The history of the development of antimalarial drugs and their use to treat rheumatic diseases, particularly lupus, is the history of tension between efficacy and toxicity. Extracts from the bark of the Andean Cinchona tree were found to be effective against malaria, and imported from South America into Europe in the 17th century and widely used to treat malaria and other febrile illnesses. There was a high level of interest in this medication as illustrated by offering of a 20,000 Franc prize in France for isolation of its active compounds; the most notable of which turned out to be quinine. It was soon recognized that large doses of quinine were associated with significant toxicities, collectively termed 'chinconism' including flushing, confusion, tinnitus, hearing loss, ataxia tremor, and visual disturbances including blindness.
Payne first reported success using quinine to treat cutaneous lupus in 1894, but widespread use of antimalarials for lupus awaited the development of less toxic derivatives. Quinacrine was developed in Germany in the 1920s and later manufactured in the USA during World War II. It was administered to millions of American soldiers in the South Pacific for malaria prophylaxis for several years with no reported retinal toxicity. Chloroquine was developed in 1934 and after its introduction was found to have significant retinal toxicity. In 1945, hydroxychloroquine was synthesized with the hope that it would be a less toxic alternative to chloroquine and have lower risk of retinal toxicity. Subsequent experience over almost a century has confirmed that quinacrine, as monotherapy, is unique among antimalarials for lupus in having no retinal toxicity. It has been widely assumed, although it is less well established, that addition of quinacrine to hydroxychloroquine, and or chloroquine to treat lupus can achieve greater therapeutic efficacy without increasing the risk of retinal toxicity.
Quinacrine was first used for discoid lupus in the 1940s and chloroquine in the 1950s. In 1956, hydroxychloroquine was reported to be effective in discoid lupus with less toxicity than chloroquine at equivalent doses. From this era, when corticosteroids were just being introduced, there are dozens of reports of the efficacy of quinacrine for discoid and systemic lupus.[4–7] Dubois described highly favorable responses to quinacrine and interestingly reported that quinacrine impaired the formation of LE cells in vitro. Frances Page in 1951 wrote that 'Quinacrine …was used in a case of lupus erythematosus. The result was so dramatic that all cases of lupus erythematosus seen in this hospital…have been treated with this drug…Eighteen cases have been observed, and only one failed to improve… In a few cases all the lesions disappeared within 6 weeks so that it was impossible to distinguish their previous sites'.
In 1959, Tye reported the effectiveness of Triquin, a combination of chloroquine, hydroxychloroquine, and quinacrine in the New England Journal of Medicine and Triquin was FDA approved. As a result, quinacrine became FDA approved as an ingredient in Triquin. In 1972, the FDA in a campaign against combination drugs, mandated cessation of sale of Triquin. Since that time quinacrine has been used without FDA approval as monotherapy. Until recently quinacrine could readily be obtained from compounding pharmacies in the USA. Unfortunately, it is now impossible to obtain.
In the ensuing 70 plus years, quinacrine, alone or in combination with hydroxychloroquine or chloroquine has been effectively used for lupus with remarkable safety. Studies in the 1990s by Feldman and Lipsker et al. reported response rates on the order of 75% when quinacrine was added to hydroxychloroquine or chloroquine for cutaneous lupus. Toubi reported improvement of the SLEDAI in 5 of 6 patients with systemic lupus treated with combination therapy. In a larger study in 2018, Ugarte reported improvement of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI in 47 lupus patients when quinacrine was added to their baseline regimens, most of which included hydroxychloroquine. Recent surveys by Mittal[16,17] and colleagues have confirmed widespread and safe use of this compound in academic dermatologic practices.
Quinacrine therefore has a place in the management of systemic lupus as a safe and effective drug that enhances is the effects of antimalarials is with reduced ocular toxicity. The case for quinacrine in lupus management has been elegantly made over the years by Wallace.[3,18] The value of quinacrine in our therapeutic armamentarium can be summarized as follows:
Of the antimalarial drugs quinacrine stands out for alleviating fatigue, and increasing focus and concentration. This may be in part a property of the drug itself rather than its direct effect on lupus. Patients who have had to discontinue quinacrine mourn the loss of its effects on mental focus and alertness.
As monotherapy quinacrine is highly effective and fast acting, particularly for cutaneous disease.
Addition of quinacrine to hydroxychloroquine or chloroquine provides greater drug exposure with less potential ocular toxicity than increasing the dose of either hydroxychloroquine or chloroquine with no infectious risk.
Recent studies have emphasized the marked increase in toxicity of hydroxychloroquine in standard doses when it has been administered for 5 to 10 years. The combination of low doses of quinacrine and hydroxychloroquine could be used for long-term maintenance with reduced risk of retinal toxicity.
There is a strong argument for performing a large clinical trial of quinacrine with the goal of reintroducing it as a drug for lupus with FDA approval. This would be a relatively straightforward process, as the drug is easily synthesized, its side effects are well understood, and there is no need for dose ranging. The weight of the evidence suggests that it would prove effective in achieving the endpoint of reduced disease activity. It is also likely to score highly in patient generated measures of improvement and satisfaction. In an era when increasingly complex and costly biologic agents are being tested, it is time to reintroduce this easily manufactured, safe, and effective drug.
Financial support and sponsorship
Supported by the Michael and Marcia Klein Lupus Research Fund.
Curr Opin Rheumatol. 2021;33(3):219-220. © 2021 Lippincott Williams & Wilkins