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Information Statement Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy A Report by the American Academy of Ophthalmology Michael F. Marmor, MD, Ronald E. Carr, MD, Michael Easterbrook, MD, Ayad A. Farjo, MD, William F. Mieler, MD, for the American Academy of Ophthalmology Introduction is not intended to be a review article, and only selected references are cited. Retinal toxicity from chloroquine and its analogue, hy- These suggestions may be varied according to the needs droxychloroquine, has been recognized for many years. The of individual patients, but provide a basic framework for the first reports concerned long-term usage of chloroquine for management of most patients. It cannot be emphasized too malaria, and later reports showed retinopathy in the treat- strongly that whatever screening regimen is followed, the ment of anti-inflammatory diseases. Chloroquine toxicity keys to early recognition of toxicity, and to the avoidance of remains a problem in many parts of the world, but is seen liability, are first informing the patient (and if possible the infrequently in the United States where the drug has largely primary care physician) of the risks and of the need for been replaced by hydroxychloroquine for the treatment of examinations, and second documenting these admonitions systemic lupus erythematosus, rheumatoid arthritis, and carefully in the record. These drugs are typically prescribed other inflammatory and dermatologic conditions. Retinal by internists, rheumatologists or dermatologists who may toxicity from hydroxychloroquine is quite rare relative to not be fully aware of the ophthalmic implications. Patients the many thousands of individuals who take this drug for and primary care physicians should understand that screen- medical indications, but it is of serious ophthalmologic ing helps to recognize toxicity early, before damage is too concern because even after cessation of the drug there is severe, but cannot prevent toxicity or guarantee that there little if any visual recovery, and sometimes a progression of will be no visual loss. visual loss. The potential permanence and severity of chlo- roquine and hydroxychloroquine toxicity make it imperative that ophthalmologists and other physicians be aware of this Hydroxychloroquine and Chloroquine disorder and take measures to minimize its occurrence and Toxicity effects. This document has been prepared because a diversity of The mechanism of chloroquine and hydroxychloroquine screening regimens have been proposed, and these vary toxicity is not well understood. These drugs have acute considerably in practicality, costs and cost/benefit ratio. effects upon the metabolism of retinal cells, including the There is need for a consensus recommendation. The Physi- photoreceptors, but it is not clear whether these short-term cians’ Desk Reference, for example, recommends quarterly metabolic effects are the cause of the slow and chronic examinations that would potentially represent an enormous damage that characterizes the clinical state of toxicity. Both burden on health care resources. Most authors concur that agents bind to melanin in the retinal pigment epithelium some screening for early toxicity is reasonable. This state- (RPE), and this binding may serve to concentrate the agents ment examines the existing data on chloroquine and hy- and contribute to, or prolong, their toxic effects. However, droxychloroquine toxicity, and suggests guidelines and no anatomic features of the RPE layer predetermine the techniques for screening that represent a balance of risks macular bull’s eye pattern often seen in hydroxychloroquine and benefits at the current state of knowledge. However, this toxicity. One could also argue that melanin binding serves as a mechanism for removing toxic agents from intracellular sites of damage. The macular localization of disease sug- Originally received and accepted: April 2, 2002. Manuscript 220214. gests that light absorption, or possibly cone metabolism, Prepared by the Task Force for Screening for Hydroxychloroquine Toxic- may play a role, but these are speculations. ity, Michael F. Marmor, MD, Chair. Approved March 2002 by the Amer- The clinical picture of hydroxychloroquine and chloro- ican Academy of Ophthalmology’s Secretariat for Quality of Care. quine toxicity is characterized most singularly by bilateral © 2002 by the American Academy of Ophthalmology ISSN 0161-6420/02/$–see front matter 1377 Published by Elsevier Science Inc. PII S0161-6420(02)01168-5 Ophthalmology Volume 109, Number 7, July 2002 bull’s eye maculopathy. At this stage of the disorder, a in individuals using the low dose levels noted above—and bull’s eye of RPE depigmentation is evident clinically in the all of these had more than 5 years of usage.1-10 This sug- central macula, often sparing a small foveal island. Obser- gests (even accounting for unreported cases) that toxicity is vant patients will notice paracentral scotomas, but many exceedingly rare within the first few years of usage with a patients have relative scotomas and are asymptomatic. On low dose. The incidence of toxicity will be higher for larger the other hand, functional loss in the paracentral retina has doses and longer periods of usage, although still numeri- been found in some cases to be the first sign of toxicity, so cally small. that careful testing of the paracentral visual field often detects abnormalities before RPE changes are visible. Symptoms or fundus changes that are unilateral are gener- Implications for Screening ally not considered sufficient to implicate drug toxicity. If drug exposure continues, the pigment epithelial atrophy and Since there appears to be a rather minimal risk of toxicity functional disturbance may gradually spread over the entire for individuals using less than 6.5 mg/kg of hydroxychlo- fundus, and advanced cases show widespread pigment epi- roquine or 3 mg/kg of chloroquine for less than 5 years, thelial and retinal atrophy with loss of visual acuity, periph- screening practices can reasonably be modified to take these eral vision and night vision. Vascular narrowing may ap- facts into account and to be maximally cost-effective. How- pear, so that advanced chloroquine or hydroxychloroquine ever, practitioners need remember that there are no estab- toxicity affects visual function much like retinitis pigmen- lished criteria for diagnosing hydroxychloroquine or chlo- tosa. roquine toxicity prior to a stage where some permanent There may be a stage of very early functional loss where visual loss is likely. Screening is aimed primarily at the cessation of the drug will allow a reversal of the toxicity. early detection and minimization of toxicity, rather than at However, clinical cases that have been studied after bilateral prevention (which can be achieved only by avoidance of the paracentral scotomas or visible bull’s eye maculopathy are drugs). This statement recommends a screening regimen evident have not shown significant clinical recovery. In fact, that reduces the minimum frequency of screening for rela- some cases have been observed to show continued depig- tively low-risk cases. We recognize that this might not mentation and functional loss over several years after the quickly catch an exceptional case of idiosyncratic or unusu- drug has been stopped.1 It is not clear whether this repre- ally precipitous toxicity. Weighing this possibility against sents damage from a continued reservoir of the drug (e.g., in cost issues and legal considerations are judgments that melanin), or a gradual decompensation of cells that had individual physicians, health plans, and of course patients been injured during the period of drug exposure. Clearance must make on their own. of these drugs from the blood can take months to years after If a baseline examination (as described below) is normal they are stopped. when chloroquine or hydroxychloroquine therapy is begun, Chloroquine, and to a lesser degree hydroxychloroquine, and dosages are at the relatively safe levels (as noted can cause whorl-like intraepithelial deposits in the cornea. above), screening during the next 5 years can be at the Although these corneal changes are not a direct marker for frequency of regular ophthalmic examinations recom- retinal damage, they do suggest drug retention and reinforce mended by the American Academy of Ophthalmology Pre- the need for regular screening. ferred Practice Pattern11for the age of the patient. For ex- Reports in older literature on chloroquine toxicity had ample, the Academy recommends that individuals between suggested that cumulative dose was the critical factor for 40 and 64 years of age have an ophthalmologic examination toxicity. However, this probably is not the sole or even most every two to four years. Annual screening during the first 5 relevant factor, judging by the many thousands of individ- years of usage is recommended only for individuals who are uals who have taken hydroxychloroquine for long periods of at higher or unknown risk because of their dosage (higher or time (and thus received a high cumulative dose) without unknown), duration of use (more than 5 years), or other evidence of toxicity. The great majority of reports of hy- complicating factors. We emphasize that this is a minimum droxychloroquine toxicity have occurred in individuals tak- recommendation that balances cost against risk, and indi- ing more than 6.5 mg/kg/day, which suggests that daily vidual users or providers of these drugs may choose to dosage is of paramount importance.2-6 Similarly, most chlo- screen more often. roquine toxicity has occurred with doses above 3 mg/kg/ Several factors (other than dosage or usage more than 5 day.7-10 Almost all of the rare reports of hydroxychloro- years) may enhance the risk of retinal toxicity. For example, quine toxicity at lower doses have occurred in individuals chloroquine and hydroxychloroquine are cleared both re- who used the drug for at least 5 years. However, toxicity nally and hepatically, and severe failure of these systems may appear relatively rapidly if especially high doses of could in theory lead to greater drug retention and thus hydroxychloroquine are used, as has been proposed recently toxicity.

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