key: cord-0811670-z9jsm54n authors: Manfredi, A; Luppi, F; Cassone, G; Vacchi, C; Salvarani, C; Sebastiani, M title: Pathogenesis and treatment of idiopathic and rheumatoid arthritis-related interstitial pneumonia. The possible lesson from COVID-19 pneumonia date: 2020-10-03 journal: Expert review of clinical immunology DOI: 10.1080/1744666x.2020.1803064 sha: 49b1a661ceeab1a1af14373503cabf0c48ca9492 doc_id: 811670 cord_uid: z9jsm54n INTRODUCTION: Main clinical manifestations of SARS-CoV-2 infection are characterized by fever, dyspnea, and interstitial pneumonia, frequently evolving in acute respiratory distress syndrome (ARDS). AREAS COVERED: Features of coronavirus disease 2019 (COVID-19) presents some common points with interstitial lung disease (ILD) both idiopathic and related to rheumatoid arthritis (RA), typically characterized by a chronic progression over time and possibly complicated by acute exacerbation (AE). The study of common pathogenetic mechanisms, such as the involvement of toll-like receptor 4, could contribute to the knowledge and treatment of idiopathic and RA-ILD. Moreover, hyperinflammation, mainly characterized by increase of effector T-cells and inflammatory cytokines, and activation of coagulation cascade, observed in COVID-19 related ARDS have been already shown in patients with AE of idiopathic and RA-ILD. A literature search was performed in PubMed, Embase, Scopus, and Web of Science, together with a manual search in COVID-resource centers of the main journals. EXPERT OPINION: Despite the uncertainty about pathogenetic aspects about COVID-19- pneumonia, it could be a possible model for other forms of ILD and AE. The great amount of data from studies on COVID-19 could be helpful in proposing safe therapeutic approaches for RA-ILD, in understanding pathogenesis of usual interstitial pneumonia and to develop new therapeutic strategies for AE. In December 2019 a novel infectious disease by a coronavirus named SARS-CoV-2 has been detected in the city of Wuhan in China and rapidly widespread worldwide. World Health Organization declared the stage of pandemic on 11 March 2020 [1] . Main clinical manifestations are fever, cough, dyspnea and interstitial pneumonia, frequently evolving in an acute respiratory distress syndrome (ARDS). Increasing data are reporting other systemic clinical manifestations, including anosmia, vomit, diarrhea, but also fatal thrombotic events and septic shock [1, 2] . The main cause of death of COVID-19 patients is characterized by respiratory failure due to interstitial pneumonia [3, 4] . a state of hyperinflammation induced by the viral infection could be responsible for the severe pulmonary involvement, frequently leading to a respiratory failure [5] . Features of COVID-19 pneumonia present some common characteristics with interstitial lung disease both idiopathic, i.e. the idiopathic interstitial pneumonias, particularly idiopathic pulmonary fibrosis (IPF), and usual interstitial pneumonia (UIP) related to rheumatoid arthritis (RA) and connective tissue diseases (CTDs), typically characterized by a chronic progression over some years [6, 7] . Aim of this review is to describe the clinical characteristics of these conditions, possible common pathogenetic aspects, to suggest possible therapeutic options for COVID-19 patients and to generate new hypotheses for the treatment of idiopathic or RA-ILD. a literature search was performed in some electronic databases, including PubMed, PubMed, Embase, Scopus, and Web of Science including the terms coronavirus 2019, COVID-19 pneumonia, SARS-CoV2, and pathogenesis of interstitial pneumonia, interstitial lung disease, usual interstitial pneumonia. Moreover, a manual search in COVID-resource centres of the main medical journals, including the categories "Internal Medicine," "Infectious Diseases," "Immunology," "Respiratory System," and "Rheumatology," was also performed searching for recently online published articles. Fever, cough, sore throat dyspnea, fatigue and myalgia represent the most common clinical manifestations at the onset of the disease. The majority of patients develop flu-like symptoms [1, 2] . Pneumonia may frequently occur, characterized by nonspecific features at chest high resolution computed tomography (HRCT), including ground-glass and/or consolidative opacities. About 10-15% of the patients develop a severe respiratory disease, that in 5% of the cases, result in a critical disease, characterized by severe respiratory failure, septic shock, and/or multiple organ dysfunction or failure [1, 4] . In this latter group, the acute worsening of respiratory function occurs about a week later the onset of the systemic symptoms, causing a clinical condition that require mechanical ventilation and support in intensive care unit, with possible progression to severe acute respiratory distress syndrome (ARDS) [4, [8] [9] [10] . At HRCT, ground glass opacities (GGO), in some cases associated to consolidations, are the most common findings [11, 12] . In 81 Chinese patients the HRCT alterations changed according to the stage of the disease. At the clinical onset, the main CT abnormalities were unilateral, multifocal GGO, but also interlobular septal thickening, thickening of the adjacent pleura, nodules, round cystic changes, bronchiolectasis, pleural effusion. In a more advanced stage (one week after the onset of the disease) lesions became bilateral and diffuse, while two weeks later the predominant CT features were GGO, whereas appearance of consolidations was also observed in some cases. Finally, GGO and reticular pattern were the predominant findings in the last stage (2-3 weeks after symptoms onset) [13] (Figure 1 ). Pathogenesis of SARS-Cov2 infection is not fully understood, and both viral and host factors appear to be involved. The virus is transmitted mainly via respiratory droplet and contact [8, 14] . Primary viral replication is presumed to occur in mucosal epithelium of upper respiratory tract, with further multiplication in lower respiratory tract [14] , giving rise to a mild viremia. Many infections are controlled at this point and remain asymptomatic [1, 14] . In contrast, clinical findings showed exuberant inflammatory responses during SARS-CoV -2 infection, further resulting in uncontrolled pulmonary inflammation, likely a leading cause of mortality. The antigen presentation cells (APC) play a central role in antiviral Article highlights • COVID-19 pneumonia resembles many pathogenetic and radiologic features of idiopathic and rheumatoid arthritis related usual interstitial pneumonia • Toll-like receptor 4 plays a crucial role in the pathogenesis of both COVID-19 and usual interstitial pneumonia • The modulation of toll-like receptor 4 could explain the safety of some disease modifying antirheumatic drugs, such as abatacept, in patients with rheumatoid arthritis related interstitial lung disease • Acute exacerbation of interstitial lung disease shares many features with acute respiratory distress syndrome in COVID-19 pneumonia • The use of tocilizumab, sarilumab and baricitinib, used in severe COVID-19 pneumonia, could also be suggested for the treatment of acute exacerbation of interstitial lung disease Figure 1 . High-resolution lung base image from contrast-enhancement arterial scan for pulmonary embolism detection in patient with long-standing COVID-19 pneumonia and pneumomediastinum. Ground-glass opacities are detected in subpleural areas mixed with focal consolidations. Moreover, computed tomography shows initial fibrotic changes with architectural distortion and bronchiolectasis. Multiple thin-walled cysts are also recognized, in keeping with smoking-related changes (courtesy by Gabriele D'Andrea, Radiology Unit, San Gerardo Hospital, ASST Monza, Monza, Italy). immunity. Antigenic peptides are presented by human leukocyte antigen (HLA) and then recognized by virus-specific cytotoxic T lymphocytes. Unfortunately, there is still lack of report about antigen presentation of SARS-CoV-2, and we can only get some information from previous researches on SARS-CoV and MERS-CoV, showing numerous HLA polymorphisms correlate to the susceptibility to these viruses [15] . Differences in the susceptibility of individuals to infection, regarding the spectrum of COVID-19 symptoms and in particular the development of ARDS remain to be fully understood. Genetic variability in histocompatibility complex (MHC) class I genes plays a role, specifically individuals presenting HLA-B*46:01 gene product may be more vulnerable to COVID-19 -due to reduced capacity for viral antigen presentation to immune cells while patients with HLA-B*15:03 may be more likely to develop immunity [16] . Nevertheless, considerable variation in disease behavior and severity among patients with pulmonary infection secondary SARS-CoV-2 have been also observed. Moreover, advanced age, male sex and preexisting conditions such as cardiovascular, pulmonary, and renal diseases make a subject more vulnerable to the more severe health consequences of COVID-19 [17, 18] . The initial onset of rapid viral replication may cause massive epithelial and endothelial cell death and vascular leakage, triggering the production of exuberant proinflammatory cytokines and chemokines [14] . As mentioned above, an aberrant immune response against the virus plays a key role in the immunopathogenesis of the disease, resulting in an hyperinflammatory state that causes pulmonary tissue damage, functional impairment, and reduced lung capacity [5, 9, 10] . Some possible mechanisms have been investigated in pathogenesis of COVID-19 pneumonia, mainly involving both innate and adaptive response and angiotensin-converting enzyme 2 (ACE2)-mediated lung fibrosis. ACE2 has been reported to have a protective role in lung fibrosis, while SARS-CoV-2 and its spike protein can reduce ACE2 expression during viral infection. The decreased ACE2 expression could lead to lung fibrosis by upregulating angiotensin 2 and activating TGF-signaling [19] . Regarding innate immunity, the involvement of toll-like receptor 4 (TLR4) could have a specific potential role in pathogenesis of both idiopathic and interstitial pneumonias related to RA and CTDs, mainly usual interstitial pneumonia (UIP) [20] [21] [22] [23] . Toll-like receptors (TLRs) and related pattern-recognition receptors represent the first line of host defense against infectious agents [20, 24] . Cell surface receptors such as TLR4 and endosomal receptors such as TLR3 recognize both extrinsic and intrinsic particles, namely pathogen-associated molecule patterns (PAMPs) such as lipopolysaccharide (LPS), but also damage-associated molecule patterns (DAMPs), produced during different forms of noninfectious tissue injury [4, 20, 25, 26] . TLR4 has been demonstrated to be involved in the induction of inflammatory damage during acute viral infections [27, 28] and TLR4 activation has been clearly identified as responsible of the severity of some viral diseases in animal models [20, 29] ; in this regard, lethal infection of mice was prevented by treatment with TLR4 antagonists, highlighting the therapeutic potential role of these molecules [29] [30] [31] . Interestingly, TLR4 knockout mice had similar survival rates or disease severity to infected wild-type mice, suggesting that some degree of TLR4 activation might be required for a protective immune response against viruses, such as SARS-Cov2 [29, 30] . Activation of TLR4 results in the recruitment of the intracellular adaptor protein, myeloid differentiation primary response 88 (MyD88), and/or toll/interleukin-1 receptordomain-containing adapter-inducing interferon-β, ultimately resulting in the expression and secretion of proinflammatory mediators [31] . As described, COVID-19-related interstitial pneumonia can be characterized by a various degree of pulmonary fibrosis, even if the long-term evolution of these alterations is unknown [11, 32] . In particular, while in the early stages of COVID-19 pneumonia ground glass opacities represent the main finding of the disease, in more advanced stages the main manifestation is interstitial change of both lungs, such as fibrous cords and reticular opacities [33, 34] . The spectrum of pulmonary fibrotic disease observed in COVID-19 is wide, ranging from fibrosis associated with organizing pneumonia to severe acute lung injury, in which there is evolution to widespread fibrotic change. In a follow-up study of 36 patients surviving MERS coronavirus infection, 12 (33%) had radiographic evidence of pulmonary fibrosis; these patients were older and had longer intensive care unit admissions. Given approximately 30% of survivors of SARS and MERS experienced persistent radiological and physiological abnormalities consistent with fibrotic lung disease, the repercussions of COVID-19 could include a large cohort of individuals with pulmonary fibrosis and persistent and potentially progressive physiological impairment [33, 34] . The TLR4 pathway has been deeply investigated as possible pathogenetic mechanism of UIP both idiopathic and RA and CTDs related [22, 23, 35, 36] . In fact, despite the presence of some conflicting data [35, [37] [38] [39] [40] [41] , many findings support a profibrotic role subsequent to TLR4 activation. For example, LPS induces lung fibroblast proliferation in mice by mean of a TLR4-dependent pathway [42] and some findings suggest that TLR4 inhibition might protect from LPS-induced pulmonary fibrosis [35] . It is well-known that the expression of both TLR2 and TLR4 is significantly increased in the lungs of patients with different ILD, suggesting either a protective compensatory response or aberrant activation leading to unresolved inflammation and tissue injury [37] . The suppression of TLR4 and TLR2 produces opposite results; in fact, the suppression of TLR4 induces inhibition of bleomycin-induced lung fibrosis, while the suppression of TLR2 exacerbates it [38] [39] [40] . Furthermore, IPF susceptibility and progression have been associated with functional genetic variants of TOLLIP, an inhibitory adaptor protein modulating innate immune responses through modulation of the canonical MyD88-dependent TLR2 and TLR4 signaling [43, 44] . Interestingly, a novel antifibrotic compound, named Mogroside IIIE, markedly decreased fibrosis through regulation of the TLR4 signaling in a murine model of bleomycin-induced pulmonary fibrosis [45] . a possible role for TLR4 has been proposed also in the pathogenesis of fibrosis in CTDs. In particular, specific DAMPs are significantly upregulated in fibrotic skin and lungs from systemic sclerosis (SSc) patients and largely colocalized with TLR4-expressing myofibroblasts [46, 47] . In mice, the genetic ablation of 2 DAMPs associated with SSc, namely fibronectin-EDA and tenascin-C, resulted in a significant attenuation of skin and lung fibrosis, suggesting a pathogenetic role for DAMP-TLR4 signaling in the development of chronic organ fibrosis [46, 47] . Moreover, knock-out mice for functional TLR4, as well as with a fibroblast-specific deletion of TLR4, were protected from fibrosis in experimental models [22, 46, 48, 49] . Rheumatoid arthritis (RA) is complicated by ILD in about 10-20% of cases, mainly showing UIP pattern, followed by a NSIP pattern [50] [51] [52] . The involvement of TLR4 in RA has been demonstrated in the pathogenesis of musculoskeletal and pulmonary involvement [21, 23, 53] . Innate immunity exhibits significant differences between idiopathic UIP and NSIP, justifying the hypothesis of possible distinctive pathogenetic features of UIP and NSIP in RA patients, also; these peculiarities could be responsible for the different clinical evolution and outcomes in RA patients showing an UIP or a NSIP pattern [23] . Differently by UIP, pathogenesis of NSIP is currently understood as an autoimmune and inflammatory-driven process and early histological studies examining lung biopsy samples show a mononuclear lymphocytic infiltrate. In NSIP a largely lymphocytic infiltrate expressing the B cell-specific antigen can be found but also a high CD4/CD8 ratio, exhibiting a Th1-type response, when compared with UIP tissue [54] . Moreover, a significantly higher expression of the chemokine receptor CXCR3 rather than CXCR4 have been found in lung tissue of patients with NSIP compared with those with IPF [55] . All these findings suggest the potential role of the host's immune response in the pathogenesis of NSIP [54] . Because of the relevant role of TLR4 in pathogenesis of RA [21, 23, [51] [52] [53] 56] , inhibition of TLR4 has been explored as a possible therapeutic target; in experimental models, the TLR4 inhibitor TAK-242, inhibited the production of interleukin (IL)-6, IL-8, matrix metalloproteinase-1, and vascular endothelial growth factor in a LPS stimulated human synovial cell line [53] . However, an anti-TLR4 monoclonal antibody (NI-0101) has failed in demonstrating its efficacy in the treatment of the disease [57] . On the other hand, considering the significant role of TLR4 in lung complications of COVID-19, we believe that there is a rationale for considering this as a possible therapeutic approach for SARS-Cov2 pulmonary infection [20, 31] . In RA, both conventional and biologic disease modifying antirheumatic drugs (DMARDs) have been implicated in the development of lung complications, both acute drug-related pulmonary toxicity and chronic lung fibrosis, with conflicting data [27, 58] . Nevertheless, some biologic DMARDS have been recently associated to a more favorable evolution of RA-ILD, such as rituximab, abatacept, tocilizumab [51, [59] [60] [61] . Specifically, in a murine model of ILD, abatacept showed an ability to significantly reduce the fibrogenic marker levels, T-cell proliferation, and M1/M2 macrophage lung infiltration [62, 63] , concurrently improving the fibrosis score at histology and the lung density at HRCT [62, 63] . Moreover, in a retrospective cohorts of RA patients, some Authors observed a good safety and effectiveness profile of abatacept in patients complicated by ILD [64, 65] . Finally, in a pooled analysis on more than 4000 RA patients treated with abatacept by the 'Clinical Abatacept Trial Program', the incidence rate of ILD in the long-extension analysis was very low [66] if compared with other similar study in RA [51] . Of interest, abatacept has been demonstrated to modulate the proinflammatory response upon cytokine-activated T cell and TLR ligand stimulation, including TLR4 [67] . Although speculative, this mechanism could explain the safety and possibly the effectiveness of abatacept in RA-ILD patients and the low rate incidence of ILD in RA patients treated with this drug. On the other hand, in consideration of its interaction with TLR4, abatacept could be evaluated as a possible therapeutic option against SARS-Cov2, before the appearance of severe ARDS. Considering the rapid evolution of systemic and lung inflammatory life-threatening involvement, it is crucial to early identify clinical and humoral markers, consequence of the reactive hyperimmune response. In this regard, the correct timing of the treatment could deeply impact on the efficacy of the therapy and minimize the possible effects on the viral replication [5, 68] . Acute exacerbation (AE) is a well-known complication of interstitial pneumonia, both idiopathic and secondary to other conditions, such as CTDs and RA [69] . Exceptionally, AE can appear also in patients without previous knowledge of ILD or represent the first clinical manifestation of ILD [70] . Diagnosis of AE of ILD in the context of rheumatic disease is quite difficult in clinical practice. Many confusing factors have to be considered, such as opportunistic infections. In this context, multidisciplinary discussion, involving pulmonologists, rheumatologists and thoracic radiologist is crucial to correctly classify the patients [70] . Currently, it is debated whether AE is an externally induced, incidental event or the result of underlying cellular mechanisms [71] . Lung pathology of IPF patients with AE is very similar to that of ARDS showing a diffuse alveolar damage (DAD) and hyaline membranes [69, 70, 72, 73] . Pathogenesis and risk factors for AE in IPF and other ILD are poorly understood [73] , but many aspects of DAD observed during SARS-Cov2 infection resemble AE observed in primary or secondary lung fibrosis [69, 70, 74] and DAD could probably be considered as the common end-stage of different lung pathologies [72] . In this regard, 2 aspects have been specifically addressed in COVID-19 pneumonia: the hyperinflammation, mainly characterized by increase of effector T cells and inflammatory cytokines, in particular IL-6, IL-1, tumor necrosis factor alpha, interferon gamma [5, [75] [76] [77] , and the activation of coagulation cascade [14, 20, 26] ; both findings have been already shown, with some differences, in patients with AE of interstitial pneumonia [72, [78] [79] [80] [81] [82] . Despite evidence is limited to small cohorts, the macrophage activation is crucial in patients with AE in IPF and it consists not only of an upregulation of proinflammatory (M1) cytokines, but also of cytokines associated with M2 [73] . Two major types of macrophage activation have been described. Classical activation (M1) is mediated by Th1 cytokines and is characterized by the secretion of proinflammatory cytokines, such as TNF-, IL-6, and IL-12 [83] . M1 macrophages are involved in promoting inflammation, extracellular matrix destruction, and apoptosis. Instead, Th2 cytokines has been shown to induce alternatively activated type 2 macrophages (M2), secreting proteins involved in repair and healing, cell proliferation, and angiogenesis. The activated macrophages secrete anti-inflammatory molecules, such as IL-10 and TGF-, inducing down-regulation of the inflammatory processes initiated by Th1 cytokines [84] . In mice, overexpression of IL-1β induces acute lung injury and leads to chronic fibrosis [85, 86] . Furthermore, it was reported that injury to alveolar epithelial cells induces M2 macrophage activation [87] and macrophage dependent fibrosis. Schupp observed that, many of the M2 cytokines upregulated in AE, were induced in IPF patients by IL-1β signaling such as CCL2, CCL22 and IL-1ra [88, 89] . Of interest, although increased IL-8 and CCL18 serum levels have already been demonstrated to be a worse prognostic factor for survival in IPF, a relationship between these cytokines and an increased risk for AE in IPF has not been shown [73] . Moreover, Schupp recorded a considerable heterogeneity in cytokine production at the moment of IPF diagnosis. M2 cytokines were high in early disease in some patients, while were low even in advanced disease in others. Therefore, the Authors concluded that some patients could be predisposed to AE and the risk for AE was, at least in part, mirrored by M2 cytokine production levels [73] . In COVID-19, the role of M1 macrophages seems to be proved for they play an important role in the pathogenesis of lung disease [90, 91] , while the activity of M2 macrophages subtype has been less investigated; however, an imbalance in M1/M2 differentiation could be present also in SARS-Cov2 patients, explaining, at least partially, why only some patients undergo to severe ARDS [20, 24, 31, 38, 73] . Similar to that observed in COVID-19, early in the development of an IPF-AE, IL-6 and IL-8 peripheral blood levels are significantly increased, and high value of IL-6 and IL-8 levels are related to a higher risk of death in all IPF patients. IL-6 is considered a cardinal stimulator of the production of most acute phase proteins in response to varied stimuli as well as a promoter of specific cellular and humoral immune responses [92] . In particular, Collard and colleagues investigated the plasma biomarker profile of IPF-AE patients in comparison to that of stable IPF and acute lung injury patients measuring not only inflammatory markers such as IL-6, but also markers of type I and II alveolar cell injury/proliferation such as receptor for advanced glycation, Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), of endothelial injury such as von Willebrand factor (vWF) and of the coagulation cascade such as protein C and plasminogen activator inhibitor-1 (PAI-1) [93] . The authors found that KL-6, SP-D, vWF, IL-6, total protein C and PAI-1 levels were significantly higher in IPF-AE patients than stable IPF patients. The authors concluded that in IPF-AE alveolar epithelial type II injury, endothelial damage and coagulation abnormalities were predominant [93] . An increase of other nonspecific inflammatory markers is observed during COVID-19 pneumonia, representing significant poor prognostic marker of disease and similar observations have been conducted on patients with noninfectious ILD [5, 26, 78, 92] . In this regard, in IPF patients, the 3-month survival rate was inversely correlated to serum ferritin levels and survival was significantly lower in patients with high values of ferritin (≥500 ng/mL) [94] ; moreover, patients developing AE-IPF showed higher levels of serum ferritin at the diagnosis of IPF [94] . Furthermore, despite the importance of ferritin in the pathogenesis and prognosis of AE-IPF has yet to be clarified, immunohistochemical staining in autopsy specimens showed that alveolar macrophages were positive for ferritin [94] . According to recent data from the Chinese cohorts, higher levels of IL-6 (>24.3 pg/mL) and D-dimer (>0.28 μg/L) would be predictive of the appearance of severe COVID-19 pneumonia, with high sensitivity and specificity when using a combination of the 2 tests (IL6 and D-dimer) [95] . Even D-dimer and coagulation cascade have been deeply investigated in interstitial pneumonia [78, 79, 81, 93] . Ishikawa evaluated 263 patients with interstitial pneumonia of different etiologies and diagnosed both as IPF, and other idiopathic interstitial pneumonias (namely desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, acute interstitial lung disease, nonspecific interstitial pneumonia, etc.), CTD-ILD, or chronic pulmonary fibrosis with emphysema. Patients with elevated D-dimer levels (more than 0.4 mcg/mL) had an increased risk of developing AE in ILD within three months from each measurement. Since the median time to AE was between the first and second month from D-dimer measurement the Authors raised a question about the efficacy of prophylactic anticoagulation for subjects with high D-dimer levels [78] . Previous studies on animal and human with pulmonary fibrosis supported anticoagulation as a therapeutic approach in IPF [96, 97] . The mortality rate from AE in subjects with IPF receiving anticoagulation (i.e., warfarin for maintenance and switching to low-molecular-weight heparin after developing AE) was low at 18% compared with 71% in patients who did not receive anticoagulation [79, 81] . On the other hand, despite an elevated D-dimer suggesting a hypercoagulable state, anticoagulation may not necessarily be a therapeutic target, given the elevated D-dimer may simply reflect upstream tissue damage from the inflammatory process. Activation of coagulation and excessive inflammatory response are intrinsic findings of ARDS patho-physiology [98] . Cellular damage during ARDS and sepsis can determine the release of mitochondrial DAMPs into the circulation, that further activate polymorphonuclear neutrophils, spreading the inflammatory response [99] . The innate host response to endothelial damage is associated with the activation of coagulation, which in turn regulates and is regulated by the inflammatory process. The pathological role of coagulation in the innate host response has been defined as immunothrombosis [98, 100, 101] , a humoral regulated process that could contribute both to the protection of endothelial integrity and to inflammatory process. Endothelial injury triggered the immune-thrombotic process by the formation of microthrombi in the microvessels [97, 98, [101] [102] [103] [104] . Diffuse endothelial damage provides to the exposure of subendothelial collagen, and to the expression of tissue factor and von-Willebrand factor on endothelial cells. According to the stage of disease, widespread presence of various morphological types of thromboemboli have been observed in patients with ARDS [103, 105, 106] . Despite some Authors reported that microthrombosis could represent a worse prognostic factor for survival [107] , the exact role of thrombosis in the propagation of lung damage is not known. According to the above reported findings, many therapeutic approaches to patients with COVID-19-related ARDS have been proposed, such as inhibition of IL-6, the use of Janus kinases 1-3 inhibitor baricitinib, corticosteroids, antithrombotic therapies (Table 1; in supplementary Table 2 are reported ongoing trials on tocilizumab) [5, 68, [108] [109] [110] . Many trials are ongoing on these drugs, all targeting the immune response of the host and not the virus itself [68] . Other possible targets, as previously reported, could be TLR4, considering the involvement of innate immunity also in virusinduced ARDS [38] [39] [40] [41] 45, 62, 63, 67] . For all these reasons, the IL-6 inhibitors, baricitinib and also TLR4 antagonists could be proposed in patients with AE related to other forms of ILD, such as IPF or RA-ILD. In these latter, where the involvement of the immune system is more evident, the use of these drugs could be more appropriate. COVID-19 pneumonia is a main medical emergency involving many thousands of people around the World. Many efforts are ongoing to understand the pathogenesis of the disease and the possible therapeutic approach [1, 111] . Many drugs, normally used in immune-mediated disorders have been proposed with different aims [5, 68, [112] [113] [114] and some trials are aiming to confirm their efficacy, mainly on the lung manifestations of COVID-19 [68] . As discussed by other authors, a relevant question concerns the possibility of identifying the right 'window of opportunity' for the therapeutic intervention [68] . In fact, different immunemediated pathways are probably activated at various stages of the disease and in different patients, and our ability to identify them could be essential for the therapeutic response [2, 5, 68] . If on the one hand the similarities with other forms of acute and chronic lung diseases could allow us to successfully propose anti-inflammatory and immune-modulator drugs already used in such diseases, on the other the investigations on COVID-19 pathogenesis could help us to have a better understanding of other rare conditions and their treatment, also [5, 68] . The ongoing research on COVID-19 could highlight many other similarities with UIP, possibly improving the knowledge in this field. For example, very recently, another common point with UIP has been reported, after the observation of a higher prevalence of smokers in COVID-19 related ARDS when compared with patients with mild disease [7, 52, 115] . In conclusion, despite the uncertainty about many pathogenetic aspects about COVID-19-related pneumonia, we are probably observing a possible model for other forms of ILD and AE. The great amount of data deriving from studies on COVID-19 could be helpful in proposing new therapeutic approach for AE of ILD and in understanding of pathogenesis of UIP related to autoimmune systemic diseases. Since 2009 our multidisciplinary team is cooperating in the diagnosis, clinical assessment and management of patients affected by systemic autoimmune disorders complicated by lung involvement. a multidisciplinary evaluation, including expert pulmonologists and rheumatologists, together with radiologists, cardiologists, thoracic surgeons, and pathologists is performed in selected cases. Differential diagnosis of an AE-ILD in the context of a rheumatic disease includes mainly opportunistic infections, pulmonary embolism and heart failure. In this context, our multidisciplinary group actively collaborate in evaluating and treating these patients [51, 60, 61, 70, 116] (see Figure 2 ). Management of both idiopathic and RA-related ILD is challenging. While in IPF the use of antifibrotic agents, nintedanib and pirfenidone, has been largely validated in various clinical trials, treatment of RA-or CTD-ILD is debated. In fact, the therapeutic approach to RA-ILD patients is complicated by some unresolved matters. First, both conventional and biologic DMARDs have been implicated in the development of drug-related pulmonary toxicity with conflicting data; secondly, there is no evidence that the lung involvement could benefit by the treatment of RA. Nevertheless, immunosuppressive drugs used in CTD or antifibrotic drugs are not effective on joint involvement of RA, suggesting that RA-ILD treatment is not the same as treating RA in patients with concurrent ILD. For all these reasons, to enhance our knowledge on pathogenesis of RA-ILD, in particular UIP pattern, could contribute not only to the development of drugs effective on lung involvement, but also to increase the safety of DMARDs effective on arthritis. TLR4 has been demonstrated to be involved in the induction of inflammatory damage during acute viral infections and TLR4 activation has been clearly identified as responsible of the severity of some viral diseases such as COVID-19 and might represent the link between viral infection, inflammation and fibrosis. In this regard, abatacept has been demonstrated to modulate the proinflammatory response upon cytokine-activated T cell and TLR ligand stimulation, including TLR4 and this mechanism could be, at least partially, explains the good safety and effectiveness of such drugs on ILD the low incidence rate of ILD in RA patients treated with abatacept. Concurrently, the TLR4 modulation could reasonably justify the safety demonstrated by abatacept in the treatment of RA patients complicated by ILD. In particular, a very low rate of AE has been reported in RA-ILD patients treated with abatacept. AE is one of the main causes of death in patients with interstitial pneumonia, both idiopathic and secondary to other conditions, such as CTDs and RA. COVID-19 pneumonia represents an impressive model of AE of ILD, resembling both the hyperinflammation, mainly characterized by increase of effector T cells and inflammatory cytokines, and the activation of coagulation cascade. Similar to that observed in COVID-19, early in the development of an IPF-AE, IL-6, and IL-8 peripheral blood levels are significantly increased, and high value of IL-6 and IL-8 levels are related to a higher risk of death in all IPF patients. Similarly, D-dimer increase, hypercoagulability and microembolism have been described in AE and anticoagulation has been evaluated as a possible therapeutic target in IPF. Therefore, the formidable effort in research on COVID-19 could contribute to the development of novel therapeutic strategy for AE of both idiopathic and secondary-ILD. Many therapeutic approaches to patients with COVID-19-related ARDS have been proposed, such as inhibition of IL-6, the use of Janus kinases 1-3 inhibitor baricitinib, antithrombotic therapies (Table 1 and supplementary Table 2 ) and should be specifically evaluated in randomized clinical trials, rather than encourage the use of drugs without evidence. All these drugs could be properly investigated in AE of ILD, in particular in patients with RA or CTD-ILD, where the involvement of the immune system and the inflammatory state is more evident. Although some experience with TLR4 inhibitors in the treatment of RA have been unsatisfactory, other molecules are currently under observation. However, since at least 15-20% of patients shows ILD, TLR4 might represent a possible target not only for the treatment of RA joint involvement, but also for a safe and additional therapy in patients with ILD. Finally, specific randomized clinical trials should be conducted on some biologic DMARDs, such as abatacept, tocilizumab or baricitinib, both to evaluate the safety on RA-ILD and the ability in prevention and treatment of AE. Acknowledgments a special thanks to Gabriele D'Andrea from the Radiology Unit of San Gerardo Hospital of Monza, for the support in iconography Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. This paper was not funded. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status Understanding of COVID-19 based on current evidence Analysis of Characteristics in Death Patients with COVID-19 Pneumonia without Underlying Diseases Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2 COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Connective tissue disease-associated interstitial lung disease Idiopathic pulmonary fibrosis Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis •• Cohomprensive review on the radiological findings of COVID-19 pneumonia Rapid progression to acute respiratory distress syndrome: review of current understanding of critical illness from COVID-19 infection Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients High-resolution chest CT features and clinical characteristics of patients infected with COVID-19 in Jiangsu, China Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study The article firstly analyzed the radiological features of COVID-19 pneumonia Virology, epidemiology, pathogenesis, and control of COVID-19 Molecular immune pathogenesis and diagnosis of COVID-19 Genomewide association study of severe Covid-19 with respiratory failure COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission Impact of sex and gender on COVID-19 outcomes in Europe Innate immune signaling and proteolytic pathways in the resolution or exacerbation of SARS-CoV-2 in Covid-19: key therapeutic targets? Toll-like receptor 4 in acute viral infection: too much of a good thing • The article fully explains the role of TLR4 in viral infection Toll-like receptor 4 is involved in inflammatory and joint destructive pathways in collagen-induced arthritis in DBA1j mice TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung Innate immunity alterations in idiopathic interstitial pneumonias and rheumatoid arthritis-associated interstitial lung diseases Regulating the adaptive immune response to respiratory virus infection Interference of the T cell and antigen-presenting cell costimulatory pathway using CTLA4-Ig (Abatacept) prevents staphylococcal enterotoxin B pathology Pathological findings of COVID-19 associated with acute respiratory distress syndrome Summary for Policymakers Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology The toll-like receptor 4 antagonist eritoran protects mice from lethal filovirus challenge Role of human TLR4 in respiratory syncytial virus-induced NF-κB activation, viral entry and replication TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines (Basel) CT screening for early diagnosis of SARS-CoV-2 infection -authors' reply Clinical and radiological features of novel coronavirus pneumonia Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy • The article reviews pathogenesis of fibrotic aspects of COVID-19 pneumonia and possible role of antifibrotic therapies Toll-like receptors in the pathogenesis of pulmonary fibrosis Toll-like receptor 4 activation attenuates profibrotic response in control lung fibroblasts but not in fibroblasts from patients with IPF Expression of toll-like receptor 2 and 4 is increased in the respiratory epithelial cells of chronic idiopathic interstitial pneumonia patients TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury Targeting TLR2 attenuates pulmonary inflammation and fibrosis by reversion of suppressive immune microenvironment TLR4 is a negative regulator in noninfectious lung inflammation Inhibiting toll-like receptor 4 signaling ameliorates pulmonary fibrosis during acute lung injury induced by lipopolysaccharide: an experimental study Lipopolysaccharide induces lung fibroblast proliferation through toll-like receptor 4 signaling and the phosphoinositide3-kinase-akt pathway Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent Mogroside IIIE, a novel anti-fibrotic compound, reduces pulmonary fibrosis through toll-like receptor 4 pathways Toll-like receptor 4 signaling augments transforming growth factor-β responses FibronectinEDA promotes chronic cutaneous fibrosis through toll-like receptor signaling Amelioration of tissue fibrosis by toll-like receptor 4 knockout in murine models of systemic sclerosis Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis Imaging aspects of interstitial lung disease in patients with rheumatoid arthritis: literature review Treatment of rheumatoid arthritis-associated interstitial lung disease: lights and shadows Rheumatoid arthritis-associated interstitial lung disease: current concepts Investigation of toll-like receptor (TLR) 4 inhibitor TAK-242 as a new potential anti-rheumatoid arthritis drug Nonspecific interstitial pneumonia Expression of chemokine receptors CXCR3 and CCR4 in lymphocytes of idiopathic nonspecific interstitial pneumonia Could toll-like receptors provide a missing link in chronic inflammation in rheumatoid arthritis? Lessons from a study on human rheumatoid tissue Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review The structure of planktonic communities of testate amoebae (Arcellinida and uglyphida) in three environments of the Upper Paraná River basin, Brazil Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicenter retrospective study Tocilizumab in patients with severe COVID-19: a retrospective cohort study • The article firstly describes a large cohort of COVID-19 patients treated with tocilizumab T-cell costimulation blockade is effective in experimental digestive and lung tissue fibrosis The effect of CTLA-4Ig, a CD28/B7 antagonist, on the lung inflammation and T cell subset profile during murine hypersensitivity pneumonitis Abatacept in patients with rheumatoid arthritis and interstitial lung disease: a national multicenter study of 63 patients Long-term deterioration of interstitial lung disease in patients with rheumatoid arthritis treated with abatacept Safety of abatacept administered intravenously in treatment of rheumatoid arthritis: integrated analyses of up to 8 years of treatment from the abatacept clinical trial program Abatacept modulates proinflammatory macrophage responses upon cytokine-activated T cell and Toll-like receptor ligand stimulation COVID-19: the new challenge for rheumatologists • The article explores the possible role of antirheumatic drugs in COVID-19 pneumonia Acute exacerbation of idiopathic pulmonary fibrosis an international working group report Acute exacerbation of interstitial lung diseases secondary to systemic rheumatic diseases: a prospective study and review of the literature • The article exhaustively review the findings of acute exacerbation of interstitial lung disease in rheumatic patients and describes a prospective cohort Acute exacerbation of idiopathic pulmonary fibrosis associated with air pollution exposure Acute lung injury Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Cytokine release syndrome Modeling cytokine release syndrome Current concepts in the diagnosis and management of cytokine release syndrome Elevated serum D-dimer level is associated with an increased risk of acute exacerbation in interstitial lung disease Anticoagulant therapy for idiopathic pulmonary fibrosis Thrombomodulin alfa for acute exacerbation of idiopathic pulmonary fibrosis: a randomized, double-blind, placebo-controlled trial A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis: a hidden subgroup? Reply: a placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis: a hidden subgroup? Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis Alternative activation of macrophages: mechanism and functions Transient expression of IL-1β induces acute lung injury and chronic repair leading to pulmonary fibrosis Interleukin-1β causes acute lung injury via αvβ5 and αvβ6 integrin-dependent mechanisms Implicating exudate macrophages and Ly-6C high monocytes in CCR2-dependent lung fibrosis following gene-targeted alveolar injury Regulation of monocyte chemoattractant protein-1 gene expression and secretion in rat pulmonary alveolar macrophages by lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-1 beta Expression of macrophagederived chemokine (MDC) mRNA in macrophages is enhanced by interleukin-1 β, tumor necrosis factor α, and lipopolysaccharide When COVID-19 encounters interstitial lung disease: challenges and management Innate Immune Signaling and Proteolytic Pathways in the Resolution or Exacerbation of SARS-CoV-2 in Covid-19: Key Therapeutic Targets? High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis Prognostic evaluation of serum ferritin in acute exacerbation of idiopathic pulmonary fibrosis Clinical features of patients infected with 2019 novel coronavirus in Wuhan Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung disease Coagulation, fibrinolysis, and fibrin deposition in acute lung injury Immunothrombosis in acute respiratory distress syndrome: cross talks between inflammation and coagulation Circulating mitochondrial DAMPs cause inflammatory responses to injury Thrombosis as an intravascular effector of innate immunity The coagulation system and its function in early immune defense Crossroads of coagulation and innate immunity: the case of deep vein thrombosis Endothelial pathomechanisms in acute lung injury Parietal and intravascular innate mechanisms of vascular inflammation The pulmonary vascular lesions of the adult respiratory distress syndrome Coagulopathy and antiphospholipid antibodies in patients with Covid-19 Early bedside detection of pulmonary vascular occlusion during acute respiratory failure COVID-19: combining antiviral and anti-inflammatory treatments On the use of corticosteroids for 2019-nCoV pneumonia Review of trials currently testing treatment and prevention of COVID-19 The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease Baricitinib as potential treatment for 2019-nCoV acute respiratory disease Tocilizumab treatment in COVID-19: a single center experience Continuous hydroxychloroquine or colchicine therapy does not prevent infection with SARS-CoV-2: insights from a large healthcare database analysis COVID-19 and smoking: a systematic review of the evidence Acute exacerbation of idiopathic pulmonary fibrosis: a clinical review