Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients

Tocilizumab is a humanized, immunoglobulin G1κ (IgG1κ) anti-human IL-6 receptor (IL-6R) monoclonal antibody approved for some immune-mediated inflammatory rheumatic diseases. Clinical evidence supports the view that this drug is an effective therapeutic option, with a good risk-benefit profile, in cytokine storm syndromes [14]. In China, its off label use has been tested in 21 ICU ARDS patients with favorable results after 24–48 h in 20/21 patients [15]. Moreover, a multicenter randomized clinical trial in COVID-19 patients with ARDS, treated with tocilizumab at a dose of 4 ~ 8 mg/kg once, and an additional same dose when fever persists within 24 h after the first administration, has been approved in China [16]. The Italian Medicine Agency has recently authorized a trial on the use of tocilizumab in COVID-19 patients with ARDS [17]. This initiative was pushed on also by promising results published on Italian newspapers. Particularly, some patients treated with tocilizumab at the “Pascale” Cancer Institute in Naples showed disease improvements within 24 h and one of them did not require mechanical ventilation 2 days after starting tocilizumab [15].

Another monoclonal antibody belonging to anti-IL-6 drug class, siltuximab, currently approved in multicentric Castleman disease with HIV-negative and human herpesvirus-8 negative, is under investigation for ARDS in COVID-19 patients. In particular, an observational case-control study evaluating siltuximab in ICU patients with ARDS-related COVID-19 is performing at Papa Giovanni XXIII hospital in Bergamo, Italy [18]. Preliminary results have shown promising outcomes as the clinical improvement in the 33% of treated ICU patients [19]. In addition, a multicenter open-label randomized clinical trial is studying the benefit risk profile of siltuximab, as a single therapeutic option or in combination with anakinra, at a single dose of 11 mg/kg, in comparison with tocilizumab or anakinra, alone or in combination, in ARDS patients with COVID-19 [20]. Evidence suggested a higher binding affinity to IL-6 involving siltuximab than tocilizumab but less insights are currently available on the effects of siltuximab in cytokine storm [21].

Based on the results expected with tocilizumab and siltuximab, other anti-IL-6 drugs, currently approved for rheumatoid arthritis, namely sarilumab and sirukumab, could be studied in ARDS and pneumonia patients with COVID-19. Notably, sarilumab has higher affinity for its target and a longer half-life than tocilizumab; thus, a sustained therapeutic effect could be achieved by administration of only one single dose [22, 23]. On March 19^th, 2020, a clinical trial evaluating the efficacy and safety of high dose and low dose of sarilumab in COVID-19 patients was started [24]. Subsequently, further clinical trials have followed, investigating the benefit risk profile of sarilumab in patients with COVID-19-related ARDS, at a dose of 200 mg or 400 mg, as single or repeated administration, subcutaneously or intravenously [25‐28].

Sirukumab neutralizes IL-6 specifically and directly by preventing its binding to its membrane receptor [29], and thus, it leads to a subsequent suppression of IL-6 biological actions. In a phase I trial, sirukumab showed linear pharmacokinetics with long half-life, low immunogenicity, and a good safety profile [30]. Accordingly, it could represent a promising pharmacological option for counteracting the high IL-6 levels occurring in ARDS patients.

Anti-TNF drugs, including infliximab, adalimumab, etanercept, golimumab, and certolizumab, could be tested also for COVID-19-related ARDS and pneumonia. In China, a clinical trial on adalimumab in COVID-19 patients was recently approved [31]. Infliximab, adalimumab, and golimumab are IgG₁ monoclonal antibodies, while etanercept is a fusion protein of two human TNF type 2 receptor moieties linked with the Fc region of a human immunoglobulin, and certolizumab is the pegylated Fab domain obtained from a humanized anti-TNF IgG monoclonal antibody [32]. Differences in the inhibitory mechanism were shown among these drugs, due to their different molecular binding patterns with TNF sites [33]. All anti-TNF drugs display higher binding affinity to soluble TNF than its membrane-bound form, with golimumab and etanercept showing the highest level [34]. Greater binding avidity to soluble TNF was reported for etanercept than infliximab and adalimumab [35]. Heterogeneity was also found in the neutralizing activity of anti-TNF drugs to soluble TNF, while that to transmembrane TNF was comparable [34]. Infliximab and adalimumab displayed a greater binding activity for FcγRII and FcγRIII than etanercept, but the latter was able to bind FcγRI with higher affinity [36]. FcγRs play important roles in the modulation of immune responses, which rely on cytokines and vasoactive mediators [37]. In addition, a review showed that the proteins coded by the virus alter the complement system control and thus contribute to lung viral damages [3]. Out of the anti-TNF drugs, the IgG₁ monoclonal antibodies have a complement-dependent cytotoxicity activity [38] that could be explored in the COVID-19 infection. The known differences in pharmacokinetics and pharmacodynamics among anti-TNF drugs support the need for testing these agents in COVID-19-related ARDS and pneumonia patients without particular priorities, in order to identify the best option. Other selection criteria, including the administration route, the possible positive or negative interactions resulting from combination with other drugs (i.e., hydroxychloroquine) and the costs (i.e., the use of biosimilar anti-TNF available) should be considered.

Anti-JAK drugs (such as ruxolitinib, tofacitinib, baricitinib, oclacitinib, fedratinib, upadacitinib, and peficitinib) [39] should be considered also among the options for clinical investigations in COVID-19-related ARDS and pneumonia patients. JAKs are involved in JAK/STAT signaling associated with the receptors of a large variety of cytokines. In particular, STAT-1 and STAT-3 pathways are activated by binding of IL-6 to its receptor (IL-6R) [40]. Tofacitinib acts as a non-selective inhibitor of all known JAKs (JAK1, JAK2, JAK3, TYK2) with moderate specificity for JAK1 and JAK3. Baricitinib inhibits selectively JAK1 and JAK2 [41]. Both are approved by the European Medicines Agency (EMA); baricitinib for rheumatoid arthritis and tofacitinib for both rheumatic disorders and ulcerative colitis. Ruxolitinib is a JAK1/JAK2 inhibitor approved by the Food and Drug Administration (FDA) for psoriasis, myelofibrosis, and rheumatoid arthritis. Upadacitinib (anti-JAK1), fedratinib (anti-JAK2), and oclacitinib (anti-JAK1) were approved by FDA for rheumatoid arthritis, myelofibrosis, and dermatitis, respectively [42]. Peficitinib (anti-JAK3) was approved for rheumatoid arthritis only in Japan [43].

Tofacitinib and upadacitinib showed potent inhibitory activities on JAK1/3-dependent cytokines, both pathways being involved in lymphocyte activation. Tofacitinib, baricitinib, and upadacitinib displayed also inhibitory actions on the JAK2/TYK2-dependent signaling of IL-3, GM-CSF, and G-CSF. Tofacitinib was shown to act as the most potent inhibitor of G-CSF (JAK2/TYK2). Moreover, tofacitinib, baricitinib, and upadacitinib inhibited IL-6 and interferon (IFN) γ (JAK1/2), as well as IL-10 and IFN-α (JAK1/TYK2), with tofacitinib appearing as the strongest inhibitor of IL-6, IFN-γ, and IL-10 signals [44]. Evidence suggests that baricitinib, fedratinib, and ruxolitinib are also inhibitors of numb-associated kinases (NAK), involved in viral endocytosis and replication. Baricitinib showed the highest affinity for AAK1 than ruxolitinib and fedratinib. Thus, besides exerting putative anti-inflammatory effects in ARDS patients, it is expected also to reduce viral infectivity [45, 46]. Of note, a clinical trial on such antiviral effect is going to start with ruxolitinib [47], and an open-label trial is evaluating its efficacy and safety at a dose of 10 mg twice a day in COVID-19 patients with ARDS [48]. Furthermore, an expanded access program of the 5 mg ruxolitinib formulation is ongoing in severe COVID-19 patients with ≥ 6 years old [49]. Finally, an open label clinical trial is evaluating the benefit risk profile of baricitinib at a dose of 2 mg a day for 10 days in moderate and severe adult COVID-19 patients [27]. Whenever JAK inhibitors could be identified as an effective pharmacological option in COVID-19-related ARDS and pneumonia, their cost and safety issues, particularly the risk of thromboembolic events for some of them, should be taken into account [50].