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Id Subject Object Predicate Lexical cue
T1 0-44 Sentence denotes COVID-19 infection and rheumatoid arthritis:
T2 45-63 Sentence denotes Faraway, so close!
T3 65-73 Sentence denotes Abstract
T4 74-201 Sentence denotes The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency.
T5 202-469 Sentence denotes Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease.
T6 470-833 Sentence denotes COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs.
T7 834-1029 Sentence denotes However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19.
T8 1030-1245 Sentence denotes In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients.
T9 1247-1262 Sentence denotes 1 Introduction
T10 1263-1470 Sentence denotes In December 2019 a new type of pneumonia supported by a novel member of the coronoviridae family named SARS-CoV-2 (severe acute respiratory coronavirus 2 syndrome) developed from Wuhan Province in China [1].
T11 1471-1587 Sentence denotes Phylogenetic analysis demonstrated that this is a different virus with ~80% nucleotide identity with SARS-CoV-1 [2].
T12 1588-1728 Sentence denotes The disease caused by SARS-CoV-2 is characterized by dry cough, fever, dyspnea and fatigue, accompanied by lymphopenia [[3], [4], [5], [6]].
T13 1729-1996 Sentence denotes In more severe cases (apparently up to 15–20% of infected patients) the picture may become more complicated by the onset of interstitial pneumonia with alveolar damage, which clinically can lead to severe Acute Respiratory Distress Syndrome (ARDS) and even death [7].
T14 1997-2273 Sentence denotes Since the initial outbreak, the epidemic has had a rapid global spread worldwide which led the World Health Organization (WHO) to declare the disease now called COVID-19 a Public Health Emergency of International Concern on 30th January 2020 and a pandemic on 11th March 2020.
T15 2274-2448 Sentence denotes The epidemiological picture is constantly evolving, and data updated as of March 17th count 159 countries involved with more than 185,000 cases and 7500 confirmed deaths [8].
T16 2449-2647 Sentence denotes In this context of growing health emergency, clarifying the relationship between COVID-19 and the population of fragile patients suffering from immune-rheumatological diseases is absolutely crucial.
T17 2648-3011 Sentence denotes On the one hand, the rapid and uncontrolled spread of the epidemic can clearly generate even more concerns in rheumatic patients, which are intrinsically characterized by an increased infectious risk due to the disease itself and to the iatrogenic effect of immunosuppressive agents such as corticosteroids and synthetic or biological disease-modifying drugs [9].
T18 3012-3259 Sentence denotes On the other hand, the growing knowledge about the pathogenesis of SARS-CoV-2 infection is leading to the introduction of drugs commonly used for the treatment of rheumatoid arthritis (RA) even for the management of more complex cases of COVID-19.
T19 3260-3416 Sentence denotes Chloroquine and hydroxychloroquine have now been permanently included, alongside antiviral drugs, in protocols for the treatment of COVID-19 pneumonia [10].
T20 3417-3697 Sentence denotes In addition, the use of interleukin 6 (IL-6) blockers seems to be very promising for the management of the massive cytokine storm associated to the development of the typical lung damage and the consequent ARDS occurring in the most aggressive patterns of SARS-CoV infection [11].
T21 3698-3912 Sentence denotes Therefore, waiting for observational data on the incidence of COVID-19 in rheumatological patients, the best strategy to manage immune-rheumatological diseases during this emergency period is still far to be clear.
T22 3913-4151 Sentence denotes The purpose of this review is to provide an overview on viral infectious risk in RA patients, with a particular focus on the knowledge about the current new pandemic and the use of anti-rheumatic drugs in this context of health emergency.
T23 4153-4197 Sentence denotes 2 The pathophysiology of COVID-19 infection
T24 4198-4285 Sentence denotes Coronaviruses are the largest viruses with a positive-sense single-stranded-RNA genome.
T25 4286-4474 Sentence denotes The host immune response is by one side essential for the resolution of COVID-19 infection, but it can also be crucial for the pathogenesis of major clinical manifestations of the disease.
T26 4475-4619 Sentence denotes The angiotensin-converting enzyme 2 (ACE2) has been identified as the host cell-surface receptor for SARS-CoV2 envelope spike glycoprotein [12].
T27 4620-4841 Sentence denotes ACE2 is a type I membrane protein expressed on cells in the kidney, heart, gastrointestinal tract, blood vessels, and, importantly, lung AT2 alveolar epithelial cells, which are particularly prone to viral infection [13].
T28 4842-4994 Sentence denotes SARS-CoV-2 infection leads to the downregulation of ACE2 expression, thus resulting in excessive production of angiotensin II by the related enzyme ACE.
T29 4995-5225 Sentence denotes It has been suggested that the stimulation of type 1a angiotensin II receptor (AGTR1A) increases pulmonary vascular permeability, thus potentially explaining the increased lung damage when the expression of ACE2 is decreased [14].
T30 5226-5474 Sentence denotes Due to this mechanism of action, it has been postulated that subjects with diabetes mellitus or hypertension using ACE-inhibitors or angiotensin receptor blockers may have an increase of both the risk of infection and the severity of COVID-19 [15].
T31 5475-5687 Sentence denotes As only scarce evidence supports this hypothesis, the European Society of Cardiology recently published a position statement that strongly recommends continuing these treatments despite the current epidemic [16].
T32 5688-5959 Sentence denotes An additional point to be clarified is also the role of the genetic predisposition for an increased risk of SARS-CoV-2 infection due to ACE2 polymorphisms that have been linked to hypertension, diabetes mellitus, and cerebral stroke, especially in Asian populations [15].
T33 5960-6162 Sentence denotes The viral RNA genome is released into the cytoplasm, and the RNA is uncoated to allow translation of the two polyproteins, transcription of the sub-genomic RNAs and replication of the viral genome [17].
T34 6163-6400 Sentence denotes Progression to ARDS is associated with the upregulation of pro-inflammatory cytokines and chemokines, known as Cytokines Release Syndrome (CRS), with a pattern very similar to that of secondary haemophagocytic lymphohistiocytosis (sHLH).
T35 6401-6600 Sentence denotes In adults, sHLH is an under-recognized, hyperinflammatory syndrome characterized by a massive and fatal hypercytokinaemia with multiorgan failure, most commonly triggered by viral infections [18,19].
T36 6601-6785 Sentence denotes Main clinical features of sHLH include unremitting fever, hyperferritinaemia and cytopenias, and pulmonary involvement (including ARDS) occurring in approximately 50% of patients [20].
T37 6786-7105 Sentence denotes A cytokine profile resembling sHLH has been reported in most severe COVID-19 infections, characterized by increased levels of a number of cytokines (interleukin-1β [IL-1β], IL-2, IL-6, IL-7, IL-8, tumor necrosis factor-α [TNF]) and chemokines (CXC-chemokine ligand 10 [CXCL10] and CC-chemokine ligand 2 [CCL2]) [21,22].
T38 7106-7205 Sentence denotes The management of this cytokine storm is one of the major unmet needs regarding COVID-19 infection.
T39 7207-7266 Sentence denotes 3 Is the risk of viral infection increased in RA patients?
T40 7267-7386 Sentence denotes The relationship between RA and infectious diseases is very complex and can be interpreted in two different directions.
T41 7387-7681 Sentence denotes On the one hand, in fact, the potential role of external microorganisms in producing acute and chronic arthritis in the form of either the direct colonization of the joints by the pathogen or the aberrant autoimmune reaction produced by the host response to the infection is well known [23,24].
T42 7682-7922 Sentence denotes Few studies have investigated a potential link between respiratory viral infections and the development of RA [25] and in particular a Korean study reported parainfluenza and coronavirus to be associated with the number of incident RA [26].
T43 7923-8074 Sentence denotes In addition, in patients with overt inflammatory arthritis, infections are a major concern as they can contribute to disease flares [[27], [28], [29]].
T44 8075-8190 Sentence denotes On the other hand, RA patients carry a documented increased risk of infection compared with the general population.
T45 8191-8460 Sentence denotes A population-based study by Doran and colleagues compared two matched groups of 609 patients with or without RA showing that RA patients had a significantly higher risk of serious (RR 1.53, 95% CI 1.41–1.65) and hospitalized (RR 1.88, 95% CI 1.71–2.07) infections [30].
T46 8461-8659 Sentence denotes Similarly, a prospective cohort study conducted on 2108 patients with inflammatory polyarthritis reported a 2- to 4-fold increased risk of hospitalized infection compared to healthy population [31].
T47 8660-8833 Sentence denotes This trend is primarily the result of a general impairment of the immune system typical of all autoimmune disorders and strictly dependent on the degree of disease activity.
T48 8834-9202 Sentence denotes In fact, it has been demonstrated by an analysis conducted in 16,242 RA patients from the US CORRONA registry that each 0.6 unit increase in Disease Activity Score 28 (DAS28) corresponded to a 25% increased rate of infections requiring hospitalization (Incident rate ratio [IRR] 1.25, p = .03) and a 4% increased rate of outpatient infections (IRR 1.04, p = .01) [32].
T49 9203-9614 Sentence denotes In addition, a subsequent report from the same registry showed that the risk of serious infections increased progressively from patients achieving clinical remission to those achieving low (adjusted IRR 1.69, 95% CI 1.32–2.15) or moderate (adjusted IRR 1.30, 95% CI 1.09–1.56) disease activity, demonstrating the importance of maintaining a good disease control in order to reduce infectious complications [33].
T50 9615-9748 Sentence denotes Another important determinant of infectious risk is the presence of comorbidities, which very often complicate the course of RA [34].
T51 9749-9981 Sentence denotes Diabetes mellitus, cardiovascular diseases, renal failure, interstitial lung disease, and chronic obstructive pulmonary disease (COPD) are all concomitant disorders associated with an increased incidence of infections in RA [27,35].
T52 9982-10150 Sentence denotes Finally, RA can also be complicated by infections caused by the iatrogenic effect of immunosuppressive therapies, which will be discussed in detail in the next section.
T53 10152-10235 Sentence denotes 4 The impact of drugs for rheumatic diseases on viral infections: what do we know?
T54 10237-10268 Sentence denotes 4.1 Corticosteroids and NSAIDs
T55 10269-10547 Sentence denotes It has now been more than 70 years that corticosteroids (CS) are pivotal for RA management and their role as remission inducer and bridging therapy for the management of disease flare has recently been renewed by the latest update of EULAR recommendations for RA treatment [36].
T56 10548-10847 Sentence denotes Even though CS efficacy in rapidly suppressing inflammation during RA initial course or flares is well recognized [37], their downside is the broad spectrum of adverse events, including severe infections and the high risk of developing comorbidities further increasing the risk of infection [27,38].
T57 10848-11117 Sentence denotes Although RCTs conducted in the past with CS showed no higher risk of infections in RA patients [[39], [40], [41]], cohort and case-control studies reported increased rates of overall infections in RA patients treated with CS, according to a dose-dependent fashion [42].
T58 11118-11273 Sentence denotes The majority of these infectious events are of bacterial etiology, but RA patients receiving CS exhibit a greater risk of developing even viral infections.
T59 11274-11472 Sentence denotes As an example, a 2012 retrospective cohort-study demonstrated an increased risk of Herpes Zoster infections with an incidence rate of 8.54 cases per 1000 patient-years in CS treated population [29].
T60 11473-11769 Sentence denotes Thus, CS on the one hand inhibit the immune response and delay the clearance of the pathogen, while on the other hand they suppress the host inflammatory response, which in the case of viral infections of the respiratory tract is the major responsible for lung damage and occurrence of ARDS [43].
T61 11770-12019 Sentence denotes The latter represented the rational for the widely use of CS for the management of Middle East respiratory syndrome (MERS)-CoV [44] and SARS-CoV [45] outbreaks, both histologically characterized by lung inflammation and diffuse alveolar damage [46].
T62 12020-12150 Sentence denotes However, evidence from the literature points to a predominantly negative effect of CS in the management of this type of infection.
T63 12151-12343 Sentence denotes A 2019 systematic review and meta-analysis including ten observational studies (n = 6548) conducted in influenza reported increased mortality (risk ratio [RR] 1.75, 95% CI 1.3–2.4; p = .0002),
T64 12344-12558 Sentence denotes increased rate of secondary bacterial or fungal infection (RR 2·0, 95% CI 1·0–3·8; p = .04), and longer stay in an intensive care unit (mean difference 2.1, 95% CI 1.2–3.1; p < .0001) in patients receiving CS [47].
T65 12559-12736 Sentence denotes Moreover, a review exploring treatments for ARDS, including six studies with a total of 574 patients, concluded that insufficient evidence exists to recommend CS treatment [48].
T66 12737-12905 Sentence denotes Overall, no clear reason exists to expect that patients with COVID-19 infection will benefit from CS, and they might be more likely to be harmed with such therapy [49].
T67 12906-13065 Sentence denotes In fact, current interim guidance from WHO on clinical management of COVID-19 infection advises against the use of CS unless indicated for another reason [10].
T68 13066-13142 Sentence denotes The role of NSAIDs in the course of viral infections is still controversial.
T69 13143-13385 Sentence denotes Ibuprofen has been demonstrated to induce an overexpression of ACE2 when used in diabetic rats [50] and this effect might theoretically increase the susceptibility and worsen the clinical course of COVID-19 infection in treated patients [15].
T70 13386-13583 Sentence denotes In addition, the use of both NSAIDs and acetaminophen could be associated with a masking of the fever rise during COVID-19, resulting in a delay in diagnosis and proper management of the infection.
T71 13585-13598 Sentence denotes 4.2 csDMARDs
T72 13599-13889 Sentence denotes The most comprehensive analysis of infectious risk in patients treated with csDMARDs is a retrospective, longitudinal study of a population-based RA cohort using an administrative database including a total of 27,710 individuals with RA and providing 162,710 person-years of follow-up [51].
T73 13890-14163 Sentence denotes Use of csDMARDs without corticosteroids was associated with a small decrease in mild infection risk (adjusted rate ratio [RR] 0.90, 95% confidence interval [95% CI] 0.88–0.93) and was not associated with increased serious infection risk (adjusted RR 0.92, 95% CI 0.85–1.0).
T74 14164-14437 Sentence denotes Similarly, another retrospective analysis conducted on 1993 patients from a claim database demonstrated a slightly reduced risk of hospitalized infection for methotrexate (adjusted RR 0.81, 95% CI 0.70–0.93) and hydroxychloroquine (adjusted RR 0.74, 95% CI 0.62–0.89) [52].
T75 14438-14584 Sentence denotes A recent systematic review and meta-analysis of the literature confirmed the lack of an increased risk of infection in patients receiving MTX (RR:
T76 14585-14615 Sentence denotes 1.14; 95% CI, 0.98–1.34) [53].
T77 14616-14708 Sentence denotes However, all these reports provided no data on the risk of stratified infection by pathogen.
T78 14710-14722 Sentence denotes 4.3 bDMARDs
T79 14723-14886 Sentence denotes The risk of infection observed in RA patients treated with bDMARDs is generally considered slightly higher (from 1.5- up to 2-fold) compared with csDMARDs [27,54].
T80 14887-15156 Sentence denotes This evidence recurred in most RCTs [55] and observational registry studies [[56], [57], [58]] and was confirmed by a recent meta-analysis which showed that this risk is progressively increasing in relation to the use of bDMARDs at higher than recommended dosages [59].
T81 15157-15308 Sentence denotes Following the results of comparative metanalyses and real-life studies, abatacept is accepted as the safest bDMARD in terms of infectious risk [60,61].
T82 15309-15394 Sentence denotes Data focused on viral respiratory infections in bDMARD cohort are still very limited.
T83 15395-15719 Sentence denotes The incidence of influenza-like infections observed in a cohort of 159 Italian patients treated with bDMARDs during the influenza season 2009–2010 was higher than the value reported in a wide sample of Italian population in the same period, even though no important complications or hospitalizations have been reported [62].
T84 15720-15967 Sentence denotes Overall, post-marketing experience is relatively reassuring that anti-TNF treated patients may not be at any specifically increased risk of influenza and that severe adverse outcomes, including death, do not appear to be exceedingly frequent [63].
T85 15969-15982 Sentence denotes 4.4 tsDMARDs
T86 15983-16293 Sentence denotes The overall risk of serious and opportunistic infections observed with Janus Kinase (JAK) inhibitors in RA patients is roughly comparable with bDMARDs [64,65], although these early years of tofacitinib and baricitinib use have raised the issue of an increased risk of Herpes Zoster virus (HZV) infections [66].
T87 16294-16538 Sentence denotes Data from tofacitinib pooled population enrolled in RCTs showed an HZV incidence rate of 4.0 per 100 patient-years (with greater incidence in geographic area with high HZV endemicity), doubling the rates of RA patients not receiving JAKis [67].
T88 16539-16690 Sentence denotes A similar picture has also been observed in the overall development program of baricitinib, with an incidence rate of 3.2 cases per patient-years [68].
T89 16691-16995 Sentence denotes The subsequent real-life experience from US claim databases revealed that the risk of HZV was higher in patients receiving tofacitinib compared to those treated with abatacept (aHR 2.01 (95% CI 1.40; 2.88) [69], and the risk of serious hospitalized HZV infection is 2-fold higher versus all bDMARDs [70].
T90 16996-17198 Sentence denotes Older age, female sex, prednisone >7.5 mg/day, prior infection, and greater number of hospitalizations were associated with increased HZV risk, whereas vaccination was associated with a lower risk [71].
T91 17199-17446 Sentence denotes More recent reports from RCTs conducted with novel JAK-1 selective inhibitors upadacitinib and filgotinib have basically confirmed the same trend, suggesting that the increase in HZV infections can be considered as a class effect of JAKis [72,73].
T92 17447-17705 Sentence denotes Although the exact mechanism by which HZV reactivation occurs in the context of JAK inhibition is unclear, the downregulation of both cell-mediated immunity and innate antiviral signaling through type I and II interferons (IFN) is likely to be involved [74].
T93 17706-17809 Sentence denotes Currently, no data are available on the risk of respiratory virus infections carried by JAK inhibitors.
T94 17811-17874 Sentence denotes 5 The management of COVID-19: a room for anti-rheumatic drugs?
T95 17875-18162 Sentence denotes Currently, 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].
T96 18163-18351 Sentence denotes 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.
T97 18352-18661 Sentence denotes 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].
T98 18662-18799 Sentence denotes Anecdotal cases have demonstrated the ability of lopinavir-ritonavir to significantly reduce viral load and improve disease outcome [77].
T99 18800-19120 Sentence denotes 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].
T100 19121-19281 Sentence denotes Consequently, lopinavir-ritonavir and remdesevir are currently the only anti-viral drugs included in the more severe case management protocols of COVID-19 [10].
T101 19282-19512 Sentence denotes 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].
T102 19513-19692 Sentence denotes 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.
T103 19693-19941 Sentence denotes Beyond 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 ).
T104 19942-20011 Sentence denotes Table 1 Potential role of anti-rheumatic drugs in COVID-19 infection.
T105 20012-20021 Sentence denotes PROS CONS
T106 20022-20227 Sentence denotes Chloroquine 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) –
T107 20228-20246 Sentence denotes Hydroxychloroquine
T108 20247-20378 Sentence denotes IL-6 inhibitors Treatment of cytokine storm manifestations during ARDS Lack of definite criteria to identify patients to be treated
T109 20379-20442 Sentence denotes Potential community-acquired pneumonia due to immunosuppression
T110 20443-20579 Sentence denotes Baricitinib Interference with viral penetration into the cell by blocking NAK-mediated endocytosis Impairment of IFN anti-viral response
T111 20580-20677 Sentence denotes Treatment of cytokine storm manifestations during ARDS Increased risk of secondary HZV infections
T112 20678-20782 Sentence denotes TNF-inhibitors Interference with viral penetration into the cell Slight increase in viral infection risk
T113 20783-20851 Sentence denotes NSAIDs – Facilitation of viral penetration by overexpression of ACE2
T114 20852-20891 Sentence denotes Delay in diagnosis due to fever masking
T115 20892-20943 Sentence denotes Corticosteroids – Increased risk of viral infection
T116 20944-21015 Sentence denotes Increased mortality and risk of secondary bacterial or fungal infection
T117 21016-21156 Sentence denotes ACE2 = angiotensin converting enzyme 2, ARDS = acute respiratory distress syndrome, NAK = numb-associated kinase; HZV = Herpes Zoster virus,
T118 21157-21221 Sentence denotes IFN = interferon, NSAIDs = nonsteroidal anti-inflammatory drugs.
T119 21223-21258 Sentence denotes 5.1 Chloroquine/hydroxychloroquine
T120 21259-21464 Sentence denotes Chloroquine 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].
T121 21465-21565 Sentence denotes The ability of chloroquine to produce an anti-viral effect has been known since the late 1960s [84].
T122 21566-21822 Sentence denotes 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].
T123 21823-22083 Sentence denotes At 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]].
T124 22084-22263 Sentence denotes 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.
T125 22264-22525 Sentence denotes 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].
T126 22526-22830 Sentence denotes 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].
T127 22831-22990 Sentence denotes More recently, hydroxychloroquine was demonstrated to be more 3-times more potent than chloroquine in an in vitro study based on pharmacokinetic models (PBPK).
T128 22991-23181 Sentence denotes 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].
T129 23183-23210 Sentence denotes 5.2 IL-6 and IL-1 blockers
T130 23211-23454 Sentence denotes As 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].
T131 23455-23629 Sentence denotes 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].
T132 23630-23831 Sentence denotes 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.
T133 23832-24015 Sentence denotes 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.
T134 24016-24188 Sentence denotes 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].
T135 24189-24421 Sentence denotes 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].
T136 24422-24885 Sentence denotes 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).
T137 24886-25048 Sentence denotes 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].
T138 25049-25191 Sentence denotes The identification of a unique definition of CRS during COVID-19 infection is crucial to better customize the management of critical patients.
T139 25192-25542 Sentence denotes 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].
T140 25543-25752 Sentence denotes Increasing ferritin level and erythrocyte sedimentation rate or decreasing platelet counts would be additional parameters potentially useful to discriminate patients requiring immunosuppressive treatment [22].
T141 25754-25773 Sentence denotes 5.3 TNF inhibitors
T142 25774-25973 Sentence denotes As 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].
T143 25974-26162 Sentence denotes Moreover, 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].
T144 26163-26377 Sentence denotes 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].
T145 26378-26530 Sentence denotes As a result, a study evaluating adalimumab in COVID-19 infection has recently been registered in the Chinese Clinical Trial Registry (ChiCTR2000030089).
T146 26532-26560 Sentence denotes 5.4 Janus kinase inhibitors
T147 26561-26672 Sentence denotes As previously described in detail, SARS-CoV-2 enters targeted cells through receptor-mediated endocytosis [12].
T148 26673-26886 Sentence denotes 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].
T149 26887-27016 Sentence denotes Inhibition of AAK1 may stop the access of the virus into lung cells and also the intracellular assembly of virus particles [102].
T150 27017-27097 Sentence denotes Of 47 AAK1 blockers approved for medical use, 6 inhibit AAK1 with high affinity.
T151 27098-27319 Sentence denotes 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].
T152 27320-27538 Sentence denotes 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].
T153 27539-27735 Sentence denotes 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].
T154 27736-28015 Sentence denotes 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].
T155 28016-28257 Sentence denotes 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].
T156 28258-28518 Sentence denotes 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.
T157 28519-28716 Sentence denotes 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).
T158 28717-28862 Sentence denotes On the other side, IFN is one of the most potent innate immune responses to prevent viral replication during the early phases of infection [110].
T159 28863-29078 Sentence denotes 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].
T160 29079-29326 Sentence denotes 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].
T161 29327-29483 Sentence denotes In particular, Influenza A viruses disrupt JAK/STAT signaling by reducing the expression of the IFN receptor and by directly inhibiting IFN signaling [114].
T162 29484-29734 Sentence denotes 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.
T163 29735-29991 Sentence denotes In 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.
T164 29993-30007 Sentence denotes 6 Conclusions
T165 30008-30146 Sentence denotes The COVID-19 epidemic represents a health emergency that is inevitably affecting the management of a complex disease such as RA [115,116].
T166 30147-30258 Sentence denotes As a chronic autoimmune inflammatory disorder, RA carries a higher infectious risk than the general population.
T167 30259-30491 Sentence denotes The use of synthetic and biologic disease-modifying drugs is associated with a potential further increase in the incidence of serious infections, but the poor control of RA disease activity is an even greater infectious risk factor.
T168 30492-30589 Sentence denotes Thus, RA patients should be encouraged to continue their treatment even during COVID-19 outbreak.
T169 30590-30779 Sentence denotes In our opinion, this strategy is reasonable as it aims to prevent disease flares that can contributes to increase patient burden, disability, poor quality of life, and healthcare use [117].
T170 30780-31037 Sentence denotes In addition, the discontinuation of ongoing treatments could lead to the need to introduce CS as bridging therapy, which may further increase the risk of viral infection, as well as being inappropriate for the management of SARS-CoV2 interstitial pneumonia.
T171 31038-31275 Sentence denotes Chloroquine and hydroxychloroquine are currently included in the treatment protocol for the management of COVID-19 infections and might be useful to prevent or mitigate the course of infection in patients with RA taking them as csDMARDs.
T172 31276-31567 Sentence denotes The use of IL-6 inhibitors as tocilizumab or sarilumab seems to be promising for the management of most critical cases of interstitial pneumonia complicated by CRS, but the identification of definite criteria to discriminate patients to be treated with these compounds is still under debate.
T173 31568-31801 Sentence denotes Finally, although baricitinib has the potential to affect SARS-CoV2 penetration into pulmonary epithelial cells, major concerns remain about the inhibition of IFNs activity which could be detrimental in the course of viral infection.