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Baseline Factors Associated with Self-reported Disease Flares Following COVID-19 Vaccination among Adults with Systemic Rheumatic Disease: Results from the COVID-19 Global Rheumatology Alliance Vaccine Survey

Authors:

Abstract

Objective To examine the frequency of, and risk factors for, disease flare following COVID-19 vaccination in patients with systemic rheumatic disease (SRD). Methods An international study was conducted from April 2 to August 16, 2021, using an online survey of 5619 adults with SRD for adverse events following COVID-19 vaccination, including flares of disease requiring a change in treatment. We examined risk factors identified a priori based on published associations with SRD activity and SARS-CoV-2 severity, including demographics, SRD type, comorbidities, vaccine type, cessation of immunosuppressive medications around vaccination, and history of reactions to non-COVID-19 vaccines, using multivariable logistic regression. Results Flares requiring a change in treatment following COVID-19 vaccination were reported by 4.9% of patients. Compared with rheumatoid arthritis, certain SRD, including systemic lupus erythematosus (OR 1.51, 95%CI 1.03, 2.20), psoriatic arthritis (OR 1.95, 95%CI 1.20, 3.18), and polymyalgia rheumatica (OR 1.94, 95%CI 1.08, 2.48) were associated with higher odds of flare, while idiopathic inflammatory myopathies were associated with lower odds for flare (OR 0.54, 95%CI 0.31–0.96). The Oxford-AstraZeneca vaccine was associated with higher odds of flare relative to the Pfizer-BioNTech vaccine (OR 1.44, 95%CI 1.07, 1.95), as were a prior reaction to a non-COVID-19 vaccine (OR 2.50, 95%CI 1.76, 3.54) and female sex (OR 2.71, 95%CI 1.55, 4.72). Conclusion SRD flares requiring changes in treatment following COVID-19 vaccination were uncommon in this large international study. Several potential risk factors, as well as differences by disease type, warrant further examination in prospective cohorts.
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Baseline Factors Associated with Self-reported Disease Flares Following COVID-19 Vaccination
among Adults with Systemic Rheumatic Disease:
Results from the COVID-19 Global Rheumatology Alliance Vaccine Survey
Lisa G. Rider,1 Christine G. Parks2, Jesse Wilkerson3, Adam I. Schiffenbauer1, Richard K. Kwok4, Payam
Noroozi Farhadi1, Sarvar Nazir1, Rebecca Ritter3, Emily Sirotich5, Kevin Kennedy6, Maggie J. Larche5,
Mitchell Levine6, Sebastian E. Sattui7, Jean W. Liew8, Carly O. Harrison9, Tarin T. Moni10, Aubrey K.
Miller4, Michael Putman11, Jonathan Hausmann12, Julia F. Simard13, Jeffrey A. Sparks14, Frederick W.
Miller1, and the COVID-19 Global Rheumatology Alliance Vaccine Survey Group
1Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental
Health Sciences (NIEHS), National Institutes of Health (NIH), Bethesda, MD, USA
2Epidemiology Branch, NIEHS, NIH, Research Triangle Park, NC, USA
3Social Scientific Systems, Durham, NC, USA
4Office of the Director, NIEHS, NIH, Research Triangle Park, NC, USA
5Department of Medicine, McMaster University, Canada
6Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton,
ON, Canada
7Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh,
Pittsburgh, PA, USA
8Section of Rheumatology, Boston University School of Medicine, Boston, MA, USA
9LupusChat, New York, NY, USA
10Department of Biochemistry and Biomedical Sciences, McMaster University Faculty of Science,
Hamilton, ON, Canada
11Medical College of Wisconsin, Milwaukee, WI, USA
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Published by Oxford University Press 2022. This work is written by US Government employees and are in the public domain in
the US.
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12Program in Rheumatology, Boston Children’s Hospital, Division of Rheumatology and Clinical
Immunology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA
(ORCID: 0000-0003-0786-8788);
13Department of Epidemiology and Population Health, and Immunology and Rheumatology (Department
of Medicine), Stanford University School of Medicine, USA
14Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Running head: Disease Flares Following COVID-19 Vaccines
Key words: COVID-19, vaccine, disease flare, systemic rheumatic diseases
Address correspondence to:
Lisa G. Rider
ORCID: 0000-0002-6912-2458
Environmental Autoimmunity Group
Clinical Research Branch
NIEHS, NIH
Building 10, Room 6-5700
10 Center Drive, MSC 1301
Bethesda, MD, USA 20892-1301
Phone: (301) 451-6272
FAX: (301) 480-2813
Email: riderl@mail.nih.gov
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Key Messages
Disease flare is uncommonly reported following COVID-19 vaccination in patients with systemic
rheumatic diseases.
Several factors were associated with disease flare following COVID-19 vaccination, but need
confirmation.
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Abstract.
Objective: To examine the frequency of, and risk factors for, disease flare following COVID-19
vaccination in patients with systemic rheumatic disease (SRD).
Methods: An international study was conducted from April 2 to August 16, 2021, using an online survey
of 5619 adults with SRD for adverse events following COVID-19 vaccination, including flares of disease
requiring a change in treatment. We examined risk factors identified a priori based on published
associations with SRD activity and SARS-CoV-2 severity, including demographics, SRD type,
comorbidities, vaccine type, cessation of immunosuppressive medications around vaccination, and
history of reactions to non-COVID-19 vaccines, using multivariable logistic regression.
Results: Flares requiring a change in treatment following COVID-19 vaccination were reported by 4.9%
of patients. Compared to rheumatoid arthritis, certain SRD, including systemic lupus erythematosus (OR
1.51, 95%CI 1.03, 2.20), psoriatic arthritis (OR 1.95, 95%CI 1.20, 3.18), and polymyalgia rheumatica (OR
1.94, 95%CI 1.08, 2.48) were associated with higher odds of flare, while idiopathic inflammatory
myopathies were associated with lower odds for flare (OR 0.54, 95%CI 0.31 – 0.96). The Oxford-
AstraZeneca vaccine was associated with higher odds of flare relative to the Pfizer-BioNTech vaccine
(OR 1.44, 95%CI 1.07, 1.95), as were a prior reaction to a non-COVID-19 vaccine (OR 2.50, 95%CI
1.76, 3.54) and female sex (OR 2.71, 95%CI 1.55, 4.72).
Conclusion: SRD flares requiring changes in treatment following COVID-19 vaccination were
uncommon in this large international study. Several potential risk factors, as well as differences by
disease type, warrant further examination in prospective cohorts.
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Introduction.
With billions of individuals worldwide now immunized with a least one dose of a COVID-19
vaccine, it is apparent that observational data support initial trial evidence, suggesting that COVID-19
vaccines are safe and effective (1). Although the initial vaccine trials did not include patients with
systemic rheumatic disease (SRD), vaccination is especially important for this population due to an
increased risk for poor outcomes from SARS-CoV-2 (2). Increased disease activity or “disease flares”
have also been reported following vaccination against SARS-CoV-2 and may reduce willingness to be
vaccinated among patients with SRD (3-7). SRD flares have been uncommonly reported following
immunization with other vaccines, including influenza and herpes zoster (8, 9).
Several plausible risk factors for SRD flares should be considered in relation to flare after
vaccination. First, comorbidities and demographic factors, which are also risk factors for developing
rheumatoid arthritis (RA) and other SRDs or are associated with disease activity, may be related to flares
after vaccination. Beyond baseline characteristics, cessation of SRD therapies could contribute to
disease flares and have been observed in studies of patients who have temporarily discontinued
methotrexate following influenza and pneumococcal vaccination (10). Variable immunogenicity of the
different vaccines may be a risk factor for disease flare, and rare reports of autoimmune sequelae, such
as Guillain-Barre syndrome and immune thrombocytopenia, have been observed following
Janssen/Johnson & Johnson and Oxford-AstraZeneca vaccines, respectively (11).
We sought to examine the frequency of flares in patients with SRD following COVID-19 vaccines
and to examine risk factors for flare following vaccination.
Patients and Methods.
Study design and population
This retrospective study examined self-reported flare requiring a change in treatment following
COVID vaccination in an international sample of SRD patients. Data were collected using the COVID-19
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Global Rheumatology Alliance (GRA) vaccine survey of adults with SRD, an online questionnaire
available in multiple languages administered using the Qualtrics platform and promoted through patient
support groups and social media (3). Informed consent was waived, as the study was determined
exempt by the Boston Children’s Hospital Institutional Review Board. The data underlying this article
were provided by the COVID-19 Global Rheumatology Alliance; data will be shared on request to the
corresponding author with permission of the COVID-19 Global Rheumatology Alliance.
A total of 11,032 participants responded to the survey from April 2 through August 16, 2021. Of
these, 2,960 participants were excluded for not completing the survey or not specifying a SRD diagnosis,
along with 580 participants who only reported a diagnosis of osteoarthritis or fibromyalgia. In the
remaining sample, 1,544 participants were excluded for being unvaccinated, and 329 were excluded for
missing data on at least one of the model covariates.
Data collection and self-reported flare outcome
The online survey is available at the COVID-19 GRA website (https://rheum-covid.org) (see
COVID-19 Vax Survey) (12). Participants were asked to report their type and year of SRD diagnosis
(Supplementary Table S1, available at Rheumatology online); individuals reporting multiple diseases
were classified based on the hierarchy of diseases established by Strangfeld, et. al. (13). Participants
who received at least one dose of a COVID-19 vaccine were asked whether they had any serious
reaction to the COVID-19 vaccine. Serious reactions were defined as lasting for at least two days and
occurring within two months of receiving the vaccination. The primary outcome of interest was a self-
reported flare of an existing SRD requiring a change in treatment (e.g., increasing dosages and/or adding
new medications) for the SRD.
Statistical Analyses
We first examined the frequency of disease flares requiring a change in treatment following
COVID-19 vaccination overall and by SRD type, demographic factors (age, gender, race/ethnicity [non-
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Hispanic white, non-white]), WHO region, and potential risk factors, including comorbid and other health
conditions (Supplementary Table S2, available at Rheumatology online), smoking status, vaccine type,
history of a serious reaction to a non-COVID vaccine, discontinuation of immunosuppressive medications
before or after receiving COVID-19 vaccine, and prior SARS-CoV-2 infection. Comorbidities were
grouped to identify patients with either cardiopulmonary or immunodeficiency conditions, as well as the
subset with obstructive lung diseases (asthma, chronic bronchitis, emphysema, or chronic obstructive
pulmonary disease [COPD]) and obesity (body mass index [BMI] ≥30 mg/m2).
We then considered the association of disease flare with SRD type and covariates in a mutually-
adjusted logistic regression model used to calculate odds ratios (OR) and 95% confidence intervals (CI).
As WHO region was strongly correlated with COVID vaccine type, WHO region was not included in the
model, since the vaccine type was expected to impact immune response. We considered both individual
comorbidities, as well as those grouped by affected organ, and determined that obstructive lung disease
as a disease group and BMI (obese vs. non-obese) best contributed to model fit. The final model
included SRD type, obstructive lung diseases, BMI, smoking status, type of COVID-19 vaccine, serious
reaction to a prior non-COVID vaccine, cessation of medications at the time of vaccination, age, sex, and
race/ethnicity.
Results.
The final analytical sample consisted of 5,619 participants with SRD who received at least one
dose of a COVID-19 vaccine (Supplementary Figure S1 for flow diagram, available at Rheumatology
online). Participant characteristics and potential risk factors for flare are detailed in Table 1. The median
age of participants was 55.5 years, and the majority were female and white. Rheumatoid arthritis was
the most frequent SRD among participants (n=1701, 30.3%), followed by idiopathic inflammatory
myopathies (824, 14.7%), systemic lupus erythematosus (791, 14.1%), Sjogren’s syndrome (540, 9.6%),
psoriatic arthritis (304, 5.4%), ankylosing spondylitis (291, 5.2%), polymyalgia rheumatica (197, 3.5%),
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vasculitis (163, 2.9%), and systemic sclerosis (135, 2.5%). The majority of subjects received a mRNA
vaccine, and 65.8% did not hold SRD medications at the time of vaccination.
Disease flares requiring changes in treatment following COVID-19 vaccination were reported by
4.9% of respondents. Flares were more commonly reported in younger respondents (median age 52.4
vs. 55.5 years) and in females (5.4% vs. 1.7%), and were less prevalent in Hispanic or Latin American
compared to white patients (2.5% vs. 5.2%) (Table 1). The prevalence of flare was higher among those
with lupus (6.7%), psoriatic arthritis (7.9%), and polymyalgia rheumatica (8.1%). Respondents with
myositis (1.9%) and systemic sclerosis (1.5%) reported the lowest flare prevalence. The prevalence of
flare was somewhat higher among patients with a history of asthma, emphysema, chronic bronchitis, or
COPD (6.1% vs. 4.6%), and in those who received the Oxford-AstraZeneca vaccine compared with than
Pfizer-BioNTech and Moderna vaccines (6.3% vs. 4.5% and 5.1%, respectively). Flares were more
frequently seen in respondents who reported serious reactions to other non-COVID-19 vaccines in the
past (11.2% vs. 4.4%). The prevalence of flares following COVID-19 vaccination did not appear to differ
by the other factors examined, including among those who stopped medications at the time of
vaccination or reported a history of COVID-19 infection (Table 1).
In a multivariable logistic regression model examining risk factors for a disease flare requiring a
change in treatment (Table 2), the odds of experiencing flare following COVID-19 vaccine were highest
among females (OR 2.71; 1.55, 4.72). Compared with respondents with rheumatoid arthritis, odds of
flare were elevated for systemic lupus erythematosus (OR 1.51, 95%CI 1.03-2.20), psoriatic arthritis (OR
1.95, 95%CI 1.20-3.18), and polymyalgia rheumatica (OR 1.94, 95%CI 1.08-2.48) and lower among
those with inflammatory myopathies (OR 0.54, 95%CI 0.31, 0.96). Other factors that were independently
associated with disease flare included receiving the Oxford AstraZeneca vaccine (OR 1.44, 95%CI 1.07,
1.95) compared to the Pfizer-BioNTech vaccine, and having a prior serious reaction to non-COVID-19
vaccine (OR 2.50, 95%CI 1.76, 3.54) compared to no prior serious reaction to a non-COVID-19 vaccine.
Age, race/ethnicity, obstructive lung diseases (asthma, emphysema, chronic bronchitis, or COPD),
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smoking, obesity, and cessation of medications at the time of vaccination were not associated with
disease flare requiring change in treatment in this sample.
Discussion.
This large international study of COVID-19 vaccination in 5,691 patients with SRD enabled
investigation of risk factors for disease flare among a diverse sample of diagnoses and following a variety
of COVID-19 vaccines. We showed that SRD flares requiring changes in SRD treatments following
COVID-19 vaccines were uncommon, occurring in only 4.9% of survey respondents. This broadly reflects
results from prior studies reporting SRD flares in adults after COVID-19 vaccination, which range from
1.5 - 15% (4-7, 14, 15). The lowest estimates to date include two international studies in which 1.5% of
4,498 patients with rheumatic diseases and 2.4% of 696 patients with systemic lupus erythematosus
reported a disease flare requiring increased treatment (4, 7), while a study of 1,500 autoimmune
rheumatic disease patients in China reported 3.5% of patients developed a disease flare requiring
treatment escalation (6). Other studies have observed higher frequencies of disease flares requiring
changes in treatment, including 11% in a study of 1,377 patients with SRD receiving mRNA vaccines (5),
5% in a study of 594 patients that also included people with multiple sclerosis (13), and 15% in a study of
more than 1,000 patients with SRD in New York City (15). These variations are likely related to
differences in the composition of study populations, vaccine exposure, and flare definitions across
studies. Notably, the frequency of disease flare following COVID-19 vaccines in the present and other
published studies are within range of the background disease flare rate of 7% from population-based
data in France from 1,200 patients with SRD (not including patients with rheumatoid arthritis) over a 3-
month period in 2020, prior to vaccine availability (16).
Our study has identified several novel characteristics as potential risk factors for disease flare
following COVID-19 vaccination, including the observation that patients with systemic lupus
erythematosus, psoriatic arthritis, or polymyalgia rheumatica were more likely to report a disease flare
requiring change in treatment following COVID-19 vaccination as compared to those with rheumatoid
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arthritis, while patients with inflammatory myopathies were significantly less likely to report a disease
flare. These findings were independent of demographic differences and other patient characteristics. A
higher frequency of flare in patients with lupus relative to patients with rheumatoid arthritis following
inactivated COVID-19 vaccines was also seen in the Chinese study (6). In the EULAR COVAX registry,
patients with inflammatory joint diseases experienced a slightly higher prevalence of flare compared to
connective tissue diseases and vasculitis; however, specific rheumatic diseases were not examined (7).
We also observed higher flare rates in female subjects in contrast to the Chinese study, in which subjects
of older age has increased risk of flare (6).
The potential for mRNA and adenoviral vector vaccines to activate Toll-like receptors, intracellular
sensors, and Type I interferon production theoretically exists, which could be hypothesized to impact
disease activity for certain SRDs, such as lupus (17). However, the observation that disease flare was
uncommon and differed by diagnosis type suggests that genetic and other susceptibility factors may also
be important. These should be verified in subsequent studies.
The association of flares with the Oxford-AstraZeneca vaccine, which is a replication-deficient
simian adenovirus vector containing the fulllength coding sequence of SARS-CoV-2 spike protein, as
compared to the Pfizer-BioNTech mRNA vaccine warrants further evaluation. Of interest, the Oxford-
AstraZeneca vaccine, female sex, and age 55 years, were associated with moderate or severe adverse
events after COVID-19 vaccination in one prior study, though not specifically with disease flares (14).
Additionally, the Oxford-AstraZeneca vaccine has been associated with other autoimmune adverse
events, including the risk of thrombotic events and autoimmune thrombocytopenia, and its association
with SRD flares may be plausible (11). The association between flares after COVID-19 vaccines in
patients who reported a serious reaction to other non-COVID-19 vaccines in the past is also notable and
suggests that an underlying immunophenotype may predispose patients to flares after COVID-19 and
possibly other vaccines.
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Prior studies in patients with SRD and systemic lupus erythematosus found a flare within 6 or 12
months prior to the COVID-19 vaccine to be associated with flares following vaccination (4, 5). A recent
study of SRD patient experiences with mRNA vaccines also reported the use of combination therapy to
treat the underlying SRD and a prior history of SARS-CoV-2 infection to be associated with flares of SRD
(5). In the present study, we lacked information about disease activity at the time of vaccination, severity
of disease flare, prior flare history, concomitant or additional immunomodulatory medications received
including dosing and timing in relation to vaccination, as well as the number of patients who discontinued
their medication before vaccination and after SRD flare. The background rate of flare was not quantified,
and the survey did not collect information on whether flares occurred after first or second dose. This will
be an important area of future research, particularly since patients who experience flares may be less
willing to receive additional recommended doses.
Strengths of this study includes the large size, the international perspective, and the variety of
SRDs exposed to different COVID-19 vaccines in the presence of varying co-morbid conditions.
Furthermore, requiring a change in treatment to define flare reduced the potential misclassification of
outcome such that flare was less likely to be conflated with common vaccine side effects, including
fatigue, fever, and joint pain. We were also able to estimate associations, taking into account multiple
covariates in adjusted models, but we cannot rule out a role for unmeasured confounding factors.
Other important limitations to these findings include the use of self-reported data collected online
in a volunteer sample, where diagnoses, disease flares and subsequent changes to treatment were not
confirmed by a medical professional. To mitigate this possible misclassification, we required both self-
report and a change in medication to increase the likelihood that this was a true flare. A previous study
revealed that many mild flares are self-managed at home without involving medical professionals (18).
There may have been selection bias due to differential response to the questionnaire, with some unable
to utilize the computer-based platform, as well as exclusion of patients too ill to respond or those who
died due to COVID-19. We were unable to determine whether flares occurred after first or second dose
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in people receiving multiple doses in the initial vaccine series, as the number of vaccine doses received
was not queried.
Because some vaccine side effects may resemble flare of underlying SRD, we required report of
medication change to enhance the specificity of the flare definition. However, some symptoms of flare
may resemble vaccine side effects such as fatigue and arthralgia, though the later are typically transient.
We lacked a comparator group to determine flare rates among patients who did not receive the vaccine
over the same period. Given the baseline frequencies of disease flares for patients with SRD, it is likely
that some of the reported disease flares were incidental and not causally related. Multiple factors could
trigger SRD flare, including infection, psychosocial stress, and poor medication adherence. The
underlying risk of flare also differs among the autoimmune and inflammatory rheumatic diseases. The
higher frequency of flares reported in patients with systemic lupus erythematosus, psoriatic arthritis and
polymyalgia rheumatica may not be related to COVID-19 vaccination, but rather to a higher background
flare rate for these SRDs.
While the GRA is a global initiative and the survey included many languages, most of the
respondents who received the vaccine were in the region of the Americas and Europe with self-reported
White race, likely due to availability of vaccine at the time the survey was conducted. Future studies will
need to include more diverse populations. Taken together, these results should be interpreted cautiously,
but call for future controlled, prospective studies to determine rates and predictors of disease flare after
COVID-19 vaccination in patients with SRD.
In summary, our results found several factors associated with potential flares of SRD following
COVID-19 vaccines. Population-based and prospective clinical studies are needed to confirm and extend
these findings.
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Acknowledgments: We thank Drs. Andrew Kroger and Gina A. Montealegre Sanchez for critical review
of the manuscript and Dr. Janet Hall for support of this work. We thank members of the COVID-19
Global Rheumatology Alliance Vaccine Survey Group who contributed to this study:
Akpabio A. Akpabio, FMCP, Deshire Alpizar-Rodriguez, MD, PhD, Francis Berenbaum, MD, PhD,
Inita Bulina, MD, Richard Conway, MB, BCh, BAO, PhD, FRCPI, LRCSI, CCD, Aman Dev Singh, MBBS,
MD, Eimear Duff, MB, BCh, BAO, FSch, MBA, Karen Durrant, RN, BSN, Tamer A Gheita, MD,
Catherine L Hill, MBBS, MD, MSc, FRACP, Richard Howard, Bimba F. Hoyer, MD, PhD, Evelyn Hsieh,
MD, PhD, Lina el Kibbi, MD, Adam Kilian, MD, Alfred H.J. Kim, MD, PhD, David Liew, MBBS, Chieh Lo,
Bruce Miller, Serena Mingolla, Michal Nudel, Candace A. Palmerlee, Jasvinder A Singh, MBBS, MPH,
Namrata Singh, MD, MSCI, Manuel F. Ugarte-Gil, MD, MSc, John Wallace, Kristen J. Young, Suleman
Bhana, MD, Wendy Costello, Rebecca Grainger, MB, ChB, PhD, FRACP, Pedro M. Machado, FRCP,
PhD, Philip C. Robinson, MBChB, PhD, FRACP, MAICD, Paul Sufka, MD, Zachary S Wallace, MD,
MPH, Jinoos Yazdany, MD, MPH, Gary Foster, BA, PhD, Lehana Thabane, PhD, Saskya Angevare,
Richard P. Beesley, Eugenia Chock, Berk Degirmenci, Christele Felix, Shangyi Jin, Elsa Mateus, Andrea
Peirce, Esra Sari, Robert Tseng, Leslie Wang, and Erick Adrian Zamora
ACR/EULAR Disclaimer Statement: The views expressed here are those of the authors and
participating members of the COVID-19 Global Rheumatology Alliance and do not necessarily represent
the views of the American College of Rheumatology (ACR), the European Alliance of Associations for
Rheumatology (EULAR), the (UK) National Health Service (NHS), the National Institute for Health
Research (NIHR), or the (UK) Department of Health, or any other organization.
Patient and public participation: Patient partners were involved in the design, conduct, reporting and
interpretation of the results of this study. Patient partners have participated in the development of this
manuscript and are listed as co-authors.
Funding: This study was supported in part by the Intramural Research Program of the National Institutes
of Health, the National Institute of Environmental Health Sciences (project Z01 ES101074 and the
Clinical Research Branch), and by the European Alliance of Associations for Rheumatology and
American College of Rheumatology Research and Education Foundation. Social & Scientific Systems
was supported under a contract with NIEHS (HHSN273201600002I).
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Disclosures: The following authors have declared conflicts of interest as follows: Adam Schiffenbauer
owns stock in Astra Zeneca; Emily Sirotich has a leadership or fiduciary role in the Canadian Arthritis
Patient Alliance; Maggie Larche has received payment or honoraria for lectures, presentations or
speaker bureaus from Abbvie, Actelion, Amgen, BMS, Boehring-Ingelheim, Fresenius-Kabi, Gilead,
Janssen, Mallinckrodt, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, Sobi and UCB; Carlene Harrison
has received grants or contracts from AstraZeneca Pharmaceuticals, Aurinia Pharmaceuticals,
GlaxoSmithKline, UCB (Union Chimique Belge), Janssen Pharmaceuticals, Lupus Therapeutics,
consulting fees from the American College of Rheumatology, and payment or honoraria for lectures or
presentations from the American College of Rheumatology, and received support for attending meetings
and travel from the Lupus and Allied Diseases Association, Inc and the American College of
Rheumatology, participated in the NIH COVID-19 Treatment Guidelines Panel, and has a leadership or
fiduciary role in LupusChat, Inc., and owns stock in Aurinia Pharmaceuticals; Michael Putman has
declared financial or non-financial interests in AbbVie (SELECT-GCA clinical site) and AstraZeneca
(MANDARA, undergoing site selection); Jonathan Hausmann had received grants or contracts from the
Rheumatology Research Foundation and the Childhood Arthritis and Rheumatology Research Alliance
(CARRA), consulting fees from Pfizer, BioGen and Novartis; Julia Simard has received grants or
contracts from NIAMS-NIH (RO1 AR077103) and NIAMS-NIH (RO1 AI154533) and the Pappas Award
from the Preeclampsia Foundation (all unrelated to this work) and she is a scientific advisor to the Lupus
Allied Diseases Association; Jeffrey Sparks has received grant funding from the National Institute of
Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the R.
Bruce and Joan M. Mickey Scholar Fund and consulting fees from AbbVie, Bristol Myers Squibb, Gilead,
Inova Diagnostics, Optum and Pfizer.
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References
1. Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, et al. BNT162b2 mRNA Covid-19
Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021;384(15):1412-23.
2. Fagni F, Simon D, Tascilar K, Schoenau V, Sticherling M, Neurath MF, et al. COVID-19 and
immune-mediated inflammatory diseases: effect of disease and treatment on COVID-19 outcomes and
vaccine responses. Lancet Rheumatol. 2021;3(10):e724-e36.
3. Sattui SE, Liew JW, Kennedy K, Sirotich E, Putman M, Moni TT, et al. Early experience of COVID-19
vaccination in adults with systemic rheumatic diseases: results from the COVID-19 Global Rheumatology
Alliance Vaccine Survey. RMD open. 2021;7(3):e001814.
4. Felten R, Kawka L, Dubois M, Ugarte-Gil MF, Fuentes-Silva Y, Piga M, et al. Tolerance of COVID-19
vaccination in patients with systemic lupus erythematosus: the international VACOLUP study. Lancet
Rheumatol. 2021;3(9):e613-e615.
5. Connolly CM, Ruddy JA, Boyarsky BJ, Barbur I, Werbel WA, Geetha D, et al. Disease Flare and
Reactogenicity in Patients with Rheumatic and Musculoskeletal Diseases Following Two-Dose SARS-CoV-
2 Messenger RNA Vaccination. Arthritis Rheumatol. 2022 Jan;74(1):28-32.
6. Fan Y, Geng Y, Wang Y, Deng X, Li G, Zhao J, et al. Safety and disease flare of autoimmune
inflammatory rheumatic diseases: a large real-world survey on inactivated COVID-19 vaccines. Ann
Rheum Dis. 2021. Nov 25:annrheumdis-2021-221736. doi: 10.1136/annrheumdis-2021-221736.
7. Machado PM, Lawson-Tovey S, Strangfeld A, Mateus EF, Hyrich KL, Gossec L, et al. Safety of
vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal diseases: results from the
EULAR Coronavirus Vaccine (COVAX) physician-reported registry. Ann Rheum Dis. 2021 Dec
31:annrheumdis-2021-221490. doi: 10.1136/annrheumdis-2021-221490.
8. Stevens E, Weinblatt ME, Massarotti E, Griffin F, Emani S, Desai S. Safety of the Zoster Vaccine
Recombinant Adjuvanted in Rheumatoid Arthritis and Other Systemic Rheumatic Disease Patients: A
Single Center's Experience With 400 Patients. ACR Open Rheumatol. 2020;2(6):357-61.
9. Nakafero G, Grainge MJ, Myles PR, Mallen CD, Zhang W, Doherty M, et al. Association between
inactivated influenza vaccine and primary care consultations for autoimmune rheumatic disease flares: a
self-controlled case series study using data from the Clinical Practice Research Datalink. Ann Rheum Dis.
2019;78(8):1122-6.
10. Park JK, Lee MA, Lee EY, Song YW, Choi Y, Winthrop KL, et al. Effect of methotrexate
discontinuation on efficacy of seasonal influenza vaccination in patients with rheumatoid arthritis: a
randomised clinical trial. Ann Rheum Dis. 2017;76(9):1559-65.
11. Klok FA, Pai M, Huisman MV, Makris M. Vaccine-induced immune thrombotic thrombocytopenia.
Lancet Haematol. 2022 Jan;9(1):e73-e80.
12. Putman M, Kennedy K, Sirotich E, Liew JW, Sattui SE, Moni TT, et al. COVID-19 vaccine
perceptions and uptake: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey.
Lancet Rheumatol. 2022 Apr;4(4):e237-e240. doi: 10.1016/S2665-9913(22)00001-7. Epub 2022 Feb 8.
13. Strangfeld A, Schäfer M, Gianfrancesco MA, Lawson-Tovey S, Liew JW, Ljung L, et al. Factors
associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19
Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2021;80(7):930-42.
14. Boekel L, Kummer LY, van Dam KPJ, Hooijberg F, van Kempen Z, Vogelzang EH, et al. Adverse
events after first COVID-19 vaccination in patients with autoimmune diseases. Lancet Rheumatol.
2021;3(8):e542-e545.
Page 16 of 24Rheumatology
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15. Barbhaiya M, Levine JM, Bykerk VP, Jannat-Khah D, Mandl LA. Systemic rheumatic disease flares
after SARS-CoV-2 vaccination among rheumatology outpatients in New York City. Ann Rheum Dis.
2021;80(10):1352-4.
16. Felten R, Scherlinger M, Guffroy A, Poindron V, Meyer A, Giannini M, et al. Incidence and
predictors of COVID-19 and flares in patients with rare autoimmune diseases: a systematic survey and
serological study at a national reference center in France. Arthritis Res Ther. 2021;23(1):188.
17. Teijaro JR, Farber DL. COVID-19 vaccines: modes of immune activation and future challenges.
Nature Reviews Immunology. 2021;21(4):195-7.
18. Bykerk VP, Shadick N, Frits M, Bingham CO 3rd, Jeffery I, Iannaccone C, Weinblatt M, Solomon
DH. Flares in rheumatoid arthritis: frequency and management. A report from the BRASS registry. J
Rheumatol. 2014 Feb;41(2):227-34.
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Table 1. Characteristics and clinical features in rheumatic disease patients receiving COVID-19
vaccines by subsequent disease flare.
Overall
(n=5,619)
n (%)
Flare
(n=274)
n (%)
No Flare
(n=5,345)
n (%)
Prevalence
of Flare
%
Age at enrollment, years
(median [Q1, Q3])
55.5
[44.4, 65.4]
52.4
[44.3, 61.5]
55.5
[44.4, 65.5]
4.9
Sex at birth
Male
802 (14.3)
14 (5.1)
788 (14.7)
1.7
Female
4,817 (85.7)
260 (94.9)
4,557 (85.3)
5.4
Race/ethnicity
White
4,602 (81.9)
237 (86.5)
4,365 (81.7)
5.2
Hispanic, Latinx or Latin American
399 (7.1)
10 (3.6)
389 (7.3)
2.5
Asian (South, East Asia)
109 (1.9)
6 (2.2)
103 (1.9)
5.5
Middle Eastern or North African
87 (1.5)
5 (1.8)
82 (1.5)
5.7
Black
78 (1.4)
4 (1.5)
74 (1.4)
5.1
American Indian/Alaska Native/Aboriginal/
Indigenous/First Nations
16 (0.3)
0 (0.0)
16 (0.3)
0.0
Other*
328 (5.8)
12 (4.4)
316 (5.9)
3.7
Systemic rheumatic disease
Rheumatoid arthritis
1,701 (30.3)
77 (28.1)
1,624 (30.4)
4.5
Idiopathic inflammatory myopathies
824 (14.7)
16 (5.8)
808 (15.1)
1.9
Systemic lupus erythematosus
791 (14.1)
53 (19.3)
738 (13.8)
6.7
Sjogren’s syndrome
540 (9.6)
22 (8.0)
518 (9.7)
4.1
Psoriatic arthritis
304 (5.4)
24 (8.8)
280 (5.2)
7.9
Ankylosing spondylitis
291 (5.2)
17 (6.2)
274 (5.1)
5.8
Polymyalgia rheumatica
197 (3.5)
16 (5.8)
181 (3.4)
8.1
Vasculitis
163 (2.9)
10 (3.6)
153 (2.9)
6.1
Systemic sclerosis
135 (2.4)
2 (0.7)
133 (2.5)
1.5
Inflammatory bowel disease
118 (2.1)
5 (1.8)
113 (2.1)
4.2
Giant cell arteritis
67 (1.2)
3 (1.1)
64 (1.2)
4.5
Psoriasis
67 (1.2)
4 (1.5)
63 (1.2)
6.0
Asthma, Chronic Bronchitis, Emphysema, or
COPD
No
4,689 (83.5)
217 (79.2)
4,472 (83.7)
4.6
Yes
930 (16.5)
57 (20.8)
873 (16.3)
6.1
BMI
Non-obese (BMI < 30 kg/m2)
4,310 (76.7)
208 (75.9)
4,102 (76.7)
4.8
Obese (BMI 30 kg/m2)
1,309 (23.3)
66 (24.1)
1,243 (23.3)
5.0
Smoking status
Never smoker
3,456 (61.5)
180 (65.7)
3,276 (61.3)
5.2
Past smoker
1,792 (31.9)
74 (27.0)
1,718 (32.1)
4.1
Current smoker
371 (6.6)
20 (7.3)
351 (6.6)
5.4
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COVID-19 vaccine
Pfizer-BioNTech
3,028 (53.9)
137 (50.0)
2,891 (54.1)
4.5
Moderna
1,035 (18.4)
53 (19.3)
982 (18.4)
5.1
Oxford-AstraZeneca
1,200 (21.4)
76 (27.7)
1,124 (21.0)
6.3
Other
356 (6.3)
8 (2.9)
348 (6.5)
2.2
Serious reaction to a non-COVID-19 vaccine
No
5,225 (93.0)
230 (83.9)
4,995 (93.5)
4.4
Yes
394 (7.0)
44 (16.1)
350 (6.5)
11.2
Withheld SRD medications at time of vaccine
No
3,700 (65.8)
183 (66.8)
3,517 (65.8)
5.0
Yes
1,498 (26.7)
79 (28.8)
1,419 (26.5)
5.3
No medications
421 (7.5)
12 (4.4)
409 (7.7)
2.8
Comorbid disease type
Cardiopulmonary
2,707 (48.2)
134 (48.9)
2,573 (48.1)
5.0
Immunodeficiency
454 (8.1)
21 (7.7)
433 (8.1)
4.6
No cardiopulmonary, no immunodeficiency
2,458 (43.7)
119 (43.4)
2,339 (43.8)
4.8
WHO region
Region of the Americas
2,999 (53.4)
127 (46.4)
2,872 (53.7)
4.2
European Region
2,414 (43.0)
140 (51.1)
2,274 (42.5)
5.8
Other Region
206 (3.7)
7 (2.5)
199 (3.7)
3.4
Prior SARS-CoV-2 infection
Yes
570 (10.1)
26 (9.5)
544 (10.2)
4.6
No
4,841 (86.2)
236 (86.1)
4,605 (86.2)
4.9
Not sure
208 (3.7)
12 (4.4)
196 (3.7)
5.8
SRDs reported by >1% of participants shown. A full listing of systemic rheumatic diseases is in
Supplementary Table 1 and full listing of comorbid diseases by type is in Supplementary Table S2, both
available at Rheumatology online.
Abbreviations: SRD, systemic rheumatic disease; BMI, body mass index; COPD, chronic obstructive
pulmonary disease
*Other participants include Pacific Islander, other, prefer not to say, and do not know/unsure.
Other vaccines include Sinovac/Sinopharm, Janssen/Johnson & Johnson, Sputnik V, Cansino,
Covishield, Verocell, and Novavax.
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Table 2. Multivariable-adjusted associations among COVID-19 vaccine-associated disease
flares requiring change in treatment and potential predictors
Multivariable OR
(95% CI)1
Age (per 5 years)
0.97 (0.92-1.02)
Sex
Male
1.00 (ref)
Female
2.71 (1.55-4.72)
Race/ethnicity
Non-Hispanic white
1.00 (ref)
Non-white
0.72 (0.49-1.05)
Systemic rheumatic disease
Rheumatoid arthritis
1.00 (ref)
Idiopathic inflammatory myopathies
0.54 (0.31-0.96)
Systemic lupus erythematosus
1.51 (1.03-2.20)
Sjogren’s syndrome
0.90 (0.55-1.48)
Psoriatic arthritis
1.95 (1.20-3.18)
Ankylosing spondylitis
1.55 (0.89-2.71)
Polymyalgia rheumatica
1.94 (1.08-2.48)
Vasculitis
1.40 (0.70-2.80)
Systemic sclerosis
0.34 (0.08-1.42)
Inflammatory bowel disease
1.01 (0.40-2.57)
Giant cell arteritis
1.01 (0.30-3.36)
Psoriasis
1.29 (0.45-3.69)
Asthma, Chronic Bronchitis, Emphysema, or
COPD
No
1.00 (ref)
Yes
1.20 (0.88-1.63)
BMI
Non-obese (BMI < 30 kg/m2)
1.00 (ref)
Obese (BMI 30 kg/m2)
0.98 (0.73-1.31)
Smoking status
Never smoker
1.00 (ref)
Past smoker
0.84 (0.63-1.12)
Current smoker
1.00 (0.62-1.62)
COVID-19 vaccine
Pfizer-BioNTech
1.00 (ref)
Moderna
1.29 (0.92-1.81)
Oxford-AstraZeneca
1.44 (1.07-1.95)
Other
0.53 (0.25-1.12)
Previous serious reaction to a non-COVID-19
vaccine
No
1.00 (ref)
Yes
2.50 (1.76-3.54)
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Withheld any SRD medication at time of vaccine
No
1.00 (ref)
Yes
1.09 (0.83-1.45)
No medications
0.72 (0.39-1.33)
Odds Ratios (OR) and 95% Confidence Intervals (CI) were calculated in logistic
regression models adjusting for all covariates show in the table and full model results are
shown. SRDs reported by >1% of participants shown. A full listing of systemic rheumatic
diseases is in Supplementary Table S1, available at Rheumatology online. Estimates are
mutually adjusted for all factors listed in the table.
Abbreviations per Table 1.
n=Number of participants with both vaccination and disease flare. N=Number of participants with
vaccination.
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... First, comorbidities and demographic factors, which are also risk factors for developing RA and other SRDs, or are associated with disease activity, may be related to flares after vaccination. Beyond baseline characteristics, cessation of SRD therapies could contribute to disease flares [62]. In their study on adult SLE, Mok et al. reported that patients with active serology and a history of arthritis and discoid skin lesions are more likely to develop disease flares after receiving the COVID-19 vaccine [63]. ...
... An international study evaluated the appearance of flares requiring a change in treatment following COVID-19 vaccination in 4.9% of adults with systemic rheumatic disease. Compared to others rheumatic disorders, SLE was associated with higher odds of flare [62]. ...
... According to recent studies, reported flare rates after vaccination in adult SLE population vary from 3% to 25% [62][63][64][65][66]. Numbers are higher in studies based on patients' self-assessment reported flares via telephonic survey or questionnaire, while medical confirmed flares remained low. ...
Article
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Pediatric systemic lupus erythematosus is a chronic autoimmune disorder with a highly variable course and prognosis. It results in functional abnormalities in the immune system due to intrinsic factors and the use of immunosuppressive therapies associated with underlying comorbidities seem to increase the risk of severe COVID-19 and poor outcomes of the disease in pediatric systemic lupus erythematosus (SLE) patients. The aim of this review is to obtain a better understanding of the existing link between this new viral infection and pediatric lupus. We have analyzed the characteristics of newly diagnosed cases of pediatric SLE following COVID-19 which have been reported in the literature and which describe the impact that COVID-19 has on patients already suffering with pediatric SLE.
... After screening the title and abstract, we reviewed the full text of 103 reports. Five studies were associated with multiple reports; hence, reports of different outcomes arising from the same study were combined [22][23][24][25], or only the report with the largest sample size and/or more outcomes of interest was included [26][27][28]. For reports that included SLE among inflammatory or rheumatic conditions but did not report the SLE-subgroup data, the authors of 14 reports provided further information via personal communication [22,23,25,27,[29][30][31][32][33][34][35][36][37][38]. ...
... Five studies were associated with multiple reports; hence, reports of different outcomes arising from the same study were combined [22][23][24][25], or only the report with the largest sample size and/or more outcomes of interest was included [26][27][28]. For reports that included SLE among inflammatory or rheumatic conditions but did not report the SLE-subgroup data, the authors of 14 reports provided further information via personal communication [22,23,25,27,[29][30][31][32][33][34][35][36][37][38]. Fig. S1, available at Rheumatology online) [40], largely due to incomplete information regarding participant selection. ...
... Post-vaccine adverse events occurred in 948 patients (44.8%) after their first vaccination [28,31,33,41,42,46,49,53,55,56], 876 patients (50.8%) after their second dose [22,25,28,33,41,42,49,52,53,55,56], and 340 patients (43.6%) after an unspecified dose [27,34]. The occurrence of adverse events after the first dose was not significantly different from that of the second dose [odds ratio (OR) 0.94 (95% CI: 0.62-1.40), ...
Article
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Aims: COVID-19 infection is associated with significant morbidity in systemic lupus erythematosus but is potentially preventable by vaccination, although the impact of the myriad vaccines among SLE patients is not established. We aimed to assess the effectiveness, efficacy, acceptance and safety of COVID-19 vaccination in SLE. Methods: We performed a systematic review of PubMed, Embase, CENTRAL, WHO Clinical Trials and ClinicalTrials.gov publications until 8th June 2022 without language, publication year or publication status restrictions. Reports with fewer than 5 patients or incomplete information on study outcomes were excluded. Risk of bias was assessed, and results reported according to PRISMA 2020 guidelines. Results: We identified 32 studies (34 reports) comprising 8269 individuals with SLE. Post-vaccine COVID-19 infections ranged 0-17% in 6 studies (5065 patients), while humoral and cellular immunogenicity, was evaluated in 17 studies (976 patients) and 5 studies (112 patients), respectively. Pooled seropositivity rate was 81.1% (95% CI: 72.6-88.5%, I2=85%, p< 0.01) with significant heterogeneity and higher rates in mRNA vaccines compared with non-mRNA vaccines. Adverse events and specifically lupus flares were examined in 20 studies (3853 patients) and 13 studies (2989 patients), respectively. Severe adverse events and moderate to severe lupus flares were infrequent. The pooled vaccine acceptance rate was 67.0% (95%CI: 45.2-85.6%, I2=98%, p< 0.01) from 8 studies (1348 patients), with greater acceptance in older patients. Conclusion: Post-vaccine COVID-19 infection, severe flares and adverse events were infrequent and pooled seropositivity and acceptance were high with significant heterogeneity. These results may inform shared-decision making on vaccination during the ongoing COVID-19 pandemic. Protocol registration: PROSPERO; https://www.crd.york.ac.uk/PROSPERO/; CRD42021233366.
... Different RDs can have different risks of disease flare. SLE, the typical representative of RDs, showed a flare rate ranging from 3% to 20% (16,19,21,29,31). Patients with RA, another common RD, shared similar flare rates in several studies (11.3% vs. 9.4% vs. 7.8%) (19,21,35). ...
... Rider et al. reported higher risks of flares for SLE, psoriatic arthritis, and polymyalgia rheumatica compared to RA (29), while some other studies found that the type of RDs had no significant effect on the occurrence of flares after vaccination (19,21). However, another study also revealed an association between the flare-ups and having more than one RDs (25). ...
... As more than one RDs may associate with either higher disease activity or more complexity in immunity, the exact effect on disease flare is still unknown. Several other risk factors, like elderly, female, allergic history, previous infection of SARS-CoV-2, and serious reaction to a non-COVID-19 vaccine, were also reported (19,21,29), even though the evidence was weak. ...
Article
Full-text available
As the coronavirus disease 2019 (COVID-19) pandemic continues worldwide, vaccination has been considered an effective measure to protect people from the COVID-19 and end the pandemic. However, for patients with rheumatic diseases (RD), concern for the induction of RD flare may combat the enthusiasm for vaccination. In general, current evidence doesn’t support the increased risk of disease flare after COVID-19 vaccination. However, the disease flare of RDs may be triggered by COVID-19 vaccinations, especially for patients with high disease activity. Most of these flares after vaccination are mild and need no treatment escalation. Considering the benefits and risks, RD patients are recommended to receive the COVID-19 vaccination but should be vaccinated when the RDs are in stable states.
... [36] The second patient-facing GRA survey investigated clinical experience and uptake/attitudes related to the novel COVID-19 vaccines. These data identified that patients with rheumatic diseases had prolonged COVID-19 symptom duration [37] and low rate of disease flare post-vaccination, [38] and identified the need to reassure patients about vaccine efficacy and safety as critical variables in vaccine uptake. [39] The Vaccination Against COVID in Systemic Lupus (VACOLUP) exclusively used social media for participant recruitment. ...
Article
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Social media has become an important venue for rheumatologists, patients, organizations, and other stakeholders to discuss recent research advances in diagnosis and management of rheumatic disorders. In this article, we describe the current state of how social media may enhance dissemination, discourse, and collaboration in rheumatology research. Social media may refer to social platforms like Twitter and Instagram or digital media like podcasts and other websites that are operated for providing as free, open-access medical education (FOAM). Twitter has been one of the most active social media venues and continues to host a vibrant rheumatology community. Examples of research discussions on Twitter include organic user tweets, educational threads (“tweetorials”), live-tweeting academic conferences, and journals posting recently-accepted articles. Some research collaborations have been initiated through social media interactions. Social media may also directly contribute to research by facilitating the recruitment of study participants and the collection of survey-based data. Thus, social media is an evolving and important tool to enhance research discourse, dissemination, and collaboration in rheumatology.
Article
Purpose of review: To summarize the findings of studies investigating patients with rheumatoid arthritis (RA) and risk of acute and postacute COVID-19 outcomes 3 years into the pandemic. Recent findings: Most studies early in the pandemic included all patients with systemic autoimmune rheumatic diseases (SARDs), not only those with RA, due to limited sample size. Many of these studies found that patients with SARDs were at higher risk of COVID-19 infection and severe outcomes, including hospitalization, hyperinflammation, mechanical ventilation, and death. Studies performed later were able to focus on RA and found similar associations, while also identifying RA-specific factors such as immunosuppressive medications, disease activity/severity, and interstitial lung disease as risk factors for severe COVID-19. After COVID-19 vaccination, the risks for COVID-19 infection and severity were reduced for patients with RA, but a gap between the general population persisted, and some patients with RA are susceptible to breakthrough infection after vaccination. Preexposure prophylaxis, effective treatments, and changes in viral variants have also contributed to improved COVID-19 outcomes throughout the pandemic. Emerging data suggest that patients with RA may be at risk for postacute sequelae of COVID-19 (PASC). Summary: Although COVID-19 outcomes have improved over the pandemic for patients with RA, some experience poor acute and postacute outcomes after COVID-19. Clinicians and patients should remain vigilant about risk mitigation for infection and consider early treatment for RA patients with COVID-19. Future studies are needed to investigate clinical outcomes and mechanisms of PASC among patients with RA.
Article
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Objective New-onset immune-mediated inflammatory diseases (IMIDs) and flares of pre-existing IMIDs have been reported following anti- SARS-CoV2 vaccination. Our study aimed at describing a retrospective cohort of patients developing new-onset IMIDs or flares of known IMIDs within 30 days after any anti-SARS-CoV2 vaccine dose. Methods We evaluated clinical records of all inpatients and outpatients referring to our institution between February 2021 and February 2022 with any clinical manifestations. We then selected those having received any anti-SARS-CoV2 vaccine dose within the prior 30 days and classified them as having or not a previous IMID according to predefined criteria. We recorded new-onset IMIDs or flares of known IMIDs and investigated any relationship with demographic, clinical and serological variables. Results 153 patients that received any anti-SARS-CoV2 vaccine dose within the previous 30 days were included of which 45 (29%) already had a diagnosis of IMID while 108 (71%) had no previously diagnosed IMID. 33 (30%) of the 108 patients, were diagnosed with a new-onset IMID. Pericarditis, polymyalgia rheumatica and vasculitis were the most frequent conditions. Among the 45 patients that already had an IMID, disease flare was the reason for referral in 69% of patients. Patients with an IMID flare had a lower number of comorbidities and tended to be younger compared with those who developed other conditions after anti-SARS-CoV2 vaccination. Conclusion We provided a retrospective overview of a cohort of patients who developed new-onset IMIDs or flares of known IMIDs within 30 days after any dose of anti-SARS-CoV2 vaccine. While vaccination campaigns proceed, postvaccination surveillance programmes are ongoing and hopefully will soon clarify whether a causal relationship between vaccines and new-onset/flares of IMIDs exists.
Article
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Objectives To investigate the association between vaccination against Covid-19 and autoimmune rheumatic disease (AIRD) flare. Methods Patients with AIRDs vaccinated against Covid-19 who consulted for disease flare between 01/12/2020 and 31/12/2021 were ascertained in Clinical Practice Research Datalink (Aurum). AIRD flare was defined as consultation for AIRD with corticosteroid prescription on the same day or the next day. Vaccination was defined using date of vaccination and product code. The observation period was partitioned into vaccine-exposed (21-days after vaccination), pre-vaccination (7-days before vaccination), and remaining vaccine-unexposed periods. Participants contributed data with multiple vaccinations and outcomes. Season adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) were calculated using self-controlled case-series analysis. Results Data for 3554 AIRD cases, 72% female, mean age 65 years, and 68.3% with rheumatoid arthritis were included. Covid-19 vaccination was associated with significantly fewer AIRD flares in the 21-day vaccine-exposed period when all vaccinations were considered (aIRR(95%CI) 0.89(0.80–0.98)). Using dose-stratified analyses there was a statistically significant negative association in 21-days after first Covid-19 vaccination but no association after the second or third Covid-19 vaccinations (aIRR(95%CI) 0.76(0.66–0.89), 0.94(0.79–1.11) and 1.01(0.85–1.20) respectively). On AIRD type stratified analyses, vaccination was not associated with disease flares. Vaccination without or after SARS-CoV-2 infection, and with vectored DNA or mRNA vaccines associated with comparable reduced risk of AIRD flares in the vaccine-exposed period after first Covid-19 vaccination. Conclusion Vaccination against Covid-19 was not associated with increased AIRD flares regardless of prior Covid-19, AIRD type, and whether mRNA or DNA vaccination technology were used.
Article
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Background We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. Methods From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. Results We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. Conclusion Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.
Article
Full-text available
Background We describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine. Methods From 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination. Results We analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%. Conclusion Among adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.
Article
Full-text available
Abstract Background The risk of severe COVID-19 and its determinants remain largely unknown in patients with autoimmune and inflammatory rheumatic diseases. The objective of this study was to assess the prevalence of COVID-19 infection in patients followed for rare autoimmune diseases as well as the predictors of COVID-19 and disease flare-ups. Methods Cross-sectional phone survey from April 9, 2020, to July 2, 2020, during which patients with autoimmune diseases followed at the National Reference Center for Rare Autoimmune diseases of Strasbourg were systematically contacted by phone and sent a prescription for a SARS-CoV-2 serology. Results One thousand two hundred thirty-two patients were contacted. One thousand fifty-five patients with a confirmed diagnosis of systemic autoimmune disease were included (4 unreachable, 4 moves abroad, 5 deaths before pandemic, 50 without consent, and 114 without autoimmune disease). Among them, 469 (44.5%) patients were tested for SARS-CoV-2 serology. Thirty-nine patients (7.9%) had SARS-CoV-2 infection (either through chest CT-scan [n = 5], RT-PCR on nasopharyngeal swab [n = 14], or serology [n = 31]) among the 496 who underwent at least one of those 3 diagnosis modalities. Of the 39 proven cases, 33 had clinical manifestations (6 asymptomatic patients were diagnosed through systematic serology testing), 31 were managed by home care, 3 were hospitalized due to a need for oxygenation, two required admission to an intensive care unit, and one died. Among patients with confirmed SARS-CoV-2 infection, reported flares were more frequent than in uninfected patients (26.3% [10/38] vs. 7.0% [32/457], p
Article
Objectives To describe the safety of vaccines against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal disease (I-RMD). Methods Physician-reported registry of I-RMD and non-inflammatory RMD (NI-RMDs) patients vaccinated against SARS-CoV-2. From 5 February 2021 to 27 July 2021, we collected data on demographics, vaccination, RMD diagnosis, disease activity, immunomodulatory/immunosuppressive treatments, flares, adverse events (AEs) and SARS-CoV-2 breakthrough infections. Data were analysed descriptively. Results The study included 5121 participants from 30 countries, 90% with I-RMDs (n=4604, 68% female, mean age 60.5 years) and 10% with NI-RMDs (n=517, 77% female, mean age 71.4). Inflammatory joint diseases (58%), connective tissue diseases (18%) and vasculitis (12%) were the most frequent diagnostic groups; 54% received conventional synthetic disease-modifying antirheumatic drugs (DMARDs), 42% biological DMARDs and 35% immunosuppressants. Most patients received the Pfizer/BioNTech vaccine (70%), 17% AstraZeneca/Oxford and 8% Moderna. In fully vaccinated cases, breakthrough infections were reported in 0.7% of I-RMD patients and 1.1% of NI-RMD patients. I-RMD flares were reported in 4.4% of cases (0.6% severe), 1.5% resulting in medication changes. AEs were reported in 37% of cases (37% I-RMD, 40% NI-RMD), serious AEs in 0.5% (0.4% I-RMD, 1.9% NI-RMD). Conclusion The safety profiles of SARS-CoV-2 vaccines in patients with I-RMD was reassuring and comparable with patients with NI-RMDs. The majority of patients tolerated their vaccination well with rare reports of I-RMD flare and very rare reports of serious AEs. These findings should provide reassurance to rheumatologists and vaccine recipients and promote confidence in SARS-CoV-2 vaccine safety in I-RMD patients.
Article
In response to the COVID-19 pandemic, vaccines for SARS-CoV-2 were developed, tested, and introduced at a remarkable speed. Although the vaccine introduction had a major impact on the evolution of COVID-19, some potential rare side-effects of the vaccines were observed. Within a short period, three scientific groups from Norway, Germany, and the UK reported cerebral venous sinus thrombosis with thrombocytopenia and anti-platelet factor 4 (anti-PF4) antibodies in individuals following AstraZeneca–Oxford vaccination and named this new syndrome vaccine-induced immune thrombotic thrombocytopenia (VITT). This syndrome was subsequently reported in individuals who received Johnson & Johnson vaccination. In this Viewpoint, we discuss the epidemiology, pathophysiology, and optimal diagnostic and therapeutic management of VITT. Presentation of an individual with possible VITT should raise prompt testing for anti-PF4 antibodies and initiation of treatment targeting autoimmune processes with intravenous immunoglobulin and prothrombotic processes with non-heparin anticoagulation.
Article
At the beginning of the COVID-19 pandemic, patients with immune-mediated inflammatory diseases were considered to be at high risk for SARS-CoV-2 infection and the development of severe COVID-19. Data collected over the past year, however, suggest that a diagnosis of inflammatory arthritis, psoriasis, or inflammatory bowel diseases does not increase risk for SARS-CoV-2 infection or severe COVID-19 compared with people without these diseases. Furthermore, substantial data suggest that certain medications frequently used in patients with immune-mediated inflammatory diseases, in particular cytokine inhibitors, might even lower the risk for severe COVID-19. Conversely, glucocorticoids and potentially B-cell-depleting treatments seem to worsen COVID-19 outcomes. Additionally, the first data on SARS-CoV-2 vaccination in patients with these diseases suggest that tolerability of vaccination in patients with immune-mediated inflammatory diseases is good, although the immune response to vaccination can be somewhat reduced in this patient group, particularly those taking methotrexate or CD20-targeted treatment.
Article
Objective To evaluate disease flare and post-vaccination reactions (reactogenicity) in patients with rheumatic and musculoskeletal diseases (RMD) following two-dose SARS-CoV-2 mRNA vaccination. Methods 1377 patients with RMD who received two-dose SARS-CoV-2-mRNA vaccination between 16 December 2020 and April 15, 2021 completed questionnaires detailing local and systemic reactions experienced within 7 days of each vaccine dose (D1, D2), and one month after D2 detailing flare of RMD. Associations between demographic/clinical characteristics and flare requiring treatment were evaluated using modified Poisson regression. Results 11 percent reported flare requiring treatment; there were no reports of severe flares. Flare was associated with prior SARS-CoV-2 infection (IRR 2.09, p=0.02), flare in the six months preceding vaccination (IRR 2.36, p<0.001) and use of combination immunomodulatory therapy (IRR 1.95, p<0.001). The most frequently reported local and systemic reactions included injection site pain (D1 87%, D2 86%) and fatigue (D1 60%, D2 80%); reactogenicity increased after D2, particularly for systemic reactions. No allergic reactions or SARS-CoV-2 diagnoses were reported. Conclusion Flare of underlying RMD following SARS-CoV-2 vaccination was uncommon. There were no reports of severe flare. Local and systemic reactions typically did not interfere with daily activity. These early safety data can help address vaccine hesitancy in patients with RMD.