Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used for the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other inflammatory and dermatologic diseases for many years. Irreversible retinal toxicity can occur following the use of each of these 4-aminoquinoline compounds.^1,2 Recently, an American Academy of Ophthalmology (AAO) task force on screening for chloroquine and hydroxychloroquine retinopathy identified high-risk factors for retinopathy associated with HCQ treatment and recommended screening guidelines to minimize the risk of this toxicity.³ Evidence exists that a significant proportion of veterans taking HCQ many not be managed according to these AAO screening guidelines.⁴ The purpose of this study is to determine the prevalence of high-risk factors for HCQ retinopathy and compliance with the AAO screening guidelines at the VASF and develop an approach to improve the risk-benefit relationship and informed consent for patients during HCQ treatment.

Following institutional review board approval, the VASF pharmacy identified the medical records of all the patients receiving HCQ between October 1, 2004, and September 30, 2005. These medical records were then reviewed with special attention to high-risk factors for retinopathy. Thereafter, the data were recorded, analyzed, and reported.

Between October 1, 2004, and September 30, 2005, the VASF pharmacy identified 109 patients who were using HCQ prescribed at VASF. Of the 109 patients taking HCQ, 87% had at least one high-risk factor for retinal toxicity as identified by the AAO task force, and 59% had 2 or more risk factors. Thirty-four percent of these 109 patients treated with HCQ had no evidence of an eye examination performed before or during their treatment with HCQ. There was no evidence of an eye examination performed in the records of 46% of the patients having 3 or more risk factors. A comparison between the results of the present study and a prior cohort of US veterans⁴ is provided in Table 1.

TABLE 1 COMPARISON OF STUDY RESULTS OF PATIENTS WITH HIGH-RISK FACTORS FOR HYDROXYCHLOROQUINE RETINAL TOXICITY

The results of the present study are similar to the results from a prior study of a cohort of US veterans.⁴ In both studies, approximately one-third of the HCQ-treated patients were not managed as recommended by the AAO Screening Guidelines for HCQ Retinopathy. For example, 30% to 40% of the HCQ-treated patients in each study had no evidence that an eye examination had been performed prior to or during treatment with HCQ. In the present study, almost half of the patients using HCQ who had 3 or more risk factors had no evidence of an eye examination performed before or during their treatment. The absence of eye examinations in these studies not only suggests that the recorded incidence of retinal disease in each study is an underestimate, but also implies that the patients who might most benefit from eye examinations are not receiving them. Therefore, it appears that a significant number of veterans taking HCQ may be at an increased risk for retinal toxicity during their treatment with HCQ. Furthermore, these results indicate that the risk-benefit relationship for patients treated with HCQ may not be optimum. The results of both of these studies, in light of the conclusions of the AAO task force, suggest it is timely to review the risks of retinal toxicity associated with HCQ treatment and develop a method to improve the risk-benefit relationship and informed consent for patients treated with this drug.

A recent review of the literature³ emphasizes that over 1,000,000 patients have used either CQ or HCQ, whereas fewer than 20 cases of retinal toxicity occurred in individuals using appropriate doses of these aminoquinolines. In addition, all of these reported patients with retinal toxicity were using the drugs for more than 5 years. Insofar as most investigators believe that HCQ is less likely to cause retinal toxicity as compared to CQ, it seems the prevalence of HCQ-induced retinal toxicity is quite low.^2,3,5 In fact, there are descriptions of large doses of HCQ without retinal toxicity that underscore the drug’s relative safety.⁶ Therefore, the incidence of retinal toxicity with HCQ treatment is probably even less than that (1 case in 50,000 treated) suggested by the literature review provided in the report from the AAO task force.³

Although the risk of retinal toxicity is minimal for patients using HCQ, this toxic retinopathy, when it becomes manifest, presents a major therapeutic problem for both the patient and the physician. More specifically, both HCQ- and CQ-induced retinal toxicity can be irreversible even if identified early. Furthermore, this toxicity not only often persists following its onset even if the drug is discontinued, but it can progress after cessation of HCQ therapy. Finally, the toxic retinal damage and the associated visual changes can be delayed in onset after the drug is discontinued.^7–12 Therefore, it is not surprising that investigators often emphasize that even if HCQ-induced retinal toxicity is recognized at an early stage of functional loss, recovery is unlikely.³

In light of the unpredictability of the onset and subsequent behavior of HCQ-induced retinal toxicity, it is essential that both patients receiving this drug and physicians prescribing HCQ are aware of the severe limitations and true value of ophthalmologic screening examinations. It should be made clear to both patient and referring doctor that ophthalmologists may help to identify HCQ-induced retinal toxicity early, but this activity most often does not prevent further retinal damage even if the drug is discontinued. Furthermore, it must be emphasized that the screening certainly does not guarantee that there will be no subsequent retinal damage and associated visual loss even if the screening examinations are performed expertly, using expensive equipment involving prolonged testing times and with full patient cooperation.

Many elegant screening examinations continue to be developed and evaluated in an attempt to diagnose retinal toxicity early and thereby minimize the toxic effects of HCQ. For example, most recently, the potential value of early paracentral visual field testing, the detection of subtle color vision defects, and fundus autofluorescence and multifocal electroretinography each have been described and compared to prior approaches used to enhance screening examinations during HCQ treatment.^13–15 However, there is no evidence that any of these newer and more elaborate tests add clinical benefit over simple Amsler grid testing at this time. Furthermore, Amsler grid testing offers many advantages. The test is inexpensive, rapid, and easy to perform for both the physician and patient. In addition, patients can perform Amsler grid testing on a regular basis in their own home. Most investigators agree that it seems reasonable to use Amsler grid testing and to continue to consider color testing, photography, and other specialized tests as optional screening devices during follow-up of patients using HCQ as reported by the AAO task force.³

Many investigators have suggested that because of the rarity of HCQ-induced retinal toxicity and because so little can be done even if the retinal damage is identified early, screening for retinal toxicity is probably not justified except in an effort to provide maximal legal protection.^3,12,16 This sentiment is clearly reflected within the report by the AAO task force, which states, “It cannot be emphasized too strongly that whatever screening regimen is followed, the keys to early recognition of toxicity, and to the avoidance of liability, are first informing the patient of the risks and of the need for examinations, and second documenting these admonitions carefully in the record.”³ Therefore, it seems essential to provide a definitive and well-documented means of informing the patient about the risk-benefit relationships associated with HCQ treatment.

To address this issue and fulfill this need, an HCQ Medication Information Form has been developed that is designed to accompany HCQ as it is dispensed by the pharmacist (Appendix). This form includes a description of the high-risk factors for retinal toxicity as identified by the AAO task force and emphasizes the importance of a baseline eye examination. The form includes pertinent facts about the onset, progression, and irreversibility of HCQ-induced toxic retinopathy, and it provides an Amsler grid with a description of its proper use. Finally, a comment is provided underscoring the potential benefits of lowering the dose of HCQ as a desired therapeutic response is achieved. This Medication Information Form not only properly informs the patient about the visual risks of taking HCQ, but also encourages the patient to participate directly in the retinal screening activity. Therefore, an emphasis is placed on the patient’s ongoing responsibility in the drug toxicity screening process. Furthermore, it encourages the patient to remind the prescribing physician of the need to reevaluate the benefits of treatment in a timely fashion. Such interaction can result in decreasing the dose or even choosing to take therapeutic vacations from HCQ treatment if the symptoms for which the drug is being used are minimal or absent.

Finally, to complete the cycle of informed consent and properly document these activities, the pharmacist notifies the ophthalmologist, primary care physician, rheumatologist, and other treating physicians that the patient has received and understood the HCQ Medication Information Form at the time the patient received the medication. This procedure should provide the information and documentation suggested by the AAO task force.³

In conclusion, two independent, retrospective clinical studies suggest that a significant number of veterans in the United States who are taking HCQ may be at increased risk for retinal toxicity. The results of both of these studies report more than one-third of the patients treated with HCQ may not be managed as recommended by the AAO task force. These clinical studies, each inspired by the efforts of the AAO task force, prompted the development of an HCQ Medication Information Form. This handout can accompany the HCQ as the pharmacist dispenses it. The form emphasizes the importance of a baseline eye examination, and it provides both drug education for the patient and an Amsler grid for the patient to use at home, allowing for an earlier diagnosis of retinal toxicity. Therefore, the use of this form should not only improve informed consent, but guarantee that the patient is fully aware of the risk-benefit relationships associated with HCQ use. In addition, it makes clear that the patient is an essential and responsible member of the HCQ retinal toxicity screening process.

The biological basis of chloroquine and HCQ toxicity to cells stems from their ability to dissipate the pH gradient across lysosomes by blocking the vacuolar ATPase. This leads to a significant increase in the intraluminal pH of lysosomal compartment and compromises the ability of the various proteases to cleave and degrade proteins targeted to this organelle. In addition, both antimalarials can bind to melanin and by some unknown mechanism affect cellular function. Together, these drugs lead to the eventual death of retinal pigment epithelium (RPE) cells.

The incidence of retinal toxicity of HCQ is actually quite low, and most cases are related to chloroquine. High-risk factors are (1) age; (2) dosage; (3) length of therapy; (4) presence or absence of liver/kidney disease; (5) retinal disease; and (6) body habitus/obesity.

Interestingly, the data demonstrate an inverse relationship between the number of high-risk factors a particular subgroup of patients may have and the likelihood to obtain an eye examination. Might this reflect their ability to access health care in general? It is probably the case that we, as physicians, need to empower patients to participate in their care by improving their understanding of the risks and benefits by educating them and communicating with them more effectively.

As with other screening programs, it is important to refine our diagnostic tools (mfERG, quantitative FAF, metabolic imaging) to capture disease processes when the biological process is still reversible. We also need to educate rheumatologists/internists to better recognize the high-risk factors so they can refer patients for screening similar to immunizations and breast and colon cancer screening programs.

To that end, the author presents a very nice and potentially useful consent form that educates and empowers patients to participate proactively in their management of possible HCQ toxicity. The uniqueness of the idea is that the patient receives this form from the pharmacist at the time of filling the drug prescription. Implicit to the author’s discussion is that such a form may also preempt possible lawsuits.

Financial Disclosures: None.

Funding/Support: None.

Financial Disclosures: None.

Author Contributions: The author designed the study, collected, analyzed, and interpreted the data, and prepared the manuscript.

Medication Information: Hydroxychloroquine (Plaquenil)

Patient Informed Consent and Minimization of Risk of Retinal Toxicity

Those at most risk for retinal toxicity from hydroxychloroquine (HCQ) include patients:

• Older than age 60 years
• Taking more than 6.5mg/kg/day
• Taking the HCQ more than 5 years
• Presence of kidney disease
• Presence of liver disease
• Presence of retinal disease (PATIENT REQUIRES AT MINIMUM A BASELINE EYE EXAM)
• Presence of excess weight

Although toxicity for the retina and associated vision loss is rare (1/50,000) during HCQ treatment, these are the facts associated with this retinal toxicity if it occurs:

• Retinal toxicity with HCQ cannot always be prevented even if properly used.
• Retinal toxicity with HCQ is usually irreversible.
• Onset of retinal toxicity may occur even after the HCQ is discontinued.
• Retinal toxicity may continue to progress even if HCQ is discontinued.

The best way to detect retinal toxicity with HCQ early is by you, the patient, performing Amsler Grid testing at frequent intervals on yourself. If you note changes in this test, call the eye clinic for an appointment. You should be seen within a few days.

It is important for you to keep in mind why you are using HCQ. Most patients use HCQ to relieve muscle pain (myalgias), joint pain (arthritis), skin problems (rashes) or to relieve fatigue as part of lupus or other collagen vascular diseases. You should discuss the possibility of decreasing your dose or even stopping HCQ if these symptoms improve or disappear with your primary health care provider to minimize the risk of retinal toxicity.

This is the best test for you to use at home to detect early signs of retinal toxicity that can accompany HCQ use. The simple test is performed in the following way:

• Use the chart at eye level in a well-lit area.
• Place the chart about 12 to 14 inches away from your eyes.
• Wear your reading glasses if you use them to read.
• Cover one eye and test the other, uncovered eye.
• Look at the center dot of the Amsler Grid.
• Test the other eye using the same technique.
• Call the eye doctor’s office if any lines or squares on the Amsler Grid look wavy, blurred, fuzzy, or missing as observed with either eye during the test.