Hydroxychloroquine belongs to the family of medicines called “antimalarials” (AMs), which are also classified as disease-modifying anti-rheumatic drugs, or DMARDs. These drugs were initially used to prevent and to treat malaria but are no longer used for those purposes; more effective drugs have since been developed. Today’s AMs are hydroxychloroquine (Plaquenil®), chloroquine (Aralen®), and quinacrine (Atabrine®). (Quinacrine is no longer marketed in the U.S.; it can be dispensed by a compounding pharmacy, although insurance companies may not pay for it.)

The antimalarial quinine was first used to treat cutaneous lupus in 1834. Subsequent reports in 1928 and 1938 showed good results with another quinine-like drug in the treatment of both discoid and subacute cutaneous lupus. In 1941, discoid lupus patients were treated successfully with Atabrine, a compound developed in Germany in the 1920s. In the mid-1940s, both hydroxychloroquine (HCQ) and chloroquine (CQ) had been synthesized. In 1955 HCQ was shown to be effective for both systemic lupus and rheumatoid arthritis. (Wallace DJ, Hahn BH, eds. Dubois’ Lupus Erythematosus. 1997:1117.)

In 1956, the U.S. Food and Drug Administration approved HCQ for symptoms of lupus and rheumatoid arthritis, particularly skin inflammation, hair loss, mouth sores, fatigue, and joint pain.

Dosing

Hydroxychloroquine is generally prescribed at a daily dose of 6.5 milligrams (or less) per kilogram of body weight. (Using this formula, the dosage for a 150-pound person would be 443 mg/day, as one kilogram equals 2.2 pounds.) Because HCQ is formulated as a 200 mg tablet, many people taking it for lupus will take two pills per day. Those who are newly diagnosed with lupus may take 400 mg once daily for several weeks while the medication builds up in their system, and then 200–400 mg daily after that. To lower the daily dosage, to adjust for low weight, or if there is kidney damage or kidney failure, HCQ may be taken every other day or tablets may be broken in half. To reduce stomach upset, HCQ is best taken with food or milk.

Benefits

Research into the wide-ranging effects of hydroxychloroquine has revealed many important benefits in the treatment of lupus; it must be noted that these benefits may be less effective in people who smoke (Arthritis Care & Research 2010; 62:393–400). Benefits include:

• Decrease in the number of disease flares.
• Decrease in damage from disease over time.
• Ability to delay absorption of ultraviolet light.
• Reduction in the number of antigen-presenting cells in the skin.

A systematic review published in Annals of Rheumatic Diseases in January 2009 looked at data on the clinical efficacy and side effects of AMs in systemic lupus, from randomized controlled clinical trials and observational studies, in 95 articles published between 1982 and 2007. The authors found:

• Strong evidence, especially with HCQ, of decreased lupus activity during pregnancy without harm to the fetus.
• Strong evidence of prevention of disease flares.
• Strong evidence of increased long-term survival.
• Moderate evidence of protection against irreversible organ damage, thrombosis (blood clot formation), and bone mass loss.

Side effects

In some people, HCQ may cause gastrointestinal problems, such as nausea, vomiting, upset stomach, cramps, or diarrhea. These may occur for the first few days a person takes the drug while the body adjusts to the medication. Loss of appetite, tiredness, weakness, or headache are uncommon side effects and typically go away over time.

Rare complications

The greatest concern people have when taking hydroxychloroquine is related to vision. Individuals beginning HCQ therapy should be informed of the possibility, although extremely rare, of retinal toxicity, and told that periodic monitoring can lead to early recognition of some symptoms. Hydroxychloroquine is the most commonly used AM, specifically because it has a lower risk for retinal toxicity than chloroquine. This may be because CQ crosses the blood-retinal barrier and HCQ does not. (There is no retinal damage associated with the use of quinacrine.)

The position statement on hydroxychloroquine retinopathy provided by the American College of Rheumatology (ACR)—and reviewed by the American Academy of Ophthalmology (AAO) in Ophthalmology 2002; 109:1377–82— recommends that all individuals starting HCQ have a complete baseline ophthalmologic exam within the first year of treatment, to include examination of the retina through dilated pupil and central visual field sensitivity testing, either by a self-testing grid chart or automated threshold central visual field testing (Humphrey 10-2 testing). Most U.S. rheumatologists also recommend an annual ophthalmologic checkup for anyone taking HCQ.

The AAO review makes several important points:

• The purpose of monitoring is to recognize early toxicity and not the prevention of toxicity.
• There is a strong suggestion from the literature that HCQ toxicity is related to dosage and duration of use. The majority of cases have occurred at more than 6.5/mg/kg/day and at more than five years of use.
• Patients who have macular degeneration or retinal dystrophy, or who have had previous HCQ use, may be more susceptible to toxicity or may at least present more complicated monitoring problems.
• Patients who have severe compromise of renal or hepatic systems might theoretically have more toxicity, as the drug is cleared from the body by these two organ systems.
• Obesity may cause an overestimation of the safe dose of HCQ, as the drug does not accumulate in fat.

Appropriate HCQ dosing standards for children or adolescents have not been sufficiently addressed in the available literature. Retinal abnormalities or new vision problems (including the inability to distinguish between colors) can indicate toxicity and should be discussed immediately with the consulting ophthalmologist. Hydroxychloroquine use in children younger than 7 may be limited by the difficulty in obtaining satisfactory evaluation of color vision in this age group. Therefore, children taking HCQ should receive an annual ophthalmologic examination.

Other rare side effects include changes in skin pigmentation and cardiomyopathy (diseases of the heart muscle).

The future

Hydroxychloroquine was previously prescribed only for people whose lupus disease activity was mild in its course; if the lupus became active, steroids or immunosuppressants would be prescribed instead. Today, however, HCQ is recommended for most individuals with lupus, whether mild, moderate, or severe, as well as during pregnancy and while breastfeeding. Given the drug’s many and varied beneficial effects and its excellent long-standing safety profile, most rheumatologists believe that hydroxychloroquine should be taken by people with lupus throughout their lifetime. Annual examinations with a qualified retina specialist are strongly encouraged, however.