A small observational study on use of Anakinra, the rheumatoid arthritis drug, to treat COVID-19 patients found that high-dose Anakinra was safe and was associated with respiratory improvements and reduced signs of cytokine storm in 72% (21/29) of patients, The Lancet Rheumatology journal reported on May 7, 2020.
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Cytokine storm is an overreaction of the body’s immune system and it may be fatal to the patient. Many different cells in the body including those of the immune system release cytokines which are small proteins. For instance, when the virus behind COVID-19 enters the lungs, immune cells attack them causing a localised inflammation. The immune systems of some patients release cytokines uncontrollably causing “cytokine storms”. It is disastrous as it leads to activation of more immune cells causing hyper-inflammation. It may harm the patient.
Overactive immune cells may attack healthy tissues such as blood vessels causing leaks, fall in blood pressure and accumulation of fluid in lungs. They may also attack many organs leading to their failure. During the storm, blood levels of the protein –ferritin- and the inflammation indicator- C-reactive protein, which is made by the liver increase. Anakinra can quieten the storm.
The study and its results
In the present study, 29 patients with COVID-19, acute respiratory distress syndrome and hyper-inflammation received standard care (of non-invasive ventilation (CPAP), hydroxychloroquine, and lopinavir/ritonavir) as well as the drug treatment (daily high-dose intravenous infusions of Anakinra at 10 mg/kg bodyweight). Sixteen patients received standard care only.
At 21 days, treatment with high-dose Anakinra was associated with progressive improvements in respiratory function in 21 (72%) of 29 patients. Ninety percent of patients (26 out of 29) survived. Five of 29 patients (17%) needed mechanical ventilation.
Most of the 16 patients who received standard treatment before the start of the study (between March 10 and 17), experienced persistent or recurrent increases in C-reactive protein. Respiratory function improved for half of the patients (8 patients, 50%), and 56% (nine of 16) survived. One patient received mechanical ventilation (6%).
The researchers conceded that the study was not a randomised controlled trial, which is the gold standard for establishing the effectiveness of a treatment.
Currently, management of COVID-19 is supportive, and the main cause of death is respiratory failure from acute respiratory distress syndrome (ARDS).
Prof. Lorenzo Dagna, head of the Unit of Immunology, Rheumatology, Allergy and Rare Diseases at San Raffaele Hospital and Vita-Salute San Raffaele University, Italy said:
“Until a vaccine is available, we urgently need to find a way to help people survive the most severe symptoms of COVID-19, and to do that without overwhelming the intensive care capacity of hospitals. A treatment that has already met strict safety tests and that is available in sufficient quantities to meet the needs of the current pandemic is ideal.”
According to Dr. Giulio Cavalli, from the Unit of Immunology, Rheumatology, Allergy and Rare Diseases at San Raffaele Hospital and Vita-Salute San Raffaele University, Italy, their study is the first to suggest that a high dose of the arthritis drug Anakinra may be able to block the overreaction of the immune system caused by COVID-19.
The US Food and Drug Administration and the European Medicines Agency have already approved the drug Anakinra to treat rheumatoid arthritis, Still’s disease, and recurrent fever. Anakinra works by blocking the pro-inflammatory cytokine IL-1.
A Viewpoint piece, also published in The Lancet Rheumatology earlier this week, explained why intravenous Anakinra might be effective and safe in treating cytokine storm syndromes generally. Anakinra, compared with other cytokine-blocking agents is suitable for critically ill patients, as it has a strong safety record and a short half-life.
High-dose Anakinra was generally safe. Among adverse effects, four patients (14%) in the high-dose Anakinra group had bacteraemia (bacteria in the blood), compared to two patients (13%) in the standard treatment group. Discontinuation of Anakinra was not followed by inflammatory relapses.
- Causes of death in patients receiving high-dose intravenous Anakinra were pulmonary thromboembolism, respiratory insufficiency, and multiorgan failure (1 patient per cause of death)
- Causes of death in the comparison group were respiratory insufficiency (3 patients), multiorgan failure (3 patients), and pulmonary thromboembolism (1 patient)
Further study of Anakinra
The researchers concluded that their study, together with pre-existing evidence of the efficacy and safety of Anakinra in patients with hyperinflammatory syndromes, suggests that Anakinra deserves consideration and controlled testing for the treatment of COVID-19.
The Lead author Dr. Scott Canna (who was not involved in the study) from the University of Pittsburgh Medical Center, USA, concurred in a linked comment:
“In view of the biological plausibility of Anakinra, the pharmacokinetic and safety profile of the drug, and a growing body of positive experience in auto-inflammation and cytokine storm, these data are promising and support prioritising this approach in the planning and enrolment of randomised controlled trials.”
The study did not impress experts at the Science Media Centre.
Prof. John R Kirwan, Emeritus Professor of Rheumatic Diseases, University of Bristol, stated:
“This is a rapid study undertaken in unusual circumstances and to gain a quick impression about whether this anti-arthritis treatment might be beneficial in seriously ill patients for whom there is currently no treatment.”
“It looks like the patients getting the treatment had a slightly better outcome – but they were also (on average) 8 years younger, and this could just as easily have been the explanation.”
Problems with interpreting the findings
Prof. Kevin McConway, Emeritus Professor of Applied Statistics, The Open University found that this paper is interesting. However he asserted that there are problems with interpreting its findings.
“First, it is observational, and not a proper randomised controlled clinical trial. Although there are comparisons between the course of the disease in patients who did and did not receive high-dose Anakinra, the treatment that they received depended on when they went to the hospital where the research was done. The patients who were given Anakinra arrived later than the others. So there might have been differences in some characteristics of the patients, or in the way they were treated in hospital, apart from the Anakinra treatment, and we can’t rule out that such differences might have explained, in whole or in part, any differences in the outcomes of treatment between the two groups.”
According to him another drawback is that the researchers carried out the study in just one hospital.
“It’s possible that the beneficial effects of Anakinra, that were observed, would not appear in another place, or might even be greater in another place, because of differences in other aspects of treatment”, he cautioned.
“Finally, it’s worth mentioning that not all the results from this small study were positive for Anakinra anyway. Patients on Anakinra had a higher survival rate than those who did not have Anakinra, and that difference was statistically significant. However, differences in the need for mechanical ventilation were not statistically significant; one might have hoped that patients on Anakinra would do better on that outcome too, but they did not.” he clarified
“We really won’t have a very good idea of how effective (or otherwise) Anakinra might be without a randomised trial, and the research paper points out that one is already going on. It is being run in several locations in Italy. But results from that trial will take time to become available. Currently, the researchers on that trial estimate that the data will not all have been completed until September 2020 and it will doubtless take some time after that to evaluate and analyse those data properly.” he concluded.
Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
Dr K S Parthasarathy is a freelance science journalist and a former Secretary of the Atomic Energy Regulatory Board. He is available at email@example.com