Both viruses use the spike (S)-proteins to engage their cellular receptor, ACE2, for cell invasion [18]. large quantity of cytokines with the aim of limiting viral diffusion and clearing the infection. However, uncontrolled immune system activation can cause terminal organ damage, growing towards multi-organ failure [6]. So far, there is no available specific antiviral treatment for COVID-19, and management is largely supportive. However, in light of the increasing understanding of SARS-CoV-2 biology and COVID-19 pathophysiology, several drugs commonly used in rheumatology have been proposed as potential COVID-19 treatments (Fig.?1). Open in a separate windowpane Fig. 1 Antiviral mechanisms of action of anti-rheumatic medicines in COVID-19 ACE: angiotensin-converting enzyme; AM: alveolar macrophage; AP2: alveolar pneumocyte type 2; ARDS: acute respiratory distress syndrome; CQ/HCQ: chloroquine/hydroxychloroquine; IL-6R: interleukin 6 receptor; MOF: multi-organ failure; NAK: numb-associated kinases; RAS: reninCangiotensin system; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; TLR: toll-like receptor. Chloroquine (CQ) and hydroxychloroquine (HCQ) are antimalarial providers with immune-modulatory activities largely used in rheumatology. These providers present also a well-known antiviral activity, involving a broad spectrum of viral varieties [7]. The medicines act by increasing endosomal pH and inhibiting toll-like receptors, interfering with virusCcell fusion, as well as interfering with the glycosylation of angiotensin-converting enzyme 2 (ACE2), Plerixafor 8HCl (DB06809) which represents the cellular receptor of the disease [8]. studies shown an antiviral activity against SARS-COV-2 at concentrations attainable at the usual therapeutic doses. Moreover, the immune-modulatory activity of these agents, limiting the systemic immune activation connected to COVID-19, could take action synergistically to the antiviral properties [9]. Several clinical tests carried out in China shown superiority of CQ treatment with respect to placebo in improving the development of COVID-19 pneumonia and advertising viral clearance [10]. Accordingly, several medical companies, including Chinese and Italian ones, included CQ and HCQ in the recommendations for treatment of COVID-19 [11, 12]. Recently, a small non-randomized trial evaluating the combination of HCQ and azithromycin in 36 SARS-CoV-2 positive subjects showed a significant effectiveness of the combination in clearing the viral nasopharyngeal carriage compared with the control treatment [13]. Azithromycin activates antiviral interferon pathways in Plerixafor 8HCl (DB06809) bronchial epithelial cells, suggesting an additive effect to its antimalarial action and a potential energy against viral spread [14]. Moreover, HCQ shows a higher antiviral activity compared with CQ on SARS-CoV-2 infected cells [15]. However, the small size and the non-randomized design limit the strength of the studies. Larger randomized medical tests (RCT) Plerixafor 8HCl (DB06809) investigating HCQ effectiveness, with or without azithromycin, in COVID-19 individuals as well as prophylactic treatment in healthcare providers have been announced in several countries, including Australia, Brazil (“type”:”clinical-trial”,”attrs”:”text”:”NCT04321278″,”term_id”:”NCT04321278″NCT04321278), Denmark (“type”:”clinical-trial”,”attrs”:”text”:”NCT04322396″,”term_id”:”NCT04322396″NCT04322396) and Spain (“type”:”clinical-trial”,”attrs”:”text”:”NCT04304053″,”term_id”:”NCT04304053″NCT04304053). The development of a CRS has a pivotal role in severe COVID-19. The prolonged viral activation prospects to a significant increase of circulating cytokines such as IL-6 and TNF, which are negatively related to the complete lymphocyte count and can trigger inflammatory organ damage [16]. IL-6 is usually central in the pathogenesis of CRS associated to SARS-CoV-2 and consequently tocilizumab, a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody, gained interest as a potential treatment of COVID-19. A retrospective study on 21 patients affected by severe COVID-19 showed that tocilizumab treatment improved the clinical manifestations in most of the patients [17]. Despite the fact that RCTs investigating the safety and the efficacy of tocilizumab in COVID-19 are still ongoing (ChiCTR2000029765; “type”:”clinical-trial”,”attrs”:”text”:”NCT04317092″,”term_id”:”NCT04317092″NCT04317092), both Chinese and Italian recommendations led to tocilizumab being launched as an option for patients with considerable and bilateral lung disease or severely ill patients with elevated IL-6 levels [11, 12]. Similarly, sarilumab, a fully human anti-IL6R antibody, is currently under investigation in severe COVID-19 (“type”:”clinical-trial”,”attrs”:”text”:”NCT04315298″,”term_id”:”NCT04315298″NCT04315298). SARS-CoV-2 shares several similarities with SARS-CoV, the coronavirus strain responsible for the 2002 SARS pandemic. Both viruses use the spike (S)-proteins to engage their cellular receptor, ACE2, for cell invasion [18]. ACE2 expression is usually upregulated by both SARS-CoV-2 contamination and inflammatory cytokine activation [19]. In SARS-CoV contamination, S-proteins can induce shedding of the ectodomain of ACE2, a process purely coupled to TNF production [20]. This loss of ACE2 activity caused by shedding has been associated to lung injury as a consequence of an increased activity of the reninCangiotensin system [21]. Although mainly exhibited for SARS-CoV, the homology between the structures of S-proteins suggests that also SARS-CoV-2 S-proteins may show a similar mechanism [22]. The increased TNF production could consequently both facilitate Efnb2 viral contamination and cause organ damage. Indeed, anti-TNF treatment has been suggested as a possible treatment option in COVID-19 [23], and a RCT investigating adalimumab.