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Antirheumatic agents in covid-19: is IL-6 the right target?
  1. Pier Leopoldo Capecchi1,
  2. Pietro Enea Lazzerini1,
  3. Luca Volterrani2,
  4. Maria Antonietta Mazzei2,
  5. Barbara Rossetti3,
  6. Giacomo Zanelli4,
  7. David Bennett5,
  8. Elena Bargagli6,
  9. Federico Franchi7,
  10. Matteo Cameli8,
  11. Serafina Valente9,
  12. Luca Cantarini10,
  13. Bruno Frediani10
  1. 1 Department of Medical Sciences, Surgery and Neurosciences, Section of Internal Medicine, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  2. 2 Department of Medical Sciences, Surgery and Neurosciences, Section of Radiology, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  3. 3 Section of Infectious Diseases, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  4. 4 Department of Medical Biotechnologies, Section of Infectious Diseases, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  5. 5 Section of Pneumology, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  6. 6 Department of Medical Sciences, Surgery and Neurosciences, Section of Pneumology, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  7. 7 Department of Medical Sciences, Surgery and Neurosciences, Section of Intensive Care, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  8. 8 Department of Medical Biotechnologies, Section of Cardiology, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  9. 9 Section of Cardiology, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  10. 10 Department of Medical Sciences, Surgery and Neurosciences, Section of Rheumatology, COVID-19 Unit, Siena University Hospital, Siena, Toscana, Italy
  1. Correspondence to Professor Pier Leopoldo Capecchi, Department of Medical Sciences Surgery and Neurosciences, Section of Internal Medicine, COVID-19 Unit, Siena University Hospital, Siena 53100, Italy; capecchipl{at}unisi.it

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The letter of Monti et al 1 on covid-19 in patients with chronic arthritis treated with immunosuppressive therapies stimulates some considerations.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects cells through the ACE-2 receptor, which is highly expressed in both the lung and the heart. Besides direct tissue injury, SARS-CoV-2 infection can also induce an exaggerated host immune response, frequently inducing a cytokine release syndrome contributing to multiorgan dysfunction. Indeed, high levels of circulating cytokines, particularly interleukin (IL)-6, IL-1β and tumour necrosis factor-alpha (TNFα), are commonly found in patients with covid-19, correlating with mortality (IL-6).2

Current therapeutic strategy involves agents counteracting viral invasion and replication, and inhibitors of cytokine-sustained inflammatory reactions. Indeed, different cytokines involved in the acute inflammatory response are currently targeted by specific medications otherwise employed in the treatment of rheumatic diseases. Agents inhibiting the activity of IL-1β, TNFα, IL-6 and the Janus Kinase 1 and 2 (JAK 1/2)-Signal Transducer and Activator of Transcription (STAT) pathway are currently under consideration in the treatment of covid-19-associated respiratory syndrome.3

We are here providing some arguments to help achieve a more rational therapeutic decision. In any case, as a general consideration, the short-term period of administration of these agents is unlikely to produce a significant immunosuppressive activity.

Acute inflammatory response to infective agents is mainly driven by innate immunity, with a rapid (30 min) increase in TNFα and IL-1β levels synergistically contributing to a subsequent rise of IL-6, which in turn inhibits TNFα and IL-1β release. Higher IL-6 levels are longer lasting, while TNFα and IL-1β levels rapidly (24–48 hours) decrease.4 Thus, the therapeutic window for anti-TNFα and anti-IL-1β agents is very narrow. As a consequence, before the administration of agents targeting specific cytokines, serum levels of these cytokines should be obtained. Further considerations arise from data from chest X-ray or CT. Consolidation pattern, often present in covid-19, recalls organising pneumonia,5 which is associated with a cytokine profile characterised by a major involvement of IL-6, rather than TNFα and IL-1β. Accordingly, the IL-6 receptor antagonist tocilizumab was effective in the treatment of refractory organising pneumonia associated with Sjögren’s disease.

Cardiovascular manifestations are also common in covid-19 infection, with a percentage of arrhythmias up to 16.7% and with 5.9% of malignant ventricular tachyarrhythmias also associated with QTc interval prolongation induced by medications and electrolyte derangement. In this regard, systemic inflammation via elevated IL-6, but not TNFα and IL-1β serum levels, has been shown to represent a novel QT-prolonging risk factor contributing to torsade de pointes occurrence in the presence of other risk factors.6

Accordingly, it seems of relevance to stress that in rheumatoid arthritis, where the arrhythmic risk is increased often leading to sudden cardiac death and levels of circulating inflammatory cytokines correlate with QTc duration, IL-6 receptor blockade by tocilizumab promptly induced a significant QTc shortening correlating with the decrease in C reactive protein and cytokine levels.6 Moreover, a single administration of the drug in subjects with non-ST-elevation myocardial infarction reduced inflammatory response and myocardial injury, with no safety issues (including infections) in the following 6 months.

In light of these considerations, pharmacological interference on the IL-6 system, either by blocking the IL-6 receptor (tocilizumab, sarilumab) or inhibiting the JAK 1/2-STAT pathway (baricitinib, ruxolitinib), should find a more rational indication in dampening the systemic inflammatory response in covid-19, not only to control lung involvement, but also to reduce acute cardiovascular complications, including QT-related arrhythmic events.

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Footnotes

  • Contributors PLC: conception and design of the work, acquisition, analysis or interpretation of data, drafting the work, final approval of the version published, agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. PEL: substantial contribution to the conception or design of the work and revising the manuscript critically for important intellectual content, final approval of the version published. LV, MAM: substantial contribution to the part of the work involving X-ray and revising the manuscript critically for important intellectual content, final approval of the version published. BR, GZ: substantial contribution to the part of the work involving virus infection and revising the manuscript critically for important intellectual content, final approval of the version published. DB, EB: substantial contribution to the part of the work involving lung injury and revising the manuscript critically for important intellectual content, final approval of the version published. FF: substantial contribution to the part of the work involving intensive care and revising the manuscript critically for important intellectual content, final approval of the version published. MC, SV: substantial contribution to the part of the work involving heart damage and revising the manuscript critically for important intellectual content, final approval of the version published. LC: substantial contribution to the part of the work involving antirheumatic agents and revising the manuscript critically for important intellectual content, final approval of the version published. BF: substantial contribution to the conception of the work and to the part of the work involving antirheumatic agents and revising the manuscript critically for important intellectual content, final approval of the version published. The authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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