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Hydroxychloroquine Blood Levels Predict Retinopathy in SLE
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Increased hydroxychloroquine blood levels can be used to predict later hydroxychloroquine retinopathy, according to findings published in Arthritis & Rheumatology.
“The American Academy of Ophthalmology (AAO) 2011 recommendations advised hydroxychloroquine weight-based dosing of 6.5 mg/kg with a maximum dose of 400 mg/day,” Michelle Petri, MD, MPH, of the Johns Hopkins University School of Medicine, and colleagues wrote. “[However,] a retrospective review of 2,361 Kaiser Permanente patients who had used hydroxychloroquine, reported toxicity at 5 years in under 1%, up to 10 years in under 2%, but almost 20% after 20 years.”
“This led, in 2016, to revised AAO recommendations that the maximum daily hydroxychloroquine should be less than 5.0 mg/kg real weight, which they thought might correlate better with risk than ideal weight,” they added. “These dosing recommendations were made without evidence that the lower dose of hydroxychloroquine would have the same efficacy for SLE activity or the same protective role against cardiovascular risk factors and thrombosis.”
To analyze the frequency of hydroxychloroquine retinopathy, as well as the ability of hydroxychloroquine blood levels to predict retinopathy risk, Petri and colleagues conducted a study of 537 patients with systemic lupus erythematosus from the Hopkins Lupus Cohort. The researchers assessed patients for hydroxychloroquine blood levels and tested for hydroxychloroquine retinopathy at each visit starting in 2013.
For their analysis, hydroxychloroquine toxicity was defined by a retina specialist at the Johns Hopkins Wilmer Eye Institute, who examined participants taking the drug. The researchers assessed the risk for hydroxychloroquine toxicity in tertiles based on the mean or maximum hydroxychloroquine levels in the blood.
According to the researchers, the frequency of retinopathy was 4.3%. Broken down by year, there was a 1% risk for retinopathy during the first 5 years, a 1.8% risk from year 6 to 10, 3.3% from 11 to 15 years, 11.5% from 16 to 20 years and 8% after 21 years of hydroxychloroquine use. In addition, older patients (P < .0001), those with higher BMI (P = .016 for trend) and longer duration of drug intake (P = .0024 and P = .0006 for trend) were associated with a greater risk for hydroxychloroquine toxicity.
The researchers found that higher hydroxychloroquine blood levels predicted later hydroxychloroquine retinopathy (P = .0124 for mean blood levels; and P = .034 for maximum).
“Hydroxychloroquine retinopathy is more common than previously thought, but the frequency slope increases after 15 years, and even for patients on it for 20 years is only about 10%,” Petri told Healio Rheumatology. “The time for therapeutic blood monitoring for hydroxychloroquine has arrived. First, because blood level monitoring can detect patients who are nonadherent and therefore cannot benefit from the benefits of hydroxychloroquine, including improved survival.”
“Also, because patients with the highest tertile are at greatest risk of hydroxychloroquine retinopathy,” she added. “Those patients would have their hydroxychloroquine dose reduced. Blood levels — which are done at Johns Hopkins — are more valid than plasma levels.” – by Jason Laday
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Barry L. Gruber, MD
The recent study from Petri and colleagues addresses the controversies arising from the latest American Academy of Ophthalmology (AAO) recommendations concerning dosing limits of hydroxychloroquine for patients with autoimmune disorders, especially systemic lupus erythematosus (SLE).
Drawing from a cohort of SLE patients, the investigators assessed the individual risk factors associated with developing retinal toxicity and reviewed the utility of obtaining blood levels. Overall the frequency of retinal abnormalities in this cohort was 4.3% — nearly half that reported in a recently published study from Kaiser Permanente, which was, in large part, the stimulus for the AAO updated guidelines. Importantly, both studies agree that the risk increases with age and duration of use, and emphasize that newer techniques available to ophthalmologists for assessing retinal fields has indeed revealed toxicity is more common than previously appreciated.
High body mass index was also an additional risk factor but, unlike the Kaiser Permanente report, chronic kidney disease was not associated with toxicity perhaps due to reduced dosing in this group preemptively. Although the updated AAO guidelines stress a limit of 5 mg/kg in dosing, Petri and colleagues determined that this dose leads to a very heterogenous distribution of blood levels and furthermore, from their data, mean blood level measurements appear to be an important predictor of toxicity.
Therefore, the concern is that many of our lupus patients will be “under-dosed” which may potentially diminish the countless well-established benefits of hydroxychloroquine in this population if dose is limited to 5 mg/kg. Practitioners should be aware of the differing opinions and data currently surfacing to optimize individual patient management.
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