Article Text

B-cell targeted therapy is associated with severe COVID-19 among patients with inflammatory arthritides: a 1-year multicentre study in 1116 successive patients receiving intravenous biologics
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  1. Renaud Felten1,2,
  2. Pierre-Marie Duret3,
  3. Elodie Bauer4,
  4. Nathanael Sedmak5,
  5. Julien H Djossou6,
  6. Massiva Bensalem1,
  7. Marc Ardizzone7,
  8. Marion Geoffroy8,
  9. Angelique Fan9,
  10. Marion Couderc9,
  11. Jean Hugues Salmon8,10,
  12. Laurent Messer3,
  13. Rose-Marie Javier1,
  14. Alain Meyer1,
  15. Emmanuel Chatelus1,
  16. Christelle Sordet1,
  17. Luc Pijnenburg1,
  18. Jérémy Fort1,
  19. Marina Rinagel1,
  20. Julia Walther11,
  21. Cassandre Fabre11,
  22. Laurent Arnaud1,
  23. Jean Sibilia1,
  24. Nicolas Meyer5,
  25. Francis Berenbaum6,12,
  26. isabelle Chary-Valckenaere4,
  27. Martin Soubrier9,
  28. Jérémie Sellam6,12,
  29. Jacques-Eric Gottenberg1,2
  1. 1Service de Rhumatologie, Centre National de Référence des Maladies Auto-immunes Systémiques Rares Est Sud-Ouest (RESO), Hôpitaux universitaires de Strasbourg, Strasbourg, France
  2. 2Laboratoire d’Immunopathologie et de Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR3572, IBMC, Strasbourg, France
  3. 3Service de Rhumatologie, Hôpital Pasteur, Colmar, France
  4. 4Service de Rhumatologie, Hôpitaux Universitaires de Nancy, Nancy, France
  5. 5Département de Santé Publique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  6. 6Service de Rhumatologie, Hôpital Saint-Antoine, Paris, France
  7. 7Service de Rhumatologie, Hôpital de Mulhouse, Mulhouse, France
  8. 8Service de Rhumatologie, Centre Hospitalier Universitaire de Reims, Reims, France
  9. 9Service de Rhumatologie, Hôpitaux Universitaires de Clermont-Ferrand, Clermont-Ferrand, France
  10. 10Faculté de Médicine, EA 3797, Reims, F-51095, Université de Reims Champagne-Ardenne, Reims, France
  11. 11Service de Pharmacie-Stérilisation, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  12. 12Inserm UMRS_938, Sorbonne Université, F-75012 Paris, France, FHU PaCeMM (Paris Center for Microbiome Medicine), APHP, Paris, France
  1. Correspondence to Dr Jacques-Eric Gottenberg, Service de rhumatologie, Centre National de Référence des Maladies Auto-immunes Systémiques Rares Est Sud-Ouest (RESO), Hôpitaux Universitaires de Strasbourg, Strasbourg, France; jacques-eric.gottenberg{at}chru-strasbourg.fr

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Dear Editor,

A potential association between rituximab and more severe COVID-19 outcomes has been previously raised, based on case reports, retrospective studies and mostly declarative registries.1–4 To further investigate this association, we focused on patients with inflammatory arthritides (IA) receiving intravenous biological agents at day hospitals to limit selection and recall bias, as well as missing data.

All patients with IA treated in day hospitals with intravenous biological agents (rituximab, abatacept, infliximab or tocilizumab) in seven clinical centres in France (Strasbourg, Colmar, Mulhouse, Nancy, Reims, Clermont-Ferrand and Saint-Antoine hospitals in Paris) were enrolled in the study. Data were collected from 1 September 2019 (5 months before the outbreak of the epidemic in France, so that all enrolled patients had been exposed to a biologic prior to the start of the epidemic) to 1 January 2021.3 In each centre, we obtained the list of all patients receiving intravenous biological agents from the hospital pharmacist. Therefore, all patients receiving one of the four drugs within the time frame of the study were enrolled in each centre. The occurrence of hospitalised COVID-19 was the primary outcome criterion, that is, SARS-CoV-2 presence confirmed by PCR and resulting in hospitalisation or death. Data were analysed with Bayesian methods in univariate and multivariate analyses using weakly informative prior (specifying that 0.05<ORx<20 a priori) or priors derived from recently published data.3 A prior distribution is a probability distribution that expresses what is already known on the parameter of interest, such as the OR, through either theoretical consideration and/or past observations, and is a fundamental part of Bayesian methods and inference. Using a prior distribution allows decreasing, at least partially, concerns about the potential lack of statistical power. In order to ensure that any difference in risk with rituximab was not primarily due to baseline differences between rituximab and other biological groups, we performed multivariate analyses accounting for risk factors of severe COVID-19 based on literature.

A total of 1116 patients receiving intravenous biological agents were enrolled: 449 with infliximab, 392 with rituximab, 170 with tocilizumab and 105 with abatacept. Ten cases of severe COVID-19 occurred: 9 in patients treated with rituximab (2.3% of total patients treated with rituximab) and 1 in a patient treated with infliximab (0.1% of patients treated with biological agents other than rituximab, 0.2% of patients treated with infliximab) (table 1 and online supplemental table 2). Four deaths occurred during follow-up, but none were related to COVID-19 (a dialysed 50-year-old man treated with tocilizumab for systemic sclerosis who developed a serious non-COVID infection, an 86-year-old woman treated with rituximab for rheumatoid arthritis, who developed a serious pulmonary bacterial infection; and a 62-year-old woman and a 70-year-old man treated with infliximab for psoriatic arthritis, who died of unexplained sudden death). In univariate analysis, the proportion of hospitalised COVID-19 was higher for patients receiving rituximab than other biological agents (9/392 vs 1/724, OR=8.5, 95% credibility interval (CrI) 2.6 to 38.6, Pr (OR >1)≈1; tables 1 and 2). Rituximab remained the only factor associated with risk of hospitalised COVID-19 (OR 7.7, 95% CrI 1.7 to 44.7) in multivariate analyses (table 1). In patients with hospitalised COVID-19 (online supplemental table 1), the median delay from last infusion to infection was 3.5 months (IQR 1.8–5.0). One patient was admitted to intensive care. The sensitivity analysis, in patients with moderate-to-severe and critical COVID-19 (ie, individuals who had SpO2 <94% on room air at sea level and who required oxygen), yielded the same results as the main analysis in patients with hospitalised COVID-19 (online supplemental table 2).

Table 1

Univariate and multivariate models assessing the association between the occurrence of hospitalised COVID-19 and each variable

Table 2

Informative prior used in multivariate analysis Model #2

The present work joins previous studies to confirm the risk of B-cell depletion with regard to the development of hospitalised and severe COVID-19.1–3 Of note, the low number of events and the number of covariates limit the robustness of the statistical analysis, which might explain that classical risk factors such as age, sex, comorbidities, body mass index and corticosteroids were not associated with severe COVID-19 in the present study. In addition, the present study is the first to provide a prevalence of severe SARS-CoV-2 infection in a cohort which includes the totality of patients receiving intravenous biological treatment. In this study, approximately 2% of rituximab-treated patients developed hospitalised COVID-19, compared with only one patient (0.1%) among those treated with infliximab, tocilizumab or abatacept.

These results strongly indicate the increased risk of severe COVID-19 in patients receiving B-cell targeted therapy. Among patients with IA, those receiving rituximab should be prioritised for vaccination against SARS-CoV-2, sufficiently in advance of treatment infusion/reinfusion.

Ethics statements

Patient consent for publication

Ethics approval

The study was authorised by the Hôpitaux Universitaires de Strasbourg Ethical Committee (#CE-2020–210) and informed consent was obtained from patients.

Acknowledgments

We thank the pharmacists at each centre for providing us with a complete list of patients, and in particular Dr Karine Demesmay from Colmar.

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @larhumato

  • Contributors All authors contributed to the concept, design and drafting of the study and approved the final version.

  • 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.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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