Screening for Hydroxychloroquine Toxicity

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Hydroxychloroquine is widely used as a low-cost and effective treatment for rheumatoid arthritis, systemic lupus erythematosus, and many other dermatologic and rheumatologic/inflammatory conditions. While it is generally well tolerated by patients, its only major downside is the potential for retinal toxicity. The risk is related to the daily dose by weight, with the lowest risk achieved by a daily dose lower than 5 mg/kg/day (based on real body weight, not ideal body weight) [1]. Patients staying with less than 5 mg/kg/day have less than 1% risk in the first 5 years of therapy and less than 2% up to 10 years.

As eye care providers, we should be concerned about the possibility of toxicity because once it sets in, it is untreatable; however, if early signs of damage are recognized before the retinal pigment epithelium (RPE) is involved, central vision can be preserved [2].

Toxicity Characteristics

Hydroxychloroquine causes damage at the level of the photoreceptors and eventual RPE changes as the outer retinal nuclear layer degenerates [3]. Toxicity is classically described as a bilateral bull’s-eye maculopathy, an appearance caused by a ring of parafoveal RPE depigmentation that spares a foveal island and this is usually seen in patients of European, African-American, and Hispanic ancestry. Many patients of Asian descent will show initial damage in a more peripheral extramacular distribution near the arcades [4]. Retinopathy can continue to progress even after the drugs are stopped and could represent a gradual decompensation of cells that were injured metabolically during the period of exposure.

Screening Recommendations

The goal of screening is not to prevent damage, but to detect early toxicity and stop the use of medication before a patient’s vision is significantly affected. All patients beginning long-term

Hydroxychloroquine therapy should have a baseline ophthalmic exam within the first year of starting the drug to document any complicating ocular conditions and to establish a record of the fundus appearance and functional status. Although baseline visual fields and SD-OCT are always useful, it is not critical to obtain them at baseline unless abnormalities or co-morbidities are present that might affect screening tests. 

Below are the American Academy of Ophthalmology’s recommendations [4]:

Considering the initial low risk of toxicity, annual screening can be postponed until after five years of exposure. However, if the risk is higher, screening should start earlier and be conducted more often than once per year, especially for patients with significant risk factors such as a low kidney function, use of concomitant tamoxifen, and/or the presence of existing macular disease. Dosage checks relative to weight are advised at each appointment.

Routine primary screening is best conducted using automated visual fields and SD-OCT due to their wide availability. Visual fields may offer more sensitivity but can be subjective. SD-OCT provides objective and generally sensitive data on potential visually significant damage. At least one objective test should verify subjective results before a toxicity diagnosis is made unless toxic changes are severe and apparent.

The 10-2 field pattern offers high-resolution macular data and works excellently for non-Asian patients. However, broader test patterns (24-2 or 30-2) are advised for Asian patients as toxicity often extends beyond the macula.  Early damage usually appears in the inferotemporal regions of the macula with a corresponding superonasal field defect, but this does not happen every time.

Ambiguous changes in the visual field should trigger retesting for consistency, or additional objective tests like multifocal ERG, which measures the electric field, can be used to corroborate the findings. Additional testing can also include SD-OCT and fundus autofluorescence imaging. 

As the damage progresses, SD-OCT will demonstrate localized thinning of the photoreceptor layers in the parafoveal region in non-Asian eyes and damage close to the arcades in many Asian eyes. Initial damage could sometimes appear as focal areas of interruption in the photoreceptor outer segments. SD-OCT results are conclusive when regional thinning occurs in a standard pattern.

Ancillary Testing 

Multi-focal ERG, similar in sensitivity to visual fields, can provide objective evidence of suspected field loss. Autofluorescence imaging can highlight early parafoveal or extramacular photoreceptor damage, seen as areas of increased autofluorescence that sometimes precede thinning on SD-OCT. Late RPE loss manifests as darker areas of reduced autofluorescence.

In conclusion, ophthalmologists need to understand these guidelines for the early detection of hydroxychloroquine retinopathy, given that these drugs are widely used in treating several inflammatory and rheumatologic conditions.


  1. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132:1453–60.
  2. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA Ophthalmol 2014;132:1105–12.
  3. Marmor MF. Comparison of screening procedures in hydroxychloroquine toxicity. Arch Ophthalmol 2012;130:461–9.
  4. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology 2015;122:110–6.
  5. Marmor MF et al.  Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision). Ophthalmology 2016;123:1386-94.

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