Rheumatoid arthritis drug baricitinib linked to decreased mortality in COVID-19 patients

November 13, 2020 – The rheumatoid arthritis drug baricitinib may block virus entry and lower mortality in patients with moderate to severe COVID-19. This is the result of translational studies by an international team coordinated by researchers from the Karolinska Institutet in Sweden. The results published in the journal Advances in sciencesupport the continuation of ongoing randomized clinical trials.

“We are pleased that the group that receives baricitinib in addition to standard care can reduce mortality by 71 percent,” says Volker Lauschke, corresponding author and associate professor for personalized medicine and drug development at the Institute of Physiology and Pharmacology at the Karolinska Institutet. “These results are particularly encouraging as the study included a large cohort of elderly patients, a group that is often excluded in other studies.”

In the study, 83 patients with COVID-19 pneumonia in Italy and Spain were treated with baricitinib in addition to standard care. Of these, 17 percent experienced an undesirable outcome that resulted in death or invasive mechanical ventilation. This compared to 35 percent in the matching control group of 83 patients who received only standard care. The patients had an average age of 81 years.

Well tolerated

The drug was generally well tolerated, according to the researchers, and reduced inflammation from the first few days of treatment. Previously reported side effects from long-term use of baricitinib, including coagulopathy and thrombosis, were not apparent in any of the patients, possibly due to treatment with anticoagulants. However, some adverse events were noted, including bacterial infections and gastrointestinal and cardiovascular complications, although these were also observed in the control group, so it is unclear what, if any, can be attributed to baricitinib.

In a previous study, the same research team reported how they used artificial intelligence (AI) to identify baricitinib as a promising candidate for COVID-19 reuse. This study also showed how the drug inhibited inflammation and reduced the viral load of SARS-CoV-2.

3D Mini Lebern

In the current study, the researchers elaborated these results by showing that interferons, cytokines made and released by host cells in response to viruses, inhibited the expression of the ACE2 receptor, which acts as the entry point for SARS-CoV-2 , significantly increase human cells. While liver damage is often observed in severe COVID-19, the mechanisms and dynamics of SARS-CoV-2 infections in this organ have not been investigated.

By combining 3D mini-organs from human liver cells, RNA sequencing and high-resolution microscopy, the scientists were able to show that barcitinib reversed the changes in ACE2 gene expression triggered by interferons and reduced SARS-CoV-2 infectivity. Interestingly, interferons did not have the same effect on the ACE2 receptor in lung organoids, suggesting that these signaling proteins affect lung and liver organs differently.

Duplicate actions

“Our results explain the dual anticytokinic and antiviral effects of baricitinib and support further evaluation in randomized controlled studies,” says Ali Mirazimi, associate professor at the Department of Laboratory Medicine at the Karolinska Institutet and co-author of the study.

The researchers note that one limitation of the study was the lack of a placebo control group, which is included in randomized controlled trials currently sponsored by the industry.

The clinical study was led by researchers from Imperial College London, UK, Complejo Hospitalario Universitario de Albacete, Spain and the University of Pisa, Italy, while the mechanistic studies on 3D models of human tissue were carried out at Karolinska Institutet.

The research was funded by the Swedish Research Council, the Strategic Research Programs for Diabetes and Stem Cells and Regenerative Medicine, the Innovative Medicines Initiative EU / EFPIA / OICR / McGill / KTH / Diamant, Ricerca Corrente Linea 1 and 3, the National Science Foundation. the National Health Institutes, the Ministry of Energy, CIBERFES, the Instituto de Salud Carlos III, the Ministerio de Economía y Competitividad, España. Ayuda cofinanciada por el Fondo Europeo de Desarrollo Regional FEDER Una Manera de hacer Europa, Imperial BRC, ECMC, NIHR and AAC.

The paper’s authors have reported several conflicts of interest, including lecture fees and research grants from pharmaceutical companies that own baricitinib. Some of the authors have founded companies that have the technologies mentioned in this study. For a full list of specs, see the full article.

Facts about baricitinib

• Baricitinib is a once-daily oral medication used to treat adult patients with moderate to severe rheumatoid arthritis.
• It acts as an inhibitor of Janus kinase, a type of enzyme that acts as an “on” or “off” switch in many cellular functions.
• The drug has two functions and acts by disrupting the inflammatory processes of the immune system, as well as by directly inhibiting the entry of the virus. It is viewed as a potential treatment candidate for COVID-19.

publication: „Die JAK-Hemmung verringert die Infektiosität der SARS-CoV-2-Leber und moduliert Entzündungsreaktionen, um Morbidität und Mortalität zu verringern“, Justin Stebbing, Ginés Sánchez Nievas, Marco Falcone, Sonia Youhanna, Peter Richardson, Silvia Ottaviani, Joanne Shen, Christian Sommerauer, Giusy Tiseo, Lorenzo Ghiadoni, Agostino Virdis, Fabio Monzani, Luis Romero Rizos, Francesco Forfori, Almudena Avendaño Céspedes, Salvatore De Marco, Laura Carrozzi, Fabio Lena, Pedro Manuel Sánchez-Jurado, Leonardo Gianluca Lacerenza, Nencion Antonio Perrella, Laura Niccoli, Lourdes Sáez Méndez, Daniela Matarrese, Delia Goletti, Yee-Joo Tan, Vanessa Monteil, George Dranitsaris, Fabrizio Cantini, Alessio Farcomeni, Shuchismita Dutta, Stephen K. Burley, Haibo Zhang, Mauro Pistello, William Li, Marta Mas Romero, Fernando Andrés Pretel, Rafaela Sánchez Simón-Talero, Rafael García-Molina, Claudia Kutter, James H. Felce, Zehra F. Nizami, Andras G. Miklosi, Josef M. Penninger, Francesco Meni Chetti, Ali Mirazimi, Pedro Abizanda and Volker M. Lauschke, Science Advances, online, 13. November 2020, doi: 10.1126 / sciadv.abe4724

For further information please contact:
Volker M. Lauschke, associate professor
Department of Physiology and Pharmacology, Karolinska Institutet
Phone: +46 (0) 8 524 87711
E-mail: [email protected]

Ali Mirazimi, Associate Professor
Clinic for Laboratory Medicine, Karolinska Institutet
Phone: +46 (0) 70-367 25 73
E-mail: [email protected]

The Karolinska Institutet is one of the world’s leading medical universities. Our vision is to expand knowledge about life and strive for better health for all. Karolinska Institutet accounts for the largest share of all academic medical research carried out in Sweden and offers the broadest range of education in medicine and health sciences in the country. The Nobel Assembly at the Karolinska Institutet selects the Nobel Prize winners in Physiology or Medicine.