Hydroxychloroquine dosing based on ophthalmology guidelines limits SLE flares, may cause retinopathy over time

The investigators emphasized that hydroxychloroquine doses of 5 mg/kg/day or less, in accordance with current ophthalmology and rheumatology guidelines, was associated with a higher risk of lupus flares, and the threshold was near 5 mg/kg/day.

April Jorge, MD, and colleagues reported that the standard dose of hydroxychloroquine successfully prevents flare of systemic lupus erythematosus (SLE), but it can cause toxicity over the long term, such as retinopathy, when doses exceed 5 mg/kg daily.1 She is from the Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston.

The researchers conducted a case-crossover study that included patients with SLE from Massachusetts General Hospital. All patients had completed 2 or more rheumatology visits and used hydroxychloroquine between January 1, 2016, and December 31, 2020, the 5-year period immediately following institution of the 2016 ophthalmology guidelines.2 Jorge and colleagues assessed the association of this dose threshold on lupus flares.

In this study, each patient served as their own control. Case periods were defined as the 6 months before a lupus flare; control periods were defined as each 6-month period prior to a visit with no flare. The exposure under study was the mean weight-based hydroxychloroquine dose assessed during each 6-month case or control period, categorized as either less than or equal to 5 mg/kg/day or greater than 5 mg/kg/day, the investigators described.

Analysis results

The study identified 342 patients with SLE who used hydroxychloroquine during the study period; of these, 168 (49%), of whom 88% were women, had at least 1 lupus flare and were included in the analysis; 80 (23%) had a moderate or severe flare. The mean patient age was 43 years. The mean baseline clinical Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 3.5; 25 (21%) had lupus nephritis, 72 (43%) used glucocorticoids, and 80 (48%) used oral immunosuppressants.

The researchers reported 308 case periods (mean, 1.8 period/patient), including 141 with moderate or severe flare periods, and 420 control periods.

The adjusted odds ratio (OR) for any lupus flare associated with hydroxychloroquine doses of 5 mg/kg/day or less vs. more than 5 mg/kg/day was 1.98 (95% confidence interval [CI], 1.03-3.79) and for moderate or severe lupus flares, the adjusted OR was 6.04 (95% CI, 1.71-21.30). The corresponding adjusted ORs were similar across subgroups but only reached significance for baseline SLEDAI scores of 4 or less (adjusted OR, 2.41; 95% CI, 1.17-4.96). The smoothed dose OR curve indicated an apparent threshold near 5 mg/kg/day of hydroxychloroquine for an increased risk of flares, the investigators reported.

In commenting on the findings, the investigators emphasized that hydroxychloroquine doses of 5 mg/kg/day or less, in accordance with current ophthalmology and rheumatology guidelines, was associated with a higher risk of lupus flares, including moderate or severe flares, and the threshold was near 5 mg/kg/day.

They cited a study3 that reported a higher risk of lupus flares associated with any dose reduction, regardless of the specific dose.

“Together, these findings suggest reduced efficacy of lower hydroxychloroquine dosing for lupus disease activity, particularly around doses of 5 mg/kg/day or less. This study highlights the need to consider individualized risks and benefits in choosing the optimal dose of hydroxychloroquine, an important medication in lupus care,” they said.

1. Jorge AM, Mancini C, Zhou B, et al. Hydroxychloroquine dose per ophthalmology guidelines and the risk of systemic lupus erythematosus flares. JAMA. published Online: September 16, 2022. doi:10.1001/jama.2022.13591
2. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF;American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386-1394. doi:10.1016/j.ophtha.2016.01.058
3. Almeida-Brasil CC, Hanly JG, Urowitz M, et al. Flares after hydroxychloroquine reduction or discontinuation: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. Ann Rheum Dis. 2022;81(3):370-378. doi:10.1136/annrheumdis-2021-221295