CHICAGO -- Serious retinal toxicity associated with hydroxychloroquine (HCQ) and other antimalarial agents is largely preventable, and the risk of it shouldn't be a reason to withhold these drugs from patients with systemic lupus erythematosus, a specialist with unique expertise said here.
Keeping doses within recommended limits and screening lupus patients after they've been taking antimalarials for 5 years is key to reducing the risk, said James T. Rosenbaum, MD, of Oregon Health & Science University in Portland, speaking at the American College of Rheumatology's 2018 State of the Art Symposium.
Rosenbaum is both a rheumatologist and an ophthalmologist -- heading OHSU's Division of Arthritis and Rheumatic Disease and serving as chief of ophthalmology at the Legacy Devers Eye Institute, also in Portland -- and is the country's leading expert on inflammatory eye conditions, said Meenakshi Jolly, MD, MS, of Rush University here, in introducing him.
Antimalarials have a long history of use in lupus, Rosenbaum explained, going back at least to the 1950s, and have proved extremely valuable in treating the condition. A major demonstrated that not only did HCQ relieve many lupus symptoms, it also had a protective effect on survival, with an odds ratio of 0.128 (95% CI 0.054 to 0.301) compared with patients not on the drug.
More recently, another study showed that combining versus either drug alone and most dramatically versus neither.
How antimalarials work in lupus isn't entirely clear, but Rosenbaum listed a number of effects that likely contribute: inhibition of lysosomal enzymes and elements in the complement pathway, reductions in lipids and thrombotic factors, and spurring apoptosis of autoreactive T and B cells. The effect, he said, is to "modify the immune response without impairing normal immunity."
"Anyone who can tolerate an antimalarial should be on an antimalarial," he said flatly.
But tolerability is the key issue, and retinal toxicity is one of the most prominent adverse effects that may force patients off the drugs.
The risk for this effect has been recognized for a long time, although the first guidelines related to it did not come out until 2002. That year the for monitoring and for dosing to minimize risk.
That guideline called for regular screening with the Amsler grid to detect vision loss, and a dosing limit of 6.5 mg/kg/day. Rosenbaum said the motivation was driven, in large part, by more restrictive recommendations in the Physicians' Desk Reference, the principal reference work for all prescription drugs at the time. The PDR suggested screening every 3 months, which rheumatologists felt was unnecessarily frequent, he explained.
But the development of optical coherence tomography (OCT) has completely revolutionized screening, Rosenbaum said, by making it possible to detect retinal toxicity before clinical vision loss occurs. At early stages, layers in the retinal pigment epithelium begin to degrade and separate, creating the so-called "flying saucer" or "sombrero" sign, which can be clearly seen on OCT scans.
Current recommendations -- -- now make fundus photography and OCT the central feature of monitoring, with a baseline fundus scan to be performed during the first year of HCQ use, and then annually with spectral domain OCT beginning in year 5 of treatment.
Screening should begin even sooner "in the presence of major risk factors," one of which is HCQ dosing above 5 mg/kg/day, as data have shown that the risk of retinal toxicity is roughly doubled with these doses relative to 4-5 mg/kg/day.
The 2016 AAO guideline, in fact, recommends dosing be limited to no more than 5 mg/kg/day, but a indicated that about half of patients were getting more than the recommended dosage.
However, Rosenbaum emphasized, the guidelines also specify that antimalarials should not necessarily be stopped at the first sign of retinal abnormality. Quoting the document, he said, the goal is "to recognize definitive signs of toxicity at an early enough stage to prevent a loss of visual acuity."
Notably, the American College of Rheumatology's most recent statement on the issue is deliberately vague, Rosenbaum said, merely calling for "periodic" ocular exams -- no specific interval given -- and that the screening plan should be tailored to individuals' risks, which are also not specified.