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LitCovid-PubTator

LitCovid-PD-FMA-UBERON

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T21","span":{"begin":4844,"end":4848},"obj":"Body_part"},{"id":"T22","span":{"begin":5595,"end":5599},"obj":"Body_part"},{"id":"T23","span":{"begin":7413,"end":7417},"obj":"Body_part"},{"id":"T24","span":{"begin":7568,"end":7573},"obj":"Body_part"},{"id":"T25","span":{"begin":8104,"end":8128},"obj":"Body_part"},{"id":"T26","span":{"begin":8145,"end":8149},"obj":"Body_part"},{"id":"T27","span":{"begin":8547,"end":8552},"obj":"Body_part"},{"id":"T28","span":{"begin":9133,"end":9137},"obj":"Body_part"}],"attributes":[{"id":"A21","pred":"uberon_id","subj":"T21","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A22","pred":"uberon_id","subj":"T22","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A23","pred":"uberon_id","subj":"T23","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A24","pred":"uberon_id","subj":"T24","obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"A25","pred":"uberon_id","subj":"T25","obj":"http://purl.obolibrary.org/obo/UBERON_0018229"},{"id":"A26","pred":"uberon_id","subj":"T26","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"},{"id":"A27","pred":"uberon_id","subj":"T27","obj":"http://purl.obolibrary.org/obo/UBERON_0000062"},{"id":"A28","pred":"uberon_id","subj":"T28","obj":"http://purl.obolibrary.org/obo/UBERON_0002048"}],"text":"5 The management of COVID-19: a room for anti-rheumatic drugs?\nCurrently, vaccines and approved targeted therapeutics for the treatment of the new SARS-CoV-2 infection are still lacking and the management of COVID-19 is only supportive, even though a multitude of compounds are now under investigation for the treatment of this emerging disease [75]. The need to urgently identify an effective approach to manage COVID-19 led to the strategy of testing the efficacy of the existing antiviral drugs commonly used for other viral infections. In particular, considering the similarity between SARS-CoV-2 and other Betacoronavirus associated with previous epidemics as SARS-CoV and MERS-Cov, the same drugs used with controversial results for these conditions (interferon, ribavirin, and lopinavir-ritonavir) have been considered even for COVID-19 [76]. Anecdotal cases have demonstrated the ability of lopinavir-ritonavir to significantly reduce viral load and improve disease outcome [77]. In addition, remdesivir, an adenosine analogue currently under development for the management of Ebola virus infection [78], has been recently recognized as a promising antiviral therapy against a wide spectrum of RNA viruses [79] and showed good preliminary in vitro results in the control of SARS-CoV-2 infection [80]. Consequently, lopinavir-ritonavir and remdesevir are currently the only anti-viral drugs included in the more severe case management protocols of COVID-19 [10]. Recent reports described the potential role of human monoclonal antibodies that bind the coronavirus spike receptor binding domain, leading to the neutralization of SARS-CoV2 capability to interact with human target cells [81,82]. However, at the moment these can only be considered as potential treatment options for the future, but they are obviously not available for the management of the current pandemic.\nBeyond the use of specific anti-viral products, many drugs commonly used in the treatment of RA have been proposed as possible therapies for COVID-19 as a consequence of the increased knowledge about the pathophysiology of the infection (Table 1 ).\nTable 1 Potential role of anti-rheumatic drugs in COVID-19 infection.\nPROS CONS\nChloroquine Anti-viral effect (increase of endosomal pH required for virus/cell fusion, inhibition of toll-like receptor activity, interference with terminal glycosylation of the cellular receptor ACE 2) –\nHydroxychloroquine\nIL-6 inhibitors Treatment of cytokine storm manifestations during ARDS Lack of definite criteria to identify patients to be treated\nPotential community-acquired pneumonia due to immunosuppression\nBaricitinib Interference with viral penetration into the cell by blocking NAK-mediated endocytosis Impairment of IFN anti-viral response\nTreatment of cytokine storm manifestations during ARDS Increased risk of secondary HZV infections\nTNF-inhibitors Interference with viral penetration into the cell Slight increase in viral infection risk\nNSAIDs – Facilitation of viral penetration by overexpression of ACE2\nDelay in diagnosis due to fever masking\nCorticosteroids – Increased risk of viral infection\nIncreased mortality and risk of secondary bacterial or fungal infection\nACE2 = angiotensin converting enzyme 2, ARDS = acute respiratory distress syndrome, NAK = numb-associated kinase; HZV = Herpes Zoster virus,\nIFN = interferon, NSAIDs = nonsteroidal anti-inflammatory drugs.\n\n5.1 Chloroquine/hydroxychloroquine\nChloroquine and hydroxychloroquine are widely used anti-malarial drugs with well-known immunomodulatory properties that have extended their use to several immuno-rheumatological diseases including RA [83]. The ability of chloroquine to produce an anti-viral effect has been known since the late 1960s [84]. Several mechanisms by which the drug is able to interfere with the growth and spread of different viruses (including SARS coronavirus) have been demonstrated in in vitro studies [85], even though the subsequent in vivo experience was controversial [86,87].\nAt clinically admissible concentrations chloroquine is able to increase the endosomal pH required for virus/cell fusion, to inhibit the toll-like receptor activity, and to interfere with terminal glycosylation of the cellular receptor ACE 2 [[88], [89], [90]]. All these functions may negatively influence the virus-receptor binding, resulting in a potential effect of the drug on both entry and post-entry stages of the SARS CoV infection. As a consequence, chloroquine has recently been included in at least 10 randomized controlled trials currently ongoing in China, where it is tested for the treatment of COVID-19 under various combination protocols with the anti-viral drugs mentioned above [91]. Interim results from more than 100 patients have demonstrated that chloroquine is superior to the control treatment in improving lung imaging findings, inhibiting the exacerbation of pneumonia, promoting a virus negative conversion, and shortening the disease course at different levels of severity [92]. More recently, hydroxychloroquine was demonstrated to be more 3-times more potent than chloroquine in an in vitro study based on pharmacokinetic models (PBPK). An oral loading dose of 400 mg twice daily, followed by a maintenance dose of 200 mg given twice daily for 4 days seems to be the best option for the management of SARS-CoV-2 infection [93].\n\n5.2 IL-6 and IL-1 blockers\nAs already described, ARDS occurring in most severe case of COVID-19 infection is mainly produced by the massive release of pro-inflammatory mediators (CRS) associated with viral replication and lung injury, leading to multiorgan failure [22]. Moreover, the high levels of these cytokines have been reported to be inversely related to the absolute lymphocytes count, with surviving T-cells functionally exhausted [94]. Since an effective immune response against viral infections depends on the activation of cytotoxic T cells, CRS might be associated with a decreased viral clearance, contributing to COVID-19 worsening. IL-6 and IL-1 play a pivotal role in this hyperinflammatory condition, suggesting the potential use of their blockers as treatment option for SARS-CoV2 related interstitial pneumonia. Data from a phase 3 RCT of IL-1 blockade (anakinra) in sepsis showed significant survival benefit in patients with hyperinflammation, without increased adverse events [95]. A small retrospective study on 21 patients affected by severe COVID-19 demonstrated that tocilizumab improved CT scan abnormalities and oxygen saturation, and normalized CRP levels and lymphocytes count in most of the patients [96]. A multicentre RCT of tocilizumab (IL-6 receptor blocker licensed for both RA and cytokine release syndrome) has been approved in China and is currently ongoing in patients with COVID-19 pneumonia and elevated IL-6 levels (ChiCTR2000029765) and a phase II study has been approved by the Italian Regulatory Drug Agency (AIFA) and will enrol 330 patients with pneumonia and early respiratory failure, with 1-month mortality reduction as primary outcome (TOCIVID-19). Moreover, the company that produces the second marketed IL-6 inhibitor sarilumab recently announced its intention to undertake a study with a similar design [97].\nThe identification of a unique definition of CRS during COVID-19 infection is crucial to better customize the management of critical patients. The presence of a large area of lung injury (≥50%) with decreased levels of CD4 and CD8 T-lymphocytes (lower than 50% of minimum normal range), and increased levels of IL-6 in peripheral blood have been recognized as the greatest risk factors of CRS in a retrospective analysis of 11 critically pneumonia Chinese patients infected with COVID-19 [98]. Increasing ferritin level and erythrocyte sedimentation rate or decreasing platelet counts would be additional parameters potentially useful to discriminate patients requiring immunosuppressive treatment [22].\n\n5.3 TNF inhibitors\nAs previously described, SARS-CoV infection is associated with a downregulation of ACE2 expression coupled with an increased activity of the renin-angiotensin system responsible for lung injury [14].\nMoreover, the viral spike protein is able to induce a TNF-α-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain, crucial for the penetration of the virus into the cell [99]. Since this process seems to be strictly coupled to TNFα production, it has been postulated that the use of TNF inhibitors may be effective in reducing both SARS-CoV2 infection and the consequent organ damage [100]. As a result, a study evaluating adalimumab in COVID-19 infection has recently been registered in the Chinese Clinical Trial Registry (ChiCTR2000030089).\n\n5.4 Janus kinase inhibitors\nAs previously described in detail, SARS-CoV-2 enters targeted cells through receptor-mediated endocytosis [12]. Some of the identified regulators of clathrin-mediated endocytosis are members of the numb-associated kinase (NAK) family, such as AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK) [101]. Inhibition of AAK1 may stop the access of the virus into lung cells and also the intracellular assembly of virus particles [102]. Of 47 AAK1 blockers approved for medical use, 6 inhibit AAK1 with high affinity. These include oncologic agents such as erlotinib, sunitinib, ruxolitinib, and fedratinib, which have all been demonstrated to inhibit infection of cells by Dengue virus, Ebola virus, and respiratory syncytial virus [103]. Unfortunately, all these compounds are able to produce adequate NAK inhibition only at doses significantly higher than those normally used in clinical practice and therefore potentially toxic for the patient [104,105]. Conversely, the JAK inhibitor baricitinib is able to effectively inhibit AAK1 and GAK at the plasma concentration obtained with the approved dosage for the treatment of RA (2 to 4 mg daily) [106]. Moreover, as a selective inhibitor of JAK 1 and 2, baricitinib is also able to produce an important dampening of host inflammatory response due to CRS (including IL-6 and interferon gamma) responsible for the more severe forms of interstitial pneumonia during COVID-19 [107,108]. Finally, the minimal interaction of baricitinib with the relevant CYP drug-metabolising enzymes makes the drug a possible candidate for inclusion in combination protocols with antiviral drugs such as lopinavir/ritonavir and remdesivir [109]. Interestingly, tofacitinib shows no detectable inhibition of AAK1 [104], whereas currently no data are available on the possible effect of other JAK inhibitors approved or tested for RA (such as upadacitinib or filgotinib) in relation to coronavirus infection. Unexpectedly, the only clinical trial evaluating the potential role of clathrin-mediated endocytosis blockade in the management of COVID-19 is currently ongoing with ruxolitinib (ChiCTR2000029580).\nOn the other side, IFN is one of the most potent innate immune responses to prevent viral replication during the early phases of infection [110]. The activation of transcription through JAK/STAT signaling pathway by IFNs leads to the upregulation of several interferon stimulated genes which have the ability to rapidly kill viruses within infected cells [111]. Almost all viruses have developed strategies to combat the effects of type 1 and type 3 IFNs by blocking the IFN signaling pathway [112] and viral encoded factors able to antagonize the JAK/STAT pathway are crucial determinants of virulence [113]. In particular, Influenza A viruses disrupt JAK/STAT signaling by reducing the expression of the IFN receptor and by directly inhibiting IFN signaling [114]. As a consequence, JAK/STAT blockade generated by baricitinib certainly produces an impairment of IFN-mediated anti-viral response, with a potential facilitating effect on the progression of SARS-CoV2 infection at the moment not yet better quantified.\nIn conclusion, evidence of the possible use of baricitinib in the treatment of COVID-19 infection remains highly controversial and further studies are warranted to better clarify its potential role in the treatment of more serious cases of viral pneumonia."}

LitCovid_AGAC

{"project":"LitCovid_AGAC","denotations":[{"id":"p51644s32","span":{"begin":4199,"end":4221},"obj":"MPA"},{"id":"p51645s8","span":{"begin":4327,"end":4344},"obj":"MPA"},{"id":"p51651s48","span":{"begin":5616,"end":5626},"obj":"CPA"},{"id":"p51653s23","span":{"begin":5958,"end":5967},"obj":"NegReg"},{"id":"p51653s25","span":{"begin":5974,"end":5983},"obj":"CPA"},{"id":"p51664s14","span":{"begin":8026,"end":8040},"obj":"NegReg"},{"id":"p51664s17","span":{"begin":8046,"end":8056},"obj":"MPA"},{"id":"p51664s21","span":{"begin":8075,"end":8084},"obj":"PosReg"},{"id":"p51664s22","span":{"begin":8078,"end":8086},"obj":"MPA"},{"id":"p51685s7","span":{"begin":11559,"end":11577},"obj":"Pathway"},{"id":"p51685s12","span":{"begin":11581,"end":11589},"obj":"NegReg"},{"id":"p51685s14","span":{"begin":11594,"end":11604},"obj":"MPA"},{"id":"p51685s22","span":{"begin":11641,"end":11651},"obj":"NegReg"},{"id":"p51685s23","span":{"begin":11652,"end":11665},"obj":"Pathway"},{"id":"p51686s18","span":{"begin":11774,"end":11802},"obj":"MPA"}],"text":"5 The management of COVID-19: a room for anti-rheumatic drugs?\nCurrently, vaccines and approved targeted therapeutics for the treatment of the new SARS-CoV-2 infection are still lacking and the management of COVID-19 is only supportive, even though a multitude of compounds are now under investigation for the treatment of this emerging disease [75]. The need to urgently identify an effective approach to manage COVID-19 led to the strategy of testing the efficacy of the existing antiviral drugs commonly used for other viral infections. In particular, considering the similarity between SARS-CoV-2 and other Betacoronavirus associated with previous epidemics as SARS-CoV and MERS-Cov, the same drugs used with controversial results for these conditions (interferon, ribavirin, and lopinavir-ritonavir) have been considered even for COVID-19 [76]. Anecdotal cases have demonstrated the ability of lopinavir-ritonavir to significantly reduce viral load and improve disease outcome [77]. In addition, remdesivir, an adenosine analogue currently under development for the management of Ebola virus infection [78], has been recently recognized as a promising antiviral therapy against a wide spectrum of RNA viruses [79] and showed good preliminary in vitro results in the control of SARS-CoV-2 infection [80]. Consequently, lopinavir-ritonavir and remdesevir are currently the only anti-viral drugs included in the more severe case management protocols of COVID-19 [10]. Recent reports described the potential role of human monoclonal antibodies that bind the coronavirus spike receptor binding domain, leading to the neutralization of SARS-CoV2 capability to interact with human target cells [81,82]. However, at the moment these can only be considered as potential treatment options for the future, but they are obviously not available for the management of the current pandemic.\nBeyond the use of specific anti-viral products, many drugs commonly used in the treatment of RA have been proposed as possible therapies for COVID-19 as a consequence of the increased knowledge about the pathophysiology of the infection (Table 1 ).\nTable 1 Potential role of anti-rheumatic drugs in COVID-19 infection.\nPROS CONS\nChloroquine Anti-viral effect (increase of endosomal pH required for virus/cell fusion, inhibition of toll-like receptor activity, interference with terminal glycosylation of the cellular receptor ACE 2) –\nHydroxychloroquine\nIL-6 inhibitors Treatment of cytokine storm manifestations during ARDS Lack of definite criteria to identify patients to be treated\nPotential community-acquired pneumonia due to immunosuppression\nBaricitinib Interference with viral penetration into the cell by blocking NAK-mediated endocytosis Impairment of IFN anti-viral response\nTreatment of cytokine storm manifestations during ARDS Increased risk of secondary HZV infections\nTNF-inhibitors Interference with viral penetration into the cell Slight increase in viral infection risk\nNSAIDs – Facilitation of viral penetration by overexpression of ACE2\nDelay in diagnosis due to fever masking\nCorticosteroids – Increased risk of viral infection\nIncreased mortality and risk of secondary bacterial or fungal infection\nACE2 = angiotensin converting enzyme 2, ARDS = acute respiratory distress syndrome, NAK = numb-associated kinase; HZV = Herpes Zoster virus,\nIFN = interferon, NSAIDs = nonsteroidal anti-inflammatory drugs.\n\n5.1 Chloroquine/hydroxychloroquine\nChloroquine and hydroxychloroquine are widely used anti-malarial drugs with well-known immunomodulatory properties that have extended their use to several immuno-rheumatological diseases including RA [83]. The ability of chloroquine to produce an anti-viral effect has been known since the late 1960s [84]. Several mechanisms by which the drug is able to interfere with the growth and spread of different viruses (including SARS coronavirus) have been demonstrated in in vitro studies [85], even though the subsequent in vivo experience was controversial [86,87].\nAt clinically admissible concentrations chloroquine is able to increase the endosomal pH required for virus/cell fusion, to inhibit the toll-like receptor activity, and to interfere with terminal glycosylation of the cellular receptor ACE 2 [[88], [89], [90]]. All these functions may negatively influence the virus-receptor binding, resulting in a potential effect of the drug on both entry and post-entry stages of the SARS CoV infection. As a consequence, chloroquine has recently been included in at least 10 randomized controlled trials currently ongoing in China, where it is tested for the treatment of COVID-19 under various combination protocols with the anti-viral drugs mentioned above [91]. Interim results from more than 100 patients have demonstrated that chloroquine is superior to the control treatment in improving lung imaging findings, inhibiting the exacerbation of pneumonia, promoting a virus negative conversion, and shortening the disease course at different levels of severity [92]. More recently, hydroxychloroquine was demonstrated to be more 3-times more potent than chloroquine in an in vitro study based on pharmacokinetic models (PBPK). An oral loading dose of 400 mg twice daily, followed by a maintenance dose of 200 mg given twice daily for 4 days seems to be the best option for the management of SARS-CoV-2 infection [93].\n\n5.2 IL-6 and IL-1 blockers\nAs already described, ARDS occurring in most severe case of COVID-19 infection is mainly produced by the massive release of pro-inflammatory mediators (CRS) associated with viral replication and lung injury, leading to multiorgan failure [22]. Moreover, the high levels of these cytokines have been reported to be inversely related to the absolute lymphocytes count, with surviving T-cells functionally exhausted [94]. Since an effective immune response against viral infections depends on the activation of cytotoxic T cells, CRS might be associated with a decreased viral clearance, contributing to COVID-19 worsening. IL-6 and IL-1 play a pivotal role in this hyperinflammatory condition, suggesting the potential use of their blockers as treatment option for SARS-CoV2 related interstitial pneumonia. Data from a phase 3 RCT of IL-1 blockade (anakinra) in sepsis showed significant survival benefit in patients with hyperinflammation, without increased adverse events [95]. A small retrospective study on 21 patients affected by severe COVID-19 demonstrated that tocilizumab improved CT scan abnormalities and oxygen saturation, and normalized CRP levels and lymphocytes count in most of the patients [96]. A multicentre RCT of tocilizumab (IL-6 receptor blocker licensed for both RA and cytokine release syndrome) has been approved in China and is currently ongoing in patients with COVID-19 pneumonia and elevated IL-6 levels (ChiCTR2000029765) and a phase II study has been approved by the Italian Regulatory Drug Agency (AIFA) and will enrol 330 patients with pneumonia and early respiratory failure, with 1-month mortality reduction as primary outcome (TOCIVID-19). Moreover, the company that produces the second marketed IL-6 inhibitor sarilumab recently announced its intention to undertake a study with a similar design [97].\nThe identification of a unique definition of CRS during COVID-19 infection is crucial to better customize the management of critical patients. The presence of a large area of lung injury (≥50%) with decreased levels of CD4 and CD8 T-lymphocytes (lower than 50% of minimum normal range), and increased levels of IL-6 in peripheral blood have been recognized as the greatest risk factors of CRS in a retrospective analysis of 11 critically pneumonia Chinese patients infected with COVID-19 [98]. Increasing ferritin level and erythrocyte sedimentation rate or decreasing platelet counts would be additional parameters potentially useful to discriminate patients requiring immunosuppressive treatment [22].\n\n5.3 TNF inhibitors\nAs previously described, SARS-CoV infection is associated with a downregulation of ACE2 expression coupled with an increased activity of the renin-angiotensin system responsible for lung injury [14].\nMoreover, the viral spike protein is able to induce a TNF-α-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain, crucial for the penetration of the virus into the cell [99]. Since this process seems to be strictly coupled to TNFα production, it has been postulated that the use of TNF inhibitors may be effective in reducing both SARS-CoV2 infection and the consequent organ damage [100]. As a result, a study evaluating adalimumab in COVID-19 infection has recently been registered in the Chinese Clinical Trial Registry (ChiCTR2000030089).\n\n5.4 Janus kinase inhibitors\nAs previously described in detail, SARS-CoV-2 enters targeted cells through receptor-mediated endocytosis [12]. Some of the identified regulators of clathrin-mediated endocytosis are members of the numb-associated kinase (NAK) family, such as AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK) [101]. Inhibition of AAK1 may stop the access of the virus into lung cells and also the intracellular assembly of virus particles [102]. Of 47 AAK1 blockers approved for medical use, 6 inhibit AAK1 with high affinity. These include oncologic agents such as erlotinib, sunitinib, ruxolitinib, and fedratinib, which have all been demonstrated to inhibit infection of cells by Dengue virus, Ebola virus, and respiratory syncytial virus [103]. Unfortunately, all these compounds are able to produce adequate NAK inhibition only at doses significantly higher than those normally used in clinical practice and therefore potentially toxic for the patient [104,105]. Conversely, the JAK inhibitor baricitinib is able to effectively inhibit AAK1 and GAK at the plasma concentration obtained with the approved dosage for the treatment of RA (2 to 4 mg daily) [106]. Moreover, as a selective inhibitor of JAK 1 and 2, baricitinib is also able to produce an important dampening of host inflammatory response due to CRS (including IL-6 and interferon gamma) responsible for the more severe forms of interstitial pneumonia during COVID-19 [107,108]. Finally, the minimal interaction of baricitinib with the relevant CYP drug-metabolising enzymes makes the drug a possible candidate for inclusion in combination protocols with antiviral drugs such as lopinavir/ritonavir and remdesivir [109]. Interestingly, tofacitinib shows no detectable inhibition of AAK1 [104], whereas currently no data are available on the possible effect of other JAK inhibitors approved or tested for RA (such as upadacitinib or filgotinib) in relation to coronavirus infection. Unexpectedly, the only clinical trial evaluating the potential role of clathrin-mediated endocytosis blockade in the management of COVID-19 is currently ongoing with ruxolitinib (ChiCTR2000029580).\nOn the other side, IFN is one of the most potent innate immune responses to prevent viral replication during the early phases of infection [110]. The activation of transcription through JAK/STAT signaling pathway by IFNs leads to the upregulation of several interferon stimulated genes which have the ability to rapidly kill viruses within infected cells [111]. Almost all viruses have developed strategies to combat the effects of type 1 and type 3 IFNs by blocking the IFN signaling pathway [112] and viral encoded factors able to antagonize the JAK/STAT pathway are crucial determinants of virulence [113]. In particular, Influenza A viruses disrupt JAK/STAT signaling by reducing the expression of the IFN receptor and by directly inhibiting IFN signaling [114]. As a consequence, JAK/STAT blockade generated by baricitinib certainly produces an impairment of IFN-mediated anti-viral response, with a potential facilitating effect on the progression of SARS-CoV2 infection at the moment not yet better quantified.\nIn conclusion, evidence of the possible use of baricitinib in the treatment of COVID-19 infection remains highly controversial and further studies are warranted to better clarify its potential role in the treatment of more serious cases of viral pneumonia."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-GO-BP

LitCovid-sentences

LitCovid-PD-HP

2_test

{"project":"2_test","denotations":[{"id":"32205186-26868298-4826910","span":{"begin":846,"end":848},"obj":"26868298"},{"id":"32205186-32020029-4826911","span":{"begin":1305,"end":1307},"obj":"32020029"},{"id":"32205186-30938227-4826912","span":{"begin":1694,"end":1696},"obj":"30938227"},{"id":"32205186-32034323-4826913","span":{"begin":3649,"end":3651},"obj":"32034323"},{"id":"32205186-4306296-4826914","span":{"begin":3750,"end":3752},"obj":"4306296"},{"id":"32205186-21550310-4826915","span":{"begin":4004,"end":4006},"obj":"21550310"},{"id":"32205186-16115318-4826916","span":{"begin":4255,"end":4257},"obj":"16115318"},{"id":"32205186-16439323-4826917","span":{"begin":4267,"end":4269},"obj":"16439323"},{"id":"32205186-26584195-4826918","span":{"begin":6373,"end":6375},"obj":"26584195"},{"id":"32205186-24800825-4826919","span":{"begin":8158,"end":8160},"obj":"24800825"},{"id":"32205186-18490652-4826920","span":{"begin":8347,"end":8349},"obj":"18490652"},{"id":"32205186-17532082-4826921","span":{"begin":8561,"end":8564},"obj":"17532082"},{"id":"32205186-28240606-4826922","span":{"begin":9503,"end":9506},"obj":"28240606"},{"id":"32205186-29753658-4826923","span":{"begin":9722,"end":9725},"obj":"29753658"},{"id":"32205186-29545548-4826924","span":{"begin":10195,"end":10198},"obj":"29545548"},{"id":"32205186-29649002-4826925","span":{"begin":10199,"end":10202},"obj":"29649002"},{"id":"32205186-18049472-4826926","span":{"begin":11046,"end":11049},"obj":"18049472"}],"text":"5 The management of COVID-19: a room for anti-rheumatic drugs?\nCurrently, vaccines and approved targeted therapeutics for the treatment of the new SARS-CoV-2 infection are still lacking and the management of COVID-19 is only supportive, even though a multitude of compounds are now under investigation for the treatment of this emerging disease [75]. The need to urgently identify an effective approach to manage COVID-19 led to the strategy of testing the efficacy of the existing antiviral drugs commonly used for other viral infections. In particular, considering the similarity between SARS-CoV-2 and other Betacoronavirus associated with previous epidemics as SARS-CoV and MERS-Cov, the same drugs used with controversial results for these conditions (interferon, ribavirin, and lopinavir-ritonavir) have been considered even for COVID-19 [76]. Anecdotal cases have demonstrated the ability of lopinavir-ritonavir to significantly reduce viral load and improve disease outcome [77]. In addition, remdesivir, an adenosine analogue currently under development for the management of Ebola virus infection [78], has been recently recognized as a promising antiviral therapy against a wide spectrum of RNA viruses [79] and showed good preliminary in vitro results in the control of SARS-CoV-2 infection [80]. Consequently, lopinavir-ritonavir and remdesevir are currently the only anti-viral drugs included in the more severe case management protocols of COVID-19 [10]. Recent reports described the potential role of human monoclonal antibodies that bind the coronavirus spike receptor binding domain, leading to the neutralization of SARS-CoV2 capability to interact with human target cells [81,82]. However, at the moment these can only be considered as potential treatment options for the future, but they are obviously not available for the management of the current pandemic.\nBeyond the use of specific anti-viral products, many drugs commonly used in the treatment of RA have been proposed as possible therapies for COVID-19 as a consequence of the increased knowledge about the pathophysiology of the infection (Table 1 ).\nTable 1 Potential role of anti-rheumatic drugs in COVID-19 infection.\nPROS CONS\nChloroquine Anti-viral effect (increase of endosomal pH required for virus/cell fusion, inhibition of toll-like receptor activity, interference with terminal glycosylation of the cellular receptor ACE 2) –\nHydroxychloroquine\nIL-6 inhibitors Treatment of cytokine storm manifestations during ARDS Lack of definite criteria to identify patients to be treated\nPotential community-acquired pneumonia due to immunosuppression\nBaricitinib Interference with viral penetration into the cell by blocking NAK-mediated endocytosis Impairment of IFN anti-viral response\nTreatment of cytokine storm manifestations during ARDS Increased risk of secondary HZV infections\nTNF-inhibitors Interference with viral penetration into the cell Slight increase in viral infection risk\nNSAIDs – Facilitation of viral penetration by overexpression of ACE2\nDelay in diagnosis due to fever masking\nCorticosteroids – Increased risk of viral infection\nIncreased mortality and risk of secondary bacterial or fungal infection\nACE2 = angiotensin converting enzyme 2, ARDS = acute respiratory distress syndrome, NAK = numb-associated kinase; HZV = Herpes Zoster virus,\nIFN = interferon, NSAIDs = nonsteroidal anti-inflammatory drugs.\n\n5.1 Chloroquine/hydroxychloroquine\nChloroquine and hydroxychloroquine are widely used anti-malarial drugs with well-known immunomodulatory properties that have extended their use to several immuno-rheumatological diseases including RA [83]. The ability of chloroquine to produce an anti-viral effect has been known since the late 1960s [84]. Several mechanisms by which the drug is able to interfere with the growth and spread of different viruses (including SARS coronavirus) have been demonstrated in in vitro studies [85], even though the subsequent in vivo experience was controversial [86,87].\nAt clinically admissible concentrations chloroquine is able to increase the endosomal pH required for virus/cell fusion, to inhibit the toll-like receptor activity, and to interfere with terminal glycosylation of the cellular receptor ACE 2 [[88], [89], [90]]. All these functions may negatively influence the virus-receptor binding, resulting in a potential effect of the drug on both entry and post-entry stages of the SARS CoV infection. As a consequence, chloroquine has recently been included in at least 10 randomized controlled trials currently ongoing in China, where it is tested for the treatment of COVID-19 under various combination protocols with the anti-viral drugs mentioned above [91]. Interim results from more than 100 patients have demonstrated that chloroquine is superior to the control treatment in improving lung imaging findings, inhibiting the exacerbation of pneumonia, promoting a virus negative conversion, and shortening the disease course at different levels of severity [92]. More recently, hydroxychloroquine was demonstrated to be more 3-times more potent than chloroquine in an in vitro study based on pharmacokinetic models (PBPK). An oral loading dose of 400 mg twice daily, followed by a maintenance dose of 200 mg given twice daily for 4 days seems to be the best option for the management of SARS-CoV-2 infection [93].\n\n5.2 IL-6 and IL-1 blockers\nAs already described, ARDS occurring in most severe case of COVID-19 infection is mainly produced by the massive release of pro-inflammatory mediators (CRS) associated with viral replication and lung injury, leading to multiorgan failure [22]. Moreover, the high levels of these cytokines have been reported to be inversely related to the absolute lymphocytes count, with surviving T-cells functionally exhausted [94]. Since an effective immune response against viral infections depends on the activation of cytotoxic T cells, CRS might be associated with a decreased viral clearance, contributing to COVID-19 worsening. IL-6 and IL-1 play a pivotal role in this hyperinflammatory condition, suggesting the potential use of their blockers as treatment option for SARS-CoV2 related interstitial pneumonia. Data from a phase 3 RCT of IL-1 blockade (anakinra) in sepsis showed significant survival benefit in patients with hyperinflammation, without increased adverse events [95]. A small retrospective study on 21 patients affected by severe COVID-19 demonstrated that tocilizumab improved CT scan abnormalities and oxygen saturation, and normalized CRP levels and lymphocytes count in most of the patients [96]. A multicentre RCT of tocilizumab (IL-6 receptor blocker licensed for both RA and cytokine release syndrome) has been approved in China and is currently ongoing in patients with COVID-19 pneumonia and elevated IL-6 levels (ChiCTR2000029765) and a phase II study has been approved by the Italian Regulatory Drug Agency (AIFA) and will enrol 330 patients with pneumonia and early respiratory failure, with 1-month mortality reduction as primary outcome (TOCIVID-19). Moreover, the company that produces the second marketed IL-6 inhibitor sarilumab recently announced its intention to undertake a study with a similar design [97].\nThe identification of a unique definition of CRS during COVID-19 infection is crucial to better customize the management of critical patients. The presence of a large area of lung injury (≥50%) with decreased levels of CD4 and CD8 T-lymphocytes (lower than 50% of minimum normal range), and increased levels of IL-6 in peripheral blood have been recognized as the greatest risk factors of CRS in a retrospective analysis of 11 critically pneumonia Chinese patients infected with COVID-19 [98]. Increasing ferritin level and erythrocyte sedimentation rate or decreasing platelet counts would be additional parameters potentially useful to discriminate patients requiring immunosuppressive treatment [22].\n\n5.3 TNF inhibitors\nAs previously described, SARS-CoV infection is associated with a downregulation of ACE2 expression coupled with an increased activity of the renin-angiotensin system responsible for lung injury [14].\nMoreover, the viral spike protein is able to induce a TNF-α-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain, crucial for the penetration of the virus into the cell [99]. Since this process seems to be strictly coupled to TNFα production, it has been postulated that the use of TNF inhibitors may be effective in reducing both SARS-CoV2 infection and the consequent organ damage [100]. As a result, a study evaluating adalimumab in COVID-19 infection has recently been registered in the Chinese Clinical Trial Registry (ChiCTR2000030089).\n\n5.4 Janus kinase inhibitors\nAs previously described in detail, SARS-CoV-2 enters targeted cells through receptor-mediated endocytosis [12]. Some of the identified regulators of clathrin-mediated endocytosis are members of the numb-associated kinase (NAK) family, such as AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK) [101]. Inhibition of AAK1 may stop the access of the virus into lung cells and also the intracellular assembly of virus particles [102]. Of 47 AAK1 blockers approved for medical use, 6 inhibit AAK1 with high affinity. These include oncologic agents such as erlotinib, sunitinib, ruxolitinib, and fedratinib, which have all been demonstrated to inhibit infection of cells by Dengue virus, Ebola virus, and respiratory syncytial virus [103]. Unfortunately, all these compounds are able to produce adequate NAK inhibition only at doses significantly higher than those normally used in clinical practice and therefore potentially toxic for the patient [104,105]. Conversely, the JAK inhibitor baricitinib is able to effectively inhibit AAK1 and GAK at the plasma concentration obtained with the approved dosage for the treatment of RA (2 to 4 mg daily) [106]. Moreover, as a selective inhibitor of JAK 1 and 2, baricitinib is also able to produce an important dampening of host inflammatory response due to CRS (including IL-6 and interferon gamma) responsible for the more severe forms of interstitial pneumonia during COVID-19 [107,108]. Finally, the minimal interaction of baricitinib with the relevant CYP drug-metabolising enzymes makes the drug a possible candidate for inclusion in combination protocols with antiviral drugs such as lopinavir/ritonavir and remdesivir [109]. Interestingly, tofacitinib shows no detectable inhibition of AAK1 [104], whereas currently no data are available on the possible effect of other JAK inhibitors approved or tested for RA (such as upadacitinib or filgotinib) in relation to coronavirus infection. Unexpectedly, the only clinical trial evaluating the potential role of clathrin-mediated endocytosis blockade in the management of COVID-19 is currently ongoing with ruxolitinib (ChiCTR2000029580).\nOn the other side, IFN is one of the most potent innate immune responses to prevent viral replication during the early phases of infection [110]. The activation of transcription through JAK/STAT signaling pathway by IFNs leads to the upregulation of several interferon stimulated genes which have the ability to rapidly kill viruses within infected cells [111]. Almost all viruses have developed strategies to combat the effects of type 1 and type 3 IFNs by blocking the IFN signaling pathway [112] and viral encoded factors able to antagonize the JAK/STAT pathway are crucial determinants of virulence [113]. In particular, Influenza A viruses disrupt JAK/STAT signaling by reducing the expression of the IFN receptor and by directly inhibiting IFN signaling [114]. As a consequence, JAK/STAT blockade generated by baricitinib certainly produces an impairment of IFN-mediated anti-viral response, with a potential facilitating effect on the progression of SARS-CoV2 infection at the moment not yet better quantified.\nIn conclusion, evidence of the possible use of baricitinib in the treatment of COVID-19 infection remains highly controversial and further studies are warranted to better clarify its potential role in the treatment of more serious cases of viral pneumonia."}

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