The Great Debate at ACR 2018: Hydroxychloroquine Dosing for SLE

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Hydroxychloroquine (HCQ) dosing took center stage on October 21 as the focus of the “Great Debate” at the 2018 American College of Rheumatology (ACR)/Association of Rheumatology Health Professionals (ARHP) Annual Meeting in Chicago, Illinois.

HCQ remains the major immunomodulatory agent used to treat systemic lupus erythematosus (SLE), but newer screening techniques have raised concern regarding potential eye toxicity. The 2016 American Academy of Ophthalmology (AAO) Recommendations for Screening for Hydroxychloroquine and Chloroquine Retinopathy recommended a maximum daily HCQ use of 5.0 mg/kg real weight. The AAO also recommends a baseline fundus examination and annual screening after 5 years for patients without major risk factors.

James T. Rosenbaum, MD, took the “pro” side of the debate, arguing that the AAO Guidelines are appropriate. Dr Rosenbaum is Professor of Ophthalmology, Medicine, and Cell Biology and Chair of the Division of Rheumatology at the Oregon Health & Science University.

On the “con” side of the debate, Michelle Petri, MD, contended the AAO Guidelines are not appropriate. Dr Petri is Director of the Lupus Center at the Johns Hopkins University School of Medicine and Johns Hopkins Hospital in Baltimore, Maryland.

Next: The "pro" side of the debate

Pro: The AAO Guidelines are appropriate
Dr Rosenbaum began with a comparison to acetaminophen, which is the leading cause of acute liver failure in the United States but “still a valuable and safe drug when used within appropriate guidelines.” He maintained that HCQ is also a valuable and safe drug if it is monitored appropriately and administered according to AAO Guidelines.

Today, optical coherence tomography (OCT) and visual fields are the mainstay of screening. Dr Rosenbaum showed images from OCT that demonstrated a thinning of the fovea in the presence of early HCQ toxicity, which he identified as a sombrero or flying saucer shape. These changes correlated with changes in the visual field test, and the combination of these complementary tests allow retinopathy to be identified early with proper screening.

The AAO Guidelines were based on an investigation of Northern California Kaiser patients taking HCQ for at least 5 years. The results showed the risk of toxic retinopathy increases according to dosage and duration of use. Dr Rosenbaum pointed out that even patients taking less than the recommended 5 mg/kg daily experienced toxicity at the 10- and 20-year marks.

While Dr Rosenbaum conceded that the results of the Kaiser study had not been exactly repeated, he argued that several studies provide substantial evidence that physicians should be limiting HCQ doses and that HCQ retinopathy is more frequent than previously appreciated. His evidence included a 2017 study from Korea, a 2018 study from North Carolina, and a study by Dr Petri being presented at ACR this year (Abstract 2897).

“Still a valuable and safe drug when used within appropriate guidelines.”

Rather than restricting the use of HCQ, Dr Rosenbaum argued that the AAO Guidelines make it easier to use HCQ safely. He ended his argument by pointing out that there may also be additional HCQ toxicities for rheumatologists to consider, including cardiomyopathy, incident atrial fibrillation, rashes, myopathy, neuropathy, ototoxicity, GI upset, and hyperglycemia. He concluded that HCQ is a valuable part of a rheumatologist’s therapeutic armamentarium, but only if appropriate guidelines are followed. 

Next: The "con" side of the debate

Con: The Guidelines are not appropriate

Rather than worrying about patients taking too much HCQ, Dr Petri instead expressed concern for patients who are taking too little. She cited studies demonstrating that 51% of individuals taking HCQ were non-adherent 80% of the time based on pharmacy refill rates, another showing that 29% of adolescents and young adults with SLE had undetectable HCQ blood levels, and a third showing HCQ adherence declining for most patients over the first year. If ophthalmologists are telling patients they might go blind, Dr Petri said, that will only worsen adherence even more.

Dr Petri argued the prevalence of blindness in rheumatologic patients treated with HCQ may not be as high as imagined. In a 2017 study of 31 patients with a diagnosis of “blindness” or “toxic maculopathy,” 11 had documented blindness with a confirmed diagnosis other that HCQ toxicity, including stroke and diabetic retinopathy. Of the 3 patients in this cohort with HCQ retinal toxicity, none had blindness or a change in vision.

Dr Petri contends that a “one rule fits all” dosing technique will not be effective, particularly for patients with SLE who are struggling for short-term control of the disease. She presented a case study in which a patient experienced severe maculopapular rash and severe arthralgias after her ophthalmologist had reduced her HCQ dosage. “Is there a blind acceptance of suboptimal dosing?” Dr Petri asked, with the pun intended but the question about efficacy a serious one. “If the HCQ dose is suboptimal, am I doing that patient a favor if her lupus is more active for the next 20 to 25 years?”

Dr Petri worries that this discussion has been colored by fear of blindness. There’s no reason to make patients so afraid of perhaps the most important drug for controlling SLE symptoms, she contends. Instead, Dr Petri argues that the message we should be giving to patients is that while retinopathy is real, it’s more common after 16 years of HCQ use and proper screening can still preserve vision. Dr Petri also reminded the audience of the positive impact of HCQ beyond skin and joint activity, including a reduction in flares, organ damage, and mortality. Patients are individuals, she concluded, and physicians need to do what is right by each individual patient.

“If the HCQ dose is suboptimal, am I doing that patient a favor if her lupus is more active for the next 20 to 25 years?”

At the end of the debate, both presenters agreed that regardless of the HCQ dose used, proper screening with new technology is necessary to enable physicians to identify retinopathy before it becomes a problem for the patient.

References:

3S092 ACR: The Great Debate: Guidelines for SLE: HCQ Dose Should Be No More Than 5 mg/kg in All Patients. Presented at: 2018 ACR/ARHP Annual Meeting; October 20-24; Chicago, Illinois.