Lower disease activity but higher risk of severe COVID-19 and herpes zoster in patients with systemic lupus erythematosus with pre-existing autoantibodies neutralising IFN-alpha

Objectives Type-I interferons (IFNs-I) have potent antiviral effects. IFNs-I are also overproduced in patients with systemic lupus erythematosus (SLE). Autoantibodies (AAbs) neutralising IFN-alpha, IFN-beta and/or IFN-omega subtypes are strong determinants of hypoxemic COVID-19 pneumonia, but their impact on inflammation remains unknown. Methods We retrospectively analysed a monocentric longitudinal cohort of 609 patients with SLE. Serum AAbs against IFN-alpha were quantified by ELISA and functionally assessed by abolishment of Madin-Darby bovine kidney cell protection by IFN-alpha 2 against vesicular stomatitis virus challenge. Serum-neutralising activity against IFN-alpha 2, IFN-beta and IFN-omega was also determined with a reporter luciferase activity assay. SARS-CoV-2 antibody responses were measured against wild-type spike antigen, while serum-neutralising activity was assessed against the SARS-CoV-2 historical strain and variants of concerns. Results Neutralising and non-neutralising anti-IFN-alpha antibodies are present at a frequency of 3.3% and 8.4%, respectively, in individuals with SLE. AAbs neutralising IFN-alpha, unlike non-neutralising AAbs, are associated with reduced IFN-alpha serum levels and a reduced likelihood to develop active disease. However, they predispose patients to an increased risk of herpes zoster and severe COVID-19 pneumonia. Severe COVID-19 pneumonia in patients with SLE is mostly associated with combined neutralisation of different IFNs-I. Finally, anti-IFN-alpha AAbs do not interfere with COVID-19 vaccine humoral immunogenicity. Conclusion The production of non-neutralising and neutralising anti-IFN-I antibodies in SLE is likely to be a consequence of SLE-associated high IFN-I serum levels, with a beneficial effect on disease activity, yet a greater viral risk. This finding reinforces the recommendations for vaccination against SARS-CoV-2 in SLE.