Chloroquine (CQ) and hydroxychloroquine (HCQ) have been prescribed for nearly 50 years mostly as malarial drugs, indicated for both the acute phase of malaria and for prophylaxis. However, they are also prescribed for rheumatologic diseases, such as rheumatoid arthritis and lupus erythematosus; for limited use in the treatment of hypercalcemia in sarcoidosis (Iannuzzi et al, 2007), and they have uses in the dermatologic and oncologic arenas.

As a result of a large longitudinal, multi-center study, HCQ has become increasingly more prescribed for conditions such as lupus erythematosus (Alarcón et al, 2007). HCQ is available as a 200mg tablet, and its dosage depends on the condition treated. Maintenance dosing for the rheumatologic diseases ranges from 200mg to 400mg per day, but the dose may be higher in the first one to three months of treatment.

At recommended dosages, the risk for retinal toxicity at five and 10 years is 1% and 2%, respectively. This increases to 20% in patients who have been using the drug for 20 years. The greatest risk for toxic retinopathy includes patients taking greater than 5 mg/kg of HCQ, greater than 2.3 mg/kg of CQ, and in those who have been on the medication for longer than five years. It is important to remember that patients’ actual weight should be used in the calculation rather than what was once proposed, their ideal weight. Additional risk factors include renal disease and concomitant tamoxifen use.

Ocular Effects

These drugs can cause several effects on the eye that are dose- and time-dependent. Less critical effects include blurred vision and corneal keratopathy, both of which are reversible and much less common with HCQ than with CQ.

The greatest adverse reaction involves retinal changes that can be visually debilitating and irreversible. The classic “bull’s-eye” maculopathy indicates that irreversible damage has occurred at the retinal level. The most recent recommendations for managing patients who take CQ and HCQ involve identifying retinal changes earlier as well as the necessary tests and timelines to follow patients (Marmor et al, 2016).

Managing Patients

An evaluation of the macular area and baseline fundus examination prior to, or early in, the initiation of therapy is important to rule out existing maculopathies that may hinder the subsequent assessment of the retina. This should happen, at the latest, one year after the initiation of therapy. If a maculopathy is present, add visual fields and spectral-domain optical coherence tomography (SD-OCT) to your diagnostic evaluation. Screen annually after patients have been on the drug for five years; sooner if the above listed risk factors are present.

Your management toolbox for patients prescribed CQ and HCQ will also include, if available, multifocal electroretinography (mfERG) and fundus autofluorescence. Visual field testing, which represents a sensitive early detection test, should be 10-2 in your non-Asian patients and 24-2 or 30-2 in Asian patients. Look for scotomas, which may appear in the superonasal or inferotemporal areas first.

The SD-OCT’s objective assessment of the macula will show retinal toxicity changes that create an ovoid appearance in the central fovea (Figure 1). This indicates perifoveal loss of the photoreceptor inner and outer segment junctions as well as perifoveal retinal thinning. It is often referred to as the “flying saucer” sign (Chen et al, 2010). The mfERG provides another objective evaluation of the macula/retinal toxicity, evidenced by depressed retinal sensitivity around the parafoveal region (Figure 2). Fundus autofluorescence, although less sensitive than the mfERG, will demonstrate increased autofluorescence in the parafoveal area in the early stages of the retinal toxicity (Figure 3).

Figure 1. Perifoveal degerative changes in hydroxychloroquine macular toxicity.

Figure 2. The tables show average responses from the fovea and each surrounding color-coded ring. The right ratio is not elevated because of the advanced stage of retinal damage in the fovea, diminishing the foveal mfERG amplitude compared to the second ring. The mfERG shows significant reduction in the amplitude in first two rings OD.

Figure 3. Cellular death demonstrated by autofluorescence.

Communicate changes from baseline or indications of status quo to the prescribing healthcare provider, who will make the decision to continue, change the dose, or stop the medication. CLS

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