key: cord-0720567-9v4xiazh
authors: Fernandez-Ruiz, Ruth; Paredes, Jacqueline; Niewold, Timothy B.
title: COVID-19 in patients with Systemic Lupus Erythematosus: Lessons learned from the inflammatory disease
date: 2020-12-19
journal: Transl Res
DOI: 10.1016/j.trsl.2020.12.007
sha: 77fba76d6995d27ef5ce5de650c56172ae20ff48
doc_id: 720567
cord_uid: 9v4xiazh

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 IFN 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, and 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.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causal agent of Coronavirus disease 2019 (COVID-19), has infected millions of people worldwide. The mortality of the virus is likely underestimated in official counts, as we have observed a 20% increase in deaths over the average expected number between March 1 and August 1, 2020 in the United States. 1 It is clear that outcomes following COVID-19 infection vary considerably between people, and some populations are at particularly high risk. Thus, there has been a need to assess the impact of COVID-19 in patients with autoimmune disease, including those with systemic lupus erythematosus (SLE).

Patients with SLE are a unique population when considering the risk of contracting and the outcomes of the infection. The underlying organ damage from SLE and the use of systemic steroids and immunosuppressants could be risk factors for the development of severe COVID-19. 2 SLE is more prevalent and severe in ancestrally African and Hispanic patients, which overlaps with high-risk groups associated with poor outcomes of COVID-19, although the association with the latter may be mediated more by social determinants of health as opposed to biologic factors. [3] [4] [5] [6] In contrast, SLE is a female-predominant disease which may represent a protective factor, as COVID-19 has been shown to affect males more severely. 3, 7-10 One interesting feature is that inflammation in SLE is often characterized by elevation of type I interferon (IFN), which has antiviral properties and could potentially be protective. This is not known, however, and even if true, it could be offset by other sociodemographic, biologic, and clinical aspects of the disease and its management. In addition, excessive complement activation with consequent development of thrombotic microangiopathy (TMA) has been identified in many patients with COVID-19 and seems to at least partially mediate organ dysfunction in severe cases, resembling a complement-mediated TMA. 11, 12 Although complement consumption is a classic feature of SLE, the classical pathway is often the main target of activation by immune complexes in SLE, whereas the alternative and lectin-based complement pathways seem to play a greater role in COVID-19 pathogenesis. 13, 14 There have been substantial scientific efforts around the world to elucidate COVID-19 pathogenesis, risk factors, optimal management, and prevention strategies. Similarly, data on the impact of the pandemic in patients with SLE has grown significantly in recent months.

Accordingly, we provide an overview of the susceptibility factors to viral infections in patients with SLE and potential immunologic and pathologic overlaps between COVID-19 and SLE, as well as data regarding the epidemiology, clinical features, outcomes, and psychosocial impact of COVID-19 in SLE patients.

SARS-CoV-2, a single-stranded RNA virus and the causal agent of COVID-19, has infected millions of people worldwide. The virus enters the cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which determines viral tropism. The type 2 transmembrane serine protease (TMPRSS2) is also required to complete the fusion process by cleaving the ACE2 molecules and activating the SARS-CoV-2 S protein. 15 The clinical spectrum of COVID-19 is broad, ranging from asymptomatic infection to life-threatening cytokine storm, acute respiratory distress syndrome (ARDS), and multiorgan dysfunction. 16 SLE is a chronic multisystem autoimmune disease characterized by dysregulated type I IFN responses and defective immune tolerance mechanisms. 17 Patients with SLE have an increased risk of mortality that is two to five times the rate of the general population. 18 Bacterial, viral, and opportunistic infections are common in SLE and account for the second leading cause of death in this group in developed countries, ranging from 25% to 50% of mortality cases. [19] [20] [21] Infections in patients with SLE tend to be more frequent during the initial five years after diagnosis, which could reflect underlying disease pathogenesis or aggressive immunosuppressive therapy at the outset of disease. 18, 22 Functional abnormalities in the immune system due to intrinsic factors and the use of immunosuppressive therapies both contribute to infection risk in patients with SLE. 20, 23 24-27 Immune cells are affected in SLE in both number and function. Lymphopenia and neutropenia can occur either due to active inflammation in SLE with increased apoptosis of immune cells or as a side effect of immunosuppressants. 28 CD8 T cell responses are impaired in SLE patients, including defects in phagocytosis and chemotaxis. 20, 29, 30 Interestingly, Katsuyama et al. recently reported the presence of CD8 T cells highly expressing CD38 in a subset of patients with SLE and high incidence of infections, independent of disease activity, organ damage and disease flares. These CD8CD 38 high T cells exhibited decreased cytotoxic capacity, degranulation, and expression of perforin and granzymes, providing a mechanism by which abnormalities in cellular immunity may lead to an increased susceptibility to infections in patients with SLE. 29 Complement dysregulation is common in SLE and worsens with disease activity.

Hypocomplementemia has been identified as an independent predictor of infection in SLE patients. 24 Interestingly, genetic deficiencies in complement components can predispose to SLE, as well as other primary immunodeficiency disorders. 31 Furthermore, low immunoglobulin (Ig) levels, particularly IgG subclasses and IgM, have been identified in patients with SLE, which may also contribute to the increased susceptibility to infections. 28, 32, 33 Herpes zoster is frequent in SLE, occurring in up to 40% of patients. 19 Certain SLE-specific factors have been associated with herpes zoster, including lymphopenia and anti-Ro antibodies.

As expected, the use of systemic glucocorticoids (sGC) and immunosuppressants such as cyclophosphamide are also associated with a greater risk of herpes zoster and other viral infections. 24, 34, 35 Cytomegalovirus (CMV) and upper respiratory tract viral infections are common in the SLE population, and may present with severe and atypical manifestations that mimic SLE flares. 28, 36 Respiratory infections are one of the most common causes of hospitalization and early mortality in patients with SLE. 22 Elderly individuals (≥65 years of age) with rheumatic conditions are at greater risk of influenza and influenza-related complications. 37 Influenza pneumonia often precedes bacterial infections, which may lead to prolonged hospitalizations and overall worse outcomes. 38 39 In patients with SLE, viral infections can also trigger SLE flares after the virus is cleared. 39, 40 In comparison, Influenza A infection in lupus-prone Fas lpr mice is cleared effectively and is not associated with worsening autoimmune features in the acute setting, although these mice can subsequently develop severe pulmonary inflammation weeks after viral clearance. 41 Notably, annual vaccination against influenza is associated with decreased hospitalization and ICU admissions in patients with SLE; hence this practice is highly encouraged. 42

In addition to the increased susceptibility to certain viral infections in SLE, the role of exogenous viruses in triggering autoimmunity has also been proposed. Epstein-Barr virus (EBV) is a potential environmental factor involved in SLE pathogenesis. 43 Although most acute EBV infections occur during childhood, EBV remains latent in B cells and can subsequently reactivate. EBV stimulates the proliferation of autoreactive B cells, acts as a superantigen in T cells, and stimulates IFN-α production by plasmacytoid dendritic cells (pDCs). 44 Additionally, studies have demonstrated evidence of molecular mimicry between EBV proteins and nuclear antigens, and the EBV nuclear antigen 2 (EBNA2) protein can bind to several SLE risk alleles, suggesting important mechanisms by which EBV can trigger autoimmunity. [44] [45] [46] The role of other viruses such as CMV in the pathogenesis of SLE is less clear.

Various lines of evidence have suggested a crucial role of type I IFNs in the course of disease and outcomes of COVID-19. The antiviral properties of type I IFNs are well known and many viruses have developed strategies to escape their inhibitory effects. 47 high levels of multiple chemokines and IL-6. 53 Consistent with these observations, a more recent study found that patients with severe and critical COVID-19 displayed significant impairment in the type I IFN response, with lack of IFN-β, low IFN-ɑ activity and plasma levels, as well as a higher SARS-Co-2 viral load, and increased TNF-α and IL-6. 54 As certain conditions such as obesity, cancer and aging may be associated with decreased type I IFN signaling, it is also possible that these conditions contribute to a dysfunctional IFN response in COVID-19. [55] [56] [57] In addition, pDC depletion and functional impairment have also been identified in patients with COVID-19, with decreased production of IFN-α by these cells in vitro. 58, 59 A single-cell gene expression study of peripheral immune cells showed upregulation of several ISGs in CD14 + monocytes, although the IFN signature was heterogeneous among COVID-19 patients and cell types. 58 Another study evaluating cells obtained from the respiratory tract of patients with COVID-19 via bronchoalveolar lavage (BAL) showed marked expression of -proinflammatory‖ ISGs compared to cells from patients with community-acquired pneumonia and SARS-CoV infection. The ISG expression presumably decreased over time in COVID-19 patients who survived when comparing cells collected from different patients ranging from days 4 to 15 from the onset of symptoms. In contrast, cells from the deceased patient showed robust ISG expression, despite being obtained at day 12 after symptom onset. 48 Although the small sample size and lack of longitudinal data for each patient are potential limitations of this study, these findings could suggest that a persistent and/or delayed type I IFN response may be associated with worse outcomes. Results from a recent study also suggest a temporal shift in the cytokine response in patients with COVID-19, ranging from an early type I IFN-predominant response to a proinflammatory response in later stages of the disease. 59 Interestingly, this study also found an impaired type I IFN response and marked reduction in proinflammatory cytokine production by circulating monocytes and myeloid dendritic cells, despite elevated levels of these cytokines in plasma, suggesting the source is likely to be the lungs rather than peripheral blood cells. 59 Several inborn errors that directly or indirectly involve type I and type III IFN pathways are also associated with life-threatening viral infections secondary to influenza, live-attenuated vaccines, and other viruses. These include genetic defects in the interferon-α/β receptor-1 and -2 (IFNAR-1 and IFNAR-2), IRF3, IRF7, IRF9, IFIH1, TLR3, TBK1, TICAM1/TRIF, STAT1 and STAT2. [60] [61] [62] TLR3 and IFIH1 (also known as MDA5) are pattern recognition receptors that bind viral RNA.

TLR3 and TLR7 induce type I IFN production via activation IRF-3 (mediated by TBK1 and TICAM1/TRIM) and IRF7, respectively. IRF9, STAT1 and STAT2 are components of the interferon-stimulated factor gene 3 (ISFG3) complex, which is part of the intracellular downstream pathway activated by type I IFN ( Figure 1 ). 63 Interestingly, the structural SARS-CoV-2 N protein has also been shown to antagonize IFN signaling by suppressing phosphorylation and translocation of STAT1 and STAT2, representing a potential viral mechanism to evade the innate immune response. 64 GATA2 deficiency, a pleiotropic syndromic disorder, is also associated with increased susceptibility to viral infections, at least partially due to the absence of pDCs in this disorder, a major cell type in producing type I IFN. 65 In agreement with the antiviral role of type I IFN, a case series identified rare missense and nonsense putative loss-of-function (LOF) variants involving TLR7 in four young previously healthy males with critical COVID-19; these variants were associated with impaired type I and type II IFN response in these patients. 66 A recent study showed that rare LOF variants involving TLR3-and IRF7-mediated type I IFN response were enriched in patients with life-threatening COVID-19 when compared to subjects with mild or asymptomatic SARS-CoV-2 infection.

Genetic defects at eight loci (TLR3, UNC93B1, TICAM1/TRIF, TBK1, IRF3, IRF7, IFNAR 1, and IFNAR2) involved in type I IFN signaling were identified in 3.5% of patients. Interestingly, prior to COVID-19, these patients had not had any life-threatening viral infections, which may relate to the increased virulence of SARS-CoV-2 compared to influenza and other common respiratory viruses ( Figure 1 ). Some of the autosomal dominant genetic disorders were newly identified, including UNC93B1 (a chaperone that regulates endosomal TLR stability), IRF7, IFNAR1, and IFNAR2 deficiencies. 67 Conversely, several risk genes linked to type I IFN have been associated with SLE, many of which are gain-of-function (GOF) variants. 68 One of such examples is the IFIH1 rs1990760 gene variant, which is associated with the presence of antidouble-stranded DNA antibodies and increased sensitivity to IFN-α in SLE. 69 Interestingly, other IFIH1 polymorphisms have been associated with increased risk or protection for the development of type 1 diabetes mellitus 70, 71 , suggesting a spectrum of immunomodulatory roles of type I IFN-related molecules that span from the development of autoimmunity to susceptibility to life-threatening viral infections.

The presence of neutralizing autoantibodies to certain type I IFNs, mainly IFN-α2 and IFN-ω, was recently demonstrated in 101 out of 987 (10%) patients with severe outcomes of COVID-19, including death, who were predominantly male (94%). 72 Interestingly, in five of these patients, the authors were able to demonstrate that the autoantibodies preceded the development of COVID-19, suggesting their development is a cause rather than a consequence of the viral infection. Furthermore, none of the patients with asymptomatic or mild COVID-19, and only 4 of 1,227 healthy individuals had detectable type I IFN autoantibodies. 72 In addition, none of the patients with LOF mutations affecting IFN pathways had neutralizing antibodies against type I IFN, strongly suggesting there seem to be at least two independent mechanisms by which dysfunctional IFN signaling leads to an increased susceptibility to life-threatening COVID-19. 67 Previous studies have found that approximately 25% of patients with SLE have anti-IFN antibodies. 73-77 The most common type I IFN autoantibodies in SLE are against IFN-α2

and IFN-ω, as seen in severe COVID-19. 77 In addition, some of these anti-IFN antibodies were shown to be effective at neutralizing type I IFN activity in vitro, and patients with neutralizing antibodies tended to have lower SLE disease activity. 76 Given the evidence that the lack of an appropriate type I IFN response is associated with worse outcomes and retrospective data suggesting improved inflammatory markers and a shorter duration of detectable virus in COVID-19 patients treated with IFN-α2b, 78 various clinical trials assessing the efficacy of type I IFN therapy in COVID-19 are ongoing. A recent phase 2 trial of nebulized IFN-1a met its primary outcome of clinical improvement in COVID-19. 79 In contrast, interim results of the World Health Organization Solidarity trial suggest IFN--1a was not effective at improving COVID-19 overall mortality, initiation of mechanical ventilation, or duration of hospital stay. 80 However, it is possible that the timing of administration is crucial to ensure the benefit of exogenous type I IFN administration in COVID-19, as an early IFN surge may be needed to achieve optimal antiviral effects, whereas a delayed response could contribute to the deleterious hyperinflammatory response. [81] [82] [83] This hypothesis may help explain some of the contradictory findings with respect to type I IFN in COVID-19, and inconsistent definitions of severe COVID-19 likely also contributes to the dissimilar observations. 84 It may be that type I or type III IFN pathway-enhancing agents are beneficial in the early stages of SARS-CoV-2 infection, while immunosuppressive drugs, such as JAK inhibitors, anti-IL1 drugs, or sGC would provide the most benefit at treating the excessive and deleterious inflammatory response (i.e., cytokine storm) that ensues in later phases of COVID-19 course. [85] [86] [87] [88] [89] [90] [91] SARS-CoV-2 enters the host cells by binding to ACE2 in the cell membrane, hence the viral tropism depends on the level of ACE2 expression in each cell type. For instance, ACE2 expression is abundant in type II pneumocytes, enterocytes, and nasal goblet secretory cells.

Interestingly, ACE2 has been postulated as an interferon-stimulated gene (ISG), as IFN-α drives ACE2 expression in human upper airway basal cells, which would suggest potential deleterious effects of type I IFN by eliciting an increased risk of SARS-CoV-2 infection and viral dissemination. 92 However, this issue is not settled as a recent study suggested that the ACE2 isoform that is induced by IFN-α, designated by the investigators as dACE2, corresponds to a novel truncated version that does not confer tropism for SARS-CoV-2. 93 Although not yet corroborated, it has also been proposed that as a consequence of the epigenetic dysregulation present in patients with SLE, demethylation of ACE2 can lead to overexpression and increased susceptibility to SARS-CoV-2, while demethylation of interferon-regulated genes and other genes related to cytokine expression may lead to the development of a cytokine storm in the setting of COVID-19. 94 Finally, most studies evaluating the risk of viral infections in patients with SLE are observational and confounded by long-term sGC and immunosuppressant use. 28 However, it is possible that the baseline increased IFN activity in SLE exerts a protective role against contracting or developing worse outcomes of COVID-19; hence, this concept should be investigated further.

Neutrophil extracellular traps (NETs) are web-like chromatin fibers with microbicidal proteins and granule enzymes released by neutrophils as a host defense mechanism against microbes.

NETs are of high relevance in SLE, as they can enhance inflammation and type I IFN responses. 95 NETs are also thought to potentiate thrombosis in antiphospholipid syndrome. 96, 97 Recent studies have suggested a key role of dysregulated NETs in COVID-19. Zuo et al.

identified that circulating NET-specific markers were significantly elevated in COVID-19 patients compared to healthy controls and in patients with critical COVID-19 on mechanical ventilation compared to those with milder disease; in addition, sera from patients with COVID-19 can trigger NET formation when exposed to control neutrophils in vitro. 98 99 NETs are also abundant in respiratory secretions and lung tissue from patients with COVID-19, a process that may be driven by SARS-CoV-2-induced neutrophil activation and NET release. This inflammatory reaction could contribute to microthrombi formation in the lungs in COVID-19. [99] [100] [101] . Therapeutic interventions to dissolve NETs or prevent their release may be beneficial in managing severe COVID-19. A clinical trial evaluating dipyridamole, an antiplatelet agent and adenosine A 2A receptor agonist with NET-suppressing properties, 102 is ongoing (NCT04391179).

Various observational studies have identified a high prevalence of antiphospholipid antibodies in hospitalized patients with COVID-19. Lupus anticoagulant (LA) positivity has been commonly found in patients with COVID-19, ranging from 42% to 83% in severe and critical COVID-19, although the prevalence may be lower when patients with milder forms are included. [103] [104] [105] [106] The presence of IgG or IgM anti-cardiolipin and anti-beta2-glycoprotein I antibodies in patients with COVID-19 seems to be less prevalent and more variable across different studies, ranging from 0-13%. 104, 105, 107, 108 Interestingly, there has been conflicting evidence on how well the presence of antiphospholipid antibodies correlate with clinically significant thrombotic episodes, with various initial studies suggesting that these represent innocent bystanders instead of pathogenic antibodies. [103] [104] [105] [107] [108] [109] [110] [111] However, a recent study has demonstrated a potential pathogenic role of antiphospholipid antibodies in severe COVID-19. This cross-sectional study showed that 50% of hospitalized patients with COVID-19 had antiphospholipid antibodies, and higher titers were associated with elevated circulating NET markers and a more severe COVID-19 course. 112 In addition, IgG fractions of antiphospholipid antibodies promoted NET release in vitro and induced accelerated venous thrombosis in mice. 112 Nonetheless, there is still a lack of longitudinal studies assessing the persistence of antiphospholipid antibodies several weeks after COVID-19 diagnosis, 108 and it is possible that this represents a transient event as it has been demonstrated in the setting of other infections. [113] [114] [115]  Dysregulation of the complement system Complement dysregulation is a classic feature of SLE, and hypocomplementemia is a marker of disease activity. 14 Complement activation has been associated with the excessive inflammatory response seen in patients with severe COVID-19, and the presence of a complement-mediated microvascular injury syndrome has been proposed based on the observed pattern of tissue damage. [11] [12] [13] SARS-CoV-2 is thought to predominantly trigger the lectin and alternative complement pathways, although the classical complement pathway could also be activated in this setting by immune complexes. 116 The C3a and C5a anaphylatoxins are potent inflammatory mediators and chemoattractants. C5a plasma levels were shown to rise proportionally to COVID-19 severity, suggesting sustained complement activation, likely triggered by SARS-CoV-2 antibodies and high levels of C-reactive protein. 117 Additionally, COVID-19 patients have a large number of monocytes and neutrophils in bronchoalveolar lavage expressing the C5a receptor (C5aR1), suggesting a role of C5a in cell recruitment to the inflamed tissues. 117 C5a may help generate thrombogenic NETs, promoting a complement/NET-driven cycle that leads to immunothrombosis. 116 Disorders of the complement system can be genetic or acquired. Age-related macular degeneration (AMD), in which the complement system is overactive, is associated with worse COVID-19 outcomes. In addition, genetic variants previously reported in association with AMD were found to also predispose to hospitalization for COVID-19. Variants affecting the C3 gene were protective, whereas complement decay-accelerating factor (CD55) variants were associated with adverse outcomes of COVID-19. 118 Conversely, patients with complement deficiency disorders may have a milder disease course. 118 Together, these findings suggest a detrimental role of hyperactive complement. Therefore, a role of complement inhibitors to target thromboinflammation in COVID-19 has been suggested, and clinical trials assessing various agents are ongoing. [119] [120] [121] Results from a small single-arm study of narsoplimab, a mannan-binding lectin associated serine protease-2 (MASP-2) blocker, are encouraging. 122 Similarly, although data remain limited, eculizumab therapy also seems to improve clinical outcomes and biomarkers of inflammation and coagulation in patients with severe COVID-19. 123, 124  The mechanistic (mammalian) target of rapamycin (mTOR) pathway mTOR is a ubiquitous kinase and nutrient sensor that modulates cell differentiation, growth, proliferation, and survival. The mTOR pathway has been shown to regulate T-cell and macrophage differentiation, and is thought to play a critical role in the pathogenesis of autoimmune and inflammatory diseases such as SLE. 125 Accordingly, phase 1/2 trials of agents blocking the mTOR pathway, including N-Acetylcysteine (NAC) and rapamycin, have demonstrated potential benefits in SLE. 126, 127 Interestingly, a role of mTOR in the dysregulated inflammatory response in COVID-19 has been postulated. 59, 128 For instance, mTOR signaling has been shown to be decreased in pDCs from COVID-19 patients, on the basis of reduced ribosomal protein S6 (pS6) expression, translating into impaired IFN-α production by these cells which may negatively impact the host antiviral response (Figure 1 ). 59 Conversely, it has been hypothesized that mTOR pathway hyperactivation in certain conditions such as obesity may enhance SARS-CoV-2 replication, providing at least a partial explanation for worse COVID-19 outcomes in obese patients. 129 

Lymphopenia is a common feature of SLE, thought to be due to complement-mediated or antibody-dependent cytotoxicity, excess apoptosis, and decreased lymphopoiesis. 134 In addition, T cell function is also impaired in SLE, which may predispose these patients to infections (see the previous section on Relationship between SLE and risk of viral infections). Reversible lymphopenia has been observed in patients with COVID-19, especially those with severe disease. 135 Although transient lymphopenia is common in the setting of viral infections, COVID-19-associated peripheral lymphopenia may persist for longer and be more severe than in other viral illnesses. 136 Among the potential mechanisms that contribute to lymphocyte depletion in COVID-19 are infection of lymphocytes by SARS-CoV-2, exhaustion, and induction of apoptosis by cell hyperactivation and/or an increase in proinflammatory cytokines and pro-apoptotic signals. [135] [136] [137] Although more pronounced in CD8+ T cells, lymphopenia has also been shown to affect CD4+ T cells. 136, 137 Various studies have also identified functional impairment or alterations in the differentiation status of T cells, with marked heterogeneity in immune cell responses. T cells in COVID-19 may range from an exhausted to an overactive phenotype. 59, [136] [137] [138] It has been proposed that a more severe disease course could be associated with a reduced CD8+ T cell pool and less activated T cells, with increased expression of co-inhibitory signals including PD1, TIM3, CTLA4 and CD38. 136, 139 However, differentiating between an exhausted phenotype and hyperactive T cells represents a challenge as they both demonstrate increased expression of inhibitory receptors. A recent multi-omics study identified certain CD8+ subpopulations correlated with COVID-19 severity, with an increase of naïve clusters and lower activated effector T cells identified in severe cases when compared to patients with moderate disease. 140 Another study using highdimensional flow cytometry identified distinct immunotypes related to disease severity in hospitalized patients with COVID-19. Interestingly, the immunotype characterized by robust CD4+ T cell activation, a paucity of circulating T follicular helper cells, and highly activated or exhausted CD8+ T cells was associated with more severe disease. 137 A potential role for T helper 17 (Th17) cells in COVID-19 has also been suggested, and significant skewing towards a Th17 functional phenotype with decreased Treg levels have been described. 136, 138, 141, 142 Similarly, patients with SLE have impaired Treg cells, greater numbers of Th17 cells and increased production of IL-17, which seems to correlate with disease activity. 143, 144 A central immunopathogenic role of dysregulated B cell responses in COVID-19 is also likely. A stronger B-cell immune response in patients with severe COVID-19 compared to milder disease has been described. 145 Poor COVID-19 outcomes are associated with suppression of germinal centers, extrafollicular B cell activation, and a large expansion of the antibody-secreting cell compartment, similar to what is seen in SLE. 59, 137, 140, 146, 147 However, whether infection-induced autoreactive B cell responses persist after the acute phase of COVID-19 or if they contribute to long-lasting symptoms experienced by some patients with COVID-19, the so-called -long-haulers‖ remain to be elucidated. Moreover, the effect of B-cell depleting therapy on COVID-19 outcomes needs to be addressed, although very limited data to date suggest the potential for detrimental effects. [148] [149] [150] Overall, the findings of pathogenic adaptive immune responses in COVID-19 further support the notion that the timely implementation of immunomodulatory therapy in selected patients may be beneficial.

SLE disease management involves the use of multiple therapeutic strategies to treat the specific manifestations, lower disease activity, and prevent irreversible organ dysfunction. 151 General standard treatment strategies involve the use of antimalarials, non-biologic and biologic immunosuppressive agents, and sGC, if necessary. sGC are generally considered a first-line treatment in the management of organ-and lifethreatening manifestations of SLE. Although sGC are effective in decreasing disease activity, their undesirable side effect profile has led to widely accepted recommendations to limit the dose and duration of treatment as much as possible. 2, [152] [153] [154] Multiple studies to date have reported significantly increased risk of serious infections in patients on sGC, with doses as low as 10 mg prednisone-equivalent, although this mostly corresponds to bacterial infections. 28, [155] [156] [157] [158] [159] [160] Hydroxychloroquine (HCQ) use is recommended in most patients with SLE, owing to multiple health benefits in patients with SLE and overall safety. [161] [162] [163] [164] Various observational studies have indicated a protective effect of HCQ against serious infections in SLE. [165] [166] [167] [168] . In vitro studies have also suggested potential anti-viral effects of HCQ by means of increasing lysosomal pH and preventing post-translational modification of synthesized proteins that are crucial for replication and dissemination of viruses. 165, 167, 169 However, human studies have failed to identify any benefit of HCQ in preventing or managing viral infections, including dengue, chikungunya, and SARS-CoV-2. 170, 171 Azathioprine (AZA), mycophenolate mofetil (MMF), and cyclophosphamide (CYC) are commonly used in SLE to manage moderate to severe manifestations. In a retrospective study from France, exposure to CYC led to an increased incidence of herpes zoster in patients with SLE during the first year after initiating therapy. 172 A systematic review and meta-analysis identified a higher incidence of infections in the CYC compared to the MMF group. 173 However, a large propensity-score matched study showed no significant differences in rates of infection or mortality between Medicaid patients with SLE using CYC versus MMF after six months of initiation of therapy. 174 A study from the Hopkins Lupus Cohort that followed 214 patients after MMF initiation reported an increased risk of developing bacterial infections but no change in the risk of viral infection. 175 Furthermore, a recent review did not find sufficient evidence to conclude that AZA, MMF, or CYC increased the risk of acute respiratory viral adverse events in patients with SLE or other rheumatic diseases. 156 Tacrolimus, a calcineurin inhibitor used as a single agent or in combination with MMF in SLE, has been associated with a relatively low incidence of severe infections in various reports, although data are scarce. 156, 176 177 . A comparison between SLE patients on sGC and tacrolimus versus those on sGC and CYC showed a similar incidence rate of herpes zoster and varicella between the two groups. 178 Belimumab, a B lymphocyte stimulator (BLyS) inhibitor, is currently the only biologic approved for use in SLE. 179 Based on data from randomized controlled trials and open-label extensions, there is no suggestion of a significantly increased risk of severe respiratory viral infections with Belimumab use. 156 Rituximab, a B-cell depleting agent, has been associated with progressive multifocal leukoencephalopathy arising from John Cunningham virus (JCV) reactivation. 159, 180 Additionally, hepatitis B (HB) reactivation is a potentially life-threatening complication from RTX therapy in patients with positive HB surface antigen or HB anti-core antibody. 181 Although data on other viral infections with rituximab (RTX) use are scarce, the frequency of upper respiratory tract infections is variable among trials but generally similar to the placebo arms. 156, 182, 183 Recently, two small studies reported high rates of severe COVID-19 and mortality in patients on RTX for various indications. 148, 149 However, larger studies and longer follow-up are needed to confirm these observations. Anifrolumab, a type I IFN blocking agent, is awaiting FDA approval for use in SLE. 184 Overall, in the randomized controlled trials, there were increased rates of herpes zoster, upper respiratory tract infections, nasopharyngitis, bronchitis, and influenza in the anifrolumab group, although the differences were not statistically significant. 156, 185, 186 Further longitudinal studies are needed to assess the risk of viral infection in anifrolumab receiving patients with SLE; however, considering its mechanism of action, an increased risk of viral infections with the use of anifrolumab is biologically plausible.

As COVID-19 was increasingly recognized as a rapidly spreading global threat, the urgent need to describe the characteristics and outcomes of patients with rheumatic diseases became evident. Early reports suggesting a potential beneficial role of chloroquine and hydroxychloroquine, which are commonly used in patients with rheumatic diseases, also drove the need to evaluate this population closely. The first studies on patients with SLE and COVID-19 emerged from the heaviest hit regions in the early phases of the pandemic and consisted of mostly case reports or small case series (Table 1) .

between March 29 and April 6, most of whom were on long-term hydroxychloroquine and had therapeutic levels of the drug. 187 Seven (41%) patients required admission to an intensive care unit, and two out of 14 hospitalized patients died of COVID-19; notably, comorbidities were highly prevalent in these SLE patients, as was use of sGC (71%) and immunosuppressants (41%), and most patients had clinically quiescent SLE. This study represented one of the first to note that patients with SLE on HCQ were not protected against COVID-19. 187 Several other groups have also suggested the lack of benefit of HCQ against contracting or developing severe COVID-19 in patients with SLE and other rheumatic diseases. [188] [189] [190] [191] [192] [193] [194] A retrospective study from Spain included 62 patients with several different rheumatic or autoimmune diseases, nine of which had SLE. They found no statistically significant betweengroup differences for rheumatologic diagnosis or baseline use of immunosuppressive therapy except for sGC use, which was more frequent in hospitalized patients. SLE was not a risk factor for severe COVID-19 requiring hospitalization, but male sex, previous lung disease, and sGC use (> 5 mg/day of prednisone) were significantly associated with hospital admission. 195 Similarly, a study from Belgium which included 18 patients with confirmed or suspected COVID-19 did not find differences in the proportion of patients who developed COVID-19 between patients on immunosuppressants and those not on these medications. However, sGC dose was found to be positively associated with a positive RT-PCR test for COVID-19, hospitalization, and various COVID-19 symptoms. 193 Several other studies from Spain, Italy, France, and Brazil have also suggested that the main risk factors for poor COVID-19 outcomes are similar to those previously reported in the general population, including age and the presence of comorbidities. 189, [196] [197] [198] Additional potential risk factors suggested by studies of SLE and other autoimmune diagnoses included the presence of interstitial lung disease, moderate or high rheumatic disease activity (or flare preceding the COVID-19 diagnosis), history of neuropsychiatric lupus, and known exposure to a confirmed COVID-19 case. [199] [200] [201] However, the small sample size, lack of confirmatory testing for many of the included patients, selection biases, insufficient identification and adjustments for confounders, and several other limitations from these observational data preclude from making definitive statements about these observations.

In response to the scarcity of data on the impact of COVID-19 in patients with immune-mediated diseases, a number of registries were established to better characterize these patients and assess their outcomes. The largest of these registries addressing rheumatic diseases is the COVID-19 Global Rheumatology Alliance (C-19-GRA). The C-19-GRA was formed over the course of a few days in response to an urgent need for information, as the rheumatology community gathered in social media. 202 The largest C-19-GRA publication to date reported on the first 600 patients entered to the registry, including 85 patients with SLE, of whom 55% were hospitalized. 203 This study found that a prednisone dose ≥10 mg/day was associated with higher odds of hospitalization in patients across all rheumatic diseases. Immunosuppressant use was not found to be associated with hospital admission for COVID-19, with the exception of tumor necrosis factor inhibitor users, in whom the odds of hospitalization were lower. 203 As New York City (NYC) was the initial epicenter of the pandemic in the United States, many patients living with rheumatic diseases were affected by COVID-19. Gartshteyn et al. published the first case series describing patients with SLE and COVID-19 in NYC. The study included ten patients with real-time reverse transcription polymerase chain reaction (RT-PCR) confirmed COVID-19 and eight with suspected infection; seven of these patients were hospitalized. Most patients (83%) in this case series were taking immunosuppressants, 39% were on sGC, and 61% had lupus nephritis. Although limited by the small number of cases, the study did not find significant differences in immunosuppressant use in patients with mild versus severe COVID-19. 204 As COVID-19 rapidly extended to other regions of the United States, other groups published on the outcomes of patients with rheumatic diseases and COVID-19. Wallace et al.

described their COVID-19 experience at a tertiary care academic center in Michigan, reporting five patients with SLE, of whom four were hospitalized, three required invasive ventilation, and one died of COVID-19. Overall, when compared to 31 patients with various rheumatic diseases, patients with SLE and COVID-19 seemed to have worse outcomes in this study; however, SLE patients were noted to have a high prevalence of comorbidities, sGC use, and more likely to be African-American, which are all known risk factors for hospitalization and mortality in COVID-19. 205 To further close the information gaps concerning the impact of COVID-19 in patients with immune-mediated diseases in one of the heaviest hit regions in the world by the pandemic, our NYC-based institution established a prospective cohort of patients with immune-mediated diseases, the Web-based Assessment of Autoimmune, Immune-Mediated, and Rheumatic Patients during the COVID-19 Pandemic (WARCOV). An initial report on patients with various immune-mediated diseases from the WARCOV cohort, which did not include any patients with SLE, identified sGC use as one of the main factors associated with higher odds of hospitalization. 157 We later reported the characteristics and COVID-19 outcomes of patients with SLE, including 41 confirmed and 42 suspected cases of COVID-19, as well as 19 patients who were tested for COVID-19 and were negative, and 124 patients with SLE from our lupus registry who did not develop COVID-19 symptoms on prospective follow-up. 192 Out of the 41 patients with RT-PCR confirmed COVID-19, 24 patients with SLE required hospitalization. Notably, no SLE-specific factors, such as immunosuppressant use, were noted to increase the odds of hospitalization. However, there was a higher proportion of patients on systemic steroids in the hospitalized (54.2%) compared to the ambulatory group (29.4%), although the difference was not statistically significant. Non-white race, having one or more comorbidities, and body mass index were identified as independent predictors of hospitalization in our patients with SLE and COVID-19, similar to the general population. 192 These findings were in agreement with smaller studies assessing outcomes of COVID-19 in patients with SLE, as previously discussed.

Several studies have compared patients with and without rheumatic/autoimmune diseases to investigate differences in risk of contracting SARS-CoV-2 and experiencing poor outcomes of the disease. In a matched study of 52 patients with various rheumatic diseases, including ten patients with SLE, compared to 104 without rheumatic diseases, D'Silva et al. found that the proportion of patients who were hospitalized for COVID-19 and mortality from the disease were similar between the two groups; however, patients with rheumatic diseases had significantly higher odds of requiring mechanical ventilation or admission to the intensive care unit ventilation compared to patients without rheumatic diseases. 206 Various studies have addressed the question of whether patients with autoimmune diseases, including SLE, increase the risk of contracting COVID-19. A recent large study from Milan, Italy, comparing 20,364 SARS-CoV-2 test-positive and 34,697 test-negative subjects, did not find an association between having an autoimmune disease (in aggregate), including SLE, and having a positive test for COVID-19. 207 A study from seven hospitals in Spain also suggested patients with SLE were not at a higher risk of testing positive for COVID-19 in the hospital setting compared to a reference population of 2.9 million people. 208 In contrast with these observations, a meta-analysis of seven case-controlled studies of patients with autoimmune diseases and COVID-19 showed two-fold higher odds of contracting COVID-19 in this population compared to controls. 209 On meta-regression analysis, sGC use was significantly associated with the risk of COVID-19. Furthermore, patients with SLE, Sjogren's syndrome, and systemic sclerosis, in aggregate, had a higher prevalence of hospitalization when compared with the other disease groups. Notably, sGC was highly prevalent in this group (60%). 209 Overall, studies seem to suggest that most patients with SLE may not be at an increased risk of contracting COVID-19. However, patients with SLE have likely implemented more strict protective behaviors to avoid exposure to SARS-CoV-2 out of fear of having worse outcomes, so this element should be factored in when considering risk for developing COVID-19 in patients with SLE 201, 210 . Other than sGC use, there is no clear evidence to suggest that the SLE population is at risk of worse COVID-19 outcomes due to specific factors related to their underlying autoimmune disease. Although studies to date have significantly improved our understanding of the associations and outcomes of COVID-19 in the SLE population, it is important to note that there are several limitations to these observational data and the results should be interpreted with caution.

There have been reports in the literature of COVID-19 shortly preceding a de novo diagnosis of SLE, presenting concomitantly or mimicking SLE, raising the possibility of SARS-CoV-2 being a trigger of autoimmunity, as it has been postulated for other viruses. 19, 111, 211 However, we need to use caution when making a diagnosis of SLE in patients with COVID-19 for various reasons.

Certain clinical diagnostic criteria of SLE overlap with COVID-19 symptoms. Also, autoantibodies can occur in response to infections, and they are usually transient and of unclear significance in this setting. 113, 114, 212 Hence, longitudinal evaluation of these patients is required to offer insights into the association between COVID-19 and de novo SLE.

Similarly, various reports have indicated that COVID-19 may worsen SLE manifestations. [213] [214] [215] However, attributing SLE flares to a biologic mechanism is challenging because many of these patients have had greater difficulty accessing healthcare during the pandemic and may suffer worsened control due to lack of medical care or difficulty continuing their SLE medications, in addition to the psychosocial stressors of the pandemic. Therefore, it is currently unclear whether COVID-19 could predispose to SLE or to cause a flare of disease in an SLE patient. Long-term longitudinal studies are needed to ascertain these associations.

It is well established that SLE is more prevalent and severe in ancestrally African and Hispanic patients. 3 In addition, patients with SLE from minority racial and ethnic groups are known to experience substantial inequities in care and are much less likely to enroll in clinical trials when compared to white patients, owing to structural racism, implicit bias, previous experiences of discrimination and injustices. 2, 216 The COVID-19 pandemic has magnified the impact of health disparities and barriers to healthcare experienced by marginalized populations around the world. Consequently, COVID-19 has disproportionately affected Indigenous communities, Black and Hispanic populations 4, 6, [217] [218] [219] , comparable to what has been identified in patients with SLE and COVID-19. 192, 220 Interestingly, a recent study suggested African ancestry populations showed a genetic predisposition for lower expression of both ACE2 and TMPRSS2, suggesting decreased susceptibility to contracting SARS-CoV-2 in this population 221 . Although these findings suggest genetic determinants of COVID-19 transmissibility and severity across populations exist, social determinants of health (SDH) are more likely responsible for the different outcomes in racial and ethnic minorities, as it has been suggested by a recent retrospective cohort study from New York. 222 Therefore, assessing the impact of SDH on severity and mortality related to COVID-19 in patients with rheumatic diseases is essential. [223] [224] [225] [226] Although telemedicine has played a significant role in securing continuity of care for patients with SLE and other rheumatic diseases during the pandemic-related lockdowns 194, 227, 228 , concerns have been raised about specific situations where a virtual consultation may be insufficient. 229 For instance, patients with SLE require routine monitoring of laboratory parameters. New patients or those with urgent concerns may require a more thorough evaluation than what is feasible by telemedicine. Furthermore, special consideration should be given to those patients who lack reliable internet connection or access to smartphones or other devices suitable for telemedicine.

Even when imperfect, telemedicine has allowed patients with SLE to be evaluated by healthcare professionals, preventing major gaps in medical attention during the pandemic, which may lead to discontinuation of SLE therapies and subsequent flares. This concept was exemplified in a study from Wuhan, China, where 60% of 101 respondents with lupus nephritis had been unable to attend their rheumatology appointments. In addition, 25% of patients discontinued their medications, mostly due to limited access to healthcare, and 5% experienced a disease flare.

Interestingly, only two patients in this study contracted SARS-CoV-2 and both had a mild COVID-19 course. 230 Similarly, in a study of 1040 patients with SLE in India, over 50% of patients had missed their follow-up appointments, 37% were unable to perform routine laboratory exams, 40% needed to change their medications due to lack of availability, and 25% presented financial difficulties during the lockdown period, 231 suggesting additional sources of stressors experienced by these patients.

HCQ is a mainstay of treatment in SLE, as it is associated with multiple health benefits in this population, including reducing the risk of flares and organ damage. 163, 232 In the early phases of the COVID-19 pandemic, limited data including in vitro and small observational studies suggested a potential benefit of HCQ in COVID-19. 233, 234 Multiple recent studies, including observational data from patients with immune-mediated diseases on long-term hydroxychloroquine as well as large randomized clinical trials, have consistently demonstrated the lack of efficacy of HCQ in preventing the viral infection or improving any COVID-19-related outcomes. 171, 190, [235] [236] [237] [238] However, for several weeks after the preclinical studies and limited observational data came to light, HCQ shortages ensued in many countries as its use was redirected toward prophylaxis or management of COVID-19, leading to inadequate supplies of the drug for many patients with SLE worldwide. 239, 240 For instance, an electronic survey distributed to the Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) members with SLE-affiliated centers aimed to evaluate physicians' experiences with hydroxychloroquine shortages during the pandemic. 241 Out of 31 responses, 55% reported HCQ shortages among patients with SLE. Most respondents (65%) in this study had been contacted by patients and pharmacies regarding difficulties accessing HCQ. 241 Similarly, a national survey to Canadian rheumatologists in April, 2020 found that 50-94% of respondents, depending on the region, had been contacted by pharmacies or patients regarding difficulties accessing HCQ. 242 In a patient-centered study in Germany, 70% of 369 respondents expressed concerns about being unable to receive HCQ prescriptions, and 9% had already reduced their HCQ dose in an attempt to overcome potential drug supply issues. 243 One of the main concerns that HCQ shortages prompted was the risk of SLE flares, which are known to occur as soon as two weeks after drug discontinuation for most patients with SLE, especially in the younger SLE population. 163, 244 In addition, due to fears of contracting SARS-CoV-2, many patients fail to seek prompt medical attention in emergent and urgent situations. 245, 246 A report from Malaysia found a 65.4% decline in hospitalizations in patients with SLE during the lockdown period compared to 2019 rates. However, the patients with SLE who presented to the hospital in 2020 were significantly sicker when compared to those admitted in 2019 with respect to Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), intensive care unit requirement, and mortality. Strikingly, only one death was attributed to COVID-19. 247 These findings are likely multifactorial; while patients with SLE may have avoided presenting to the hospital due to fear of contracting COVID-19 until it was inevitable, it is also possible that different factors such as lack of close monitoring of clinical or laboratory parameters, issues with access or self-adjustments of the doses of SLE medications, have also contributed to higher severity and mortality rates in this population.

Finally, it is evident that the COVID-19 pandemic has had a profound psychosocial impact in patients with SLE. Multiple factors inherent to the pandemic have acted as stressors in the general population, potentially increasing the risk of mental health disorders; these include disinformation, uncertainty, collective fear, in addition to the declared states of emergency and lockdowns, resulting in financial concerns and social isolation. 248 Patients with SLE have faced numerous additional challenges during the pandemic. The fears of worse outcomes if contracting COVID-19, as well as the aforementioned concerns about access to healthcare and medication availability in this population, may affect the emotional and mental health of patients with SLE even further. Accordingly, a study from Poland showed a higher risk of anxiety, depression, and sleep disorders in SLE patients when compared to non-SLE patients during the COVID-19 pandemic. 249 In addition, in a cohort of patients with rheumatoid arthritis and SLE in the Philippines, a considerable proportion of patients were experiencing moderate to severe stress (12%), moderate to extremely severe anxiety (39%), and depression (28%). 250

Many of the immune system pathways important to COVID-19 infection are active in SLE, providing a valuable comparison and lessons to be learned in instances when the two conditions co-exist. It seems that besides sGC use, most risk factors for worse outcomes of COVID-19 in patients with SLE are similar to those identified in the general population.

However, the impact of additional factors requires further study. It is possible that some of the factors in SLE offset one another, such as any potential protective effect from type I IFN being offset by immunosuppressive agents, for example. These complexities hold promise for a greater understanding of COVID-19 immunopathogenesis in the broader population, and lessons learned through years of human SLE research seem highly relevant to challenges presented by this new viral pathogen. 

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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

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

Adaptor protein NF-κ activator

IFNAR, IFN-α/-β receptor

IFN, Interferon; IRF, interferon regulatory factor; ISG, IFN-stimulated genes; ISGF3, interferon-stimulated gene factor 3

Myeloid differentiation primary response 88; mTORC1, mechanistic target of rapamycin complex 1

SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2

Signal Transducer and Activator of Transcription

TANKbinding kinase 1; TLR, Toll-Like Receptor; TNF-α, Tumor necrosis factor-α

Tumor necrosis factor receptor-associated factor

We would like to thank Dr. Bruce Cronstein for revising some sections of the manuscript to ensure readability.All authors have read the journal's authorship agreement and policy on disclosure of potential conflicts of interest. All authors have disclosed potential conflicts of interest.