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  1. L. Boekel1,
  2. E. Stalman2,
  3. L. Wieske2,
  4. F. Hooijberg1,
  5. Y. Besten1,
  6. M. Leeuw1,
  7. S. Atiqi1,
  8. L. Kummer3,
  9. K. van Dam2,
  10. M. Steenhuis3,
  11. Z. van Kempen4,
  12. J. Killestein4,
  13. W. Lems1,5,
  14. S. Tas5,
  15. R. van Vollenhoven5,
  16. M. Nurmohamed1,5,
  17. M. Boers1,6,
  18. M. van Ham3,
  19. T. Rispens3,
  20. T. Kuijpers7,
  21. F. Eftimov4,
  22. G. J. Wolbink1,5
  23. on behalf of The T2B! immunity against SARS-CoV-2 study group
  1. 1Reade, Locatie Dr. Jan Van Breemenstraat, Rheumatology, Amsterdam, Netherlands
  2. 2Amsterdam UMC, locatie AMC, Neurology and Neurophysiology, Amsterdam, Netherlands
  3. 3Sanquin Research and Landsteiner Laboratory, Immunopathology, Amsterdam, Netherlands
  4. 4Amsterdam UMC, locatie VUmc, Neurology, Amsterdam, Netherlands
  5. 5Amsterdam Rheumatology and immunology Center, Rheumatology and Clinical Immunology, Amsterdam, Netherlands
  6. 6Amsterdam UMC, locatie VUmc, Epidemiology and Data Science, Amsterdam, Netherlands
  7. 7Amsterdam UMC, locatie AMC, Pediatric immunology, Amsterdam, Netherlands


Background Concerns have been raised regarding risks of COVID-19 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases (IMIDs) treated with immunosuppressants, but data on COVID-19 breakthrough infections in these patients are still scarce.

Objectives The primary objective was to compare the incidence and severity of COVID-19 breakthrough infections with the SARS-CoV-2 delta variant between fully vaccinated IMID patients with immunosuppressants, and controls (IMID patients without immunosuppressants and healthy controls). The secondary objective was to explore determinants of breakthrough infections.

Methods In this study we pooled data collected from two large ongoing prospective multi-center cohort studies (Target to-B! [T2B!] study and ARC study). Clinical data were collected between February and December 2021, using digital questionnaires, standardized electronic case record forms and medical files. Post-vaccination serum samples were analyzed for anti-RBD antibodies (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC study only). Logistic regression analyses were used to assess associations with the incidence of breakthrough infections. Multivariable models were adjusted for age, sex, cardiovascular disease, chronic pulmonary disease, obesity and vaccine type.

Results We included 3207 IMID patients with immunosuppressants and 1810 controls (985 IMID patients without immunosuppressants and 825 healthy controls). The incidence of COVID-19 breakthrough infections was comparable between patients with immunosuppressants (5%) and controls (5%). The absence of SARS-CoV-2 IgG antibodies after COVID-19 vaccination was independently associated with an increased incidence of breakthrough infections (P 0.044). The proportion of asymptomatic COVID-19 breakthrough cases that were additionally identified serologically in the ARC cohort was comparable between IMID patients with immunosuppressants and controls; 66 (10%) of 695 patients vs. 64 (10%) of 647 controls. Hospitalization was required in 8 (5%) of 149 IMID patients with immunosuppressants and 5 (6%) of 86 controls with a COVID-19 breakthrough infection. Hospitalized cases were generally older, and had more comorbidities compared with non-hospitalized cases (Table 1). Hospitalization rates were significantly higher among IMID patients treated with anti-CD20 therapy compared to IMID patients using any other immunosuppressant (3 [23%] of 13 patients vs. 5 [4%] of 128 patients, P 0.041; Table 1).

Table 1.

Determinants of the severity of COVID-19 breakthrough infections.

Conclusion The incidence of COVID-19 breakthrough infections in IMID patients with immunosuppressants was comparable to controls, and infections were mostly mild. Anti-CD20 therapy might increase patients’ susceptibility to severe COVID-19 breakthrough infections, but traditional risk factors also continue to have a critical contribution to the disease course of COVID-19. Therefore, we argue that most patients with IMIDs should not necessarily be seen as a risk group for severe COVID-19, and that integrating other risk factors should become standard practice when discussing treatment options, COVID-19 vaccination, and adherence to infection prevention measures with patients.

Disclosure of Interests None declared

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