Concern Raised About High Hydroxychloroquine Dosing

Janis C. Kelly

February 15, 2017

Dosing guidance meant to reduce the risk for hydroxychloroquine (HCQ) retinal damage is followed for only half of HCQ-treated rheumatology patients who are also seen by an ophthalmologist, according to a study published online January 30 in Ophthalmology.

"The published ophthalmology screening guidelines have had no appreciable impact on clinical practice, highlighting a persistent deficiency in patient care and a significant medico-legal risk," write Rebekah A. Braslow, MD, from the Division of Ophthalmology, NorthShore University Health System, Glenbrook Hospital, Glenview, Illinois, and colleagues. HCQ dose-related retinopathy can affect up to 20% of patients after 20 years of intake, the authors note. However, for patients who are treated with HCQ below the guideline of 5.0 mg/kg measured body weight, the incidence is less than 1% at 5 years and only 2% at 10 years, according to a 2016 update of guidelines for retinal toxicity screening from the American Academy of Ophthalmology (AAO).

Therefore, the threshold dose should be calculated using actual body weight rather than ideal body weight, and the maximum safe dose is 5.0 mg/kg. For example, the threshold dose would be 400 mg/day for a patient weighing 175 pounds.

To assess the effect of AAO guidelines on rheumatologist HCQ prescribing behavior, Dr Braslow's team reviewed electronic medical records (EMRs) at NorthShore University Health System in Glenview, Illinois, for the subset of rheumatology patients prescribed HCQ between 2009 and 2016 who were also seen by a NorthShore staff ophthalmologist. This included 554 patients started on HCQ since 2009, of whom 92 were started before issuance of the original AAO guidelines in 2011.

The researchers did not report on what proportion of HCQ-treated rheumatology patients were not seen by ophthalmologists or on the reasons ophthalmology examinations were ordered. In addition, the authors emphasize that their study focused only on prescribing behavior, not on rates of retinal damage among the patients studied.

Among the 92 patients who started on HCQ treatment before the 2011 guidelines, 54.3% were prescribed a higher-than-recommended dose compared with 49.4% of the 462 patients who initiated treatment after publication of the guidelines (P = .381).

Furthermore, patients started on excess doses tended on stay on those doses. Of patients currently taking HCQ, 43% were receiving doses more than 50 mg above the calculated target dose, and several were receiving up to 450 mg HCQ in excess. Most of those (84%) were maintained on their initial dose.

These findings were of particular concern because HCQ use has increased, not only for rheumatoid arthritis and for lupus but also for adjunctive cancer therapy, diabetes, and heart disease. Dr Braslow and colleagues estimate that overall use of HCQ has increased fivefold at NorthShore since 2009.

Megan Krause, MD, a rheumatologist at the University of Kansas, Kansas City, and a member of the American College of Rheumatology (ACR) Committee on Rheumatologic Care, told Medscape Medical News that the ACR position statement on screening for HCQ retinopathy incorporates the current AAO guidance and has been widely distributed to the ACR membership. ACR's screening guidance was issued first in 2003 and has been regularly updated since then, most recently in August 2016. Dr Krause was not involved in the current study.

Opting for lower starting doses of HCQ might reduce risk for retinal damage in rheumatology patients. Dr Braslow and colleagues suggest that choosing the proper HCQ starting dose should not require a "screening referral" to an ophthalmologist, and that "creative use of the EMR to guide proper dosing would facilitate the correct choice by non-ophthalmologists, by providing electronic prompts and templates for HCQ prescribers."

This differs from ACR's guidance, Dr Krause said. "ACR's position is that HCQ-treated patients should have access to eye examinations at baseline and periodically over the duration of therapy to facilitate early recognition of potential retinal toxicity, particularly as current technologies have the potential for detecting retinopathy before patients become aware of visual loss." The timing and extent of surveillance monitoring should be individualized, taking into account the patient's risk factors for HCQ-related toxicity.

Dr Krause emphasized that the purpose of periodic eye exams in patients taking HCQ is "to recognize toxicity, if it occurs, at the earliest possible stage."

Stopping HCQ is recommended if toxicity develops, but the ACR position paper acknowledges that there are situations in which this is not a simple decision, such as the patient with early toxicity, tenuous evidence of maculopathy, a good response to HCQ, and no desirable alternatives to HCQ treatment. In such cases, the ACR recommendation is for the rheumatologist, ophthalmologist, and patient to decide jointly whether to stop HCQ or to continue cautiously with close monitoring and "with the knowledge that some vision could be lost."

The ACR position paper describes appropriate HCQ dosing to avoid toxicity as "an area of some uncertainty," pointing to previous AAO recommendations of 6.5 mg/kg ideal body weight, later revised to 5 mg/kg actual body weight.

Dr Krause said that multiple factors likely play a role in HCQ dosing patterns. She explained that the most common doses range from 200 to 400 mg, but the size of the tablets leads to practical increments of 100 mg. Both Dr Krause and the study authors note that the limited doses available might contribute to the use of higher HCQ doses by limiting dosage flexibility.

Kaleb Michaud, PhD, associate professor of rheumatology and immunology, University of Nebraska Medical Center, Omaha, who was not involved in the study, told Medscape Medical News that, in view of decades of experience with HCQ in rheumatology, he doubts that an EMR alert system would have much effect.

Dr Michaud, who is also codirector of the National Data Bank for Rheumatic Diseases, said. "While we should monitor those with the highest doses, it's difficult for EMR data to record nonstandard ways of taking HCQ. As the authors note, since HCQ pills only come in 200-mg pill sizes, and the recommended limit is 5 mg/kg, then each pill covers up to a 40-kg range in weight. It's easy to imagine that half of the patients would be getting too much with an extra pill, but the physician may believe it's better than getting too little by not taking the pill. I just don't see how an EMR alert is going to help in the majority of these cases — only those extreme cases where removing one pill will still allow for enough medication to be of use."

Dr Michaud also suggested that rheumatologists might be less concerned about retinal adverse effects of HCQ doses above 5 mg/kg if patients have regular eye screening, as recommended by ACR. He also noted that the authors of the current study do not report any data on actual retinopathy in the patients studied. "I would have preferred to see how many patients taking HCQ had any related ocular toxicities," Dr Michaud said.

The study was supported by intramural research funds from the Division of Ophthalmology, NorthShore University Health Care System. Dr Braslow is employed by the NorthShore University Health Care System. Dr Krause and Dr Michaud have disclosed no relevant financial relationships.

Ophthalmology. Published online January 30, 2017. Abstract

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