Long-Term Risk for Retinopathy Greater with Higher Hydroxychloroquine Doses

April M. Jorge, MD

The long-term risk for hydroxychloroquine retinopathy was progressively greater in patients who received higher doses of hydroxychloroquine in the first 5 years of use, according to new research published in Annals of Internal Medicine.

A large, contemporary cohort with active surveillance retinopathy screening reported an 8.6% overall cumulative incidence of hydroxychloroquine retinopathy after 15 years, although most cases were mild and severe bull’s eye retinopathy was rare.

“The long-term risk for incident hydroxychloroquine retinopathy observed in this real-world contemporary cohort was lower than the estimated risk based on the 2014 prevalence study that led to the current hydroxychloroquine screening and dosing guidelines but much higher than that reported in older studies done before the routine use of spectral domain optical coherence tomography [SD-OCT] for retinopathy screening,” wrote study author April M. Jorge, MD, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School.

The usage of hydroxychloroquine is recommended for all patients with systemic lupus erythematosus, with wide-ranging benefits, as well as other inflammatory diseases, including rheumatoid arthritis. However, its major long-term toxicity is hydroxychloroquine retinopathy, a complication which can cause permanent vision loss in its advanced stage of bull’s-eye retinopathy.

Guidelines from the American Academy of Ophthalmology in 2016 recommended annual screening for hydroxychloroquine retinopathy with SD-OCT imaging of the retina after 5 years of use and avoiding doses higher than 5 mg/kg of body weight to minimize risk. However, to date, data on the incidence of hydroxychloroquine retinopathy with long-term use and the effect of hydroxychloroquine dose on the risk remain lacking.

The retrospective cohort study identified patients aged 18 years or older from a systemwide program who initiated hydroxychloroquine treatment between January 2004 and December 2014 for a rheumatic or dermatologic condition.

For inclusion in the cohort, investigators required at least 1 prescription for hydroxychloroquine after 5 years for inclusion in the cohort. All participants were thus eligible for the annual SD-OCT screening starting at 5 years of use. Incident hydroxychloroquine retinopathy was assessed by central adjudication of SD-OCT with severity assessment (mild, moderate, or severe).

Exposure to hydroxychloroquine was assessed from pharmacy dispensing records. Risk for hydroxychloroquine retinopathy was estimated over 15 years of use according to the weight-based dose of hydroxychloroquine, categorized as at most 5, 5 to 6, or higher than 6 mg/kg per day.

The primary study population consisted of 3325 patients with data on SD-OCT imaging and hydroxychloroquine dispensing 60 months or more after initiation. Among this population, 2173 (65.4%) used 5 mg/kg or less, 532 (16.0%) used 5 to 6 mg/kg, and 620 (18.6%) used more than 6mg/kg.

Investigators identified 81 cases of incident hydroxychloroquine retinopathy (2.4%) in the primary study population. The cumulative incidences of nonhydroxychloroquine retinopathy in the study cohort were 2.5% at 10 years and 8.6% at 15 years. A total of 56 cases (69%) were mild, with 17 (21%) moderate and 8 (12%) severe.

Moreover, the cumulative incidence of hydroxychloroquine retinopathy was progressively higher for each higher weight-based dose of hydroxychloroquine. At 15 years, the incidences were 2.7% (95% CI, 1.5% to 4.8%) for 5mg/kg or less per day, 11.4% (95% CI, 4.0% - 29.9%) for 5 to 6 mg/kg per day, and 21.6% (95% CI, 14.6% to 31.4%) for more than 6 mg/kg per day.

In the secondary outcome of moderate or severe hydroxychloroquine retinopathy, the cumulative incidence was highest in the group receiving more than 6 mg/kg (5.9% at 15 years).

“Because most mild and moderate cases are typically asymptomatic and unlikely to progress to severe retinopathy after hydroxychloroquine is withdrawal, our findings suggest that, under current screening recommendations and dosing patterns, loss of visual acuity from hydroxychloroquine retinopathy should be rare,” Jorge wrote.

The study, “Hydroxychloroquine Dose and Risk for Incident Retinopathy: A Cohort Study,” was published in Annals of Internal Medicine.