Keep HCQ Blood Levels Up to Avoid Cardiovascular Disease in Lupus Save

People taking hydroxychloroquine (HCQ) for systemic lupus erythematosus (SLE) showed markedly increased risk for atherosclerotic cardiovascular disease when blood levels of the drug were low and when long-term adherence was poor, a prospective study showed.

Those with HCQ blood levels below 200 ng/mL ("very low") and whose prescription-fill data indicated they had the drug less than 80% of the time had a mean predicted cardiovascular disease risk of 6.6% compared with 4.5% for those with drug levels at or above 750 ng/mL, the threshold for therapeutic efficacy, reported Shivani Garg, MD, PhD, of Yale University in New Haven, Connecticut, and colleagues.

When drug exposure diminished over time, as frequently happens in lupus patients, their cardiovascular risk calculus worsened along with it, the researchers noted in Arthritis Care & Research. Patients who transitioned into lower categories of both HCQ blood levels and drug possession had an estimated cardiovascular disease risk of 5.7% versus 3.2% for those with no longitudinal change in these parameters.

Other factors raising the estimated cardiovascular disease risks included comorbid kidney disease, higher SLE Damage Index scores, and longer disease duration before entering the study. Patients using biologic drugs along with HCQ showed a relatively lower risk for cardiovascular disease.

"These findings underscore that monitoring both PDC [percentage days covered] and HCQ blood levels is essential given PDC captures adherence over time and HCQ blood levels reflect the actual biological availability and exposure to the drug that can be influenced by individual metabolism, clearance, and absorption," Garg and colleagues wrote. The increased risk with suboptimal exposure "may warrant preventive therapies," especially for those who also have renal impairment or other "risk-enhancing conditions," the researchers observed.

Treatment adherence has long been a problem in lupus management. Lifelong daily dosing is called for, and side effects such as retinopathy can build over time. Patients may develop "dosing fatigue" or become concerned about adverse effects, and thus skip doses and/or refills. In addition, more recent research has shown that HCQ blood levels vary among patients on a given dose. Other studies have suggested a narrower therapeutic index for HCQ than commonly believed.

How these issues relate to cardiovascular disease risk hasn't been examined in detail before, Garg's group noted. Vascular disease is a common feature in SLE, which causes inflammation and damage in various body tissues. Therefore, the researchers looked at data from an ongoing cohort study at the University of Wisconsin, including 248 patients treated with HCQ who had two clinic visits a year apart, the first at enrollment. These individuals had HCQ blood levels measured at both visits and their electronic records included prescription fill dates. Garg and colleagues used those data to calculate the percentage of days that participants had HCQ on hand (i.e., the PDC).

Participants' cardiovascular disease risk was estimated with the American Heart Association's (AHA) PREVENT calculator, which takes kidney function, as well as conventional risk factors (smoking, blood lipids, etc.), into account.

Mean participant age was 47, and 90% were women. Median blood level for HCQ at baseline was 786 ng/mL; mean PDC for the 6 months prior to study baseline was 87%.

PREVENT estimates for 10-year cardiovascular disease risk averaged 3.3%. That's below the calculator's threshold of 5% separating low from moderate future risk; AHA guidelines call for medical and behavioral interventions for individuals with values above 5%.

Only 29 patients in the cohort had "very low" HCQ blood levels at baseline, and of those, 16 also had PDC below 80% during the run-up to enrollment. During follow-up, 135 participants had no change in categories for either blood levels or adherence; 97 showed improvement in one or the other category, and nine improved in both. Just seven patients worsened in both categories.

Limitations to the study included the small numbers of participants in some HCQ usage categories. Garg and colleagues also noted that PDC is an imperfect surrogate for adherence, as it "does not capture intermittent or sporadic patterns of daily use or non-use."

"This limitation underscores the complementary value of HCQ blood levels, which reflect actual recent biological exposure independent of prescription fill patterns," the researchers wrote. "Therefore, there is a need for interventions targeting both sustained long-term HCQ intake and achieving therapeutic blood levels (≥750 ng/mL) to optimize cardiovascular risk and improve outcomes in SLE. This approach could optimize the use of HCQ therapy and ensure a therapeutic steady state at the individual patient level."

Source Reference: Garg S, et al "Optimizing hydroxychloroquine blood levels and long-term hydroxychloroquine intake could lower ASCVD risk and prevent polypharmacy in systemic lupus erythematosus" Arthritis Care Res 2026; DOI: 10.1002/acr.80128.