Severe COVID-19–Related Outcomes Found Worse in Men With RA

Jennifer Lubell

September 29, 2022

A retrospective study that analyzed sex disparities in patients with COVID-19 and rheumatoid arthritis found that men had more baseline comorbidities and increased risk of COVID-19–related outcomes, compared with females.

“Differences in genetics between sex and sex steroid hormones may play a role in predisposition to COVID-19 infection as well as modulating the disease progression,” according to Xiaofeng Zhou, PhD, senior director at Pfizer, New York, and the study’s lead author.

Zhou presented her findings at The Lancet Summit: Sex and gender in rheumatology in late September.

Patients with chronic rheumatic diseases treated with immunomodulatory therapies may be at higher risk for more severe COVID-19 outcomes, including hospitalization, complications, and death. Research on sex-based disparities in RA patients with COVID-19 in the United States is limited, said Zhou, who embarked on a retrospective cohort study to examine the demographic and clinical characteristics of RA patients with COVID-19 and estimate the risk of possible COVID-19 outcomes by sex.

Zhou and colleagues used U.S. COVID-19 data collected through electronic health records by Optum during 2020 to June 2021. The study included adult patients with RA and a COVID-19 diagnosis (≥ 1 diagnosis code or positive SARS-CoV-2 laboratory test) and ≥ 183 days of database enrollment who received treatment with immunomodulatory therapies prior to the diagnosis date. They were stratified by sex.

Investigators used logistic regression to estimate the risk of 11 possible COVID-19–related outcomes within 30 days of the COVID-19 diagnosis (hospitalization, ICU admission, pneumonia, kidney failure, thrombotic event, heart failure, acute respiratory distress syndrome [ARDS], sepsis/septic shock, mechanical ventilation/extracorporeal membrane oxygenation [ECMO], in-hospital death, and all-cause mortality), adjusting for demographics and baseline clinical covariates.

A total of 4476 COVID-19 patients with RA (78% females) took part in the study. Male patients trended older (64 vs 60 years) and had lower African American representation and Medicaid enrollment than females, but they had more baseline comorbidities such as hypertension (55% vs 45%), hyperlipidemia (45% vs 33%), diabetes (25% vs 20%), coronary artery disease (28% vs 12%), and chronic kidney disease (20% vs 15%).

Eight of the 11 COVID-19 outcomes were significantly more likely to occur in men than women (hospitalization: odds ratio [OR], 1.32 [95% CI, 1.11-1.56]; ICU admission: OR, 1.80 [95% CI, 1.36-2.40]; mechanical ventilation/ECMO: OR, 1.48 [95% CI, 1.04-2.11]; in-hospital death: OR, 1.53 [95% CI, 1.13-2.07]; all-cause mortality: OR, 1.42 [95% CI, 1.09-1.86]; sepsis: OR, 1.55 [95% CI, 1.20-2.02]; kidney failure: OR, 1.46 [95% CI, 1.15-1.85]; ARDS: OR, 1.39 [95% CI, 1.15-1.69]).

Sex Hormones Factor Into Risk

The data illustrated that men with RA had more baseline comorbidities and increased risk of COVID-19 outcomes than females.

Sex hormones regulate virus entry into host cells, respiratory function, immune response, the cardiovascular system, and coagulation, explained Zhou.

Estrogen and progesterone in women could help develop stronger and efficient immune responses to viruses and reduce virus entry into the host cells. Also, “larger number of copies of ACE2 genes in women, [which] is linked with protection in the lungs against edema, permeability, and pulmonary damage, could be associated with lower incidence of severe COVID-19 outcomes, such as respiratory-related mortality and mortality,” Zhou said.

By comparison, androgens in men may increase virus entry into the host cells and promote unfavorable immune response through the induction of cytokine production and reducing the antibody response to the virus. This could lead to severe infection, Zhou said.

Sex-based differences in steroid hormones may also explain the higher incidence of morbidity and fatality that’s been observed in other studies of male patients with other infectious diseases, such as severe acute respiratory syndrome and Middle East respiratory syndrome.

Study Bolsters Evidence on Sex Disparities

The results add real-world evidence to the limited literature on sex disparities in COVID-19 outcomes among patients with RA in the United States, Zhou said. “The differential role in sex steroid hormones among women and men may shed light on clinical management of COVID-19 patients and the need to consider sex-specific approaches in clinical trials in preventing and treating COVID-19 patients,” she said.

Considering that all patients are recommended to get COVID-19 vaccinations, “It is difficult to say how this impacts clinical practice,” said Janet Pope, MD, MPH, professor of medicine in the division of rheumatology at the University of Western Ontario, London, Ontario, Canada, who was not involved with the study.

Sharing results with some patients may help to encourage vaccination, thus reducing risk of poor COVID-19 outcomes, Pope said.

In future studies, Zhou suggests using multiple databases and considering other geographies beyond the United States to further understand the etiology of sexual dimorphism in COVID-19 and expand generalizability. “In addition, future research will seek to provide insights into health equity gaps in the management of COVID-19. This may inform development of precision medicines and vaccines, especially among patients on immunosuppressive treatments,” she said.

The study was sponsored by Pfizer. Zhou and other study authors are Pfizer employees and hold Pfizer stock.

The Lancet Summit: Sex and gender in rheumatology: Abstract P.37. Presented Sept. 22, 2022.

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