Risks for Hydroxychloroquine Retinopathy Described in Detail
Older patients prescribed hydroxychloroquine (HCQ) have a higher risk of developing retinal damage from taking the medication, according to a new analysis.
In addition to known risk factors such as a higher weight-based HCQ dose and higher cumulative dose, researchers also found that female sex, chronic kidney disease stage III, and tamoxifen use were associated with HCQ retinopathy.
The findings provide “evidence for other key risk factors for hydroxychloroquine retinopathy beyond hydroxychloroquine exposure itself,” wrote April Jorge, MD, of the Division of Rheumatology, Allergy, and Immunology at Massachusetts General Hospital, Boston, and colleagues.
April Jorge, MD
“It is the largest cohort study to date looking specifically at the association of [HCQ] retinopathy with risk factors,” said Christina Weng, MD, MBA, a professor of ophthalmology at Baylor College of Medicine, Houston, in an interview with Medscape Medical News. She was not involved with the research. Some of the associations, such as tamoxifen use, “have been suggested before in smaller studies, but never on this scale,” she said.
Christina Weng, MD, MBA
“It’s provided reinforcement of findings that we have seen from prior research and also some new glimpses into strengthening some associations that were identified, but not yet fully understood, in prior work,” she continued.
Study Details
Researchers identified patients in the Kaiser Permanente Northern California (KPNC), Oakland, California, health system who began taking HCQ between July 1, 1997, and December 14, 2014. To be included, patients needed to have at least 5 years of continuous enrollment in the KPNC system and at least one prescription for HCQ after more than 5 years of starting the drug. Patients were followed from HCQ initiation to their last retinopathy screening study, up to December 31, 2020.
The study was published in JAMA Network Open on May 9.
Of the 4677 users followed for the study, 83% were women, and the average age starting HCQ was 52. Most patients were White (58.1%), while 13.7% were Asian, 10.5% were Black, and 17.7% were Hispanic.
More than 60% of patients had an initial dose > 5 mg/kg/d, though the mean initial dose of HCQ was 4.4 mg/kg/d. After 5 years, only 34.4% of patients were using a daily dose over 5 mg/kg.
Of the entire cohort, 125 patients (2.7%) developed HCQ retinopathy. As expected, cumulative HCQ exposure was associated with a higher retinopathy risk: For every 100 g of HCQ cumulative exposure, risk rose by 64% (hazard ratio [HR], 1.64; 95% CI, 1.44-1.87).
Age was a significant risk factor for retinal damage from HCQ use. Individuals who began taking the drug at 65 years or older were nearly six times more likely to develop retinopathy than those who started HCQ when they were younger than 45. In people aged 55-64 years, this risk was nearly four times higher, and individuals aged 45-54 years when starting the drug were 2.5 times more likely to have retinal damage than those younger than 45.
Other risk factors were female sex (HR, 3.83; 95% CI, 1.86-7.89), chronic kidney disease stage III (HR, 1.95; 95% CI, 1.25-3.04), and tamoxifen use (HR, 3.43; 95% CI, 1.08-10.89), although only 17 patients were taking tamoxifen during the study.
Researchers also found that the type of HCQ retinopathy varied by race. Of the 125 cases in the cohort, 102 had a parafoveal pattern, and 23 had a pericentral pattern. Asian individuals were 15 times more likely, and Black individuals were more than five times more likely to develop this pericentral type than White patients.
This association in Asian patients has also been found in previous studies, Weng said, and many eye practices now screen their Asian patients with a 30-2 Humphrey visual field — rather than the more commonly used 10-2 — to examine areas farther outside the center.
This study also found this association in Black patients, though only five Black patients developed HCQ retinopathy over the study period.
“More studies and larger studies will be very helpful in strengthening or dispelling some of the associations that have been seen here,” Weng said.
‘More Room for Personalized Medicine’
The team found a “relatively linear” relationship between HCQ dose and retinopathy risk, with higher daily doses correlating with higher incidence. While 2016 guidelines from the American Academy of Ophthalmology advise using < 5 mg/kg, "what we found is it's not that straightforward [where there's] just this one cutoff," Jorge told Medscape Medical News in an interview. "It does seem like the higher the dose of medication per bodyweight and the longer duration of use, there is a higher risk of retinopathy."
These findings leave “a bit more room for personalized medicine” with patients, she explained. “For an elderly female patient with CKD, aiming for a dose < 5 mg/kg might be more appropriate; however, a young male patient without any additional risk factors may be able to exceed 5 mg/kg and continue to have a low risk for HCQ retinopathy," she said.
“For anyone, I think it really is more of an individual risk-benefit evaluation,” rather than strict cutoffs, she continued.
“Guidelines are just that: They’re guidelines,” added Weng, “and treatment plans should be tailored to each individual patient.”
As the study authors also discussed, “the goal is to treat the patient with the lowest dose that is still effective and also be mindful of the duration that a patient is left at higher doses,” Weng said. “But ultimately, we need to control these diseases, which can cause damage across multiple organ systems in the body. While it’s important to be aware of the potential retinopathy adverse events, we also don’t want physicians to feel restricted in their use of this very effective drug.”
The work of three co-authors on the current study was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Jorge’s work on the study was supported by an award from the Rheumatology Research Foundation and a grant from NIAMS.
Jorge reported clinical trial agreements with Bristol Myers Squibb and Cabaletta Bio outside of this study. Weng has served as a consultant for Allergan/AbbVie, Alcon, Apellis Pharmaceuticals, Alimera Sciences, DORC, Novartis, Genentech, Regeneron, RegenxBio, Iveric Bio, and EyePoint Pharmaceuticals. Weng also disclosed financial relationships with Springer Publishers (royalties) and DRCR Retina Network, Alimera Sciences, and Applied Genetic Technologies Corporation (research).
