The incidence of retinopathy among patients with systemic lupus erythematosus (SLE) treated with hydroxychloroquine increased with longer duration of use, but could be predicted by monitoring blood levels of the drug, a prospective cohort study found.
Among those whose exposure to hydroxychloroquine was ≤5 years, the prevalence of retinal toxicity was 0.97%, increasing to 1.83% after 6 to 10 years, to 3.30% for 11 to 15 years, and to 11.46% for 16 to 20 years (P for trend = 0.0006), according to Michelle Petri, MD, of Johns Hopkins University School of Medicine in Baltimore, and colleagues.
Among patients in the lowest mean tertile of hydroxychloroquine blood levels (0 to 741 ng/mL), the rate of retinopathy was 1.2%, rising to 3.7% for those with blood levels of 741.5 to 1,176.5 ng/mL and to 7.9% for those with levels of 1,177 to 3,513 ng/mL (P for trend = 0.0027), the researchers reported online in .
Hydroxychloroquine, also known as Plaquenil, is the only medication that has demonstrated improved survival in SLE. It also decreases disease flares by half, has shown antithrombotic and antidiabetic effects, and is associated with complete renal remission when given in combination with mycophenolate mofetil (Cellcept). These benefits, however, were shown using older dosing regimens.
Retinopathy is the major adverse effect with hydroxychloroquine, and reported risk factors have included daily doses above 400 mg, cumulative doses exceeding 1,000 g, use beyond 5 years, obesity, age >60, and renal or hepatic dysfunction.
In 2011, the American Academy of Ophthalmology recommended that hydroxychloroquine dosing be weight-based, at 6.5 mg/kg (maximum 400 mg/day), except for patients who were short or obese, whose dosages should be based on ideal body weight. Data at that time suggested that retinopathy associated with hydroxychloroquine was only 0.1% after 10 years. However, from Kaiser Permanente in 2014 found rates of almost 20% by year 20 of use, leading the academy to revise its recommendations to a maximum daily dose below 5 mg/kg of real weight.
To provide a clearer picture of the prevalence of retinopathy over time and whether monitoring blood levels of hydroxychloroquine, which has been an effective tool for determining adherence, would help predict the development of ocular toxicity, Petri and colleagues analyzed data from the prospective Hopkins Lupus Cohort. In that group of patients, hydroxychloroquine levels have been routinely measured at every visit since 2013, and retinal examinations included the newer screening tests such as spectral-domain optical coherence tomography.
The analysis included 537 patients who underwent retinal testing. A total of 92% were women, and most were white or African American. Blood levels of hydroxychloroquine were obtained from 492 patients, with a median number of levels being seven per patient.
The overall prevalence of hydroxychloroquine toxicity was 4.3%. The obese had higher rates (5%), as did those with older age, with rates of 0.5% for those age <45, but 10.1% for those age >60. African Americans had lower daily doses of hydroxychloroquine (4.46 vs 4.84 mg), but showed no differences in blood levels or rates of retinopathy.
Similar to what was seen for mean tertiles of hydroxychloroquine, the prevalence of retinal toxicity increased according to maximum tertiles (P=0.0143 for trend):
- 0 to 1,182 ng/mL: 1.2%
- 1,183 to 1,752 ng/mL: 4.8%
- 1,753 to 6,281 ng/mL: 6.7%
"Our data agree that the prevalence of hydroxychloroquine retinopathy, using newer screening technologies, is much higher than previously reported," Petri and colleagues wrote.
Their rates, however, were considerably lower than those seen in the Kaiser Permanente study. "This may reflect our local practice, where a dosing limit of 400 mg maximum daily was used, and reductions were made for renal insufficiency and in the elderly," the investigators noted.
They also pointed out that, "importantly," there were no cases of blindness.
"Monitoring hydroxychloroquine blood levels is an important step to improved medication adherence in patients with SLE. We now introduce the concept of hydroxychloroquine blood level monitoring to reduce overdosage," they stated.
"The clinical impact of our study is that practitioners would be able to either decrease hydroxychloroquine dose or increase monitoring in patients with the highest tertile of blood levels," they concluded.
Other prospective studies will be needed to confirm these results.
Disclosures
The Hopkins Lupus Cohort is funded by the NIH.
Petri and co-authors disclosed no relevant relationships with industry.
Primary Source
Arthritis & Rheumatology
Petri M, et al "Hydroxychloroquine blood levels predict hydroxychloroquine retinopathy" Arthritis Rheum 2019; doi:10.1002/art.41121.