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New Emirates Medical Journal

Volume 3, 2 Issues, 2022
ISSN: 0250-6882 (Online)
This journal supports open access

Open Access Article

Repurposing Ruxolitinib in Combating COVID-19: A Mini-review



Inshia Begum1, Fathima Murthuza1, Juwairiya Syed Iqbaluddin1, Hafsah Fatima Arsal1, *
1 Department of Medical Education & Research, Dubai Health Authority, Al Riyadh St - Umm Hurair 2 Dubai, UAE

Abstract

Background:

The pandemic caused by Coronavirus Disease 2019 (COVID-19), also known as Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-CoV-2), is believed to be one of the greatest threats to global health in the 21st century. Recent collective evidence has warranted Ruxolitinib as a potential agent in recovery. Ruxolitinib is a potent and selective inhibitor of Jack kinase (JAK) 1 and 2 with modest to marked selectivity against tyrosine kinase 2 and JAK3, respectively.

Objective:

The review aims to outline the current evidence regarding the repurposed treatment for COVID- 19 and to give an insight into the clinical trials. There has been considerable interest in introducing existing therapeutic agents against COVID-19 to reduce the severity of illness and ease the burden on public healthcare systems.

Methods:

A literature search was conducted using keywords like ‘Ruxolitinib trial’ and ‘COVID-19 Ruxolitinib’ on PubMed, Google Scholar, Science Direct, and Cochrane databases to select research papers and articles on the topic published from January to October 2020. Inclusion criteria were restricted to articles on Ruxolitinib and COVID, whereas the exclusion criteria stipulated that any study done on COVID-19 involving mixed treatment regimen with Ruxolitinib and other drugs or any studies not pertinent to the purpose of the study were omitted.

Conclusion:

Based on the successful outcomes of various researches conducted and clinical trials performed, the use of Ruxolitinib has shown significant improvement and faster clinical recovery among COVID-19 patients of varying severity of infection, advanced age and multiple comorbidities. This review provides an overview of various such studies with their promising outcomes.

Keywords: COVID-19, SARS-CoV-2, JAK1/2 inhibitors, Efficacy, Safety, Ruxolitinib, Coronavirus.


Article Information


Identifiers and Pagination:

Year: 2022
Volume: 3
Issue: 1
First Page: 42
Last Page: 46
Publisher Id: nemj-3-42
DOI: 10.2174/0250688202666210715141439

Article History:

Received Date: 02/2/2021
Revision Received Date: 09/6/2021
Acceptance Date: 15/6/2021
Electronic publication date: 21/01/2022
Collection year: 2022

© 2022 Begum et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at Department of Medical Education & Research, Dubai Health Authority, Al Riyadh St - Umm Hurair 2 Dubai, UAE; Tel: 04 219 1920; E-mail: hafsah.fa22@gmail.com




1. INTRODUCTION

The recent emergence of the pandemic caused by Coronavirus Disease 2019 (COVID-19), also known as Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-CoV-2), poses challenges to the public health and scientific communities. Claiming millions of lives, it is believed to be one of the greatest threats to global public health in the 21st century. The outbreak has been spreading rapidly despite strict public health measures, ravaging the global economy and causing profound human fatalities. As of June 3, 2021, the number of COVID-19 cases worldwide was approximately 172, 666, 073, along with 3,711,545 deaths [1].

2. OBJECTIVE

Repurposing the existing therapeutic agents to reduce the severity of illness and ease the burden on public healthcare systems has been of considerable interest. One such drug in clinical trials is Ruxolitinib. This review outlines the clinical trials to provide evidence supporting the effectiveness of the repurposed treatment for COVID-19.

3. METHODS

A literature search was conducted using keywords like ‘Ruxolitinib trial’ and ‘COVID-19 Ruxolitinib’ on PubMed, Google Scholar, Science Direct, and Cochrane databases to select research papers and articles on the topic published from January to October 2020. Inclusion criteria were restricted to articles on Ruxolitinib and COVID-19, whereas the exclusion criteria stipulated that any study done on COVID-19 involving mixed treatment regimen with Ruxolitinib and other drugs or any studies not pertinent to the purpose of the study were omitted. The search term ‘COVID-19 Ruxolitinib’ produced 58 results in PubMed and ten articles were selected which reported exclusive treatment with Ruxolitinib. The same keyword search in Wiley Library did not generate additional studies. Finally, the search in ScienceDirect returned 164 results, out of which two more studies were included.

4. DISCUSSION

4.1. COVID 19: Pathogenesis and Cytokine Storm

Scientists employ the knowledge of pathological processes and the immune responses to SARS-CoV-2 to develop clinical therapeutic strategies. The pathogenesis of COVID-19 involves viral replication and over-exuberant inflammatory reactions due to immune dysregulation [2]. Consequently, a cytokine storm syndrome is triggered, releasing large amounts of cytokines and immune cells that infiltrate and destroy organs causing lung lesions, respiratory dysfunction, multiple organ damage, and death [3]. The JAK/STAT signaling pathway, which forms the main regulatory cell signaling pathways, controls the activation of cytokines. Therefore, inhibiting JAK kinase activity and thus preventing STAT activation prevent several cellular responses [4], providing an attractive therapeutic approach for COVID-19 treatment.

4.2. Ruxolitinib

The FDA approved Ruxolitinib, a potent JAK1 and JAK2 inhibitor, for Myelofibrosis [5], Polycythemia Vera [6], Hemophagocytic Lymphohistiocytosis [7], and Acute Graft-Versus-Host Disease [8], to reduce the high level of cytokine release associated with these disorders. Preclinical studies have demonstrated that Ruxolitinib could potentially reduce pro-inflammatory cytokine production, including interferon-g (IFN-g) and interleukins, such as IL-2, IL-6, IL-12, and IL-23 [9]. Due to Ruxolitinib’s anti-inflammatory and immunomo- dulatory properties, it is currently being assessed as a potentially curative option for severe COVID-19.

4.3. Clinical Effectiveness of Ruxolitinib in Patients with COVID-19

Acute Respiratory Distress Syndrome (ARDS), characterized by refractory hypoxemia, is a major complication in severe cases of COVID-19, affecting 20%-41% of hospitalized patients [10]. It can result in respiratory failure and death. Therefore, whether inhibition of Janus kinases could also reverse severe COVID infection and its associated ARDS became a major point of interest and area of research of several recently published clinical trials and studies on Ruxolitinib (Table 1). A trial conducted by Cao et al. described the results of a prospective, multicenter, single- blinded randomized phase II trial involving 43 patients with severe COVID-19, out of which 22 patients received 5 mg Ruxolitinib twice daily (b.i.d), and 21 were given a placebo based on the current standard of care. Numerically, patients treated with Ruxolitinib showed no significant chest computed tomography improvement (p = 0.495) and faster clinical recovery by day 14, with no mortality in the Ruxolitinib group and no new safety signals recorded [11].

La Rosée et al. [12] conducted a retrospective analysis of patients with severe COVID-19, stratifying them using COVID Inflammation Score (CIS), which involved chest X-ray, laboratory markers of inflammation, and coagulation profile as parameters to identify patients who would benefit from Ruxolitinib treatment. Out of 105 patients, 14 patients with CIS ≥ 10 out of 16 points received Ruxolitinib with a median dose of 7.5 mg b.i.d, resulting in 86% improvement in the clinical course, as indicated by a significant reduction in CIS by day 7 with sustained clinical improvement in 78% without Ruxolitinib-induced toxicity [12].

Likewise, Capochiani et al. [13] treated 18 critically ill patients with COVID-19 related progressive ARDS with 20 mg Ruxolitinib b.i.d for two days followed by a two-step dose de-escalation performed at 10 mg and 5 mg over two weeks. Following this treatment, 16 patients showed notable improvement in respiratory response within 48 hours and did not require mechanical ventilation, and by the end of 2 weeks, they had regained complete respiratory function with no fatalities [13]. Their study provided evidence that a short-term high dose initiating schedule can result in a faster and clinically more relevant response.

Age and associated comorbidities emerged as major risk factors for severe complications and deaths in individuals with COVID-19 [14]. A prospective observational study by Vannucchi et al. (2020) [15] described the compassionate use of Ruxolitinib in 34 patients with severe COVID-19 not requiring mechanical ventilation. The study included patients of advanced age (median age, 80.5 years) and high-risk comorbidities. They observed clinical improvements in 85.3% of patients after treatment with a median dose of 20 mg/day with a median exposure time of 13 days and an overall survival rate of 94.1% by 28 days [15]. Successful treatment with Ruxolitinib was also observed in a case of an elderly patient from a hospital in Germany who had severe COVID-19 associated ARDS requiring invasive ventilation [16].

A recent case report described a hematopoietic stem cell transplant recipient with concomitant chronic Graft Versus Host Disease (cGVHD) suffering from severe COVID-19 who showed clinical improvement after Ruxolitinib treatment and exhibited good tolerance [9]. A similar result was achieved in a 55-year-old man with myelofibrosis and significant comorbidities who developed COVID-19 and recovered without the need for mechanical ventilation [17]. Likewise, Rojas and Sarmiento from Chile reported 2 cases of severe COVID- 19, one with a history of acute lymphoblastic leukemia and the other with multiple myeloma, who responded well to Ruxolitinib 10 mg b.i.d, with repeat chest CT scan showing near-complete regression of the pulmonary infiltrates within a week and inflammatory markers normalizing within two weeks [18, 19].

Table 1
Published clinical trials on Ruxolitinib.

4.4. Side-effects of Ruxolitinib in COVID-19 Patients

Although the previous studies achieved satisfactory outcomes, few reports showed unexpected results. In a recent case report, two elderly patients with SARS-CoV-2 infection developed severe drug-induced cutaneous reactions and a rapid drop in hematocrit values after compassionate use of Ruxolitinib [20]. Cao et al. reported adverse events in two patients, where one developed transient hypertension while the other developed lymphopenia that improved without interrupting the drug [11]. Negative effects, such as polyomavirus-related fatal encephalopathy [21], meningitis [22], and the emergence of opportunistic infections [2], have also been observed.

4.5. Ruxolitinib’s Influence on SARS-CoV-2 Clearance

Recent research has suggested that dysregulation of the JAK-STAT pathway, particularly IL-6 blockade, is associated with viral persistence, as IL-6 contributes to host defense against infections required for viral clearance [23]. Notably, concerns have been raised about Ruxolitinib unfavorably slowing down viral clearance and production of the SARS- CoV-2 antibody due to its unknown mechanism of SARS-CoV-2 viral clearance. Nevertheless, Cao et al. reported that specific SARS-CoV-2 antibody production, virus clearance, and lymphocyte recovery were similar in both the treatment and control groups [11].

4.6. Clinical Trials

Preliminary research studies and case reports have demonstrated encouraging results that call for further controlled trials to clarify the role of Ruxolitinib in the treatment of COVID-19. Several questions remain to be addressed, including whether Ruxolitinib treatment shows efficacy in severely affected patients with ARDS on invasive ventilation (NCT04362137) and whether treatment with low dose Ruxolitinib (5 mg bid), when compared to placebo, is effective in preventing moderately affected patients from progression to severe/critical disease stages (NCT04362137). Moreover, it is unclear whether laboratory or combined clinical inflammation scores can be used to define optimal timing for initiating medical treatment, as proposed by a currently active trial using the newly developed COVID Inflammation Score (CIS) that is now prospectively being evaluated by the RuxCoFlam trial (NCT04338958). Five registered clinical trials (Table 2) are currently investigating the efficacy and/or safety of Ruxolitinib for COVID-19 (NCT04362137, NCT04414098, NCT04331665).

Table 2
Registered clinical trials to investigate the use of Ruxolitinib in COVID-19.

5. RESULTS

Various studies and clinical trials have provided evidence of the effectiveness of Ruxolitinib in COVID-19 patients, particularly patients within the age range of 30-80 (median age of 60), severe COVID-19 infection with ARDS and multiple comorbidities including hypertension, diabetes and cardiovascular disease. It was observed that treatment with Ruxolitinib resulted in faster improvement of respiratory function, reduction in mechanical ventilation usage and increased survival rate. This literature review provides an overview of such studies and their promising outcomes.

CONCLUSION

In conclusion, this literature review suggests that Ruxolitinib has the potential to overcome the therapeutic challenges of COVID-19 infection and the complications caused by immune hyperactivation related to the JAK/ STAT signaling pathway. From the discussion above, it is clear that Ruxolitinib showcases impressive clinical outcomes with a favorable side effect profile in patients with severe manifestations of COVID-19, especially in elderly patients with high-risk comorbidities. Overall, while the results are promising, larger controlled studies are urgently needed to confirm the possibility of treating COVID-19 with Ruxolitinib.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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Editor-in-Chief

Abdullah Shehab
Emirates Cardiac Society
Emirates Medical Association
Dubai
(United Arab Emirates)
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