COVID-19 in patients with rheumatic disease: finally, a denominator

The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. eabd4585; see also p. 404

In the past year, considerable gains in our understanding of the immunobiology of COVID-19 have provided key insights into the centrality of interferons in the immune response against severe acute respiratory syndrome coronavirus 2. Several studies attest to the involvement of interferons. For instance, Zhang and colleagues 1 screened a large cohort of patients with severe COVID-19 for the presence of predicted loss-of-function variants in 13 genes associated with Toll-like receptor signaling molecules and the type I interferon pathway identified in cases of severe influenza and other viral infections. Of 659 patients with severe COVID-19, 23 (3·5%) harbored known or new mutations in eight of the genes, attesting to the importance of these pathways in viral defense. In a second study, Bastard and colleagues 2 reported a remarkable finding that 135 (13·7%) of 987 patients with life-threatening COVID-19 harboured autoantibodies against type I interferons (mostly against interferon [IFN]-α2 and IFN-ω) with most showing neutralising capacity in vitro. Such antibodies were only detected in 4 (0·3%) of 1227 unexposed, healthy individuals. These papers add to a growing body of literature affirming the importance of interferons in COVID-19, which has direct and indirect implications for the field of rheumatology. Of particular and immediate importance is how these data might affect the development programme of a new class of biological agents designed to therapeutically target the type I interferon pathway in patients with systemic lupus erythematosus (SLE) and allied conditions. The documentation of naturally occurring autoantibodies against a cytokine is not remarkable, as low concentrations of such antibodies have been reported in studies of healthy blood donors, which showed most of the donors to have trace amounts. 3 In the largest study examining the prevalence of antibodies against five cytokines including type I interferons in 8972 blood donors, high concentrations of antibodies to type I interferons were found in less than 1% of participants, with no epidemiological associations with variables such as age, sex, or smoking, 3 similar to findings in control populations (type I interferon antibodies in <1%) in the COVID-19 study. 2 These autoantibodies have also been found in intravenous immunoglobulin preparations and in patients undergoing therapy with type I interferon for infections such as hepatitis C. 4 The biological role of such antibodies is uncertain, and whether they are deterministic (ie, have an immunoregulatory function) or stochastic (ie, appear in response to physiological elevations) is debated. Under some circumstances, naturally occurring anti-cytokine antibodies have been shown to be pathogenic across a range of haematological, pulmonary, and infectious diseases. 5 Such immune dysregulatory syndromes can be monogenic (eg, defects in the AIRE gene) or polygenic (eg, antibodies against interleukin [IL]-17, IL-22, IFN-γ, and granulocyte-macrophage colony-stimulating factor), with polygenic syndromes now classified as inborn errors of immunity, although no specific genes have been identified. 6 Autoantibodies against type I interferon might be clinically important, as they have been associated with a history of severe viral infections in patients with RAG1/2 gene deficiency, an inborn error of immunity associated with diseases with prominent autoimmune features. 7 Autoantibodies against one or more cytokines have been reported in a number of rheumatological conditions, but their biological role remains undefined. The notable exception is SLE, in which autoantibodies against numerous cytokines, including type 1 interferon, have been reported in 27% and 42% of individuals in two studies. 8 These antibodies have varying capacity to neutralise type I interferon bioactivity, depending on the study and assay used, but their presence has been associated with reduced type I interferon in serum and lowered disease activity. 9 However, no clear evidence shows that in the absence of immunosuppression or comorbidities, patients with SLE are at increased risk of developing severe COVID-19 due to subclinical immunodeficiency, and more robust epidemiological studies are needed. 10 Absence of evidence of de novo vulnerability to viral infections in patients with SLE, despite the high prevalence of neutralising autoantibodies to type I interferons, perhaps should not be surprising. In the study by Bastard and colleagues, 2 the presence of such antibodies appeared to antedate illness with COVID-19, and none of the patients had a history of severe influenza or other severe viral illnesses before COVID-19. This observation suggests that in individuals with subclinical immunodeficiency and anti-type I interferon antibodies, infection with COVID-19 might, in some unique way, tip the balance to the advantage of the pathogen, whereas this might not happen in response to other common viral infections. Prospective studies examining the potential influence of autoantibodies against type I interferons on the incidence and severity of viral infection in patients with SLE and other rheumatological disorders is needed. Finally, what might these data forecast regarding the development programmes for biological therapeutics targeting type 1 interferons? Previous clinical trials of monoclonal antibodies directed against type 1 interferons have largely been unsuccessful on the basis of efficacy. By contrast, anifrolumab, an IgG1 monoclonal antibody that targets the type I interferon receptor—allowing it to neutralise the entire family of type I interferons, including IFN-α, IFN-β, IFN-δ, and IFN-ω—has completed two large phase 3 trials (NCT02446912, NCT02446899). Despite some inconsistency in trial outcomes, anifrolumab showed efficacy across clinical, laboratory, and quality of life domains in SLE. 11 One limitation is that all drugs directed at type I interferons share a safety concern of increased risk of herpes zoster infection, which has been as high or higher than that seen with Janus kinase (JAK) inhibitors. However, most infections observed in clinical trials have been non-serious. 12 Although risk of simple upper respiratory infections might also be increased with anifrolumab, no evidence to date shows an increased risk of other serious viral infections. Careful monitoring of outcomes in patients on this drug (and other drugs capable of inhibiting type I interferon) who contract COVID-19 should be of the highest priority. Small molecules, particularly JAK inhibitors, are also of concern given their capacity to broadly inhibit interferon signaling and associated risk of herpes zoster infection. Many JAK inhibitors are currently in clinical trials for COVID-19, a logical step given their potent anti-inflammatory capacity, and baricitinib was granted emergency use authorisation in the USA (Nov 19, 2020) in combination with the antiviral drug remdesivir for hospitalised patients with COVID-19. Yet concerns remain over the countervailing effects of these drugs on interferon pathways. 12 Moving forward, if drugs targeting interferons and interferon pathways advance to approval in SLE and other autoimmune diseases, clinicians should consider the broader implications of anti-type I interferon therapies on protective immune responses to other viral infections. Ultimately, some form of heightened risk mitigation might be required. Monitoring for viral complications will be wise with the future use of these drugs. As new immune-based therapeutics are developed that target new molecules and pathways for immune diseases, clinicians should return to lessons learned from inborn errors of immunity, which might help us to prepare for future discoveries. © 2021 Shutterstock 2021 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. We developed three different protein arrays to measure hallmark IgG autoantibodies associated with Connective Tissue Diseases (CTDs), Anti-Cytokine Antibodies (ACA), and anti-viral antibody responses in 147 hospitalized COVID-19 patients in three different centers. Autoantibodies were identified in approximately 50% of patients, but in <15% of healthy controls. When present, autoantibodies largely targeted autoantigens associated with rare disorders such as myositis, systemic sclerosis and CTD overlap syndromes. Anti-nuclear antibodies (ANA) were observed in ∼25% of patients. Patients with autoantibodies tended to demonstrate one or a few specificities whereas ACA were even more prevalent, and patients often had antibodies to multiple cytokines. Rare patients were identified with IgG antibodies against angiotensin converting enzyme-2 (ACE-2). A subset of autoantibodies and ACA developed de novo following SARS-CoV-2 infection while others were transient. Autoantibodies tracked with longitudinal development of IgG antibodies that recognized SARS-CoV-2 structural proteins such as S1, S2, M, N and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. COVID-19 patients with one or more autoantibodies tended to have higher levels of antibodies against SARS-CoV-2 Nonstructural Protein 1 (NSP1) and Methyltransferase (ME). We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.