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Abstract
Background There is a lack of data on SARS-CoV-2 vaccination safety in children and young people (CYP) with rheumatic and musculoskeletal diseases (RMDs). Current vaccination guidance is based on data from adults with RMDs or CYP without RMDs.
Objectives To describe the safety of SARS-COV-2 vaccination in adolescents with inflammatory RMDs and adults with juvenile idiopathic arthritis (JIA).
Methods We described patient characteristics, flares and adverse events (AEs) in adolescent cases under 18 with inflammatory RMDs and adult cases aged 18 or above with JIA submitted to the European Alliance of Associations for Rheumatology COVAX registry.
Results A total of 110 cases were reported to the registry. Thirty-six adolescent cases were reported from four countries, most with JIA (42%). Over half (56%) reported early reactogenic-like AEs. One mild polyarthralgia flare and one serious AE of special interest (malaise) were reported. No CYP reported SARS-CoV-2 infection postvaccination.
Seventy-four adult JIA cases were reported from 11 countries. Almost two-thirds (62%) reported early reactogenic-like AEs and two flares were reported (mild polyarthralgia and moderate uveitis). No serious AEs of special interest were reported among adults with JIA. Three female patients aged 20–30 years were diagnosed with SARS-CoV-2 postvaccination; all fully recovered.
Conclusions This is an important contribution to research on SARS-CoV-2 vaccine safety in adolescents with RMDs and adults with JIA. It is important to note the low frequency of disease flares, serious AEs and SARS-CoV-2 reinfection seen in both populations, although the dataset is limited by its size.
- Arthritis, Juvenile
- COVID-19
- Vaccination
Data availability statement
Data are available on reasonable request. Data are available on reasonable request. Applications to access the data should be made to the European Alliance of Associations for Rheumatology (EULAR).
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
There is a lack of data on SARS-CoV-2 vaccine safety in children and young people (CYP) with rheumatic and musculoskeletal diseases (RMDs) as they were excluded from SARS-CoV-2 vaccine clinical trials.
Although initial data in the wider CYP population and on SARS-CoV-2 vaccine immunogenicity in CYP with RMDs is reassuring, many questions regarding the safety and efficacy of SARS-CoV-2 vaccines in this population are unanswered.
WHAT THIS STUDY ADDS
In these data on 36 adolescents with inflammatory-RMDs and 74 adults with juvenile idiopathic arthritis (JIA), there were rare reports of RMD flare (adolescents: 2%, adults: 3%), only one report of serious adverse events (AEs) among adolescents, and no reports of serious AEs in adults with JIA.
The frequency and profile of early non-serious local and systemic reactions was similar to findings observed in the general population.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study will support discussions with patients and the public regarding the safety of SARS-CoV-2 vaccines and the development of recommendations by competent organisations.
These data should provide some reassurance to medical professionals, vaccine recipients and their families, and increase confidence in SARS-CoV-2 vaccine safety in CYP and adults with RMDs.
Introduction
While initial data on SARS-CoV-2 vaccines in children and young people (CYP) under 18 years of age are reassuring,1 there is a lack of data on CYP with immune-mediated rheumatic and musculoskeletal diseases (RMDs), as they were excluded from initial vaccine trials. Consequently, current CYP RMD vaccination advice is based on data from adults with RMDs, or CYP without RMDs.2 Immunosuppressed adults are recommended to have third primary and booster doses of SARS-CoV-2 vaccines in some countries; in some countries such as the UK, this was extended to children aged 5 and over with severe immunosuppression,3 again primarily based on research in adults.
Reduced SARS-CoV-2 vaccine immunogenicity4–6 and breakthrough infections7 have been documented in adult patients with RMD; as CYP with RMDs are often treated with similar medications to adults, it is vital to understand how they respond to SARS-CoV-2 vaccination. Limited data have now shown that adolescents with juvenile idiopathic arthritis (JIA) on tumour necrosis factor inhibitors (TNFi) have good immunogenicity, safety and tolerability to SARS-CoV-2 vaccines,8 9 but many questions are yet unanswered.
Elucidating population-specific vaccine safety concerns are important to setting vaccination recommendations. RMD disease flares are of particular concern, and are documented in CYP with JIA who had SARS-CoV-2 infection.10 Another essential consideration are influences on individual choices to get vaccinated; surveyed adults and parents of children with RMDs indicated SARS-CoV-2 vaccine hesitancy is due to lack of medical advice and information on vaccine safety/efficacy, concerns around medication contraindications and vaccine suitability for CYP.11 Evaluating vaccine efficacy is also crucial for this age group as it could influence individual decisions regarding protective and social distancing measures (eg, mask-wearing and avoidance of face-to-face contact), which in turn could influence whether CYP have uninterrupted access to education. Further data are clearly needed to guide vaccination recommendations and improve public and clinical trust in vaccination in immunosuppressed CYP globally.
The European Alliance of Associations for Rheumatology (EULAR) launched a COVAX registry on 2 February 2021 to document SARS-CoV-2 vaccination and vaccine-associated flares and adverse events (AEs) among patients with RMD; AE of special interest were listed a priori based on prior knowledge of the vaccines. We describe the characteristics and outcomes of adolescents with inflammatory RMDs, and adults with JIA submitted to the EULAR Coronavirus vaccine (COVAX) physician-reported registry.
Methods
Data were entered ad hoc by the treating clinical team directly into the data entry website or transferred from national COVID-19 registries. The EULAR COVAX Registry data were collected and managed using REDCap hosted at The University of Manchester, UK.12 The EULAR COVAX registry was determined ‘not human subjects’ research’ by the UK Health Research Authority and the University of Manchester and no consent to collect anonymised data was required.
Adolescent cases were included if under 18, ‘partially vaccinated’ (≥14 days after dose 1 to <14 days after dose 2) or ‘fully vaccinated’ (≥14 days after dose 2/single dose of Janssen) according to the Centers for Disease Control and Prevention definitions.13 The Pfizer/BioNTech vaccine was approved for use in 5–11 years old in Europe on 25 November 2021,14 and in the UK on 22 December 202115—due to this, we do not yet have data on CYP under the age of 12. Adult JIA cases were included if aged 18 or above, had a RMD diagnosis of either non-systemic or systemic JIA (ns-JIA; s-JIA), ‘partially vaccinated’ or ‘fully vaccinated’ (according to prior definitions). Cases were included if reported before the cut-off date of 13 January 2022.
Flares were reported by the reporting clinician, who provided the date, type (eg, arthritis flare, cutaneous flare), and severity of the flare; flare type and severity are categorical variables in predefined lists. RMD disease activity is based on the reporting clinician’s evaluation at the time of the first vaccine dose based on the data available to them (eg, medical records, direct patient reports, physical exams). The EULAR COVAX registry collects data on all adult and paediatric rheumatic diseases, therefore, a standardised measure of disease activity was not recorded, similar to the EULAR COVID-19 registry.16
Results
Adolescents with inflammatory RMDs
Of 36 patients from Italy, Spain, France and the UK, 44% were fully and 56% partially vaccinated. Most (58%) were female and the median age was 15 (IQR: 14.5–17) (table 1). The most common RMDs were ns-JIA (28%), s-JIA (14%), systemic lupus erythematosus (14%) and spondyloarthritis/psoriatic arthritis (14%). The majority were in remission (64%) or had minimal (22%) disease activity at time of vaccination. The most frequent RMD medications were methotrexate (MTX; 36%), antimalarials (22%), TNFi (19%) and glucocorticoids (14%); median prednisolone-equivalent glucocorticoid dose at time of vaccination was 5 mg/day.
Characteristics of 36 adolescents with inflammatory RMDs from the EULAR COVAX registry, stratified by vaccination status
Ninety-two per cent received Pfizer/BioNTech vaccines, 6% Moderna and 2% AstraZeneca/Oxford. Most (67%) received two doses, 31% had received 1 dose and 2% three doses. All fully vaccinated cases received Pfizer vaccines. Median time between first and second vaccine doses was 24 days (IQR: 21–31). Median time from first and second dose to reporting was 50.5 days (IQR: 27–100.5) and 44 days (IQR: 6–79), respectively.
One fully vaccinated female patient aged 15–18 years old with reactive arthritis experienced a mild polyarthralgia flare post-vaccination. She was in remission and taking MTX which was not altered before or after vaccination. She received two Pfizer vaccine doses 30 days apart; the flare occurred the same day as the second dose suggesting reactogenicity rather than true disease flare. She had no previous SARS-CoV-2 infection and, at time of reporting 160 days after her second dose, reported no further AEs.
Over half (56%) of the adolescents reported AEs, primarily common early reactogenic-like AEs experienced within 7 days of vaccination including fever (25%), pain at injection site (22%) and muscle pain (17%). There was one serious (important medical event) AE in a female patient aged 15–18 years old with systemic sclerosis who received one Pfizer vaccine and had no SARS-CoV-2 infection before vaccination. She experienced severe malaise which started 11 days post-vaccination and was ongoing at time of reporting 14 days after vaccination. She was in remission and taking mycophenolate mofetil which was held 3 days pre-vaccination and restarted 8 days after.
No CYP had SARS-CoV-2 post-vaccination between vaccination and time of reporting. Nine were diagnosed with SARS-CoV-2 pre-vaccination, with a median of 257 days (IQR: 94–299) between previous infection and first vaccination. The proportion with AEs post-vaccination was equal independent of prior SARS-CoV-2 infection.
Adults with JIA
Of 74 cases from 11 countries, 77% were fully and 23% partially vaccinated. Most (73%) were female and the median age was 26 (IQR: 23–31) (table 2). Eighty-five percent had ns-JIA and 15% had s-JIA. Three-quarters were in remission (45%) or had minimal (28%) disease activity at time of vaccination. The most common RMD medications were TNFi (54%), MTX (26%), IL-6 inhibitors (8%) and glucocorticoids (8%); median prednisolone-equivalent glucocorticoid dose at time of vaccination was 5 mg/day.
Characteristics of 74 adults with JIA from the EULAR COVAX registry, stratified by vaccination status
Sixty-eight per cent received Pfizer/BioNTech vaccines, 14% Moderna and 14% AstraZeneca/Oxford. Most (82%) received two doses, 11% had received one dose and 7% had three doses. Median time between first and second doses was 25 days (IQR: 21–31). Median time from first and second dose to reporting was 120 days (IQR: 75–145) and 89 days (IQR: 43–122), respectively.
Sixty-two per cent of the patients reported AEs, primarily early reactogenic-like AEs within 7 days of vaccination including fever (35%), pain at injection site (22%) and fatigue (18%). There were no serious AEs reported among adults with JIA.
Two fully vaccinated female ns-JIA patients aged 20–30 years old experienced flares; both had two Pfizer doses 21 days apart and minimal disease activity. The first had a secondary RMD diagnosis of Ehlers-Danlos Syndrome and received non-steroidal anti-inflammatory drugs (NSAIDs) on demand but no disease modifying anti-rheumatic drug (DMARD) treatment. She experienced mild reactogenicity following vaccination and had a mild polyarthralgia flare 15 days after her second dose, resulting in a medication change. She had no previous SARS-CoV-2 infection and, as of 99 days after the second dose, experienced no further AEs. The second patient was taking MTX and TNFi, which were not changed due to vaccination. She had mild reactogenicity following vaccination, then a moderate uveitis flare 32 days after her second dose, requiring a change in medication. She had no previous SARS-CoV-2 infection, and, as of 122 days after the second dose, had no further AEs.
Four adults with JIA were diagnosed with SARS-CoV-2 pre-vaccination, a median of 140 days (IQR: 125–238) between previous infection and vaccination.
Three female patients aged 20–30 years old were diagnosed with SARS-CoV-2 post-vaccination—all fully recovered from the infection, had minimal disease activity and did not change their medication before or after vaccination. One with ns-JIA had two Pfizer doses 21 days apart and 140 days before her SARS-CoV-2 diagnosis. She had a secondary diagnosis of Ehlers-Danlos Syndrome and was taking abatacept. The second ns-JIA patient was taking MTX and TNFi and had two doses of Pfizer 21 days apart. She received one booster dose with Moderna 226 days after the second Pfizer dose. The SARS-CoV-2 infection was diagnosed 17 days after the booster. The other patient with s-JIA had two doses of CoronaVac/Sinovac 28 days apart; she was diagnosed with SARS-CoV-2 74 days later. She had a secondary RMD diagnosis of undifferentiated connective tissue disease and was taking antimalarials and colchicine.
Discussion
To the authors’ knowledge, this is the largest physician-reported dataset on SARS-CoV-2 vaccine safety in adolescents with RMDs and adults with JIA. Overall, these data present a reassuring picture of rare disease flares and AEs after full or partial SARS-CoV-2 vaccination. While 56% of adolescents with RMDs and 62% of adults with JIA reported early reactogenic-like AEs, this was not unexpected as they are considered normal minor early side effects in the general population.17 The rare reports of SARS-CoV-2 infection post-vaccination are also encouraging, although most vaccinations collected in the database were reported within a few months of vaccination and we do not collect follow-up data so cannot firmly comment on COVID-19 vaccine efficacy.
For comparison, the US reports 75% of mRNA-based SARS-CoV-2 vaccine recipients experience local adverse reactions, and 69% systemic adverse reactions in the 7 days following vaccination; similar to this study, the most frequently reported reactions were injection site pain, fatigue, headache and myalgia.18 Clinical trials of the Pfizer, Moderna, AstraZeneca, Sinopharm and CoronaVac vaccines in healthy children and adolescents also show similar results; predominantly mild to moderate reactogenic AEs in the first few days following vaccination and few reports of serious AEs related to the vaccine.19–25 The WHO has determined the Pfizer and Moderna vaccines safe for use in children and adolescents, and now recommends children with existing health conditions be prioritised for vaccination.
Few cases reported disease flares following vaccination (2% in adolescents with RMDs, 3% in adults with JIA), a similar figure to the 4% of cases reporting disease flares post-vaccination observed in the wider population of adults with RMDs from the EULAR COVAX registry.26 Existing data on adolescents with RMDs has also showed similarly low levels of vaccine AEs and disease flares across their cohort, as well as post-vaccine SARS-CoV-2 infection, although this was limited to a 3-month follow-up period.27 Patient-reported survey data from Turkey on Pfizer/CoronaVac vaccine AEs among adolescents and young adults with RMDs also showed low levels of serious AEs and early reactogenic-like AEs, although reported higher levels of disease flare (11%).28 The Global Rheumatology Alliance also conducted a survey among adults with RMDs to capture their early experiences of SARS-CoV-2 vaccination, again with similar proportions of common AEs and very few serious AEs, while 13% reported a postvaccine disease flare,29 perhaps related to the difficulty in distinguishing some reactogenic-like AEs from rheumatic disease flares (eg, arthralgia, myalgia, fatigue), and the tendency for these reactogenic-like AEs to be more often interpreted by patients as rheumatic disease flares.
Importantly, we had no reports of paediatric inflammatory multi-system syndrome or myocarditis AEs. Reported rates of myocarditis are 1.7 per 100 000 individuals vaccinated with two doses, range from 1.4 to 1.7 per 100 000 for the Pfizer/BioNTech vaccine, and 4.2–6.0 following the Moderna vaccine. For individuals under 18 who received the Pfizer/BioNTech vaccine, this rate ranges from 1.0 to 13.7 per 100 000.22–24 30 Our lack of reports of myocarditis is therefore not unexpected, due to our small sample size and low numbers of individuals receiving the Moderna vaccine.
However, our study has important limitations. The EULAR COVAX registry relies on voluntary case submission. This means there is potential for selection bias in the data, and careful consideration is needed when assessing the generalisability of these results. This potential bias could mean over-reporting of disease flares and serious AEs, although it is encouraging that our observations of disease flare and serious AEs are very low and not unusual in comparison to other studies. Additionally, data reported to the EULAR COVAX registry is based on reports from rheumatologists or other healthcare providers, not patients themselves, and no information is collected on levels of post-vaccine antibodies. Of note, this sample size is small and not enough to evaluate any associations between adolescent RMD/adult JIA population-specific factors and the safety of SARS-CoV-2 vaccination. Therefore, no causal conclusions can be drawn from this dataset, and the observations noted here should not be taken as an exact reflection of the wider CYP RMD population.
In summary, we observed reassuringly low frequencies of disease flares, serious AEs and SARS-CoV-2 reinfection following SARS-CoV-2 vaccination in adolescents with RMDs and adults with JIA, which should provide reassurance to paediatric vaccine recipients, their families, paediatric rheumatologists, and other health professionals, and promote confidence in the safety of SARS-CoV-2 vaccination in CYP with or without RMDs. Further research is needed to more deeply examine the safety and efficacy of SARS-CoV-2 vaccination in CYP with RMDs or other CYP taking immunomodulatory/immunosuppressive medications, particularly in those under the age of 12.
Data availability statement
Data are available on reasonable request. Data are available on reasonable request. Applications to access the data should be made to the European Alliance of Associations for Rheumatology (EULAR).
Ethics statements
Patient consent for publication
Acknowledgments
We wish to thank all healthcare providers who entered data into the registry. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing: (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages and (4) procedures for importing data from external sources.
References
Footnotes
Twitter @pedrommcmachado, @carmona_loreto, @InitaBulina
Collaborators In addition to the authors listed above, the following colleagues also contributed to the EULAR COVAX registry by submitting 1 - 4 cases included in this analysis: Emoke Stenova, Theodoros Dimitroulas, Nicolas Roux, Patrick Durez, Amelie Leurs, Anna Carbone, Eric Hachulla, Eric Toussirot, Gözde Kübra Yardımcı, Jose A Gomez Puerta, Natalia de la Torre Rubio, Pavol Masaryk, Viviane Queyrel, Rachel Jeffrey, Raphaele Seror, Sharon Floyd, Simona Rednic, Eva Strakova, Umut Kalyoncu, Vanda Mylnarikova.
Contributors SL-T and KLH had access to the study data, developed the tables, wrote the first draft of the manuscript, vouch for the data and analyses, and are guarantors for this manuscript. All authors contributed to data collection and interpretation of the data. SL-T and KLH directed the work and had final responsibility for the decision to submit for publication. All authors contributed intellectual content during the drafting and revision of the work and approved the final version to be published.
Funding This work was supported by the European Alliance of Associations for Rheumatism (EULAR).
Competing interests SL-T and BR have nothing to disclose. PMM reports consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, and is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC). AS reports personal fees from lectures for AbbVie, MSD, Roche, BMS, and Pfizer. EM reports LPCDR received support for specific activities: grants from Abbvie, Novartis, Janssen-Cilag, Lilly Portugal, Sanofi, Grünenthal S.A., MSD, Celgene, Medac, Pharmakern, GAfPA; grants and non-financial support from Pfizer; non-financial support from Grünenthal, outside the submitted work. LG reports Amgen, Galapagos, Lilly, Pfizer, Sandoz; consulting fees: AbbVie, Amgen, BMS, Celltrion, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis, UCB, all unrelated to this manuscript. LC reports fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as Abbvie Spain, Eisai, Gebro Pharma, Merck Sharp & Dohme España, S.A., Novartis Farmaceutica, Pfizer, Roche Farma, Sanofi Aventis, Astellas Pharma, Actelion Pharmaceuticals España, Grünenthal, and UCB Pharma. IB reports speaker fees from AbbVie, Pfizer, Janssen, Boehringer Ingelheim, all unrelated to this manuscript. DC reports speakers fees from Novartis, GSK, all unrelated to this manuscript. JZ reports speaker fees from Abbvie, Novartis, Janssen/Johnson & Johnson, all unrelated to this manuscript. AR reports research grants and consultant fees from Amgen and Pfizer, all unrelated to this manuscript. KLH reports non-personal speaker’s fees from Abbvie and grant income from BMS, UCB, and Pfizer, all unrelated to this manuscript, and is supported by the NIHR Manchester Biomedical Research Centre. XM is an Associate Editor for this journal.
Provenance and peer review Not commissioned; externally peer reviewed.