Editorial

COVID-19: an unexpected indication for

E D I TO R I A L
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anti-rheumatic therapies?

In December 2019, a novel coronavirus, currently the evolution of COVID-19 pneumonia and promoting
defined as Severe Acute Respiratory Syndrome viral clearance [10]. Accordingly, several medical agen-
Coronavirus 2 (SARS-CoV-2), was identified as the cies, including Chinese and Italian ones, included CQ
aetiological agent of a cluster of pneumonia in Wuhan, and HCQ in the recommendations for treatment of
China [1]. Since this outbreak, the novel coronavirus dis- COVID-19 [11, 12]. Recently, a small non-randomized
ease (COVID-19) has spread worldwide. By 30 March trial evaluating the combination of HCQ and azithromy-
2020, COVID-19 had reached pandemic proportions, cin in 36 SARS-CoV-2 positive subjects showed a sig-
involving >110 countries and >600 000 cases [2]. Most nificant efficacy of the combination in clearing the viral
cases of COVID-19 are self-limiting, but up to 20% of nasopharyngeal carriage compared with the control
infected patients show a severe or critical disease, treatment [13]. Azithromycin activates antiviral interferon
including severe pneumonia and multi-organ failure [3]. pathways in bronchial epithelial cells, suggesting an
Systemic immune abnormalities feature in severe additive effect to its antimalarial action and a potential
COVID-19. Despite peripheral blood showing a reduced utility against viral spread [14]. Moreover, HCQ shows a
lymphocyte number, there is a hyperactivation state of T higher antiviral activity compared with CQ on in vitro
cells, with an increase of Th17 and a high cytotoxic ac- SARS-CoV-2 infected cells [15]. However, the small size
tivity of CD8 [4]. Moreover, patients with severe COVID- and the non-randomized design limit the strength of the
19 show increased serum IL-6 levels and reduced num- studies. Larger randomized clinical trials (RCT) investi-
ber of circulating NK cells. Globally, these clinical and gating HCQ efficacy, with or without azithromycin, in
serological abnormalities characterize a cytokine release COVID-19 patients as well as prophylactic treatment in
syndrome (CRS) [5]. During CRS, the systemic activation healthcare providers have been announced in several
of immune cells causes the release of a large quantity of countries, including Australia, Brazil (NCT04321278),
cytokines with the aim of limiting viral diffusion and Denmark (NCT04322396) and Spain (NCT04304053).
clearing the infection. However, uncontrolled immune The development of a CRS has a pivotal role in severe
system activation can cause terminal organ damage, COVID-19. The persistent viral stimulation leads to a sig-
evolving towards multi-organ failure [6]. nificant increase of circulating cytokines such as IL-6
So far, there is no available specific antiviral treatment and TNFa, which are negatively related to the absolute
for COVID-19, and management is largely supportive. lymphocyte count and can trigger inflammatory organ
However, in light of the increasing understanding of damage [16]. IL-6 is central in the pathogenesis of CRS
SARS-CoV-2 biology and COVID-19 pathophysiology, associated to SARS-CoV-2 and consequently tocilizu-
several drugs commonly used in rheumatology have mab, a humanized anti-IL-6 receptor (IL-6R) monoclonal
been proposed as potential COVID-19 treatments antibody, gained interest as a potential treatment of
(Fig. 1). COVID-19. A retrospective study on 21 patients affected
Chloroquine (CQ) and hydroxychloroquine (HCQ) are by severe COVID-19 showed that tocilizumab treatment
antimalarial agents with immune-modulatory activities improved the clinical manifestations in most of the
largely used in rheumatology. These agents present also patients [17]. Despite the fact that RCTs investigating
a well-known antiviral activity, involving a broad spec- the safety and the efficacy of tocilizumab in COVID-19
trum of viral species [7]. The drugs act by increasing are still ongoing (ChiCTR2000029765; NCT04317092),
endosomal pH and inhibiting toll-like receptors, interfer- both Chinese and Italian recommendations led to tocili-
ing with virus–cell fusion, as well as interfering with the zumab being introduced as an option for patients with
glycosylation of angiotensin-converting enzyme 2 extensive and bilateral lung disease or severely ill
(ACE2), which represents the cellular receptor of the patients with elevated IL-6 levels [11, 12]. Similarly, sari-
virus [8]. In vitro studies demonstrated an antiviral activ- lumab, a fully human anti-IL6R antibody, is currently
ity against SARS-COV-2 at concentrations achievable at under investigation in severe COVID-19 (NCT04315298).
the usual therapeutic doses. Moreover, the immune- SARS-CoV-2 shares several similarities with SARS-
modulatory activity of these agents, limiting the systemic CoV, the coronavirus strain responsible for the 2002
immune activation associated to COVID-19, could act SARS pandemic. Both viruses use the spike (S)-proteins
synergistically to the antiviral properties [9]. Several clin- to engage their cellular receptor, ACE2, for cell invasion
ical trials conducted in China demonstrated superiority [18]. ACE2 expression is upregulated by both SARS-
of CQ treatment with respect to placebo in improving CoV-2 infection and inflammatory cytokine stimulation

C The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: [email protected]
V
Editorial

FIG. 1 Antiviral mechanisms of action of anti-rheumatic drugs in COVID-19

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ACE: angiotensin-converting enzyme; AM: alveolar macrophage; AP2: alveolar pneumocyte type 2; ARDS: acute re-
spiratory distress syndrome; CQ/HCQ: chloroquine/hydroxychloroquine; IL-6R: interleukin 6 receptor; MOF: multi-
organ failure; NAK: numb-associated kinases; RAS: renin–angiotensin system; SARS-CoV-2: Severe Acute
Respiratory Syndrome Coronavirus 2; TLR: toll-like receptor.

[19]. In SARS-CoV infection, S-proteins can induce by members of the numb-associated kinase (NAK) fam-
shedding of the ectodomain of ACE2, a process strictly ily, which have been proposed as targets to limit intra-
coupled to TNFa production [20]. This loss of ACE2 ac- cellular viral traffic. Tyrosine kinase inhibitors, targeting
tivity caused by shedding has been associated to lung NAK family members, showed good antiviral activity
injury as a consequence of an increased activity of the in vitro [25]. JAK inhibitors, including baricitinib, ruxoliti-
renin–angiotensin system [21]. Although mainly demon- nib and fedratinib, show the ability to inhibit NAK, limit-
strated for SARS-CoV, the homology between the struc- ing also systemic inflammatory response and cytokine
tures of S-proteins suggests that also SARS-CoV-2 S- production through the inhibition of the canonical JAK–
proteins may show a similar mechanism [22]. The STAT pathway [26]. Among these, baricitinib is the only
increased TNFa production could consequently both fa- JAK inhibitor to reach, at therapeutic and well-tolerated
cilitate viral infection and cause organ damage. Indeed, doses, plasmatic concentrations sufficient to inhibit NAK
anti-TNFa treatment has been suggested as a possible members [27]. A RCT investigating baricitinib efficacy in
treatment option in COVID-19 [23], and a RCT investi- COVID-19 is currently ongoing (NCT04320277).
gating adalimumab in COVID-19 has recently been reg- Severe COVID-19 represents the first example of an
istered (ChiCTR2000030089). infectious disease successfully treatable with immune-
Clathrin-dependent endocytosis is crucial for viral in- modulating therapies. While the ongoing outbreak of
vasion of pneumocytes [24]. This process is promoted COVID-19 requires the urgent development of a vaccine,

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 Editorial

this unexpected indication for anti-rheumatic therapies 9 Wang M, Cao R, Zhang L et al. Remdesivir and
underlines the need to better understand how infectious chloroquine effectively inhibit the recently emerged novel
agents trigger the immune system to produce severe coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:
clinical manifestations, especially in the case of 269–71.
pandemics. 10 Gao J, Tian Z, Yang X. Breakthrough: chloroquine
phosphate has shown apparent efficacy in treatment of

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Funding: No specific funding was received from any COVID-19 associated pneumonia in clinical studies.
funding bodies in the public, commercial or not-for- Biosci Trends 2020;14:72–3.
profit sectors to carry out the work described in this 11 SIMIT – Società Italiana di Malattie Infettive e Tropicali –
manuscript. Sezione Regione Lombardia. Vademecum per la cura
delle persone con malattia da COVI-19. Edizione 2.0, 13
Disclosure statement: The authors have declared no
marzo. 2020. http://www.simit.org/medias/1569-covid19-
conflicts of interest.
vademecum-13-03-202.pdf.

Bruno Lucchino 1, Manuela Di Franco1 12 National Health Commission & State Administration of
and Fabrizio Conti1 Traditional Chinese Medicine. Diagnosis and treatment
protocol for novel coronavirus pneumonia (7th interim
1
Rheumatology Unit, Department of Internal Clinical, edition). Beijing, China, 2020. http://www.kankyokansen.
Anesthesiologic and Cardiovascular Sciences, Sapienza org/uploads/uploads/files/jsipc/protocol_V7.pdf (9 April
University of Rome, Rome, Italy 2020, date last accessed).
Accepted 01 April 2020
13 Gautret P, Lagier J-C, Parola P et al.
Correspondence to: Manuela Di Franco, Rheumatology Unit,
Hydroxychloroquine and azithromycin as a treatment of
Department of Internal Clinical, Anesthesiologic and
COVID-19: results of an open-label non-randomized clin-
Cardiovascular Sciences, Sapienza University of Rome, Viale
ical trial. Int J Antimicrob Agents 2020 (in press), doi:
Del Policlinico 155, 00161 Rome, Italy. E-mail: manuela.
10.1016/j.ijantimicag.2020.105949.
[email protected]
14 Schögler A, Kopf BS, Edwards MR et al. Novel antiviral
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