key: cord-351407-7vx9lzi0
authors: Mehta, Puja; Ciurtin, Coziana; Scully, Marie; Levi, Marcel; Chambers, Rachel C.
title: JAK inhibitors in COVID-19: need for vigilance regarding increased inherent thrombotic risk
date: 2020-07-06
journal: Eur Respir J
DOI: 10.1183/13993003.01919-2020
sha: 
doc_id: 351407
cord_uid: 7vx9lzi0

There is accumulating evidence that COVID-19 is a hypercoagulable state. Reports of thrombotic events and autopsy findings of pulmonary thrombotic microangiopathy [1] in patients with COVID-19 are rising. Bompard et al. recently reported a cohort study of 137 patients with COVID-19 pneumonia, in which retrospective review of computed tomography pulmonary angiography (CTPA) scans demonstrated a cumulative incidence of pulmonary emboli (PE) of 24% overall and 50% in intensive care [2]. Although it was initially thought that insidious venous thromboembolic events (VTE) were mainly confined to ventilated patients [3], we now understand thrombotic risk to be a wider problem in COVID-19. An overexuberant host inflammatory response, in selected patients with severe COVID-19, may contribute to the high mortality. We recently recommended screening for virally-driven hyperinflammation in COVID-19 and proposed that immunomodulation in this subgroup of patients, may improve outcomes [4]. There are several ongoing, randomised controlled trials evaluating the therapeutic potential of Janus Kinase inhibitors (JAKi) in severe COVID-19 (table 1). JAKi have a purported advantage over other immunomodulatory strategies in COVID-19, as they may exert dual anti-inflammatory (blockade of multiple, pro-inflammatory cytokines simultaneously) and anti-viral effects (impeding cellular viral endocytosis [5, 6]) and have convenient oral administration, with relatively short half-lives. JAKi may interrupt the signalling of several pro-inflammatory cytokines implicated in the pathogenesis of hyperinflammation, including interleukin (IL)-6, which has been the focus of several clinical trials in COVID-19. JAKi may also inhibit the entry of the SARS-CoV-2 virus into the AT2 alveolar epithelial cells; baricitinib (a JAK1/2 inhibitor), is a numb-associated kinase (NAK) inhibitor, with a particularly high affinity for AP2-associated protein kinase 1 (AAK1), a pivotal regulator of clathrin-mediated viral endocytosis [5]. We recommend vigilance to the potentially increased thrombotic risk associated with JAKi, given the hypercoagulability of COVID-19 and our recent thromboprophylaxis recommendations for all hospitalised patients with COVID-19 [7].

There is accumulating evidence that COVID-19 is a hypercoagulable state. Reports of thrombotic events and autopsy findings of pulmonary thrombotic microangiopathy 1 in patients with COVID-19 are rising. Bompard et al recently reported a cohort study of 137 patients with COVID-19 pneumonia, in which retrospective review of computed tomography pulmonary angiography (CTPA) scans demonstrated a cumulative incidence of pulmonary emboli (PE) of 24% overall and 50% in intensive care 2 . Although it was initially thought that insidious venous thromboembolic events (VTE) were mainly confined to ventilated patients 3 , we now understand thrombotic risk to be a wider problem in COVID-19. An overexuberant host inflammatory response, in selected patients with severe COVID-19, may contribute to the high mortality. We recently recommended screening for virally-driven hyperinflammation in COVID-19 and proposed that immunomodulation in this subgroup of patients, may improve outcomes 4 . There are several ongoing, randomised controlled trials evaluating the therapeutic potential of Janus Kinase inhibitors (JAKi) in severe COVID-19 (Table 1) . JAKi have a purported advantage over other immunomodulatory strategies in COVID-19, as they may exert dual anti-inflammatory (blockade of multiple, pro-inflammatory cytokines simultaneously) and anti-viral effects (impeding cellular viral endocytosis 5, 6 ) and have convenient oral administration, with relatively short half-lives. JAKi may interrupt the signalling of several pro-inflammatory cytokines implicated in the pathogenesis of hyperinflammation, including interleukin (IL)-6, which has been the focus of several clinical trials in COVID-19. JAKi may also inhibit the entry of the SARS-CoV-2 virus into the AT2 alveolar epithelial cells; baricitinib (a JAK1/2 inhibitor), is a numb-associated kinase (NAK) inhibitor, with a particularly high affinity for AP2-associated protein kinase 1 (AAK1), a pivotal regulator of clathrin-mediated viral endocytosis 5 . We recommend vigilance to the potentially increased (Table 1) . It is unclear whether the presumed prothrombotic risks are dependent on JAK selectivity, drug specificity, dose or treatment duration or are confounded by indication. Whilst there is evidence of dose-dependent increased thrombotic risk associated with tofacitinib (five-fold increased risk of PE compared with tumour necrosis factor therapy in RA) 8 , a recent meta-analysis did not show an overall JAKi class pro-thrombotic signal 9 .

Although a significantly increased incidence of thrombotic events (DVT and PE) was reported with bariticitinb in RA trials 10 , this has not been observed in extension studies and recent trials in atopic dermatitis 11 . Post-marketing surveillance may delineate the true risk and whether this is disease-specific. It is unclear which JAK isoform (selectivity) confers impact on the efficacy or influences safety of these therapies for their licenced indications (e.g. rheumatoid arthritis) or in the new disease setting of COVID-19. It is important to note that at high doses, JAKi can become 'pan-JAK' inhibitors and exhibit non-selectivity 12 Discussion continues regarding whether JAKi have a causal role in thrombotic events, or whether this represents a higher background thrombotic risk 13 . Indeed VTE risk in RA (0.3-0.7 /100 patient years) is greater compared with the general population (0.1-0.4 / 100 patient years) 13 . Intriguingly, ruxolitinib, unlike baricitinib, does not carry a VTE warning, despite both being selective JAK 1/2 inhibitors. Conversely there is a suggestion that ruxolitinib may lower the inherently raised thrombotic risk in myeloproliferative neoplasms 14 . Extrapolating this reassurance for ruxolitinib to COVID-19 is inappropriate as data for baricitinib and ruxolitinib is derived from different disease populations and their respective safety signals may be confounded by indication.

Clinical trials in COVID-19 using immunomodulation, including JAKi, intend to recruit patients with the most severe disease, and it is hypothesised that these patients are more hypercoagulable. We recommend risk mitigation strategies including consideration of exclusion of patients with high thrombotic risk, treatment with standard or intermediate-dose low molecular weight heparin prophlyaxis 7 during hospitalisation and consideration of increased thrombotic risk associated with JAKi, given the hypercoagulability of COVID-19. 

COVID-19 and its implications for thrombosis and anticoagulation

Pulmonary embolism in patients with Covid-19 pneumonia

Venous thromboembolism in SARS-CoV-2 patients: only a problem in ventilated ICU patients, or is there more to it?

COVID-19: consider cytokine storm syndromes and immunosuppression

COVID-19: combining antiviral and anti-inflammatory treatments

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Coagulation abnormalities and thrombosis in patients with COVID-19

Increased risk of blood clots in lungs and death with higher dose of Xeljanz (tofacitinib) for rheumatoid arthritis

Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials

Cardiovascular Safety During Treatment With Baricitinib in Rheumatoid Arthritis

Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials

The emerging safety profile of JAK inhibitors in rheumatic disease

Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk?

The impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta-analysis

PM drafted the manuscript. All authors contributed to discussions, revised and approved the manuscript.

PM is an MRC-GSK EMINENT clinical training fellow with project funding outside the submitted work. PM receives co-funding by the NIHR University College London Hospitals Biomedical Research Centre (UCLH BRC). CC, MS, ML have nothing to disclose. RCC reports grants from UKRI MRC, grants from GlaxoSmithKline, grants from NIHR ULCH BRC outside the submitted work.