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Mathian et al described the clinical course and heterogeneity of COVID-19 in 17 systemic lupus erythematosus (SLE) patients.1 SLE subjects could be at higher risk of developing COVID-19, with more severe symptomatology and need for hospitalisation due to multiple underlying risk factors.1 2 Type-I interferons (IFN), including IFNα, play fundamental roles in immunity and are crucial in antiviral responses.3 Defects in IFN signalling pathways, secondary to monogenic inborn errors or to blocking autoantibodies, promote immunodeficiency and recurrent infections.4 5 Dysregulation in type-I IFN pathway also plays key pathogenic roles in SLE.6 A recent report showed association between anti-type-I IFN autoantibodies in 10% of subjects with life-threatening COVID-19 in the general population.7 A comprehensive evaluation of multiple anticytokine autoantibodies showed the presence of anti-type-I IFN autoantibodies in 11% of SLE subjects in the pre-COVID-19 era.8 We hypothesised that SLE patients having anti-IFNα autoantibodies at baseline (prior to 2020) may be at higher risk of developing COVID-19, and that the presence of these autoantibodies may help in guiding management and preventive strategies.
Ten SLE females who developed COVID-19 between 1 April and 1 October 2020 were identified among lupus subjects followed at the National Institutes of Health, Bethesda, MD, USA under IRB-approved SLE natural history protocol 94-AR-0066 (online supplemental methods, table 1). Seven patients had mild to moderate COVID-19 symptoms that were managed at home with supportive care. Three patients had severe symptoms requiring hospitalisation, supplemental oxygen and/or steroids and convalescent plasma infusion. All patients had full recovery. Eight patients were on daily prednisone (range 5–20 mg/day) when COVID-19 symptoms developed. Seven patients were taking hydroxychloroquine prior to COVID-19 and continued it during the infection. One patient (patient 2) had received rituximab in February 2020 and developed COVID-19 in May 2020. Another patient (patient 9) developed COVID-19 while on belimumab.
Biobanked plasma from healthy controls (HC; n=119) and the 10 SLE subjects were tested for anti-IFNα IgG autoantibodies by ELISA (online supplemental methods). Values 2 SD above mean in HC samples were considered positive. Anti-IFNα autoantibodies was detected in 4 out of the 10 SLE patients (patients 2, 3, 9, 10) who developed COVID-19 (40%; figure 1A). Longitudinal assessments of lupus plasma samples confirmed the presence of anti-IFNα autoantibodies preceding the infection as far back as 2017 (figure 1A). Patients with anti-IFNα autoantibodies had higher rates of hospitalisation requiring oxygen (two out of four) compared with those without (one out of six). Of the two patients (patients 2 and 9) who had received anti-B-cell therapy in the prior years, both had persistent anti-IFNα autoantibodies. These results suggest that the prevalence of anti-IFNα autoantibodies is higher in those patients with confirmed COVID-19 than what has been previously reported in SLE.8
We evaluated if the plasma positive for anti-IFNα autoantibodies could block IFNα signalling in vitro (online supplemental methods). Out of the four SLE subjects with anti-IFNα autoantibodies, half of the samples (two subjects; patients 3 and 9) blocked recombinant human IFNα-induced signal transducer and activator of transcription 1 (STAT1) phosphorylation in HC peripheral blood mononuclear cells (PBMCs) at 10% concentration (figure 1B). These patients had the highest anti-IFNα autoantibodies titers. None of the COVID-19 SLE plasma samples negative for anti-IFNα autoantibodies (n=6) inhibited STAT1 phosphorylation by rhIFNα.
In this initial assessment, 40% of SLE patients who developed confirmed COVID-19 were positive for anti-IFNα IgG autoantibodies in samples obtained prior to SARS-CoV-2 infection. In general, positive autoantibodies were present several years before and in some patients persisted despite B-cell targeted therapy. Previous reports in the same cohort showed that SLE subjects had anti-IFNα autoantibodies prevalence of 11%.8 Therefore, those SLE patients who developed confirmed COVID-19 during this initial wave of the pandemic had enrichment in anti-IFNα autoantibodies. Plasma samples with the highest titers of anti-IFNα autoantibodies inhibited signalling of IFNα in vitro, suggesting that levels of these autoantibodies may affect their blocking ability. A worse outcome in COVID-19 patients positive for anti-IFNα autoantibodies in the general population was recently reported, and suggested that these antibodies may precede infection based on two prestored plasma samples.7 Our findings support this hypothesis, as SLE patients who developed confirmed COVID-19 had anti-IFNα autoantibodies detected prior to the infection, suggesting a potential pathogenic role for these autoantibodies in increasing susceptibility to SARS-CoV-2 infection.
Our study is limited by the small sample size. Whether the presence of autoantibodies will contribute to modulating the severity and outcome of the SARS-CoV-2 infection in SLE requires systematic assessment in larger numbers of patients. The natural history of these autoantibodies should also be further evaluated in longitudinal studies.
This report highlights the key role that IFNα and autoantibodies against this cytokine may play in both SARS-CoV-2 infection and in SLE pathogenesis. The presence of anti-IFNα autoantibodies may prove a helpful prognostic marker to predict which SLE patients may develop COVID-19 and could inform preventive measures and management of this subset of patients.
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Correction notice This article has been corrected since it published Online First. The provenance and peer review statement has been included.
Contributors SG, SN and MJK contributed to the conception and design of the study. SG, SN, JC and SH were involved in the acquisition of data. SG, SN, SH and MJK contributed to the analysis and interpretation of data. All authors contributed to drafting and/or revising the manuscript.
Funding This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (ZIA AR041199).
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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