Skip to content

Impact of Hydroxychloroquine Dose on Risk of Lupus Flares

In This Article

  • A recent Massachusetts General Hospital study quantified the impact of hydroxychloroquine (HCQ) dose guidelines on systemic lupus outcomes
  • Ophthalmology and rheumatology guidelines recommend no more than 5 mg/kg/day after research found a greater risk for retinopathy with long-term use than previously known
  • Systemic lupus patients taking less than 5 mg/kg/day of HCQ had a six-fold higher risk of a moderate to severe lupus flare than patients taking a higher dose
  • An HCQ dose above approximately 5.5 mg/kg/day was not associated with a continuing decrease in the odds of having a lupus flare, suggesting the optimal dose may be slightly above current guidelines
  • Providers should weigh the benefits against the risks on an individual basis when deciding on dosage, as more research is needed to understand the HCQ retinopathy risk

A higher dose of hydroxychloroquine (HCQ) than recommended by current ophthalmology and rheumatology guidelines may be optimal to control lupus flares, according to a recent study at Massachusetts General Hospital.

April Jorge, MD, a rheumatologist in the Division of Rheumatology, Allergy and Immunology at Mass General, has been investigating the most appropriate use of HCQ in lupus patients. "There are a lot of unanswered questions about hydroxychloroquine, which has been this cornerstone of lupus treatment," she says. "When I speak to rheumatologists, I think the general sense is to follow the existing guidelines, but also to be skeptical that we need more data to know the optimal way to use this medication."

History of Hydroxychloroquine Guidelines for Lupus

Hydroxychloroquine, an antimalarial drug approved by the FDA in 1955, plays a significant role in treating systemic lupus erythematosus (SLE) and lupus nephritis. Its influence on the immune system helps control lupus flares and reduces disease mortality.

A study published in JAMA Ophthalmology in 2014 revealed a higher risk of eye toxicity from long-term HCQ use than previously known. The medication impairs lysosome function and may accumulate in retinal cells over time. However, the same study also reported that many patients used HCQ for decades without harm to their retina.

The American Academy of Ophthalmology (AAO) followed these findings in 2016 with new guidelines to maximize eye safety. The guidelines recommend no more than 5 mg/kg/day, a reduction from 6.5 mg/kg/day. In 2019, the European Alliance of Associations for Rheumatology released the same updated recommendations for HCQ use for systemic lupus.

Dr. Jorge points out, however, that the 2014 study focused on eye risk irrespective of the medication's role in lupus outcomes. While rheumatologists want to follow guidelines for eye care, there may be times when the guideline is not appropriate for lupus care, she says. "The risk of hydroxychloroquine retinopathy is known, but more research is needed to clarify exactly how high that risk is. The concerns that led to the change in guidelines were primarily based on one observational study."

Dr. Jorge's findings follow the 2021 joint statement on hydroxychloroquine use from the AAO, American College of Rheumatology (ACR), American Academy of Dermatology, and Rheumatologic Dermatology Society. The medical societies highlighted the clinical value of HCQ and the importance of concurrent retinopathy screening. They stated a low risk of retinopathy in the presence of appropriate precautions and called for more evidence before stopping HCQ use.

Impact of Hydroxychloroquine Guidelines on Lupus Care

Dr. Jorge's recent work, reported in JAMA Network, examined the influence of the 5 mg/kg/day cutoff on systemic lupus outcomes. "We hypothesized that there would be a higher risk of lupus flares if we used a lower dose in accordance with the guidelines," she says.

Dr. Jorge applied a case-crossover study design, which compares patients to themselves rather than others. Factors such as sex, age, race, ethnicity, and access to care vary among individuals and could introduce bias. "One of the hallmarks of lupus is how heterogenous it is for different people," explains Dr. Jorge. "We wanted to take away the time-invariant potential confounders."

The case-crossover study design also allowed investigators to detect significant differences using a smaller sample size. Dr. Jorge and colleagues analyzed 342 patients (88% female) with SLE. Patients were categorized as taking a low HCQ dose (less than or equal to 5 mg/kg/day) or a high HCQ dose (greater than 5 mg/kg/day).

Investigators looked at the number of flares across six-month periods for each patient. They considered mild, moderate and severe lupus flares, as ranked by the revised Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index (rSFI).

Low-dose Group Faced Higher Risk of Lupus Flares

The findings validated the team's hypothesis: Taking less than 5 mg/kg/day was associated with a higher risk of lupus flare. In particular, patients in the low-dose group experienced significantly more moderate or severe flares.

Findings were adjusted for glucocorticoid use, immunosuppressant use and disease activity that was recorded just before each six-month period. Use of other lupus treatments, disease duration and presence of lupus nephritis did not increase the risk of flares. Low disease activity at baseline significantly correlated with an increased risk of flares for the low-dose group.

Finding the Optimal Hydroxychloroquine Dose

The study also revealed that the efficacy of HCQ in controlling flares did not increase linearly with higher doses. At around 5.5 mg/kg/day and higher, the decreasing odds of a flare leveled out.

Limited data exists on the optimal HCQ dose for lupus patients. The existing research primarily looks at outcomes of patients using 400 mg/day, which has historically been the convention. But the average dose has decreased over time.

"It might be that we don't need to use much more than 5 mg/kg/day, but that should be studied further," says Dr. Jorge.

Interpreting the Results

Dr. Jorge and colleagues have highlighted the importance of balancing the risks and benefits of HCQ as a lupus treatment. Although rare, HCQ may also cause a range of other side effects such as gastrointestinal problems, skin discoloration, behavioral changes, and muscle weakness. They hope to help guide treatment decisions that clinicians make with their patients.

"Our findings show that we might need to be using a higher dose of the medication than recommended to get the full clinical benefit and better control disease activity for patients with lupus," explains Dr. Jorge. "If you think a patient is at a higher risk of flaring, maybe you need to use a higher dose in the short term. But maybe you wouldn't use that high dose for 20 years because of the retinopathy concerns."

She emphasizes the need for more data on the impact of hydroxychloroquine dose on the risk of flares. The duration of a higher dose is also in question. "We may need to revisit the guidelines and make them a little more nuanced for a higher dose of medication in certain circumstances," she says.

The results of a follow-up study, which rheumatology fellow Jacquelyn Nestor, MD, PhD, presented at the ACR convergence meeting in November 2022, supported these findings. Dr. Nestor, Dr. Jorge and colleagues assessed hospitalizations for lupus flares in a larger cohort of patients across the Mass General Brigham network. They again found that using less than 5 mg/kg/day of HCQ compared to more was associated with a higher risk, this time, of hospitalization for a lupus flare.

Understanding a Hydroxychloroquine Retinopathy Diagnosis

"I think there's a misconception that when someone is diagnosed with hydroxychloroquine retinopathy, they always have blindness or vision loss," reflects Dr. Jorge. She notes that her research currently underway has shown that most people diagnosed with hydroxychloroquine retinopathy on screening tests don't have any visual symptoms.

"Most likely, they have very mild changes," she says. "They might develop vision loss years later if they stay on the medication, but I think that is manageable by screening for retinopathy and detecting it early."

Dr. Jorge aims to identify predictors of hydroxychloroquine retinopathy to help identify which lupus patients would safely benefit from a higher HCQ dose. She highlights the value of Mass General Brigham's Research Patient Data Registry, which offers a large database of clinical patients. She previously worked with the organization's biobank to create a clinical phenotype for patients with lupus.

Learn about the Division of Rheumatology, Allergy and Immunology

Refer a patient to the Allergy & Clinical Immunology Unit


Massachusetts General Hospital's Clinical Epidemiology Program utilizes multidisciplinary collaborations, big data and omics sciences to advance rheumatology and COVID-19 care.


Clinicians in the Division of Rheumatology, Allergy and Immunology found that for patients with rheumatic and musculoskeletal diseases who develop COVID-19, the risks of death and other severe outcomes have declined since early in the pandemic but remain considerable.