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Hydroxychloroquine Use and Risk in the Management of Systemic Lupus Erythematosus

Researchers examine SLE patients’ perceptions regarding the risks of HCQ-induced retinopathy, calling for increased patient education. Plus: How HCQ is caught up in the COVID-19 pandemic.

Hydroxychloroquine is considered to be an effective treatment option for systemic lupus erythematosus (SLE) to sustain disease remission and reduce the risk of irreversible renal damage. Several studies have demonstrated that hydroxychloroquine (HCQ) improves survival, reduces the frequency of flares, minimizes the risks of major organ damage, and has protective effect on cardiovascular health in SLE.1-4

HCQ also has been demonstrated to have a lower risk of drug toxicity than other disease-modifying anti-rheumatic drugs (DMARDs).5 The medication is generally well tolerated, with the most common adverse events being gastrointestinal upset, dermatologic changes, and headache. (See below the Author’s Note regarding HCQ use during the COVID-19 pandemic.)

Irreversible retinopathy is one of the more feared long-term side effects of HCQ. The risk is estimated to be less than 2%, when HCQ is appropriately dosed at < 5 mg/kg of actual body weight with appropriate ophthalmology monitoring.6 The American Academy of Ophthalmology (AAO) recommendations on screening for hydroxychloroquine and chloroquine retinopathy identified several risk factors for the development of HCQ-induced retinopathy:7

  • dosing above 5 mg/kg/day of actual body weight
  • duration of use > 5 years
  • tamoxifen use
  • significant renal disease
  • pre-existing retinal and macular disease.

 According to the AAO recommendations, a baseline ophthalmology evaluation followed by annual follow up after 5 years of continuous use of either HCQ or chloroquine is the standard of care for low-risk patients.7 Retinopathy is typically screened by spectral-domain optical coherence tomography and automated visual field tests.7

Despite the beneficial effects of HCQ in SLE, it is not uncommon to encounter patients with concerns about HCQ-induced retinopathy; some patients may elect to discontinue hydroxychloroquine due to these concerns. However, there is a lack of data regarding SLE patients’ perception of the risks and benefits of hydroxychloroquine treatment. Patients who self-discontinue hydroxychloroquine without any evidence of retinopathy could be needlessly deprived of the drug’s benefits.8 The objectives of this study were to assess SLE patients’ perception of the risks and benefits associated with the use of HCQ, and their awareness of the risk factors of HCQ-induced retinopathy.

Hydroxychloroquine is considered to be an effective treatment option for systemic lupus erythematosus and is now being used in the treatment of COVID-19 as well. (Image: istock)


Patients were recruited for participation through an email listserv of the Lupus Alliance of Upstate New York (LAUNY) database from March 2019 to April 2019. LAUNY is a nonprofit organization established in 1976 that serves 33 counties in the state of New York. There were approximately 3,000 emails listed in the listserv, including SLE patients and their relatives. Emails were sent to all 3,000 members, requesting that they volunteer to participate in an anonymous survey by clicking on a link in the email. This electronic invitation was sent twice, two weeks apart, in February 2019.

Survey data was automatically recorded using a Google document platform. No financial remuneration or gift was provided to participating individuals. Participation was voluntary, anonymous, and restricted to adults 18 years or older. The study was approved by the Albany College of Pharmacy and Health Science Institutional Review Board.


Demographic variables collected included age, gender, weight, height, self-designated race, and highest level of education. We collected data on the participants’ use of prescription drugs, OTC medications, and herbal medicines for the treatment of SLE. Disease-related information collected included the duration of SLE, duration and current dose (if currently used) of HCQ, whether baseline and follow-up ophthalmology evaluations were conducted (to their knowledge), and history of any abnormal ophthalmology findings.

In addition, participants’ perceptions of the risks and benefits of HCQ therapy were queried with an electronic questionnaire. Patients were asked to respond to statements using the following choices: strongly agree, agree, disagree, strongly disagree, I don’t know, or, not applicable. Appropriate descriptive statistical methods were used to depict patient demographics and perception and risk awareness.


A total of 94 respondents participated in the survey. Demographic data are presented in Table I. The majority of the respondents were women (98%). The median time since the SLE diagnosis of the responders was 10 years. Nearly the entire cohort (97%) were high school graduates and 70% had an associate’s or higher degree. Out of the 94 responders, 18 (19%) reported that they had an ophthalmology exam in the past.

Almost all responders (n=89; 94%) were either current or past users of HCQ (see Table II). This group was defined as the “HCQ analysis cohort.” Other commonly prescribed SLE medications such as belimumab, mycophenolate mofetil, azathioprine, cyclosporine A, cyclophosphamide were used by 4% to 24% of the responders.  From the open-ended question, responders shared that they used the following SLE-related prescription, OTC, or herbal drugs:

  • methotrexate (n=7)
  • tacrolimus (n=1)
  • corticosteroid (either oral or topical, n=29)
  • NSAIDs (n=17)
  • turmeric (n=6)
  • fish oil (n=5)
  • DHEA (dehydroepiandrosterone) (n=4)
  • CBD (cannabidiol) (n=3)
  • medical marijuana (n=2)
  • glucosamine/chondroitin (n=2)
  • low dose naltrexone (n=1)
  • co-enzyme Q, (n=1)
  • herbs (eg, aloe, milk thistle).


The HCQ cohort was further analyzed regarding the perceived risk, benefit, and awareness questionnaire (see Table III). Eighty-six individuals (97%) reported undergoing regular ophthalmology examinations. A baseline eye examination was reported in 73 (82%). Ninety-two percent (n=82) reported that their rheumatologists informed them about HCQ-associated retinopathy, and 74% (n=66) perceived retinopathy as a serious side effect. In contrast, only 43% (n=38) of HCQ patients reported that pharmacists provided them information concerning retinopathy. A significant proportion (n=59, 66%) of responders were informed about HCQ induced retinopathy through the internet. The majority of HCQ cohort (n=57, 64%) desired to continue receiving HCQ and a relatively small percentage (n=14, 16%) desired discussing discontinuation of HCQ due to concerns of retinopathy. One-third of the cohort (n=29, 33%) desired a discussion concerning the general side effects of HCQ with their healthcare professionals.

Most of the HCQ cohort was relatively unaware of the risk factors for HCQ retinal toxicity. Almost 60% (n=53) of responders had either incorrect knowledge regarding the relationship between renal function and HCQ toxicity (n=18) or admitted that they unaware of this association (n=35). Only one-third of the responders were aware of weight-based dosing of the HCQ to avoid retinal toxicity (n=29).  Fifteen percent (n=13) of responders were concerned about possible HCQ drug interactions.

The authors assessed the weight-based dosing of HCQ in the analysis cohort. Among 94 responders, 66 individuals were current HCQ users. Two individuals provided invalid HCQ doses, and three individuals did not provide their body weight, which allowed for the evaluation of 61 survey responders for HCQ weight-based dosing appropriateness. The criterion for an excessive HCQ dose was > 5 mg/kg/day. Twenty individuals out of 61 (33%) were categorized as overdosed, based on their self-reported weight and HCQ daily dose.


In the presented survey of 89 SLE patients who previously or currently used HCQ, we found that approximately one-quarter were unaware of HCQ-induced retinopathy. Lack of knowledge concerning individual risk factors for HCQ-induced retinopathy ranged from 13% to 39%. In addition, despite the fact that 92% of patients were counseled regarding HCQ toxicity by their rheumatologists and 97% had regular ophthalmology examinations, still, one out of six were concerned about the eye toxicity to the point of considering drug discontinuation.

A majority of the subjects in this study reported present or past use of hydroxychloroquine. Similarly, Wallace et al reported HCQ use in most of the subjects in their cohort.9 In the presented cohort, 80% of the patients reported having a baseline ophthalmology screening evaluation before initiation of HCQ. Almost all the participants (97%) had regular ophthalmology follow-up. Previous studies have reported variable data on clinicians’ compliance to ophthalmology guidelines regarding HCQ toxicity monitoring ranging from 50 to 85%.10-12

More than 90% patients reported that retinopathy was discussed as a side effect, by their rheumatologist. However, more than 50% patients did not recall their pharmacists discussing this topic. A majority of the patients recognized retinopathy as a serious side effect of HCQ and 16% of the subjects expressed their desire to stop HCQ because of fear of retinal toxicity. Similar to the presented study, Cabral reported 21% SLE patients were concerned about HCQ toxicity.13 Cabral concluded that fear has been a factor affecting adherence, therefore, making patients aware that HCQ is well tolerated and could improve adherence.

Nineteen percent of the presented questionnaire responders reported a history of abnormal ophthalmology examination. This percentage is considered high, given that the median duration of therapy of our cohort was only 5 years, and most HCQ retinal toxicity occurs after a longer duration on the drug. However, because the authors could not capture the specific nature of ocular abnormalities in the HCQ cohort, it is unclear whether they represented HCQ-associated retinopathy.

Interestingly, although most of the patients were aware of the risk of HCQ-associated retinopathy, only two-thirds recognized duration of therapy and dose of the medication as being associated with this risk. In addition, almost half of the cohort (46%) either denied any knowledge or had incorrect knowledge regarding weight-based dosing of HCQ. Patients were unable to assess their risk of HCQ-associated retinopathy, and this may have hindered their ability to accurately estimate the probability of developing this complication.


This study has a limitation in that there may have been a selection bias in the HCQ analysis cohort as survey responders may have differed from those who declined participation. Such a bias may explain why responders were highly educated with 85% having at least some college education. Third, the low response rate to the questionnaire and geographically limited area (based on a New York listserv) of cohort may have impaired the results from being generalizable to all SLE patients. Finally, as this survey was self-reported, the authors could not verify the validity of the reported medical assessments, such as the frequency of ophthalmology visits or the nature of abnormal eye exams.


Overall, the results suggest that patient education concerning HCQ-induced retinopathy should be intensified. Because time is often limited during office visits, novel educational approaches should be considered including use of online resources, patient support groups, and detailed counseling by pharmacists and other allied healthcare professionals.

Educating patients regarding the risk factors associated with higher chances of retinopathy is important to ensure appropriate dosing based on weight, kidney function, concomitant drug use and adherence to ophthalmology exam guidelines. The authors surmise that such approaches may lead to a better patient understanding of HCQ-induced retinopathy, better adherence, and lower rates of this complication.

Authors’ Note: HCQ and COVID-19

This project was completed in May 2019 and this manuscript was prepared later in 2019, when the current COVID-19 epidemic was unforeseen. At this time of submitting this manuscript, we are facing unprecedented global public health crisis around the novel coronavirus, and coincidentally, hydroxychloroquine (HCQ) is being considered as a potentially effective agents to improve COVID-19 outcome. While there is no definitive clinical outcome data available at the time of this writing (March 30, 2020) to support HCQ’s efficacy to treat COVID-19 infection, there is a reported shortage of this drug due to institutional and individual hoarding. Consequently, patients who have been using HCQ to treat their rheumatic conditions, (eg, lupus, rheumatoid arthritis, Sjogren’s syndrome) may be at risk of not getting the medication that they have been relying on for years.

To date, HCQ’s utility in COVID-19 has been extrapolated from limited data such as in vitro studies or case studies for which we cannot be sure of causality of efficacy due to low evidence level study design. In a situation like the COVID-19 outbreak, urgency may not allow the medical and scientific community to carry out high-quality time-consuming trials. However, bad data only make clinical decisions even more difficult. Therefore, in the near future, good trial data is needed to guide clinical usage of HCQ in terms of proper dose and duration of treatment if found to be effective for COVID-19. In addition, production of HCQ should be mobilized to meet the supply demand of rheumatic patients’ use and additional use for COVID-19.

Lastly, in line with the purpose of this manuscript, patients and clinicians should be aware that this drug is not free from side effects and that risk versus benefit should be discussed to guide patient centered decision-making in individual circumstances and disease severity.

Note that on April 11, 2020, the Infectious Diseases Society of America released its medication-based recommendations for treating patients diagnosed with COVID-19 in the context of a clinical trial; HCQ is included. As of mid-May, 2020, UW Medicine is launching an RCT trial on outpatients with COVID-19 to test the effectiveness of HCQ and HCQ with azithromycin, as well as on HCQ's role in preventing the virus.


Reviewed by Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP

Disclosures: This research was supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. At the time this study was performed, Drs. Kwon and Banerjee were affiliated with The Center For Rheumatology in Albany, NY. Dr. Farrell receives part of her resident salary support from Janssen.

Last updated on: May 18, 2020
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