951 when Page, extrapolating from the observations he made during the Second World War, demonstrated a clear success in treating 18 patients with cutaneous lupus. This was the beginning of a new era. Hydroxychloroquine (HCQ), an analogue of chloroquine, came on the market in 1955 and, over the course of a few decades, became the cornerstone of SLE treatment.

Pharmacokinetics and pharmacodynamics of antimalarials

The most commonly used antimalarial in the United States for the treatment of SLE is HCQ. HCQ's bioavailability in healthy volunteers ranges between 0.67 and 0.74. HCQ and chloroquine have a very large volume of distribution and distribute extensively in tissues (particularly those containing melanin). Plasma protein binding of chloroquine ranges between 50% and 67%. Chloroquine apparently binds more avidly to corneal tissue than HCQ. Based on eye examinations, 95% of patients on chloroquine had corneal deposits, while this was seen only in 10% of the patients who were using HCQ. Transplacental distribution is slow and the relative peak concentration in the fetus was only 1% of that in the mother. In 16 rheumatoid arthritis (RA) patients, chloroquine remained in the skin for 6–7 months after cessation of therapy. Chloroquine appears to concentrate in muscles. This observation led to a study that was designed to assess the effects of chloroquine on the heart, which were described only on rare occasions before. Chloroquine and its main metabolite were investigated in 12 volunteers that were given 3 mg/kg of intravenous chloroquine. The systolic blood pressure fell by 10 mm Hg, with an increase in the heart rate and a prolongation of the QR interval (from 81 to 92 ms) but without change in the QTc interval. The half-life of HCQ in the blood is 50 ± 16 days. The renal clearance of unchanged HCQ accounted for only 21% of the dose. In contrast to HCQ, between 28% and 47% of a chloroquine dose is excreted unchanged in the urine. Although hepatic metabolism is the principal route by which chloroquine is excreted, small amounts (between 0.7% and 4.2%) are excreted through breast milk. There is a linear relationship between the dose used and the clinical response and toxicity. In one study, a group of 34 RA patients had decreased morning stiffness and a better overall response with higher HCQ concentrations (697 ng/ml compared to 248 ng/ml). When the blood concentrations of HCQ were above 800 ng/ml, 80% of patients reported side effects, whereas no patients had side effects with blood concentrations below 400 ng/ml. Important drug–drug interactions were described with D-penicillamine and cimetidine but not with other medications used in combination with antimalarials.

Mechanisms of action