Tocilizumab in Treatment for Patients With COVID-19—Reply | JAMA Internal Medicine | JAMA Network
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Comment & Response
April 5, 2021

Tocilizumab in Treatment for Patients With COVID-19—Reply

Author Affiliations
  • 1Department of hematology, Université de Paris, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker, INSERM, Imagine Institute, Paris, France
  • 2Department of Rheumatology, Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, INSERM, Le Kremlin Bicêtre, France
  • 3Centre of Research in Epidemiology and Statistics (CRESS), Université de Paris, INSERM, INRAE, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Hôtel-Dieu, Paris, France
JAMA Intern Med. 2021;181(7):1020-1021. doi:10.1001/jamainternmed.2021.0407

In Reply We thank the authors of these letters for their interest in the important topic of patients hospitalized with pneumonia and COVID-19.1 First, in all letters, the authors claim that tocilizumab (TCZ) is not effective or is poorly effective in patients hospitalized with COVID-19. Among the 4 published randomized clinical trials of TCZ in patients hospitalized and not requiring assisted ventilation, 2 are positive and 2 are negative.1-4 These apparent contrasting results may be explained by differences in study populations. In the trials by Stone et al2 and Salvarani et al3 (the negative trials), numbers of patients received no supplemental oxygen at baseline and the 28-day mortality rate was low (4.9%2 and 2.4%3), vs 11.5% and 9.8% in our trial1 and that of Salama et al4 (the positive trials), respectively. In addition, in the study by Salvarani et al,3 23% of the patients in the usual care arm received TCZ as a rescue. Of note, the 2 positive randomized clinical trials included identical patients (with oxygen requirement) and showed similar results on their primary end points (ventilation or death), with hazard ratios of 0.58 (95% CI, 0.33-1.00)1 and 0.55 (95% CI, 0.33-0.93),4 respectively. Although not yet peer reviewed, the REMAP-CAP randomized clinical trial5 showed that TCZ reduced organ support-free days and decreased mortality from 35.8% to 28% (odds ratio = 1.64; 95% CI, 1.25-2.14) in patients who were critically ill. Taken together, these data suggest that TCZ could be beneficial to prevent ventilation or death in the population of patients with more severe cases of COVID-19.

Second, in their comments, Yang and Liu and Rossi et al suggest that the effects of TCZ should be amplified by using either a lower or a higher dose, respectively. We agree with Rossi et al when they point out partial inhibition of C-reactive protein production in our control group, whereas a rapid decrease of C-reactive protein, as soon as day 4, was observed in the TCZ group. In most of the studies, patients could receive a second dose of TCZ in case of no response (half of the patients in our study1), which did not seem to increase toxic effects, particularly the risk of bacterial infections, which was actually reduced in most studies.1-4 Thus, the question of using higher doses might be raised. However, due to the complexity of the cytokine network, as suggested by Bell and Pollara, treatment combinations, and mainly TCZ plus dexamethasone, should be considered in these patients with severe disease, and in this context the infectious risk could be an issue.

In conclusion, we agree that the question of the dose is an important issue and could be solved by a more precise monitoring of serum C-reactive protein, interleukin-6, and interleukin-6 receptor levels. The 2 other important issues for defining the role of TCZ in treatment of COVID-19 are the type of patients who may benefit from this drug (probably patients worsening on oxygen or just entering an intensive care unit) and the evaluation of longer-term survival. Ongoing meta-analyses should respond to these questions.

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Article Information

Corresponding Author: Olivier Hermine, MD, PhD, Université de Paris, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker, INSERM, Imagine Institute, 24 Boulevard Montparnasse, Paris, France (ohermine@gmail.com).

Published Online: April 5, 2021. doi:10.1001/jamainternmed.2021.0407

Conflict of Interest Disclosures: None reported.

References
1.
Hermine  O, Mariette  X, Tharaux  PL, Resche-Rigon  M, Porcher  R, Ravaud  P; CORIMUNO-19 Collaborative Group.  Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial.   JAMA Intern Med. 2021;181(1):32-40. doi:10.1001/jamainternmed.2020.6820 PubMedGoogle ScholarCrossref
2.
Stone  JH, Frigault  MJ, Serling-Boyd  NJ,  et al; BACC Bay Tocilizumab Trial Investigators.  Efficacy of tocilizumab in patients hospitalized with Covid-19.   N Engl J Med. 2020;383(24):2333-2344. doi:10.1056/NEJMoa2028836 PubMedGoogle ScholarCrossref
3.
Salvarani  C, Dolci  G, Massari  M,  et al; RCT-TCZ-COVID-19 Study Group.  Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial.   JAMA Intern Med. 2021;181(1):24-31. doi:10.1001/jamainternmed.2020.6615PubMedGoogle ScholarCrossref
4.
Salama  C, Han  J, Yau  L,  et al.  Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia.   N Engl J Med. 2021;384(1):20-30. doi:10.1056/NEJMoa2030340PubMedGoogle ScholarCrossref
5.
The REMAP-CAP investigators et al.  Interleukin-6 receptor antagonists in criticially ill patients with Covid-19—preliminary results.   medRxiv 2021:2021.01.07.21249390.Google Scholar
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