Overall risk for hydroxychloroquine retinopathy low, increases with higher doses

The overall risk for incident retinopathy in patients who received hydroxychloroquine for 5 or more years was low but progressively increased with higher doses, according to researchers.

Hydroxychloroquine, which is recommended for patients with systemic lupus erythematosus and other inflammatory conditions, can have a “critical long-term adverse” impact: vision-threatening retinopathy, Ronald B. Melles, MD, an ophthalmologist affiliated with Kaiser Permanente Northern California, and colleagues wrote in Annals of Internal Medicine.

There has been limited research on the association between long-term hydroxychloroquine use and retinopathy, as well as the effects of hydroxychloroquine dose, which current guidelines recommend to be 5 mg/kg of body weight per day or lower, according to the researchers.

“Recent studies have found that lower dosing of hydroxychloroquine is associated with higher risk for lupus flares and hospitalizations compared with higher dosing, suggesting a clinically meaningful tradeoff in drug efficacy,” they wrote.

Melles and colleagues conducted a cohort study to better understand the long-term risk for incident hydroxychloroquine retinopathy and how much dosage affects that risk.

Using pharmacy and health records, the researchers assessed data from 3,325 people who received hydroxychloroquine for at least 5 years between 2004 and 2020 and classified any retinopathy cases they identified as mild, moderate or severe. They then approximated the risk for retinopathy development after 15 years based on average dosing levels in the first 5 years.

Of the participants, the researchers found that 81 developed hydroxychloroquine retinopathy: 56 cases were mild, 17 moderate and eight severe. They also noted cumulative incidences of 2.5% and 8.6% at 10 and 15 years, respectively.

Additionally, the researchers found that greater hydroxychloroquine dose was associated with a progressively higher risk. At 15 years, retinopathy cumulative incident rates were:

• 2.7% for 5 mg/kg per day or lower;
• 11.4% for 5 to 6 mg/kg per day; and
• 21.6% for higher than 6 mg/kg per day.

“We observed a progressively higher retinopathy risk for each higher hydroxychloroquine dose group,” they wrote. “We observed a higher risk for hydroxychloroquine retinopathy for patients who had CKD stage 3 or higher or were older than 55 years in addition to the risk associated with hydroxychloroquine dose.”

Melles and colleagues noted that the American Academy of Ophthalmology’s 2016 guidelines recommend avoiding using doses higher than 5 mg/kg of body weight to minimize the risk for hydroxychloroquine retinopathy and annual screening for hydroxychloroquine retinopathy with spectral domain optical coherence tomography (SD-OCT) imaging of the retina after 5 years of use.

“Our risk estimates, combined with the excellent intra-rater reliability of retinopathy outcomes per SD-OCT ... suggest that the true incidence of retinopathy is higher than reported before the use of routine screening with SD-OCT,” they wrote. “Fortunately, we observed that severe bull's-eye retinopathy was rare with routine screening. Because most mild and moderate cases are typically asymptomatic and unlikely to progress to severe retinopathy after hydroxychloroquine is withdrawn, our findings suggest that, under current screening recommendations and dosing patterns, loss of visual acuity from hydroxychloroquine retinopathy should be rare.”