COVID-19 in patients with systemic lupus erythematosus: lessons learned from the inflammatory disease

Abstract

As the world navigates the coronavirus disease 2019 (COVID-19) pandemic, there is a growing need to assess its impact in patients with autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). Patients with SLE are a unique population when considering the risk of contracting COVID-19 and infection outcomes. The use of systemic glucocorticoids and immunosuppressants, and underlying organ damage from SLE are potential susceptibility factors. Most patients with SLE have evidence of high type I interferon activity, which may theoretically act as an antiviral line of defense or contribute to the development of a deleterious hyperinflammatory response in COVID-19. Other immunopathogenic mechanisms of SLE may overlap with those described in COVID-19, thus, studies in SLE could provide some insight into immune responses occurring in severe cases of the viral infection. We reviewed the literature to date on COVID-19 in patients with SLE and provide an in-depth review of current research in the area, including immune pathway activation, epidemiology, clinical features, outcomes, and the psychosocial impact of the pandemic in those with autoimmune disease.

Fig 1

Convergent type I interferon and proinflammatory cytokine pathways shared between SLE and COVID-19. Binding of viral RNA to toll-like receptor (TLR)3 and TLR7 induces activation of interferon regulatory factor (IRF)3 and IRF7, respectively, which is mediated by several adaptor proteins. Once active, IRF3 and IRF7 translocate to the nucleus and induce transcription of interferon (IFN)-α or IFN-β. TLR7 (and TLR8) activation also leads to nuclear translocation of NF-κB and induction of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α). Binding of IL-17, secreted by Th17 cells, to its receptor (IL-17R) activates the adaptor protein NF-κ activator (Act1) and TRAF6, inducing the nuclear translocation of NF-κB. IL-6 binding to its receptor (IL-6R) activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, in turn activating the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 mediates phosphorylation of S6K (not shown), which promotes the formation of the TLR-MyD88 complex and IRF7-mediated production of type I IFN. Activated mTORC1 also stimulates transcription of IRF7 mRNA by a 4E-BP phosphorylation-dependent mechanism (dashed arrow), and induces NF-κB activity. Type I IFNs, secreted in an autocrine and paracrine matter, bind to the IFN-α/-β receptor (IFNAR), leading to assembly and translocation to the nucleus of the interferon-stimulated gene factor 3 (ISGF3), which is composed of STAT1, STAT2 and IRF9. Once in the nucleus, ISGF3 binds to promoters of IFN-stimulated genes (ISG), stimulating their transcription. IRF1 is also induced in response to type I IFN, which activates the transcription of proinflammatory cytokines. A red X mark is located next to each component of the pathway that is impaired by loss-of-function genetic variants (1–7), autoantibodies against type I IFN (8), or SARS-CoV-2 proteins. Act1, adaptor protein NF-κ activator; IFN, interferon; IFNAR, IFN-α/-β receptor; IRF, interferon regulatory factor; ISG, IFN-stimulated genes; ISGF3, interferon-stimulated gene factor 3; mTORC1, mechanistic target of rapamycin complex 1; MyD88, myeloid differentiation primary response 88; PI3K, phosphatidylinositol 3-kinase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; STAT, signal transducer and activator of transcription; TBK1, TANK-binding kinase 1; TLR, toll-like receptor; TNF-α, tumor necrosis factor-α; TRAF, tumor necrosis factor receptor-associated factor; TRIF, TIR-domain-containing adapter-inducing interferon-β. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)