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Spectrum of short-term inflammatory musculoskeletal manifestations after COVID-19 vaccine administration: a report of 66 cases
  1. Francesco Ursini1,2,
  2. Piero Ruscitti3,
  3. Vincenzo Raimondo4,
  4. Rossella De Angelis5,
  5. Fabio Cacciapaglia6,
  6. Erika Pigatto7,
  7. Domenico Olivo8,
  8. Ilenia Di Cola9,
  9. Felice Galluccio10,
  10. Francesca Francioso5,
  11. Rosario Foti11,
  12. Antonio Tavoni12,
  13. Salvatore D'Angelo13,
  14. Corrado Campochiaro14,
  15. Francesca Motta15,
  16. Maria De Santis15,
  17. Silvia Bilia12,
  18. Caterina Bruno16,
  19. Giacomo De Luca14,
  20. Marcella Visentini17,
  21. Jacopo Ciaffi1,
  22. Luana Mancarella1,
  23. Veronica Brusi1,
  24. Martina D’Onghia1,
  25. Giovanna Cuomo18,
  26. Enrico Fusaro19,
  27. Lorenzo Dagna14,
  28. Serena Guiducci10,
  29. Riccardo Meliconi1,2,
  30. Florenzo Iannone20,
  31. Annamaria Iagnocco21,
  32. Roberto Giacomelli22,
  33. Clodoveo Ferri4,23
  1. 1 Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
  2. 2 Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
  3. 3 Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, Università degli Studi dell'Aquila, L'Aquila, Italy
  4. 4 Rheumatology Unit, Rheumatology Hospital 'Madonna dello Scoglio', Cotronei, Italy
  5. 5 Rheumatology Clinic, Università Politecnica delle Marche, Ancona, Italy
  6. 6 Rheumatology Unit, Department of Emergence Medicine and Transplantation, Università degli Studi di Bari Aldo Moro, Bari, Italy
  7. 7 Rheumatology Outpatient Clinic, Villa Salus Hospital, Mestre, Italy
  8. 8 Rheumatology Outpatient Clinic, San Giovanni di Dio Hospital, Crotone, Italy
  9. 9 Department of Biotechnological and Applied Clinical Sciences, Università degli Studi dell'Aquila, L'Aquila, Italy
  10. 10 Department of Rheumatology, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy
  11. 11 Rheumatology Unit, Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele Catania, Catania, Italy
  12. 12 Department of Clinical Immunology, University of Pisa, Pisa, Italy
  13. 13 Rheumatology Institute of Lucania (IReL), Rheumatology Department of Lucania, Regional Hospital San Carlo, Potenza, Italy
  14. 14 Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS Ospedale San Raffaele, Milano, Italy
  15. 15 Division of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Italy
  16. 16 Rheumatology Outpatient Clinic, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro, Italy
  17. 17 Department of Translational and Precision Medicine, University of Rome La Sapienza, Rome, Italy
  18. 18 Clinical Immunology Outpatient Clinic, University of Campania Luigi Vanvitelli, Caserta, Italy
  19. 19 Rheumatology Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
  20. 20 Rheumatology Unit, Department of Emergence Medicine and Transplantation (DETO), Università degli Studi di Bari Aldo Moro, Bari, Italy
  21. 21 Academic Rheumatology Centre, MFRU and Dipartimento Scienze Cliniche e Biologiche, Università degli Studi di Torino, Torino, Italy
  22. 22 Unit of Allergology, Immunology, Rheumatology, Department of Medicine, Campus Bio-Medico University Hospital, Roma, Italy
  23. 23 Rheumatology Unit, University of Modena and Reggio Emilia, Modena, Italy
  1. Correspondence to Professor Clodoveo Ferri, Rheumatology Unit, University of Modena and Reggio Emilia, Modena 41124, Italy; clferri{at}

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In the past months, mass vaccination represented the turning point of the global battle against the COVID-19 pandemic, an unprecedented challenge for physicians, healthcare professionals, health systems and pharmaceutical companies. More than 6 billion doses of vaccine have been administered to date, covering nearly 50% of the world’s population. Although the vaccination campaign is still thwarted by spread of fake news disseminated by a ubiquitous antivaxxer movement, accumulating real-life data1 confirm the favourable safety profile already demonstrated in phase III clinical trials.2

Despite the lack of a steady literature evidence,3 the potential role of vaccines in promoting autoimmunity continues to intrigue many researchers. The theoretical basis of this association relies on the possible molecular mimicry between macromolecular components of the vaccine and specific human proteins and the exuberant immune response elicited by adjuvants contained in vaccines.4

Adverse events (AEs) associated with COVID-19 vaccines are usually mild and mainly restricted to injection site reactions. Interestingly, among systemic AEs, arthralgia is one of the most common.2 To the best of our knowledge, only isolated cases5 of arthritis developed after COVID-19 vaccine administration has been described; however, in a recently published survey including 1377 participants with rheumatic diseases, 11% of the respondents reported flare requiring treatment following injection of mRNA-based vaccines.6

The ‘COVID-19 and Autoimmune Systemic Diseases’ is a collaborative network of Italian rheumatologists, equally distributed across the country, spontaneously born in response to the COVID-19 pandemic with the aim to contribute to the advancing knowledge about COVID-19 and rheumatic diseases, by providing real-life data obtained from participating centres. To date, more than 60 rheumatologists from 40 different rheumatology clinics are affiliated to the study group.

In December 2020, we published a web-based survey form and invited all members of the study group to inform cases of inflammatory musculoskeletal manifestations (eg, synovitis, tenosynovitis, enthesitis, inflammatory spinal pain or girdles pain/stiffness with serological evidence of inflammation) with onset within 4 weeks from the administration of the first or second dose of one of the COVID-19 vaccines approved in Italy (BNT162b2, mRNA-1273, AZD1222 and Ad26.COV2.S), prospectively encountered during routine clinical practice since the beginning of the vaccination campaign, in January 2021, and up to August 31, 2021. Exclusion criteria were a history of any inflammatory rheumatic disease, isolated arthralgia/myalgia without clear evidence of inflammation, or vague and/or non-specific musculoskeletal complaints. Written informed consent was obtained from all patients.

By using this approach, we built a case series comprising 66 individual patients reported by 16 different rheumatology centres; most of them (59%) received the BNT162b2 vaccine. The average delay between the day of the ‘trigger’ injection (44.4% coinciding with the first dose) and arthritis onset was 11–13 days.

Stratification according to the predominant pattern of involvement at presentation (table 1) revealed that girdles pain/stiffness with acute-phase reactant elevation resembling polymyalgia rheumatica (PMR-like) was the most common (41%) clinical picture followed by oligoarthritis (32%) and polyarthritis (27%). Polyarticular and PMR-like cases were mainly symmetric (83% and 89%, respectively); involvement of small joints and tenosynovitis (39%) were significantly more frequent in polyarthritic forms (61% and 39%, respectively), while enthesitis was more common in oligoarthritic presentation (14%). Of note, two patients (one in the polyarticular group and one in the oligoarticular group, respectively) had also inflammatory back pain with evidence of active sacroiliitis and/or spondylitis on MRI. Detection of autoantibodies in sera was an uncommon finding; HLA-B27 status was obtained in only 21 (31.8%) patients, of which one in the polyarthritis subgroup tested positive.

Table 1

Clinical features of the patients stratified according to the pattern of presentation

Most patients were treated with glucocorticoids (50%–78%), non-steroidal anti-inflammatory drugs (33%–52%) or analgesics (14%–28%), while disease-modifying antirheumatic drugs were used in five (28%) patients with polyarthritis, five (24%) patients with oligoarthritis and only three (11%) patients with PMR-like presentation.

Despite the limitation of a very short follow-up, the clinical course seemed excellent in patients with PMR-like onset with 74% achieving full remission of symptoms after 2 weeks; on the other hand, 67% of patients with polyarthritis had active disease after an average follow-up of 6 weeks.

In conclusion, despite the fact that a clear cause–effect relationship is far to be ascertained, our data suggest that inflammatory musculoskeletal symptoms may occasionally develop in close temporal association with COVID-19 vaccine administration. However, even assuming a direct causal relationship, we feel that the overall safety of COVID-19 vaccines remains unaffected, and the benefits of vaccination largely outweigh the minimal risks associated with such uncommon inflammatory complications, probably reflecting a transient reactogenic response to the vaccine rather than a structured, chronic inflammatory joint disease.

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  • Handling editor Josef S Smolen

  • Contributors FU and CF designed the study, analysed the results and prepared the first draft of the letter. All the other authors contributed to the data collection and critical revision of the draft.

  • 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, conduct, reporting or dissemination plans of this research.

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