May 7, 2020

expert reaction to study looking at use of arthritis drug anakinra in hospitalised patients with severe COVID-19

A study, published in The Lancet Rheumatology, looks at the use of arthritis drug anakinra to treat hospitalised patients with severe COVID-19.

Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:

“This publication describes a small case series (N=29) of COVID-19 affected hospitalised patients treated with intravenous anakinra in addition to standard of care in a single centre in Italy in March 2020.  The authors contrast the outcomes from these patients, all of whom had evidence of inflammation, to the outcomes in 16 patients in a similar condition treated in the same hospital prior to the time at which anakinra was included among the treatments given.

“Although there was a higher proportion of people (5/29 17%) in the anakinra group that were mechanically ventilated on day 21 (compared to 1/16 in the standard treatment group), the mechanical ventilator free survival was higher (72%) in the anakinra group than among patients that were given standard treatment (50%).  In addition mortality was 3/29 (10%) among anakinra recipients compared to 7/16 (44%) of the standard treatment recipient group.

“Inflammatory responses to COVID-19 infection carry a high risk of complications and death and the use of medicines which control inflammation is logical.  Many different treatments are available to do this including anti TNF antibodies, anti IL-6 antibodies and an anti-INF gamma antibody.  These agents are used to treat a range of inflammatory diseases, particularly in children, and any may be effective in controlling the ‘cytokine storm’ which occurs in some patients with COVID-19.  The danger with these drugs is the risk of secondary bacterial infection and sepsis, which can also be lethal in COVID-19 patients, so the potential benefits might be offset by harm due to secondary infections.  This is why these treatments need to be carefully studied in randomised controlled trials, so we can properly judge the benefits and risks of the treatments before bringing them into widescale use.

Does the press release accurately reflect the research?

“Yes.

Is this good quality research?  Are the conclusions backed up by solid data?

“The paper describes a case series of COVID-19 patients treated with anti-inflammatory therapy.  The outcome is compared to a ‘historical’ population treated in the same centre prior to the start of the study.

How does this work fit with the existing evidence?

“A number of studies are being conducted looking at anakinra in COVID-19 but none have reported data to date.

Have the authors accounted for confounders?  Are there important limitations to be aware of?

“The case series group were more likely to be female and were generally younger than the control population and fewer of these patients had chronic diseases known to increase risk of severe COVID-19/death.  As a result, there is a possibility that the favourable results might have been due to population differences rather than to the use of anakinra.

What are the implications in the real world?  Is there any overspeculation?

“The use of anti cytokine treatment to control inflammation in COVID-19 is logical.  However without randomised studies we cannot be sure whether outcomes reported are indeed improved.  Randomised trials are ongoing and results are eagerly awaited.”

Prof John R Kirwan, Emeritus Professor of Rheumatic Diseases, University of Bristol, said:

“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.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This paper is interesting, but there are problems with interpreting its findings.  That’s for several reasons.  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.

“It is also relevant that the study was carried out 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.

“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.

“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.”

‘Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study’ by Giulio Cavalli et al. was published in The Lancet Rheumatology at 23:30 UK time on Thursday 7 May 2020.

DOI: 10.1016/S2665-9913(20)30127-2

Declared interests

Dr Penny Ward: “Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”

Prof John R Kirwan: “No conflicts of interest to declare.”

Prof Kevin McConway: “Prof McConway is a member of the SMC Advisory Committee, but his quote above is in his capacity as a professional statistician.”