Time to Monitor Serum Hydroxychloroquine Levels in Lupus?
Shivani Garg, MD, PhD
Shivani Garg, MD, PhD, an assistant professor of medicine and medical director of the Lupus and Lupus Nephritis Clinics at the School of Medicine and Public Health, University of Wisconsin-Madison, presented the findings of an observational study that confirmed and extended the results from an earlier study carried out by her research group that the ideal serum hydroxychloroquine level lay somewhere between a lower limit of 750 ng/mL and an upper limit of 1150 ng/mL for most patients with SLE.
The new study also showed that as estimated glomerular filtration rate (eGFR) increases, so does serum levels of hydroxychloroquine in the blood. This suggested that monitoring serum hydroxychloroquine levels may be particularly useful in people with chronic kidney disease.
Justification to Monitor
Alfred Kim, MD, PhD
Alfred Kim, MD, PhD, told Medscape Medical News that Garg's data gave justification to the idea that serum hydroxychloroquine levels need to be checked as a matter of routine.
'I think rheumatologists have been behind in checking drug blood levels in general. We don't check as routinely as compared to say nephrologists and gastroenterologists,' said Kim, who is an associate professor of medicine and associate professor of pathology and immunology at Washington University School of Medicine, St. Louis.
One of the known long-term risks associated with taking hydroxychloroquine is retinal toxicity, which is why regular eye examinations are undertaken. It takes time for the eye damage to accumulate, however, so 'how do you assume without knowing the levels that you're actually not introducing risk or not knowingly introducing risk downstream?'
Kim said there has been a tendency 'to follow clinical response and assume that if patients are not showing acute toxicity, that there will be no long-term toxicity.' This is 'obviously incorrect,' he said, and added that a 'culture change' is happening.
Optimum Dose Debated
'Hydroxychloroquine, or HCQ, is the cornerstone of lupus treatment as it prolongs both disease- and damage-free survival. However, the optimum dose of hydroxychloroquine is under great debate,' Garg said during her presentation.
Hydroxychloroquine is dosed according to body weight, with a recommended dose of 5 mg/kg. Prior data have shown that doses above this level double the risk for retinopathy compared with the level of 4-5 mg/kg/d, while those at 5 mg/kg/d or below are associated with a two- to six-fold increased risk for disease flares.
Measuring serum levels of hydroxychloroquine reflects metabolism, clearance, and adherence, Garg argued, and thus measuring and monitoring these levels could be a potential solution to ensuring the perfect balance between toxicity and efficacy.
Considering that 65% of hydroxychloroquine is cleared by the kidneys, one of the aims of the study was to identify if there are any thresholds of kidney function associated with supratherapeutic levels over time.
Study Design and Findings
Garg and colleagues combined prospectively collected data from two longitudinal cohorts from France and the US, encompassing a total of 1240 patients with SLE who had been treated with hydroxychloroquine.
The median age of the cohort was 40 years, and 92% were women. Just over half (58%) were being treated with doses of more than 5 mg/kg/d and 42% with doses of 5 mg/kg/d or lower. The cumulative hydroxychloroquine dose was 2318 g, and mean serum levels of the drug were 947 ng/mL. The mean SLE Disease Activity Index (SLEDAI) was 2.8, and 4.4% had experienced cardiac or retinal toxicity.
On the first study visit, patients gave whole blood samples to have serum hydroxychloroquine levels measured using liquid chromatography in tandem with mass spectrometry or mass spectrometry alone.
Researchers collated data on patient outcomes, including disease activity measured by SLEDAI, and toxicity, notably retinopathy and cardiotoxicity. Analyses were then performed to find the upper threshold for serum hydroxychloroquine levels at which toxicity occurred and the threshold at which a 'ceiling effect' for disease response occurred. Data were also analyzed according to patients' eGFR at the baseline visit, and any subsequent visits if available.
Results showed that serum hydroxychloroquine levels in excess of 1150 ng/mL were associated with 2.2-fold increased risk for systemic toxicity, even after excluding retinopathy. Moreover, serum hydroxychloroquine levels above this limit did not appear to provide any further clinical benefit.
Results also showed that having an eGFR < 60 mL/min/1.73 m2— indicating stage 3 or greater chronic kidney disease — was associated with a 2.5-fold greater likelihood of serum hydroxychloroquine levels in excess of 1150 ng/mL, risking toxicity.
Garg told Medscape Medical News: 'Right now, we don't monitor because we didn't know how to interpret the [serum] levels. This study gave data on this.'
In the long run, the findings could mean that patients with serum hydroxychloroquine levels within the proposed target 'get a green check. But if the levels are too high, you might need to scale down the dose.'
This study received no commercial funding. Garg and Kim had no financial disclosures or conflicts of interest to report.
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