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] . Phylogenetic analysis demonstrated that this is a different virus with~80% nucleotide identity with SARS-CoV-1 [2] . The disease caused by SARS-CoV-2 is characterized by dry cough, fever, dyspnea and fatigue, accompanied by lymphopenia [3] [4] [5] [6] . 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] . 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. 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] .
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. 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] . 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. Chloroquine and hydroxychloroquine have now been permanently included, alongside antiviral drugs, in protocols for the treatment of COVID-19 pneumonia [10] . 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] .
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. The purpose of this review is to provide an overview on viral infectious risk in RA patients, with a particular focus on the https://doi.org/10.1016/j.autrev.2020.102523 Received 7 March 2020; Accepted 19 March 2020 knowledge about the current new pandemic and the use of anti-rheumatic drugs in this context of health emergency.
Coronaviruses are the largest viruses with a positive-sense singlestranded-RNA genome. 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. The angiotensin-converting enzyme 2 (ACE2) has been identified as the host cell-surface receptor for SARS-CoV2 envelope spike glycoprotein [12] . 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] . SARS-CoV-2 infection leads to the downregulation of ACE2 expression, thus resulting in excessive production of angiotensin II by the related enzyme ACE. 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] . 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] . 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] . 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] .
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] . 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). 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] . Main clinical features of sHLH include unremitting fever, hyperferritinaemia and cytopenias, and pulmonary involvement (including ARDS) occurring in approximately 50% of patients [20] . 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 (CXCchemokine ligand 10 [CXCL10] and CC-chemokine ligand 2 [CCL2]) [21, 22] . The management of this cytokine storm is one of the major unmet needs regarding COVID-19 infection.
The relationship between RA and infectious diseases is very complex and can be interpreted in two different directions. 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] . 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] . In addition, in patients with overt inflammatory arthritis, infections are a major concern as they can contribute to disease flares [27] [28] [29] . On the other hand, RA patients carry a documented increased risk of infection compared with the general population. 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] . 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] . 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. 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] . 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] .
Another important determinant of infectious risk is the presence of comorbidities, which very often complicate the course of RA [34] . 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] .
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.
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] . 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] . 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 dosedependent fashion [42] . The majority of these infectious events are of bacterial etiology, but RA patients receiving CS exhibit a greater risk of developing even viral infections. 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] .
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] . 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] . However, evidence from the literature points to a predominantly negative effect of CS in the management of this type of infection. 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), 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] . 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] . 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] . 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] .
The role of NSAIDs in the course of viral infections is still controversial. 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] . 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.
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] . Use of csDMARDs without corticosteroids was associated with a small decrease in mild infection risk ( [52] . A recent systematic review and meta-analysis of the literature confirmed the lack of an increased risk of infection in patients receiving MTX (RR: 1.14; 95% CI, 0.98-1.34) [53] . However, all these reports provided no data on the risk of stratified infection by pathogen.
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] . 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] . Following the results of comparative metanalyses and real-life studies, abatacept is accepted as the safest bDMARD in terms of infectious risk [60, 61] .
Data focused on viral respiratory infections in bDMARD cohort are still very limited. 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] . 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] .
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] . 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] . 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] . 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 2fold higher versus all bDMARDs [70] . 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] . 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] . 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] .
Currently, no data are available on the risk of respiratory virus infections carried by JAK inhibitors.
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] . 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.
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) .
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] . 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] .
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] . 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] .
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] . 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] .
The 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] .
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] .
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] . 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).
As 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 numbassociated 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 [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).
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] . 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.
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.
The COVID-19 epidemic represents a health emergency that is inevitably affecting the management of a complex disease such as RA [115, 116] . As a chronic autoimmune inflammatory disorder, RA carries a higher infectious risk than the general population. 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. Thus, RA patients should be encouraged to continue their treatment even during COVID-19 outbreak. 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] . 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.
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. 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. 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.