乌鸦传媒

Monitoring blood levels of hydroxychloroquine (HCQ) among patients with systemic lupus erythematosus (SLE) could help preserve the anti-thrombotic effects of the drug without increasing the risk for retinal toxicity, researchers reported.

Rates of thrombosis declined by 13% for every increase of 200 ng/mL in overall mean blood levels of HCQ, for a rate ratio of 0.87 (95% CI 0.76-1, P=0.0559) after adjustment for age, ethnicity, hypertension, lupus anticoagulant, and levels of C3 complement. Significant reductions also were seen specifically for the most recent blood level measurement, with a rate ratio of 0.87 (95% CI 0.78-0.98, P=0.0249), said Michelle Petri, MD, and colleagues from Johns Hopkins University School of Medicine in Baltimore.

Furthermore, as shown in their study online in , the rates of thrombotic events decreased by 69% in SLE patients whose mean blood levels of HCQ exceeded 1,068 ng/mL compared with those whose levels were below 648 ng/mL, for a rate ratio of 0.31 (95% CI 0.11-0.86, P=0.0237).

Thrombosis is a major concern in SLE, associated with both morbidity and mortality, with disease activity, hypertension, renal abnormalities, and antiphospholipid antibodies all playing a role.

Numerous studies have demonstrated that HCQ lowers the risk of thrombotic events in SLE, with its anti-platelet effects, lowering of antiphospholipid antibodies, and improvement of renal function. The drug also reduces flare and mortality risks.

HCQ has been used for more than half a century, and while the optimal dosing regimen has not been established, conventional dosing regimens extended up to 6.5 mg/kg of actual body weight.

In 2016, the that HCQ be given in dosages less than 5 mg/kg because of concerns about retinal toxicity. A found that short-term organ damage was not associated with those dose reductions, but that study did not consider drug levels or thrombotic events.

A further prospective study, also by Petri's team, demonstrated that patients with the highest tertile of HCQ blood levels did have an increased risk for future retinopathy, "indicating a role in monitoring blood levels to reduce toxicity." The highest tertile of HCQ blood level in that analysis ranged from 1,177 to 3,513 ng/mL.

To explore the potential benefits of routine monitoring of blood levels for balancing thrombosis prevention with retinopathy risk, Petri and co-authors analyzed data from the longitudinal Hopkins Lupus Cohort, which was established 35 years ago.

The analysis included 739 patients, 93% of whom were women; mean age was 43. A total of 43% of the participants were African-American, and 46% were white.

Participants were required to have had at least one HCQ blood level measurement done at the Johns Hopkins clinical laboratory.

Common disease manifestations included arthritis in 69% of patients, oral/nasal ulcers in 53%, photosensitivity in 49%, proteinuria in 44%, and malar rash in 43%. Laboratory findings included antinuclear antibodies in 97%, anti-double stranded DNA in 61%, lupus anticoagulant in 21%, leukopenia in 51%, and thrombocytopenia in 18%.

During 2,330 person-years of follow-up, 38 patients had thrombotic events (5.1%), with 18 having venous thrombotic events such as deep venous thrombosis/pulmonary embolism and 20 having arterial events including stroke and myocardial infarction.

Tertiles of HCQ blood levels were determined for two separate measurements: overall mean level and most recent level. For the mean level, the tertiles were 0-648 ng/mL, 648-1,068 ng/mL, and ≥1,068 ng/ML, while for the most recent level, the tertiles were 0-667, 668-1,191, and ≥1,192 ng/mL.

Forest plot analyses revealed that a mean blood level of 1,068 ng/mL and a most recent blood level of 1,192 ng/mL were protective against thrombosis, with adjusted rate ratios of 0.34 (95% CI 0.12-0.94, P=0.0374) and 0.40 (95% CI 0.16-1.04, P=0.0614) -- "with the latter P value just missing statistical significance," the authors noted.

The overall thrombotic event rate reduction of 69% remained statistically significant after adjustment for age, ethnicity, hypertension, lupus anticoagulant, and complement C3, with a rate ratio of 0.34 (95% CI 0.12-0.94, P=0.0374), the researchers reported.

"Together, these data suggest that hydroxychloroquine whole blood levels were predictive of thrombotic events in SLE in a dose-dependent manner and suggest an opportunity for personalized drug dosing approaches beyond empirical dosing recommendation," Petri and colleagues wrote.

They said the study also suggests that following the recommendation that daily doses be maintained below 5 mg/kg per day might interfere with the drug's anti-thrombotic properties. "Targeting the hydroxychloroquine blood level to 1,068 ng/mL was associated with protection. It should be possible to target this level and still avoid the 'upper tertile' that we previously proved was associated with retinopathy," the investigators concluded.

A limitation of the study, they said, was its observational design.

Comment