Several inflammatory cytokines that correlate with adverse clinical outcomes in COVID-19 employ a distinct intracellular signalling pathway mediated by Janus kinases (JAKs). JAK-STAT signalling may be an excellent therapeutic target (Luo 2020).
Baricitinib (Olumiant®) is a JAK inhibitor approved for rheumatoid arthritis. Using virtual screening algorithms, baricitinib was identified as a substance that could inhibit ACE2-mediated endocytosis (Stebbing 2020). Like other JAK inhibitors such as fedratinib or ruxolitinib, signaling inhibition may also reduce the effects of the increased cytokine levels that are frequently seen in patients with COVID-19. There is some evidence that baricitinib could be the optimal agent in this group (Richardson 2020). Other experts have argued that the drug would be not an ideal option due to the fact that baricitinib causes lymphocytopenia, neutropenia and viral reactivation (Praveen 2020) as well as pancreatitis (Cerda-Contreras 2020). There is also a dose-dependent association with arterial and venous thromboembolic events (Jorgensen 2020). It is possible that the pro-thrombotic tendencies could exacerbate a hypercoagulable state, underscoring the importance of restricting the use of baricitinib to clinical trials. Several studies are underway in Italy and the US, among them a huge trial (ACTT-II), comparing baricitinib and remdesivir to remdesivir alone in more than 1,000 patients.
- So far, one observational study provides some evidence for a synergistic effect of baricitinib and corticosteroids (Rodriguez-Garcia 2020). Patients with moderate to severe SARS-CoV-2 pneumonia received lopinavir/r and HCQ plus either corticosteroids (controls, n=50) or corticosteroids and baricitinib (n=62). In the controls, a higher proportion of patients required supplemental oxygen both at discharge (62% vs 26%) and 1 month later (28% vs 13%),
Ruxolitinib (Jakavi®) is a JAK inhibitor manufactured by Incyte. It is used for myelofibrosis, polycythemia vera (PCV) and certain chronic graft versus host diseases in patients following a bone marrow transplant. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality.
- In a retrospective study, 12/14 patients achieved significant reduction of the “COVID-19 Inflammation Score” with sustained clinical improvement in 11/14 patients (La Rosée 2020). Treatment was safe with some signals of efficacy to prevent or overcome multi-organ failure. A Phase II RCT has been initiated (NCT04338958).
Find the entire treatment chapter at https://covidreference.com/treatment
Acalabrutinib – Anticomplement therapies – Azithromycin – Camostat – Chloroquine – Colchicine – Convalescent plasma – Corticosteroids – Cytokine blockers – Famotidine – Favipiravir – G-CSF – Human recombinant soluble ACE2 – Hydroxychloroquine – Ibrutinib – Iloprost – Interferons – JAK inhibitors – Leflunomide – Lopinavir – Monoclonal antibodies – N-acetylcysteine – Oseltamivir – (other) Protease inhibitors – (other) RdRp inhibitors – REGN-COV2 – Umifenovir