COVID Question: Is Hydroxychloroquine Safe in Rheumatoid Arthritis?

The psychiatric events that have been reported among patients with COVID-19 treated with hydroxychloroquine generally haven't been seen in rheumatoid arthritis patients who have used the drug, a multinational cohort study found.

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Compared with sulfasalazine, the short-term (30-day) meta-analytic hazard ratio of the development of depression among patients with rheumatoid arthritis treated with hydroxychloroquine was a nonsignificant 0.96 (95% CI 0.79-1.16), according to Jennifer C.E. Lane, MD, of the University of Oxford in England, and colleagues.

In addition, the long-term on-treatment (until discontinuation) meta-analytic hazard ratio was 0.94 (95% CI 0.71-1.26), the investigators reported in their study online in Rheumatology.

In March 2020, the FDA authorized the emergency use of chloroquine/hydroxychloroquine for COVID-19, and as of June, more than 200 clinical trials had been initiated to evaluate hydroxychloroquine as a treatment for severe acute respiratory syndrome in COVID-19, with conflicting results but largely suggesting a lack of efficacy.

In late June, the National Institutes of Health stopped its clinical trial, which had enrolled almost 500 patients, because of a lack of benefit. Another randomized trial of 821 patients also found no benefit as post-exposure prophylaxis.

Adverse neuropsychiatric effects have long been described for both hydroxychloroquine and chloroquine, with rare events including depression, psychosis, and suicidal behavior. There has been an increase in reports of these events with high-dose hydroxychloroquine use as a COVID-19 treatment during the pandemic, Lane and co-authors noted.

One mechanism of action of hydroxychloroquine is the disruption of function of lysosomes, similar to what occurs in lysosomal storage diseases, which are associated with neurodegeneration and neuropsychiatric symptoms.

"New reports of serious side effects associated with hydroxychloroquine used in COVID-19 are concerning to the rheumatology community, leading to confusion and anxiety for patients who are taking hydroxychloroquine for autoimmune conditions," the researchers observed.

In an effort to address these concerns, the team reviewed electronic health records and administrative claims data for rheumatoid arthritis patients from the year 2000 in 10 sources from three countries such as the U.S. Optum Electronic Health Record dataset, the U.K. Clinical Practice Research Datalink, and the IQVIA Database Analyzer Germany, with propensity score matching for new users of hydroxychloroquine or sulfasalazine.

Sulfasalazine was chosen as the active comparator, as it has a similar second-line conventional disease-modifying antirheumatic drug indication for rheumatoid arthritis but has been considered to have a low risk of depression, the investigators explained.

Outcomes other than depression included suicide or suicidal ideation and hospitalization for psychosis. The analysis included 918,144 patients who initiated treatment with hydroxychloroquine and 290,383 who started on sulfasalazine. Most patients were ages 55 to 65, and more than three-quarters were women.

In the various databases, the most common of the outcomes was depression, ranging from rates of 1.99 per 1,000 person-years to 17.74 per 1,000 among users of hydroxychloroquine, while the least common was suicide/suicidal ideation, with rates ranging from 0.32 per 1,000 for both hydroxychloroquine and sulfasalazine users to 14.08 per 1,000 in sulfasalazine users.

Meta-analyses were conducted that included the rates of the three outcomes in the different databases. As was seen for depression, there was no overall short-term increased risk for suicide/suicidal ideation, with hazard ratios in the individual databases ranging from 0.27 (95% CI 0.06-1.29) to 10.46 (95% CI 0.51-216.29), and a nonsignificant meta-analytic hazard ratio of 0.94 (95% CI 0.49-1.77).

Long-term hazard ratios for suicide/suicidal ideation ranged from 0.55 (95% CI 0.20-1.49) to 2.36 (95% CI 0.21-26.87), and a meta-analytic hazard ratio of 0.77 (95% CI 0.56-1.07).

No association was seen for hydroxychloroquine and risk of acute psychosis.

While there has been an increase in reports of psychiatric events associated with hydroxychloroquine use during the COVID pandemic, this increase "may be multifactorial, with an increase in external stressors such as social isolation, financial uncertainty, and increased misuse of drugs and alcohol," Lane and colleagues wrote.

"Our study identifies no increased risk [with hydroxychloroquine] in rheumatoid arthritis patients when compared with sulfasalazine and provides evidence to users and clinicians alike that the reports presented during the pandemic are likely to be related to further causes aside from hydroxychloroquine," the team concluded.

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