Journal Information
Vol. 19. Issue 2.
Pages 120-121 (February 2023)
Vol. 19. Issue 2.
Pages 120-121 (February 2023)
Letter to the Editor
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Anakinra as a potential alternative in the treatment of severe acute respiratory infection associated with SARS-CoV-2 refractory to tocilizumab: comment
Anakinra, una alternativa potencial en el tratamiento de la infección respiratoria grave por SARS-CoV-2 refractaria a tocilizumab: comentario
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Ismael Francisco Aomar-Millána,
Corresponding author
iaomarmillan@hotmail.com

Corresponding author.
, Juan Salvatierrab, José Luis Callejas-Rubioa, Enrique Raya-Álvarezb
a Servicio de Medicina Interna, Hospital Clínico Universitario San Cecilio, Granada, Spain
b Servicio de Reumatología, Hospital Clínico Universitario San Cecilio, Granada, Spain
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Dear Editor,

We have read with interest the article by Figuero-Pérez et al. published in the last issue of your journal suggesting the usefulness of anakinra in severe respiratory SARS-CoV-2 infection refractory to tocilizumab1 and would like to make some observations.

The clinical course of SARS-CoV-2 infection has three distinct clinical phases2. In the initial phase there is viral replication with flu-like symptoms and then some patients progress, between day 6 and 13 of symptom onset, to a hyperinflammatory phase with the development of pneumonia that may progress to respiratory distress syndrome.

The pathogenesis of severe SARS-CoV-2 infection involves dysregulation of the immune response with lymphopenia, increased pro-inflammatory cytokines (IL-1, IL-2, IL-6, IL-7 or TNF alpha) and a decrease in gamma-interferon. This leads to a systemic inflammatory syndrome with elevated acute phase reactants such as C-reactive protein and ferritin3.

Treatment of this inflammatory phase with drugs such as dexamethasone or tocilizumab has been shown to reduce mortality4,5.

Anakinra, an IL-1 receptor antagonist, has recently obtained EMA approval for treatment in adult patients with COVID-19 pneumonia and risk of progression to severe respiratory failure based on the SAVE MORE clinical trial which demonstrated a reduction in 28-day mortality and hospital stay in those treated early with anakinra6.

There is little evidence regarding rescue therapy in patients with poor clinical outcome despite corticosteroids and/or immunomodulators. In an article published by our group7, we analysed 143 patients with moderate/severe SARS-CoV-2 pneumonia and hyperinflammation treated with various regimens based on the protocols of that date. We observed that in those who had not responded to corticosteroids with or without tocilizumab, treatment with anakinra could be a useful alternative. Our patients received 100mg/12h on day 1 if they weighed between 50 and 60kg, 100mg/8h between 60 and 75kg or 100mg/6h if they weighed >75kg. Subsequently all received 100mg/12h from day 2 to day 6. After adjustment for age and clinical severity indices, anakinra administration was associated with a reduced risk of mortality (HR; .518, 95% CI .265–.910, p=.0437).

In the case published by Figuero-Pérez et al.1 we consider that it cannot be suggested that the patient's clinical improvement was due to anakinra when a single dose of 100mg was administered. Given that the half-life of anakinra is 4−6h and that of tocilizumab around 6 days, it is likely that the patient’s improvement was due to the effect of tocilizumab. There is currently no consensus on the optimal doses of anakinra in this clinical setting, but higher and longer doses have been used in the literature8,9.

References
[1]
L. Figuero-Pérez, A. Olivares-Hernández, R.A. Escala-Cornejo, E. Terán-Brage, Á López-Gutiérrez, J.J. Cruz-Hernández.
Anakinra as a potential alternative in the treatment of severe acute respiratory infection associated with SARS-CoV-2 refractory to tocilizumab.
Reumatol Clin (Engl Ed), 17 (2021), pp. 559-561
[2]
D. Atri, H.K. Siddiqi, J.P. Lang, V. Nauffal, D.A. Morrow, E.A. Bohula.
COVID-19 for the cardiologist: basic virology, epidemiology, cardiac manifestations, and potential therapeutic strategies.
JACC Basic Transl Sci, 5 (2020), pp. 518-536
[3]
G. Cavalli, N. Farina, C. Campochiaro, G. De Luca, E. Della-Torre, et al.
Repurposing of biologic and targeted synthetic anti-rheumatic drugs in COVID-19 and hyper-inflammation: a comprehensive review of available and emerging evidence at the peak of the pandemic.
[4]
J. Villar, C. Ferrando, D. Martínez, A. Ambrós, T. Muñoz, et al.
Dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.
Lancet Respir Med, 8 (2020), pp. 267-276
[5]
RECOVERY Collaborative Group.
Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
Lancet, 397 (2021), pp. 1637-1645
[6]
E. Kyriazopoulou, G. Poulakou, H. Milionis, S. Metallidis, G. Adamis, et al.
Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.
Nat Med, 27 (2021), pp. 1752-1760
[7]
I.F. Aomar-Millán, J. Salvatierra, Ú Torres-Parejo, N. Faro-Miguez, J.L. Callejas-Rubio, et al.
Anakinra after treatment with corticosteroids alone or with tocilizumab in patients with severe COVID-19 pneumonia and moderate hyperinflammation. A retrospective cohort study.
Intern Emerg Med, 16 (2021), pp. 843-852
[8]
E. Pontali, S. Volpi, G. Antonucci, M. Castellaneta, D. Buzzi, et al.
Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease.
J Allergy Clin Immunol, 146 (2020), pp. 213-215
[9]
G. Cavalli, G. De Luca, C. Campochiaro, E. Della-Torre, M. Ripa, et al.
Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study.
Lancet Rheumatol, 2 (2020), pp. e325-e331

Please cite this article as: Aomar-Millán IF, Salvatierra J, Callejas-Rubio JL, Raya-Álvarez E. Anakinra, una alternativa potencial en el tratamiento de la infección respiratoria grave por SARS-CoV-2 refractaria a tocilizumab: comentario. Reumatol Clin. 2023;19:121.

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