key: cord-0806071-qqbdjlzf authors: Zhou, Bangyi; Li, Siying; Ye, Jujian; Liu, Yi; Hu, Longtai; Tang, Yan; Wu, Zhijian; Zhang, Peidong title: Immunopathological events surrounding IL-6 and IFN-α:a bridge for anti-lupus erythematosus drugs used to treat COVID-19 date: 2021-10-14 journal: Int Immunopharmacol DOI: 10.1016/j.intimp.2021.108254 sha: db5d2c7e448549db20ccf964c4747e70b38698f1 doc_id: 806071 cord_uid: qqbdjlzf With the outbreak and rapid spread of COVID-19, the world health situation is unprecedentedly severe. Systemic lupus erythematosus (SLE) is a common autoimmune disease, which can cause multiple organ damage. Numerous studies have shown that immune factors have important roles in the pathogenesis of both COVID-19 and SLE. In the early stages of COVID-19 and SLE pathogenesis, IFN-α expression is frequently increased, which aggravates the virus infection and promotes SLE development. In addition, increased IL-6 levels, caused by different mechanisms, are observed in the peripheral blood of patients with severe COVID-19 and SLE, stimulating a series of immune cascades that lead to a cytokine storm, as well as causing B cell hyperfunction and production of numerous of antibodies, aggravating both COVID-19 and SLE. In this review, we explore the background immunopathological mechanisms in COVID-19 and SLE and analyze the advantages and disadvantages of commonly used SLE drugs for patients with COVID-19, to optimize treatment plans for patients with SLE who develop COVID-19. COVID-19 has become a global public health emergency. In the early stage of the disease, the main symptoms are fever, cough and fatigue. In severe cases, dyspnea, chest pain, and even fatal respiratory diseases may occur [1, ] . At present, no specific drugs for treatment of COVID- 19 have been identified, and the focus remains optimized supportive treatment [1] . Vaccination is considered an effective means to control the pandemic [2] ; up to now, there are over 200 million confirmed cases of COVID-19 worldwide, including more than 4 million deaths. In the context of such a severe global health situation, it is vital to explore the relationship between COVID-19 and systemic lupus erythematosus (SLE). Patients with SLE have increased susceptibility to infection [3] , and immunosuppressants, which are the standard drugs for treatment of SLE, can also be used to treat patients with COVID-19 [4, 5] . In the absence of clear understanding of the connection between COVID-19 and SLE, the rationale underlying the medication for SLE and COVID-19 remains open to question. In this review, we explore the advantages and disadvantages of commonly used SLE drugs in the context of COVID-19, with the aim of optimizing treatment plans for patients with SLE. SLE is an autoimmune disease characterized by abnormal autoantibody production and immune complex deposition. In addition to various skin lesions, SLE patients often have symptoms such as fever, fatigue, muscle soreness, scarring alopecia and diarrhea [6] . Immune factors are important in the occurrence and development of SLE. In patients with COVID-19, immune dysfunction is also clearly observed. The condition of patients with COVID-19 can very easily be aggravated by changes in immune status; for example, development of cytokine storm can potentially lead to acute respiratory distress syndrome (ARDS) or even death. Clinically, SLE and COVID-19 can interact with one another. Slimani et al. [7] reported a previously healthy individual who developed varicella like rash and SLE after suffering from COVID-19, while Ramirez et al. [8] investigated 471 patients with SLE using questionnaires, 60% of whom said they had experienced symptoms related to COVID-19, such as myalgia, rhinorrhoea, fever, dry cough, fatigue, sore throat and diarrhea. 14 of them were diagnosed with the disease. Therefore, management of the co-occurrence of COVID-19 and SLE is an important clinical challenge. The occurrence and development of SLE is established as closely related to infection, primarily the complex immune response after infection, and there has been report of cases of SLE caused by COVID-19 [9] . Levels of IL-1β, IL-6, GCSF, IFN-γ, TNF-α, and other proinflammatory mediators are increased in the peripheral blood of patients with COVID-19 [10] [11] [12] . These proinflammatory mediators, especially IFN-α and IL-6, play an important role in the occurrence and development of SLE. This paper will be based on IFN-α and IL-6 as the centre to explore the immunopathological events that may be shared by COVID-19 patients and SLE patients. IFN-α has a key role in SLE pathogenesis [13] , and the strong expression of IFN-α in the early stage of COVID-19 can lead to harmful inflammatory responses and immunopathological changes [14] . When SARS-CoV-2 infects the body, it proliferates rapidly, producing numerous neutrophil extracellular traps (NETs) and activating the neutrophil specific death program, NETosis, to capture and inactivate the virus. Decreased complement C1q in patients with COVID-19 or mutation of DNase I in patients with SLE can limit the degradation and clearance of NETs [15, 16] . The presence of excessive NETs leads to immune system exposure to various autoantigens, including those against double-stranded DNA (dsDNA). These autoantigens can stimulate B lymphocytes, through the antigen presentation process, causing production of large numbers of autoantibodies, including anti-dsDNA and anti-neutrophil cytoplasmic antibodies, among others. The immune complex (IC) formed by antigen and antibody also stimulates various phagocytic cells, such as dendritic cells, which produce large quantities of IFN-α when clearing IC, potentially leading to serious organ damage. IFN-α can both disrupt regeneration of the lung epithelium, aggravating viral infection, and promote the occurrence of SLE [17] . Clinically, it can be observed that the IFN response was high in mild to moderate patients, whereas it was reduced in more severe patients, and it has been suggested that exogenous type 1 interferon can be used to inhibit the activity of SARS-CoV-2, which may be related to the effect that IFN-α can further stimulate NET production. However, it is undeniable that the wide expression of IFN-α can lead to immunopathological changes during virus infection, which may be related to up regulating BAFF expression and promoting B cell differentiation [6, [18] [19] [20] [21] [22] [23] [24] [25] [26] ( Fig. 1 ). Levels of IL-6 are significantly increased in the plasma of patients with severe COVID-19 and correlate positively with disease severity [12] . Biologics targeting IL-6 have also been reported to be effective in treating COVID-19 infection [27] . Increased or imbalanced IL-6 levels also mediate tissue inflammation and organ damage in individuals with SLE [28, 29] . Damage associated molecular patterns and pathogen associated molecular patterns released after virus infection can bind with pattern recognition receptors on macrophages, activate NF-κB, and promote a cascade involving the release of a series of chemokines, thus generating numerous cytokines, including IL-6, TNF-α, and IL-1β, and leading to cytokine storm [30] . In addition, the nucleocapsid and spike proteins on the virus surface can induce HEK293T cells (among other cells) to produce COX-2 through the ERK/NF-κB pathway, and COX2 can induce IL-6 production [31, 32] . Further, large quantities of IL-6 can induce endothelial cells to activate and express factors such as VWF, FVIII and TF, resulting in hypercoagulable state. It can also induce neutrophil infiltration and nitric oxide (NO)-mediated increases in vascular permeability, resulting in lung injury [33] . In addition, IL-6 can activate JAK-STAT and MAPK cascades through the signal transducer, gp130 [34, 35] , thereby promoting SLE development. Studies have shown that severe COVID and acute SLE flares show similarities in extrafollicular B cell response, which is mediated by the activation of immature CD11c+ B cell clusters. These cells are differentiated into IgD-CD27-double negative B cells (DN2 cells), and are prepared for the differentiation of antibody secreting cells (ASC) through T-bet-driven networks and BAFF. The response of this extrafollicular reaction is closely related to IL-6 [36, 37] . As activated B cells, ASC can produce cytokines such as IL-10, IL-35, TNF-α, IL-17 and GM-CSF [38] . Anti SARS-CoV-2 IgG in patients with severe coronavirus-19 can promote macrophage hyperinflammatory response and produce a large number of classical cytokine storm mediators, such as IL-1 β、 IL-6, IL-8 and TNF [39] . Current evidence suggests that SARS-CoV-2 can invade host T-lymphocytes by binding of its S-glycoprotein with the ACE2 receptor [10, 40] . On virus invasion, ACE2 expression on the cell membrane is down regulated, affecting the normal function of the renin angiotensin system. The resulting compensatory increase of angiotensin II (Ang II) and its effect on angiotensin type 1 receptor increase the permeability of pulmonary vessels, promote lung injury, and induce endothelial cells to express TF and plasminogen activator inhibitor 1 (PAI-1), resulting in hypercoagulable state [11, 41, 42] . Ang Ⅱ can also bind to NF-κB to promote the transcription and production of IL-6, TNF-α, TNF-β, IFN-γ, GM-CSF, and other inflammatory cytokines, thereby promoting SLE development (Fig. 2 ). The prevalence of COVID-19 in patients with SLE patients is only somewhat increased [6, 8] . This may be related to the beneficial effects of treatment for SLE, which will be discussed in detail later in this review. Patients with SLE may be more likely to be infected with SARS-CoV-2 [6, 43, 44] . The underlying mechanism may be related to genetic factors shared between SLE and primary immunodeficiency disease, where genes involved in SLE susceptibility also participate in the occurrence and development of immunodeficiency [45] . Immune abnormalities in patients with SLE, such as lymphocytic reduction and IL-2 deficiency [46] ， also increase their susceptibility to infection. Moreover, patients with SLE are often treated with corticosteroids and immunosuppressants, which also increase their risk of infection to some extent. Researchers continue to have different opinions regarding whether immunosuppression should be used to treat patients with SLE. Therefore, we comprehensively analyzed relevant available data, including clinical research and investigations of pathological mechanisms, and applied the available information to provide new medication recommendations based on possible common mechanisms underlying both COVID-19 and SLE. From the mechanism and the results of in vitro experiments, hydroxychloroquine may be able to inhibit SARS-CoV-2 infection and transmission by blocking virus-receptor binding [47] [48] [49] . In the early stage when there were no vaccines and specific treatments, many people used these mechanisms to perform empirical treatments. At that time, opinions on the clinical benefits of hydroxychloroquine were widely divided. Some support the use of it [50] , others oppose it because of concerns that the side effects of HCQ，such as retinopathy and rush, will exceed its potential benefits [51, 52] . Then a recent large-scale randomized clinical trial proved that hydroxychloroquine has no clinical benefit in inhibiting SARS-CoV-2 infection and spread and no treatment-related serious adverse events were reported [53] . And a study found that there is no difference in terms of either clinical symptoms, severity or proportion of positive nasopharyngal PCR in patients on HCQ compared to matched controls [54] . Therefore, we believe that it is safe to continue taking hydroxychloroquine for SLE patients who have been taking chloroquine or hydroxychloroquine safely even if they suffer from COVID-19. However, based on current studies, we no longer recommend hydroxychloroquine as a treatment for COVID-19. Non-steroidal anti-inflammatory drugs (NSAIDs) are mainly used to relieve symptoms in patients with SLE and act by inhibiting COX [55, 56] . As the SARS-CoV-2 infection induced COX-2 upregulation [57] , leading to a cascade of pro-inflammation cytokines [58] , the use of NSAIDs in the early stage of virus invasion could effectively prevent the development of ARDS [59] . And current studies support that NSAIDs use are not associated with higher mortality or increased severity of COVID-19 [60, 61] . Therefore, we believe that NSAID can be safely used to relieve the symptoms of COVID-19 patients. And we propose that patients with SLE should continue to take NSAIDs to maintain the stability of their symptoms during the COVID-19 pandemic. Patients with co-morbid SLE and COVID-19 may benefit from increasing their dose of NSAIDs during the early stage of virus infection. As glucocorticoids inhibit the activity of lymphocytes important for combatting the new coronavirus [62] and prednisone (dose ≥ 10 mg/day) is associated with increased hospitalization rates of patients with COVID-19 [61] , there has been considerable focus on whether glucocorticoid use should continue during the pandemic. Nevertheless, glucocorticoids also inhibit the infiltration of excessive macrophages, T-lymphocytes, and neutrophils, as well as the associated release of large quantities of IL-2, IL-6, TNF-α, and other cytokines, thereby reducing the risk of immune storm [63] [64] [65] and respiratory distress symptoms [66, 67] . In addition, glucocorticoids can prevent the complications of COVID-19 [68] . Hence, glucocorticoid treatment may be beneficial for patients with severe COVID-19. In addition, glucocorticoids can induce the production of inducible nitric oxide synthase, and the NO generated by this factor can inhibit the SARS-CoV replication cycle [69] , which may be beneficial for patients with SLE who have long-term reliance on glucocorticoids. Clinically, some studies have shown that dexamethasone can effectively reduce the mortality rate of patients with COVID-19 [70, 71] . We suggest that patients with SLE who do not have COVID-19 should continue to take lowdose glucocorticoids to maintain the stability of their condition. Patients with SLE and COVID-19 should be managed according to disease severity, where patients with mild complications should continue to use glucocorticoids to maintain a stable condition and use antiviral drugs to counter the side effects of glucocorticoids, and those with severe comorbid disease can be treated with high dose glucocorticoids to prevent the development of cytokine storm. Serum IgG in the COVID-19-infected lung can promote severe lung damage [72] . Cyclophosphamide, which can inhibit B lymphocyte proliferation and antibody production, may also prevent severe lung symptoms in patients with COVID-19 [73] . Further, there is evidence that cyclophosphamide can effectively alleviate SARS-CoV-2 related ARDS by reducing cytotoxic T-lymphocytes [74] . Moreover, clinical studies do not provide sufficient evidence that cyclophosphamide increases the risk of SARS-CoV-2 infection in SLE patients [62] . Based on these pieces of evidence, we encourage patients with SLE to continue taking cyclophosphamide to maintain stable disease, while for patients with comorbid SLE and COVID-19, cyclophosphamide can be used to help prevent lung injury. Mycophenolic acid (MPA), an in vivo metabolite of mycophenolate mofetil, has anti-SARS-CoV-2 activity in vitro [75] . This may reflect the role of MPA as an inhibitor of inosine monophosphate dehydrogenase, which downregulates purine biosynthesis and thus inhibits virus replication. Further, MPA can inhibit MERS-CoV papain-like protease (PLpro) and may also inhibit SCoV2-PLpro [76] , the expression of which weakens the host antiviral IFN pathway and is also involved in viral RNA synthesis [77] . Furthermore, MPA can also inhibit IL-6 production [78] , and high levels of IL-6 have consistently been reported in patients with COVID-19, and are associated with poor prognosis and risk of death [65] . Finally, the halfmaximum effective concentration of mycophenolate mofetil is only 0.87 µm, which is very easy to achieve at the therapeutic dose [75] ; hence, the use of mycophenolate mofetil may reduce inflammatory storms and improve patient prognosis. As mycophenolate mofetil does not increase the risk of respiratory virus infection, nor did it cause worse clinical outcomes [62, 79] , we support its continued use for treatment of patients with SLE, according to their original prescription. Further, patients with both SLE and COVID-on SARS-CoV-2 is not clear, combinations of other drugs may be more effective to facilitate rehabilitation of patients with both COVID-19 and SLE. As a JAK/STAT pathway inhibitor [80] , methotrexate may cooperate with SARS-CoV-2 to rapidly disable JAK-STAT signaling, thereby reducing the sensitivity of host T-lymphocytes to interferon therapy [81] . Therefore, methotrexate treatment may be detrimental to patients with early SARS-CoV-2 infection; However, are also vitro experiments demonstrating that methotrexate can effectively inhibit SARS-CoV-2 replication which may be related to purine biosynthesis inhibition by methotrexate [82] [83] [84] . Further, clinical reports indicate that the use of methotrexate may prevent the spread of SARS-CoV-2 and does not influence mortality and hospitalization rates in patients with COVID-19 [85, 86] . In addition, activation of the JAK-STAT pathway can stimulate IL-6 production, along with that of other inflammatory cytokines and Ang II-induced thromboinflammation [81, 87] . Blocking JAK-STAT can both antagonize IL-6 production and block the production of various other inflammatory and pro-inflammatory factors, thereby preventing hypercoagulable state and lung injury in patients with COVID-19 [88, 89] . Hence, high dose methotrexate treatment may benefit patients with severe COVID-19 [90] . Since there is currently no evidence that methotrexate can increase the SARS-CoV-2 infection rate, we recommend that patients with SLE continue to take methotrexate to maintain stable symptoms, and that patients with severe COVID-19 and SLE should receive high dose methotrexate to reduce the risk of immune storm. Leflunomide, a type of dihydroorotate dehydrogenase inhibitor, is effective in infected animals by inhibiting virus replication and ameliorating cytokine/chemokine storms [91] . Teriflunomide, an active metabolite of leflunomide, also has definite antiviral effects at the cellular level [91] and patients treated with leflunomide had better inflammation level control and were discharged more quickly than those in the control group [92] . This feature of leflunomide may be beneficial to patients with SLE and COVID-19 and available data indicated that leflunomide is beneficial for SLE patients, regardless of whether they have COVID-19. Calcineurin inhibitor(CNI), including Cyclosporin A (CsA) and tacrolimus, can block NF-κB by inhibiting calcineurin, may interfere with the initial steps of cytokine storm release in severe COVID-19 [93] , and can inhibit the replication of a variety of coronaviruses at low micromolar concentrations without cytotoxicity [94] . These mechanisms may be of benefit to patients with COVID-19. Indeed, there is clinical evidence that CsA and tacrolimus are beneficial for COVID-19 patients [93, 95] ; however, patients with COVID-19 often have accompanying hypertension and hypercoagulable state, due to the compensatory increase in angiotensin II and CNI can cause high blood pressure and thrombosis as side effects [96, 97] , emphasizing the need to monitor blood pressure when treating patients with SLE and COVID-19, and to consider the safety of CNI in cases with hypertension or hypercoagulable state occurs. Nevertheless, due to the strong immunosuppressive function of CsA and tacrolimus, alisporivir, a non-immune substitute molecule for CsA, may be a better choice. alisporivir can effectively inhibit the postcell phase of the SARS-CoV-2 life cycle in vitro [98] . Therefore, we recommend that patients with COVID-19 take alisporivir to combat the virus and prevent immune storms, and that patients with SLE should continue to be treated with CNI, regardless of whether or not they have COVID-19. Due to findings that azathioprine-treated ferrets had prolonged infection times [99] , there are concerns that the immunosuppressive function of azathioprine could increase the risk of infection [96] . Moreover, there is clinical evidence that azathioprine may be associated with increased risk of severe COVID-19 [100] . However, a review of 180 studies found no evidence that azathioprine increases the risk of respiratory viral infections [62] . Hence, the effect of azathioprine on the development of COVID-19 warrants further research. If a patient with SLE has stable clinical symptoms, there is currently insufficient evidence to change their treatment or destabilize them clinically [101] . Belimumab has been the first biologic agent approved for SLE therapy so far. Belimumab mainly acts by binding to and antagonizing soluble BAFF [102] , so that it has a rapid and harmful effect on B lymphocytes in the early developmental stage, especially naive B cells [103] . In addition, studies have found that the extrafollicular pathways are also the pathways by which BAFF affects the activation and differentiation of naive B cells. Through the extrafollicular pathway, BAFF can strongly prevent naive B cells from producing antibodysecreting cells (ASC) [104, 105] . And it has been proven that critically ill patients with COVID-19 displayed a robust activation of extrafollicular B cell responses and ASC expansions, which are similar to those previously reported in SLE [36, 104] . Although there is still a lack of discussion and research on the performance of belimumab in COVID-19. But we may expect that Belimumab, which inhibits the differentiation of naive B cells into ASC, but not into regulatory B cells [106] , will down-regulate the excessive inflammatory response in patients with severe COVID-19. And taht will be of great benefit to patients with comorbid SLE and COVID-19. leading to prolonged infection time [99] . 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