Higher Hydroxychloroquine Dose Progressively Increases Incidence of Retinopathy
Key findings
- This long-term, real-world study investigated the incidence of hydroxychloroquine retinopathy at varying doses and levels of adherence in 3,325 patients who had serial, expert-adjudicated retinal scans
- The overall cumulative incidence of hydroxychloroquine retinopathy was 2.5% at 10 years of use and 8.6% at 15 years
- Of the 81 cases of hydroxychloroquine retinopathy, 56 (69%) were of the mild, typically asymptomatic stage; only eight (10%) were severe
- A higher average dose of hydroxychloroquine in the first five years of use was associated with a higher cumulative incidence of retinopathy—22% at 15 years for patients who used >6 mg/kg daily and 11% at 15 years for those who used 5 to 6 mg/kg daily
- If contemporary dosing and surveillance guidelines are followed, loss of visual acuity associated with hydroxychloroquine treatment should be rare
Long-term hydroxychloroquine toxicity leads to retinopathy, which in its advanced "bull's eye" stage, can cause permanent vision loss. Joint 2020 guidelines of the American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society and American Academy of Ophthalmology recommend keeping dosing below 5 mg/kg daily.
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That guidance is based mainly on a cross-sectional study published in JAMA Ophthalmology that found the prevalence of hydroxychloroquine retinopathy was 7.5% among long-term users and odds of retinopathy were five times greater at dosages higher than 5 mg/kg per day.
Massachusetts General Hospital researchers have now gathered data on the incidence of hydroxychloroquine retinopathy with long-term use, a more accurate guide to future risk than prevalence. They report in the Annals of Internal Medicine that the long-term risk was greater in patients who received higher doses of hydroxychloroquine in the first five years of use. Still, most cases of retinopathy were detected in the mild, asymptomatic stage.
The authors, all affiliated with the Division of Rheumatology, Allergy and Immunology at Mass General, are April M. Jorge, MD, clinical rheumatologist, Hyon K. Choi, MD, director of the Clinical Epidemiology Program and clinical rheumatologist, Yuqing Zhang, ScD, director of Epidemiological and Biostatistical Methods, and colleagues.
Methods
The primary study population included 3,325 adults identified in a health network database who had a rheumatic or dermatologic condition, started hydroxychloroquine treatment between January 2004 and December 2014, and continued to use the medication for at least five years:
- ≤5 mg/kg daily—65% of patients
- 5–6 mg/kg daily—16%
- >6 mg/kg daily—19%
The dates of hydroxychloroquine initiation were selected such that all patients were eligible for annual screening with spectral domain optical coherence tomography (SD-OCT) starting at five years of use (SD-OCT screening became available in 2009). The scans were adjudicated by expert ophthalmologists masked to hydroxychloroquine dose.
The researchers also analyzed an expanded secondary study population of 4,677 patients who met the same inclusion criteria, except they started hydroxychloroquine between July 1997 and December 2014.
Overall Risk
81 cases of incident hydroxychloroquine retinopathy (2.4%) occurred in the primary study population after a median duration of use of nine years (range, 5–16 years):
- Cumulative incidence—2.5% at 10 years, and 8.6% at 15 years
- Severity—56 cases (69%) were mild, 17 (21%) were of moderate severity, and eight (10%) were severe
The secondary study population had 164 cases of incident hydroxychloroquine retinopathy (3.5%), with a cumulative incidence of 11.5% at 20 years from treatment initiation.
Risk Associated With Weight-based Dose
The cumulative incidence of hydroxychloroquine retinopathy was progressively higher for each higher dosage:
- ≤5 mg/kg daily—2.7% (95% CI, 1.5%–4.8%)
- 5–6 mg/kg daily—11.4% (95% CI, 4.0%–29.9%)
- >6 mg/kg daily—21.6% (95% CI, 14.6%–31.4%)
This pattern was similar regardless of retinopathy severity. The results were similar when the researchers accounted for covariates that potentially predict hydroxychloroquine retinopathy.
In the secondary study population, the cumulative incidence of hydroxychloroquine retinopathy was likewise associated with weight-based hydroxychloroquine dose and continued to increase through 20 years of use.
Guidance for Prescribers
Retinopathy risk is considerably lower with shorter doses and duration of hydroxychloroquine use. Even with long-term use, though, loss of visual acuity is rare if contemporary dosing and surveillance guidelines are followed. Also, previous work published in Retina has shown that mild and moderate cases of hydroxychloroquine retinopathy are unlikely to become severe after the drug is withdrawn.
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