Background: Chloroquine and hydroxychloroquine belong to the quinolone family. They are related drugs with different therapeutic and toxic doses with similar clinical indications for use and manifestations of retinal toxicity.

Initially, chloroquine was given for malaria prophylaxis and treatment, and, later, it was used by rheumatologists for treating rheumatoid arthritis, systemic/discoid lupus erythematosus, and other connective tissue disorders. Dermatologists use these drugs for cutaneous lupus. Since it is far less toxic to the retina, hydroxychloroquine has replaced chloroquine, except for individuals who travel in areas endemic with malaria.

Expanded use of these drugs for nonmalarial disease entities has resulted in prolonged duration of therapy and higher daily dosages leading to cumulative doses greater than those used in antimalarial therapy. The first reports of retinal toxicity attributed to chloroquine appeared during the late 1950s. In 1958, Cambiaggi first described the classic retinal pigment changes in a patient receiving chloroquine for systemic lupus erythematous (SLE) treatment. In 1959, Hobbs established a definite link between long-term use of chloroquine and subsequent development of retinal pathology. In 1962, J Lawton Smith coined the term bull's eye maculopathy, regarded as the classic finding of macular toxicity. Many reports on chloroquine retinopathy exist. In contrast, only a few cases of hydroxychloroquine toxicity have been reported.

Pathophysiology: Chloroquine has an affinity for pigmented (melanin-containing) structures, which may explain its toxic properties in the eye. Melanin serves as a free-radical stabilizer and as an agent that can bind toxins. Although it binds potentially retinotoxic drugs, it is unclear whether the effect is beneficial or harmful. Chloroquine and its principal metabolite have been found in the pigmented ocular structures at concentrations much greater than in any other tissue in the body. With more prolonged exposure, the drug accumulates in the retina. The drug is retained in the pigmented structures long after its use is stopped. The kinetics of chloroquine metabolism are complicated, with the half-life increasing as the dosage is increased. In patients with retinopathy, 5 years or more after discontinuation, traces of chloroquine have been found in plasma, erythrocytes, and urine.

Frequency:

• In the US: Two trends are consistent in literature, despite the variability of the statistics; the incidence of retinopathy increased with both the dose and the duration of treatment.

  Bernstein estimated an incidence of 10% in unmonitored patients taking 250 mg/d of chloroquine and 3-4% in unmonitored patients taking 400 mg/d of hydroxychloroquine.

• Internationally: Incidence from 1-28% has been reported.

Mortality/Morbidity: See Clinical for detailed information.

Race: No known racial predilection exists.

Sex: No known sexual predilection exists.

Age: No known age predisposition exists.

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