What are the ocular side effects of hydroxychloroquine (Plaquenil) and how can they be mitigated?

From the Guidelines

Hydroxychloroquine can cause serious ocular side effects, primarily retinopathy, which may lead to permanent vision loss, and to mitigate these risks, patients should undergo baseline ophthalmologic examination before starting treatment, followed by regular screenings, typically annual exams after 5 years of use for low-risk patients, and earlier or more frequent monitoring for high-risk individuals, as recommended by the 2021 American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and American Academy of Ophthalmology joint statement 1. The most concerning complication is bull's eye maculopathy, characterized by damage to the central retina. Other ocular effects include corneal deposits, ciliary body dysfunction, and rarely, lens opacities. Some key points to consider:

• Risk factors that require closer monitoring include daily doses exceeding 5 mg/kg of real body weight, kidney or liver disease, concurrent tamoxifen use, and treatment duration beyond 5 years.
• Modern screening should include automated visual fields and spectral domain optical coherence tomography, as recommended by the 2016 revision of the recommendations on screening for chloroquine and hydroxychloroquine retinopathy 1.
• Dose adjustment based on real body weight rather than ideal body weight is recommended, with most patients not exceeding 400 mg daily.
• Early detection is crucial as retinopathy may progress even after medication discontinuation, but identifying changes before advanced damage occurs can prevent significant vision loss, as noted in the 2016 study on recommendations for screening for chloroquine and hydroxychloroquine retinopathy 1. The mechanism of toxicity involves disruption of lysosomal function and accumulation of the drug in melanin-containing tissues like the retinal pigment epithelium. It is essential to weigh the benefits of hydroxychloroquine against the potential risks, particularly for patients with pre-existing ocular conditions or those taking high doses for extended periods, and to follow the guidelines set forth by the American College of Rheumatology, American Academy of Dermatology, Rheumatologic Dermatology Society, and American Academy of Ophthalmology joint statement 1.

From the FDA Drug Label

1. 2 Retinal Toxicity Irreversible retinal damage was observed in some patients treated with hydroxychloroquine sulfate and it is related to cumulative dosage and treatment duration. In patients of Asian descent, retinal toxicity may first be noticed outside the macula Risk factors for retinal damage include daily hydroxychloroquine sulfate dosages ≥ 5 mg/kg of actual body weight, durations of use greater than five years, renal impairment, use of concomitant drug products such as tamoxifen citrate, and concurrent macular disease Within the first year of starting hydroxychloroquine sulfate, a baseline ocular examination is recommended including best corrected distance visual acuity (BCVA), an automated threshold visual field (VF) of the central 10 degrees (with retesting if an abnormality is noted), and spectral domain ocular coherence tomography (SD-OCT) For patients at higher risk of retinal damage, monitoring should include annual examinations which include BCVA, VF and SD-OCT. For patients without significant risk factors, annual retinal exams can usually be deferred until five years of treatment. In patients of Asian descent, it is recommended that visual field testing be performed in the central 24 degrees instead of the central 10 degrees If ocular toxicity is suspected, discontinue hydroxychloroquine sulfate and monitor the patient closely given that retinal changes and visual disturbances may progress even after cessation of therapy.

The ocular side effects of hydroxychloroquine (Plaquenil) include irreversible retinal damage, which is related to cumulative dosage and treatment duration.

• Risk factors for retinal damage include:
  • Daily dosages ≥ 5 mg/kg of actual body weight
  • Durations of use greater than five years
  • Renal impairment
  • Use of concomitant drug products such as tamoxifen citrate
  • Concurrent macular disease To mitigate these risks, the following monitoring is recommended:
• A baseline ocular examination within the first year of starting hydroxychloroquine sulfate, including:
  • Best corrected distance visual acuity (BCVA)
  • Automated threshold visual field (VF) of the central 10 degrees
  • Spectral domain ocular coherence tomography (SD-OCT)
• Annual examinations for patients at higher risk of retinal damage, including BCVA, VF, and SD-OCT
• Discontinuation of hydroxychloroquine sulfate if ocular toxicity is suspected, with close monitoring of the patient given that retinal changes and visual disturbances may progress even after cessation of therapy 2.

From the Research

Ocular Side Effects of Hydroxychloroquine

The ocular side effects of hydroxychloroquine (Plaquenil) can be significant and may lead to serious vision loss. Some of the known side effects include:

• Keratopathy
• Ciliary body involvement
• Lens opacities
• Retinopathy, which is the major concern and can cause:
  • Bull's eye maculopathy
  • Parafoveal retinal pigment epithelial atrophic changes
  • Paracentral scotomas
  • Central and peripheral field loss
  • Decreased vision
  • Glare
  • Blurred vision
  • Light flashes
  • Metamorphopsia

Risk Factors for Ocular Toxicity

Several risk factors can increase the likelihood of ocular toxicity from hydroxychloroquine, including:

• Daily dosage of hydroxychloroquine
• Cumulative dosage (risk increases sharply towards 1% after 5-7 years of use or a cumulative dose of 1000g) 3, 4
• Duration of treatment
• Coexisting renal or liver disease
• Patient age
• Concomitant retinal disease
• High-dose nonsteroidal antiinflammatory drugs 3

Screening and Mitigation

To mitigate the risk of ocular toxicity, regular screening is recommended, including:

• Baseline examination before starting hydroxychloroquine therapy
• Annual screening after 5 years of therapy, or sooner if there are unusual risk factors 4
• Use of objective tests such as multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) 4
• Visual field testing, including 10-2 automated fields 5, 4
• Fundus examinations to document any visible changes 4
• Patient awareness of the risk of toxicity and the importance of regular screening 4, 6

Management of Ocular Toxicity

If ocular toxicity is suspected or confirmed, the management options include:

• Cessation of hydroxychloroquine therapy, which is the only effective management of the toxicity 6
• Collaboration with the rheumatologist or physician managing the patient to decide on the best course of action 6