ACR, medical societies reach consensus on hydroxychloroquine retinopathy
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With proper dosing — 5 mg/kg or less per day — the risk for retinal toxicity associated with hydroxychloroquine use is less than 2% for up to 10 years, according to a joint statement from four medical societies.
Released by the American College of Rheumatology, American Academy of Ophthalmology, the American Academy of Dermatology and the Rheumatologic Dermatology Society, and published in Arthritis & Rheumatology, the statement also declares that widespread use of more sensitive tests, such as optical coherence tomography (OCT), can now detect early retinopathy and preserve eye function in patients receiving the drug.
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“Prescribing clinicians and eye care specialists share responsibility for safely prescribing hydroxychloroquine (HCQ) and screening for the potential risk of retinopathy,” James T. Rosenbaum, MD, of the departments of medicine, ophthalmology and cell biology at Oregon Health & Science University, and colleagues wrote.
“Two relevant national societies, the ACR and the AAO, have independently offered management guidelines, but this is the first joint statement to emphasize points of agreement that should be recognized by practitioners in all specialties,” they added. “The ACR and AAO are joined in this statement with the AAD and RDS.”
To promote the need for collaborative management of hydroxychloroquine retinopathy, and combat the dearth of information on proper dosage, the four societies recruited a working group of seven rheumatologists, two ophthalmologists and two dermatologists. Members were brought into the group based on their expertise and publication record, with considerations made for gender, age and U.S. geographic diversity.
The working group consulted the literature to determine whether any new developments in their fields may require changes to the basic principles of management described in the AAO’s 2016 guidelines. In addition, the committee identified which parts of those 2016 recommendations that were applicable and acceptable to the physicians most likely to prescribe hydroxychloroquine.
“Hydroxychloroquine is unusual in that the prescribing doctor is rarely the doctor who monitors the safety,” Rosenbaum told Healio Rheumatology. “Guidelines from ophthalmologists were published in 2016 but prescribers like rheumatologists and dermatologists have remained skeptical. This statement signifies a coming together with agreement and with the hope for better communication.”
According to the joint statement, effective communication between health care providers is a key factor in the management of hydroxychloroquine. It is the responsibility of the rheumatologist, dermatologist or other non-ophthalmic clinician to prescribe the drug properly, but the responsibility of the ophthalmologist or other eye care professional to screen correctly for toxicity, the authors wrote. In addition, it is the responsibility of all involved to advise patients regarding the risk for retinopathy, and to work together to ensure optimal care.
Regarding hydroxychloroquine dosing, data suggest that an average daily regimen of 5 mg/kg in actual weight, or less, provided a low risk for toxicity — less than 2% for up to a decade of use. Higher average daily amounts increase the risk for retinopathy to approximately 10% after 10 years, with the risk continuing to rise with longer duration of use. According to the statement, high daily doses of hydroxychloroquine relative to body weight, and cumulative doses, are the primary risk factors for eye toxicity. Patients with renal insufficiency may need lower doses and closer monitoring, they added.
However, for patients with a normal screening exam in a given year, the risk for retinopathy in the ensuing year is less than 5%, even after 20 years of use.
For screening, the statement recommends a baseline retinal exam within the first few months of hydroxychloroquine use, to rule out any underlying disease that might compromise eye function or make it harder to recognize retinopathy. Meanwhile, the “mainstays” of early retinopathy detection are OCT and automated visual fields.
“The key to effective management of HCQ to avoid retinopathy is proper dosing, awareness of additional risk factors, and effective screening with modern techniques, in particular OCT,” Rosenbaum and colleagues wrote. “For this to succeed, eye care providers need to communicate with patients and with clinicians who prescribe HCQ.”
“It is important that the drug is not stopped prematurely, but also that it is not continued in the face of definitive evidence of retinal toxicity except in some situations with unusual medical need,” they added. “It is essential that patients are aware of the risks, dosage, the importance of screening, and how HCQ contributes to control of their disease. Overall, the risk of retinopathy is very low if these principles are followed.”
Perspective
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It has been 80 years since chloroquine compounds were first shown to be an effective therapy for the treatment of patients with lupus. By the mid-1940s, hydroxychloroquine was synthesized in Germany and, by 1955, efficacy was noted in both rheumatoid arthritis and systemic lupus erythematosus. It is now quite clear, from an abundance of evidence, that essentially every patient with a diagnosis of lupus is likely to benefit from ingesting hydroxychloroquine on a lifelong basis.
Accordingly, this bears heavily on the question of long-term safety; particularly as it relates to ocular toxicity, an issue that appears to be more common than previously recognized. Thus, this most recent publication, offering monitoring guidelines as formulated by four separate societies in a Herculean joint effort to compile all the evidence to date that bears on this subject and coalesce the subspecialty perspectives, is a very welcome and worthy contribution.
A working group of rheumatologists, ophthalmologists and dermatologists, notable for their expertise in this topic, carefully addressed the 2016 guidelines issued by the American Academy of Ophthalmology to formulate a “revised” joint statement from those most likely to be prescribe this medication and those that monitor for toxicity. This effort addresses focal concerns such as dosing, risk factors for toxicity and retinal monitoring in terms of frequency and best available techniques.
Dosing 5 mg/kg (actual body weight) appears to have low frequency of toxicity (<2% for up to 10 years) while higher dosing over longer durations leads to higher rates (10% after 10 years). This group felt that monitoring by blood levels may be useful in the future, but is not quite ready for prime time. In patients with renal insufficiency, doses should be reduced qualitatively rather than formulaic.
Modern techniques for monitoring retinal toxicity should be employed to detect early disease, such as optical coherence tomography (OCT) and other related techniques, especially among East Asians as the toxic phenotypic pattern may be variable. The OCT should be performed by clinicians experienced with these techniques and interpretation. After a recommended baseline exam to exclude confounding underlying conditions, most patients may safely wait 5 years for a repeat exam.
As the long-term use of hydroxychloroquine in lupus has evolved towards becoming the rule rather than the exception, it is imperative that we recognize how to most safely prescribe and minimize medication-related toxicity.
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David A. McLain, MD, MACR, FACP, FRCP
Eye toxicity with hydroxychloroquine (HCQ) has been known for over 65 years. It is melanotropic and is deposited in tissues with high melanin content like ciliary bodies, skin and the retinal pigment epithelium (RPE). HCQ is excreted by the liver and kidney, and is minimally removed during dialysis; therefore, persistent liver and renal dysfunction potentiate its toxicity.
It has been suggested from in vitro studies with cultured RPE cells that HCQ alters RPE lysosomal pH, which results in higher levels of lipofuscin, a yellowish brown, auto fluorescent, and lipid-containing pigment. It also accumulates in the cytoplasm of cells during aging, and is associated with photoreceptor degeneration and the accumulation is promoted by oxidative stress. This is an active area of aging research, particularly as it relates to neurodegeneration.
HCQ is a lipophilic base that passes easily across cell membranes and into acidic intracellular vesicles, altering lysosome stability. This leads to inhibition of cytokine and prostaglandin production, suppression of antigen presentation, and effecting toll-like receptor signaling and leukocyte activation, which gives rise to immunosuppressive, antithrombotic, antiproliferative and photoprotective effects.
Although rare, retinopathy is a major worry for most patients and clinicians using HCQ. Non-adherence to HCQ has been estimated to be as high as 51%; in addition, blood monitoring has found undetectable HCQ levels in 29-64% of patients regularly filling their HCQ prescriptions.
It should be noted that HCQ does not distribute in fatty tissue, consequently, there is a danger of overdosage if obese patients are dosed based on weight alone. Another potential source of toxicity is dosing a patient based on their initial weight and then continuing this dosage after the patient undergoes significant weight loss. While HCQ retinopathy is rare, this joint statement should help us in daily practice in our interactions with our patient’s eye doctors.
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