Systemic glucocorticoids confound SARS–CoV‐2 acquisition or even clinical outcomes in patients with autoimmune disease treated with biologics: comment on the article by Simon et al

To the Editor: We read with great interest the brief report by Dr. Simon et al (1) in which they assessed the immune responses to SARS–CoV-2 infection or vaccination against SARS–CoV-2 in 14 patients with autoimmune disease (AID) and B cell depletion. Serum samples from AID patients treated with rituximab who had SARS–CoV-2 infection and those who were vaccinated against SARS–CoV-2 had lower levels of IgG antibodies against the S1 domain of the spike protein (mean ± SD at optical density of 450 nm, 2.9 ± 2.2 and 0.2 ± 0.3, respectively) than healthy controls (mean ± SD 5.4 ± 2.5). These findings suggest that B cell depletion may be associated with an increased risk of COVID-19 acquisition or even adverse outcomes in AID patients. We note that, although Simon et al stated that a large limitation was the small number of patients with B cell depletion who were exposed to SARS–CoV-2 infection or vaccination, there was no information in the article on whether biologic medications with or without concomitant glucocorticoids were given, with glucocorticoids deemed as a confounding factor. Glucocorticoids lead to broad immunosuppressive effects and are recommended by current guidelines as part of the standard care for AID (2). In a national cohort from The Netherlands (3), glucocorticoids were used alone or combined with biologics in 6% and 45% of AID patients, respectively. Studies conducted during the COVID-19 pandemic showed that systemic glucocorticoids increased the risk of SARS–CoV-2 acquisition or even resulted in adverse outcomes. In a retrospective cohort study of 213 AID patients from Detroit, glucocorticoids were associated with a 5.48-fold increased rate of hospital admission among those who tested positive for SARS–CoV-2 (odds ratio [OR] 5.48, 95% confidence interval [95% CI] 1.28–26.1) (4). In a meta-analysis of COVID-19 susceptibility in AID patients, Fagni et al (5) stated that use of 2.5 mg or more of prednisone daily was associated with a significantly higher probability of SARS–CoV-2 acquisition (OR 2.89, 95% CI 1.26–6.62) and use of 10 mg or more of prednisone daily was associated with a doubled risk of hospitalization (OR 2.05, 95% CI 1.06–3.96). However, although the relative risk associated with glucocorticoids has been generally shown as linear to daily dosage and treatment duration (6), information on the effects of glucocorticoids plus biologics on SARS–CoV-2 acquisition in AID patients remains scarce. We suggest that the available data do not show that glucocorticoids on their own increase the risk of SARS–CoV-2 acquisition or even the risk of adverse outcomes. First, AID patients often receive courses of systemic glucocorticoids to reduce disease activity during the initial episode and the subsequent flares, and thus a broad overlap is found between glucocorticoid usage and disease activity (7). Thus far, studies have not yet shown which of these 2 variables is the major contributor to risk. Second, patients with connective tissue diseases (CTDs) have a higher risk of SARS–CoV-2 acquisition than patients without CTDs. In a meta-analysis that comprised 319,025 patients from 62 studies, CTD patients had the highest prevalence of COVID-19 (3.4%) compared with other AIDs, which is likely due to the higher proportion of patients with CTDs versus other AIDs who use glucocorticoids (60.3%) (8). Third, an increased risk of SARS–CoV-2 acquisition associated with glucocorticoid usage comes as a consequence of pandemic outcomes in low-resource settings (9,10). AID patients in low-resource settings may potentially be exposed to factors that result in adverse outcomes compared with their counterparts in high-income countries.