Article Text

Flares of mixed cryoglobulinaemia vasculitis after vaccination against SARS-CoV-2
  1. Marcella Visentini1,
  2. Laura Gragnani2,
  3. Stefano Angelo Santini3,4,
  4. Teresa Urraro5,
  5. Annalisa Villa1,
  6. Monica Monti2,
  7. Andrea Palladino1,
  8. Luisa Petraccia2,
  9. Francesca La Gualana1,
  10. Serena Lorini2,
  11. Silvia Marri2,
  12. Francesco Madia2,
  13. Lucia Stefanini1,
  14. Stefania Basili1,
  15. Massimo Fiorilli1,
  16. Clodoveo Ferri6,7,
  17. Anna Linda Zignego2,
  18. Milvia Casato1
  1. 1 Department of Translational and Precision Medicine, University of Rome La Sapienza, Rome, Italy
  2. 2 MASVE Interdepartmental Center, Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
  3. 3 Department of Basic, Clinical, Intensive and Perioperative Biotechnological Sciences, Catholic University School of Medicine, Rome, Italy
  4. 4 Synlab Italia, Monza, Italy
  5. 5 Rheumatology Unit, M Scarlato Hospital, Scafati, Italy
  6. 6 Rheumatology Unit, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy
  7. 7 Rheumatology Unit, Madonna dello Scoglio Hospital, Cotronei, Italy
  1. Correspondence to Dr Marcella Visentini, Department of Translational and Precision Medicine, University of Rome La Sapienza, 00185 Rome, Lazio, Italy; marcella.visentini{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Studies on the safety and immunogenicity of SARS-CoV-2 vaccination in patients with inflammatory rheumatic diseases have so far not included mixed cryoglobulinaemia (MC) vasculitis.1–3 We report a prospective observational multicentre study on this disorder.

Participants were followed at four tertiary referral centres and were instructed to promptly inform the attending physicians about unusual events felt as possibly related to vaccination. Seventy-one patients were recruited: they had infection-cured hepatitis C virus (HCV)-related MC, either uncomplicated (HCV-MC, n=50) or complicated by low-grade non-Hodgkin’s lymphoma (MC-NHL, n=8), or essential MC (EMC, n=13). The characteristics of the patients, exclusion criteria and definition of bona fide vaccination-related flare are described in online supplemental methods.

Overall, 9 of 71 (12.7%) patients had postvaccination MC vasculitis flare. However, 8 of 71 patients had experienced within 12 months before vaccination spontaneous flares, where 7 cases required rituximab and 3 of them (37.5%) had postvaccination flare (see online supplemental information). Thus, to exclude the confounding effects of high proneness to spontaneous flare as the facilitator and of rituximab as the preventor, we further restricted the evaluation of postvaccination flare rate to 63 patients off-therapy and without spontaneous flares for 20–48 months before vaccination (see online supplemental information). In none of them rituximab was postponed in view of vaccination.

Six of the 63 patients (9.5%) with stable MC had bona fide vaccination-related flares (table 1). Flares were more frequent in patients with EMC (3 of 8, 37%) than with HCV-cured HCV-MC or MC-NHL (3 of 55, 5.4%) (p=0.023). Flares were characterised by purpura, new onset in one case, which subsided within 1–2 weeks; in three cases the purpura was so diffuse (online supplemental figure 1) that one patient defined it as ‘never experienced before’ and another refused the second dose. Two patients also had flare of peripheral neuropathy that had remained stable for several months. Cryoglobulins (online supplemental figure 2A) increased in 2 of 6 patients with and in 0 of 25 patients without flare tested (p=0.032).

Table 1

Demographic, clinical and immunological features of patients who had flare of stable MC vasculitis bona fide caused by vaccination against SARS-CoV-2

Anti-SARS-CoV-2 IgG responses were measured 8–14 days after the second dose of vaccine in 50 patients. Five of 43 (11.6%) rituximab-free and 5 of 7 (71%) rituximab-treated patients (p=0.002) proved seronegative (<7 binding antibody units /mL) (online supplemental figure 2B). Seronegativity was more frequent (p=0.04) among patients with EMC (2 of 5) than with HCV-MC (1 of 33) (online supplemental figure 2C), suggesting lower immune dysregulation in HCV-MC due to reversion of B cell abnormalities after clearance of infection.4 Among rituximab-treated patients, seronegativity correlated with B cell count <5 cells/µL (online supplemental table 2). No correlations were found between seronegativity and vasculitis flare or cryocrit level (online supplemental figure 2D,E).

Concerning possible mechanism(s) of post-vaccination flare, it is interesting that pathogenic rheumatoid factor-specific B cells expanded in MC are unresponsive to the stimulation of the B cell receptor and of toll-like receptors (TLR) 7 and 9, but can be activated by the simultaneous engagement of these receptors5; thus, vaccination-induced immune complexes acting as autoantigen for rheumatoid factor-specific B cells and vaccine nucleic acids acting as TLR 7/9 ligands could work together in activating pathogenic B cells in vivo.

The overall rate of postvaccination flare observed in patients with MC is similar to that reported in other autoimmune rheumatic diseases1–3; importantly, flares did not endanger patients and subsided spontaneously. This reassures the safety of SARS-CoV-2 vaccination in patients with MC.

While in other inflammatory rheumatic diseases lack of immunogenicity of the SARS-CoV-2 vaccine was mostly attributed to immunosuppression especially with rituximab,1 2 the 11.6% seronegativity rate in treatment-free patients with MC suggests that disease-related factors may impair vaccine immunogenicity in this disorder. Two patients contracted mild COVID-19, one (rituximab-treated, seronegative) 3 weeks after and one (rituximab-untreated, seropositive) 17 weeks after the second dose of vaccine (see online supplemental information). Our observations encourage administering vaccine booster6 to patients with MC and postponing vaccination of rituximab-treated patients after B cell repopulation.

Ethics statements

Patient consent for publication

Ethics approval

This study was performed in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Sapienza University of Rome (prot. 0486/2021). The participants provided informed consent.


Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • Handling editor Josef S Smolen

  • Contributors MV and LG contributed equally to this paper. Study design: MV, LG, MF, CF, ALZ, MC. Sample collection: LG, TU, MM, LP, SL, SM, FM. Experiments and data analysis: SAS, AV, AP, FLG. Tables and figures: MV, MF. Data interpretation: MV, LG, SAS, LS, SB, MF, CF, ALZ, MC. Writing of the manuscript: MV, MF, MC. Critical proof-reading of the manuscript: all authors.

  • Funding The study was funded by the Sapienza University Intramural Research Programme (grants RM11916B7567F9E4 and RM120172B8BE02DA) and by department funds of the centres participating in the study.

  • 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.