Abstract
Objective To determine if coronavirus disease 2019 (COVID-19) vaccines were associated with adverse events of special interest (AESIs) and healthcare use among adults with rheumatoid arthritis (RA).
Methods Among adults with RA who received at least 1 COVID-19 vaccine, a self-controlled case series (SCCS) analysis was conducted to evaluate relative incidence (RI) rates of AESIs (Bell palsy, idiopathic thrombocytopenia, acute disseminated encephalomyelitis, pericarditis/myocarditis, Guillain-Barré syndrome, transverse myelitis, myocardial infarction, anaphylaxis, stroke, deep vein thrombosis, pulmonary embolism, narcolepsy, appendicitis, and disseminated intravascular coagulation) in any 21-day period following vaccination compared to control periods. Secondary outcomes included emergency department (ED) visits, hospitalizations, and rheumatology visits. A matched non-RA comparator group was created and a separate SCCS analysis was conducted. RI ratios (RIRs) were used to compare RA and non-RA groups.
Results Among 123,466 patients with RA and 493,864 comparators, the majority received mRNA vaccines. For patients with RA, relative to control periods, AESIs were not increased. ED visits increased after dose 2 (RI 1.06, 95% CI 1.03-1.10) and decreased after dose 3 (RI 0.93, 95% CI 0.89-0.96). Hospitalizations were lower after the first (RI 0.83, 95% CI 0.78-0.88), second (RI 0.86, 95% CI 0.81-0.92), and third (RI 0.89, 95% CI 0.83-0.95) doses. Rheumatology visits increased after dose 1 (RI 1.08, 95% CI 1.07-1.10), and decreased after doses 2 and 3. Relative to comparators, patients with RA had a higher AESI risk after dose 3 (RIR 1.28, 95% CI 1.05-1.56). Patients with RA experienced fewer ED visits (RIR 0.73, 95% CI 0.58-0.90) and hospitalizations (RIR 0.52, 95% CI 0.36-0.75) after dose 4.
Conclusion COVID-19 vaccines in patients with RA were not associated with an increase in AESI risk or healthcare use after every dose.
- COVID-19
- health administrative data
- rheumatoid arthritis
- routinely collected health data
- safety
- vaccination
Although adverse events of special interest (AESIs) following coronavirus disease 2019 (COVID-19) vaccination are considered rare, emerging reports have suggested that the risk of AESIs may be higher in certain subgroups of individuals.1-3 There is an incomplete understanding of the full safety profiles of COVID-19 vaccinations within specific subpopulations such as individuals with rheumatoid arthritis (RA), who were excluded from clinical trials for COVID-19 vaccines.4,5 Consequently, individuals with RA and their physicians have been concerned about the safety of COVID-19 vaccines. Passive surveillance data for individuals with RA have been limited.6,7 However, evidence suggests that vaccine immunogenicity/reactogenecity may be affected by RA or associated immunosuppressive therapies, which may therefore lead to different safety profiles compared to the general population.3 As large sample sizes are needed to detect rare AESIs, population-based data are vital to provide confidence in measures of vaccine safety.
Self-controlled case series (SCCS) design studies offer advantages in evaluating vaccination safety8 by using a case-only design where individuals serve as their own control, to mitigate potential biases.9,10 Further, when a vaccine is administered in multiple doses, multiple risk and control periods can be assessed while controlling for clustering.11
Strengthening the evidence around the safety of COVID-19 vaccinations can help increase vaccine confidence.12-14 Our objective was to determine, using a population-based sample, whether COVID-19 vaccination is associated with an increased risk of AESIs and healthcare use (emergency department [ED] visits, hospitalizations, and rheumatology visits) among adults with RA. We also evaluated whether AESIs and healthcare use were higher for COVID-19–vaccinated adults with and without RA.
METHODS
Study design. We constructed population-based cohorts of adults with and without RA, who received at least 1 COVID-19 vaccination from June 14, 2020 (6 months prior to the start of Ontario’s COVID-19 vaccination program) until August 1, 2021. A SCCS analysis was performed with each cohort.
Ethics approval. Projects that use data collected by ICES under section 45 of Ontario’s Personal Health Information Protection Act (PHIPA), and use no other data, are exempt from research ethics board review. The use of the data in this project was authorized under section 45 and approved by ICES’ Privacy and Legal Office. ICES is a prescribed entity under PHIPA. Section 45 of PHIPA authorizes ICES to collect personal health information, without consent, for the purpose of analysis or compiling statistical information with respect to the management, evaluation, or monitoring of the allocation of resources to or planning for all or part of the health system.
Setting and data sources. This study was conducted in Ontario, Canada, where information for all residents on all contacts with a single-payer healthcare system are captured within health administrative data. Databases used in this study were using linked unique encoded identifiers and analyzed at ICES (formerly the Institute for Clinical Evaluative Sciences).
The Registered Persons Database (RPDB) was used to identify inclusion criteria and to obtain demographic characteristics of the cohort. COVID-19 vaccination status (product, date administered, and dose number) were ascertained from the COVaxON database. To identify outcomes and comorbidity, we used physician claim diagnosis codes from the Ontario Health Insurance Plan (OHIP) and identified hospital discharge diagnosis codes from inpatient hospital admissions (from the Canadian Institute for Health Information’s Discharge Abstract Database) and ED visits (from the National Ambulatory Care Reporting System; Supplementary Table S1, available from the authors upon request). Rheumatology visits were identified by linking the ICES Physician Database and OHIP billing claims database. Information on prior SARS-CoV-2 infections was obtained from the C19INTGR database, which includes all Ontario SARS-CoV-2 PCR test results, but not home antigen test results. Prior influenza vaccination administered in physician offices and pharmacies was ascertained from the OHIP database and the Ontario Drug Benefit database, respectively.
Study population. Adults with an RA diagnosis were identified based on having at least 1 hospitalization or at least 3 physician diagnosis codes for RA within 2 years, with at least 1 by a rheumatologist, internist, or orthopedic surgeon (case definition sensitivity and positive predictive value 78%, specificity 100%).15
We included adult individuals (aged ≥ 18 years) with OHIP coverage for at least 6 months prior to their first COVID-19 vaccine. A separate general population cohort was sampled from the RPDB, and 4 non-RA comparators were matched on sex, age (± 2 years), and region of residence for each individual with RA. All individuals were required to have received at least 1 COVID-19 vaccination from December 2020 (the first vaccination wave) until January 2022 (to permit a maximum follow-up date to March 2022). We excluded long-term care residents, and individuals who received COVID-19 vaccines outside of Ontario.
Patient characteristics. Characteristics included age, sex, neighborhood income quintile (assigned from census estimates, based on postal code regions), rural residence, prior SARS-CoV-2 infection, past influenza vaccination, COVID-19 vaccine characteristics, comorbidities, and frailty. Comorbidities (predating vaccine exposure) included whether or not patients had a history of hypertension, chronic respiratory disease, diabetes, chronic heart disease, chronic kidney disease, advanced liver disease, dementia, stroke, or transient ischemic attack. Frailty was defined using the Johns Hopkins Adjusted Clinical Groups, ACG frailty indicator, System Version 10.
Outcomes. AESIs were treated as a composite outcome and included Bell palsy, idiopathic thrombocytopenia, acute disseminated encephalomyelitis, myocarditis, pericarditis, Guillain-Barré syndrome, transverse myelitis, acute myocardial infarction, anaphylaxis, stroke, deep vein thrombosis, pulmonary embolism, narcolepsy, appendicitis, and disseminated intravascular coagulation. An individual would require at least 1 of the mentioned diagnoses to satisfy the AESI definition. The decision to group the AESIs as a composite outcome was made a priori, given that we suspected few events for each of these AESIs had they been considered separately.16 Diagnosis codes to ascertain these conditions are detailed in Supplementary Table S1 (available from the authors upon request). With the exception of Bell palsy, all AESIs were defined as a hospitalization or ED visit with a diagnosis code for the conditions of interest. Event dates were defined according to admission dates (as opposed to discharge dates). Bell palsy was additionally ascertained using diagnosis codes from physician billing claims, since this condition is more likely to be managed entirely in ambulatory clinics (without ED or hospital contact).
Secondary outcomes included all-cause hospitalizations, ED visits, and rheumatology visits.
Risk and control periods. The SCCS design requires the partitioning of an individual’s observation period into control and postvaccination risk periods to compare the incidence of events within risk and control periods (Figure). The prevaccination baseline control period was defined as the 6 months prior to the first COVID-19 dose but exclusive of the 14 days prior to the first dose (washout period), to avoid a “healthy vaccinee effect” (ie, patients may wait until they are in relatively good health before receiving a vaccine). Control periods between doses started on day 22 from the last dose and ended 14 days prior to the next dose. A final control period commenced after the final dose risk period (up to a maximum of 6 months). AESIs, hospitalizations, and ED visits all required a 21-day risk period, and a sensitivity analysis was performed to extend the risk period up to 42 days. For rheumatology visits, a 30-day risk period was used for the primary analysis, with an alternate 3-month risk window used in the sensitivity analysis. This risk period after exposure is based on the concept that if individuals with RA experience a flare after a vaccine, delays in seeing their rheumatologist may be because of potential access issues heightened during the pandemic.17
Description of risk and control periods for SCCS analysis. In this example, a patient with RA received a COVID vaccine 3 times in the follow-up period. In the case of matched non-RA comparators, the risk and control periods were similarly derived. AESI: adverse event of special interest; COVID: coronavirus disease 2019; ED: emergency department; RA: rheumatoid arthritis; SCCS: self-controlled case series.
Analysis. Events were ascertained across control and risk periods. Conditional Poisson regression was used to estimate incidence ratios (IR; the ratio of the incidence in each dose risk period vs the control periods). IRs in each risk period vs the control period in individuals with RA were compared to the IRs of non-RA comparators, by constructing the ratio of IRs (RIRs) within each postvaccination risk window. Differences in the relative incidence of events by age and sex subgroups were evaluated using subgroup analyses. Sensitivity analyses on extended risk windows were additionally performed.
Analyses were conducted using SAS Enterprise Guide, version 7.14 (SAS Institute).
Role of funding source. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
RESULTS
Cohort characteristics. We studied 123,466 individuals with RA and 493,864 comparators. Most individuals (70.74%) were female, and the median age of the RA group was 65.0 (IQR 55.0-74.0) years, with a median duration since RA diagnosis of 9.34 (IQR 4.16-17.10) years. The majority (99.72%) received at least 1 mRNA vaccine, with 81.88% receiving at least 1 BNT162b2 vaccine and 46.45% receiving at least 1 mRNA-1273 vaccine. Among individuals with RA, 8727 (7.07%) received > 3 doses, 89,583 (72.56%) received 3 doses, 23,652 (19.16%) received 2 doses, and 1504 (1.22%) received a single dose. Among the non-RA population, 373,735 (75.68%) received 3 doses and only 7963 (1.61%) received > 3 doses. The RA cohort had a slightly higher prevalence of hypertension (52.58% vs 46.49%), chronic respiratory disease (33.07% vs 23.84%), and chronic kidney disease (6.83% vs 4.28%) compared to the comparator cohort, respectively (Table 1).
Characteristics of adults with RA and age, sex, and region matched non-RA general population comparators at the time of their first vaccine dose.
AESIs. Relative to control periods, AESI rates were not significantly increased (Table 2). This remained consistent regardless of the dose. The RI after the first, second, third, and fourth doses were 1.05 (95% CI 0.90-1.22), 0.89 (95% CI 0.75-1.04), 1.12 (95% CI 0.95-1.31), and 1.06 (95% CI 0.60-1.87), respectively. Relative to non-RA comparators, individuals with RA had similar RI rates of AESIs over all doses, except for dose 3 where individuals with RA had a slightly higher relative incidence rate (RIR 1.28, 95% CI 1.05-1.56).
Risk of AESIs and health services use in the postvaccination periods in adults with RA and non-RA matched comparators.
All-cause ED visits and hospitalizations. Among individuals with RA, relative to control periods, ED visits remained comparable after the first and fourth doses (Table 2). ED visits were statistically higher after the second dose (RI 1.06, 95% CI 1.03-1.10) and reduced after the third dose (RI 0.93, 95% CI 0.89-0.96). In non-RA comparators, ED visit rates were appreciably higher after both second (RI 1.11, 95% CI 1.08-1.13) and fourth doses (RI 1.39, 95% CI 1.17-1.65) relative to control periods. When comparing individuals with RA to their non-RA comparators, ED visit rates remained comparable after the first 3 doses. Individuals with RA experienced lower ED visits relative to comparators after the fourth dose (RIR 0.73, 95% CI 0.58-0.91).
Individuals with RA experienced lower hospitalizations after the first (RI 0.83, 95% CI 0.78-0.88), second (RI 0.86, 95% CI 0.81-0.92), and third (RI 0.89, 95% CI 0.83-0.95) doses relative to control periods. Thus, when evaluating healthcare use as a composite of both ED visits and hospitalizations among individuals with RA, there was no appreciable increase in healthcare use during risk periods after all doses. In fact, there was a decrease in ED visits and hospitalizations after dose 1 (RI 0.95, 95% CI 0.92-0.99) and 3 (RI 0.90, 95% CI 0.87-0.94), and normalization after dose 2 (RI 1.04, 95% CI 1.00-1.07).
Relative to comparators, hospitalizations remained comparable except for the risk period after the fourth dose where individuals with RA experienced fewer hospitalizations (RIR 0.52, 95% CI 0.36-0.75). Overall healthcare use (hospitalizations and ED visits) was again similar, except after the fourth dose where individuals with RA had reduced utilization (RIR 0.72, 95% CI 0.58-0.89).
Rheumatology visits. Compared to control periods, rates of rheumatology visits were more frequent after the first dose (RI 1.08, 95% CI 1.07-1.10), and were slightly lower after doses 2 (RI 0.95, 95% CI 0.93-0.96) and 3 (RI 0.92, 95% CI 0.91-0.94). For dose 4, there was no significant difference (RI 1.01, 95% CI 0.94-1.08; Table 2).
Subgroup and sensitivity analysis. Age- and sex-specific relative rates of AESIs, hospitalizations, ED visits, and rheumatology visits among individuals with RA are shown in Table 3. ED visits were appreciably higher after the second dose regardless of age. When separated by sex, females experienced more ED visits after the second dose (RI 1.06, 95% CI 1.02-1.11), whereas this increase was not observed in males (RI 1.05, 95% CI 0.98-1.12). Hospitalizations were reduced after the first 3 doses regardless of age and sex. However, the reduced hospitalization rate did not reach statistical significance in males after the third dose (RI 0.89, 95% CI 0.80-1.00). When hospitalizations and ED visits are combined, individuals with RA had reduced utilization after dose 3, and this was consistent regardless of sex or age. Compared to control periods, rheumatology visits slightly increased after the first dose in both younger and older patients with RA and among both sexes.
Age- and sex-specific relative rates of AESIs and health services use among individuals with RA.
With the use of alternate risk windows (Supplementary Table S2, available from the authors upon request), the only notable difference observed was that the rate of hospitalizations and ED visits combined increased after the second dose, which reached statistical significance (RI 1.07, 95% CI 1.04-1.10). There continued to be no significant increase in AESIs after each dose. The trend observed for rheumatology visits continued to remain the same, where the frequency of visits increased after dose 1 (RI 1.04, 95% CI 1.03-1.05), reduced after doses 2 (RI 0.92, 95% CI 0.91-0.93) and 3 (RI 0.90, 95% CI 0.89-0.91), and then normalized after dose 4 (RI 1.03, 95% CI 0.98-1.09).
DISCUSSION
In this study, COVID-19 vaccination in patients with RA was not consistently associated with an increase in AESI risk, healthcare use, or rheumatology visits after every dose. We did detect an increase in ED visit rates after the second dose, although the same pattern was also observed in patients without RA. In fact, we observed lower all-cause hospitalizations for patients with RA during the first 3 postvaccination periods. Collectively, these findings are highly reassuring, particularly since concerns of vaccination side effects can lower confidence in COVID-19 vaccinations.12,13
Our findings are in keeping with previous studies.18-20 Syversen et al reported similarly low rates of adverse events in 1100 patients with immune-mediated inflammatory diseases (IMIDs), including RA, vs healthy controls.18 Wieske et al also found a relatively low frequency of serious adverse events in 2081 individuals with IMIDs undergoing COVID-19 vaccination.19
Interestingly, our study demonstrated an increase in ED visit rates after the second dose both in individuals with or without RA. It is unclear what is driving this increase in visits, but there may be the possibility that this increase is a result of the vaccination exposure. Some studies have shown that certain AESIs (such as myocarditis and pericarditis) and nonsevere side effects are increased after sequential doses.21-23 Although our AESI rates did not detect a similar trend and our hospitalizations were reduced, it may be possible that an increase in local or less severe side effects (such as expected local or systemic reactions like myalgias, fever, and headaches) after subsequent doses prompted more frequent ED visits. This statistically significant increase may not have persisted with doses 3 and 4 as individuals with poor vaccine experiences may have then declined further COVID-19 vaccinations.
Our study detected lower rates of hospitalizations after the first 3 COVID-19 vaccine doses both in individuals with and without RA. The explanation for these findings may be multifactorial. First, the lower health services use may be observed because of the protective effects of earlier COVID-19 vaccinations. With vaccine receipt, individuals may be at lower risk of SARS-CoV-2 infection (and hospitalization). Second, it is possible that the lower rates observed could be attributable to the “healthy vaccinee effect,” where individuals choose to be vaccinated when they feel well, thereby reducing health services use. We made our best attempts to account for the phenomenon in our study design by incorporating a washout period where the 2 weeks prior to the vaccine were excluded from our analyses.
Rheumatology visits were slightly higher after the first dose, lower after the second and third doses, and equivocal after the fourth dose. Given that our administrative database could not directly ascertain RA-related flares after COVID-19 vaccines, we used rheumatology visits as a proxy. We do not know if the observed increase in rheumatologist visits after the first vaccine dose may be a result of RA flare, or the increased availability of rheumatology visits that coincided during the rapid uptake of COVID-19 vaccines in Ontario.24 Li et al studied 5493 vaccinated and unvaccinated individuals with RA using a propensity-weighted cohort study design, finding no clear association between RA flare and COVID-19 vaccination.25 Connolly et al26 and Pinte et al27 noted similar results. Further, several explanations may explain the decline in specialist visits with subsequent vaccine doses. First, patients may cancel physician visits because of transient nonserious adverse vaccination reactions. Additionally, patients who received multiple COVID-19 vaccine doses may comprise a subgroup of patients who are more resilient to disease flares postvaccination. These patients may differ from patients who only chose to get vaccinated once. We note that access to healthcare services during the COVID-19 pandemic may have been difficult because of myriad factors including pandemic-related restrictions; however, this would have been highest in the prevaccination period and during the initial stages of vaccine roll-out.28 We could not use medication changes as an indicator of flare, since drug data were unavailable, except for older adults.
This study has several strengths. Ontario has a universal, publicly funded healthcare system and a centralized COVID-19 vaccine registry, and patients with RA are identified using a validated algorithm.15 This minimized any potential selection biases and misclassification of RA status or vaccination exposure. Further, the SCCS design helps deal with unmeasured factors like disease severity (unavailable in administrative health data) and medications. In this cohort, the majority of patients with RA received 3 doses of COVID-19 vaccines, generating sufficient sample sizes up to the third dose. These findings are reassuring, particularly given the current multidose vaccination strategy. Less than 10% of the cohort received a fourth dose, and thus our results related to the fourth dose are less precise.
Our results must be considered in the context of several potential limitations. First, we could not control for the possibility that individuals may have avoided additional COVID-19 vaccine doses if they experienced an adverse event after prior doses, thereby selecting for potential healthy users in our analysis of subsequent vaccine doses. Second, access to physicians, including rheumatologists, was problematic at times throughout the COVID-19 pandemic, thereby underestimating healthcare use.17 Third, COVID-19 infection can cause many of the events within our composite AESI definition, which could inflate event rates particularly in the prevaccination control periods. Separately, during postvaccination risk and control periods, increased surveillance bias may have resulted in increased case detection of milder cases of AESIs. Although SCCS designs take time-independent confounders into consideration, there may have been changes in a variety of time-dependent covariates such as disease status, drugs (particularly immunosuppressive therapies), SARS-CoV-2 activity levels within the community, and protective behaviors that we were not able to incorporate. Lastly, our study end date was March 2022, and we could not evaluate bivalent mRNA vaccines, which were in use after the fall of 2022 in Ontario. However, AESIs after bivalent booster vaccine have been reported to be consistent with monovalent doses in a prior large-scale monitoring registry study.29
In conclusion, this large population-based study did not find a clear pattern of increased risk of AESIs or overall healthcare use following COVID-19 vaccination in patients with RA. These findings will help decision makers (ie, health ministry, COVID-19 vaccination programs), people with RA, and physicians to make informed decisions about COVID-19 vaccination recommendations. Ongoing surveillance is needed to study the safety profile of newer COVID-19 vaccines, including bivalent formulations.
ACKNOWLEDGMENT
The study was supported by ICES (formerly known as the Institute for Clinical Evaluative Sciences), which is funded by the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care. Parts of this material are based on data and information compiled and provided by the MOH, the Canadian Institute for Health Information, Cancer Care Ontario, and Public Health Ontario (case-level data from the Case and Contact Management System [CCM] and COVID-19 laboratory data). We also thank the staff of Ontario’s public health units who are responsible for COVID-19 case and contact management and data collection. The authors are grateful to the Ontario residents without whom this research would be impossible. This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario MOH Postal Code Conversion File, which contains data copied under license from Canada Post Corporation and Statistics Canada. We thank IQVIA Solutions Canada Inc. for use of their Drug Information File. The opinions, results and conclusions reported in this paper are those of the authors and are independent of the data sources; no endorsement is intended or should be inferred.
Footnotes
This project was supported by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Working Party and the COVID-19 Immunity Task Force. JCK received a Clinician-Scientist Award from the University of Toronto Department of Family and Community Medicine. JW received support from the Arthritis Society Stars Career Development Award. SB is a James McGill Professor of Medicine.
The authors declare no conflicts of interest relevant to this article.
- Accepted for publication September 7, 2023.
- Copyright © 2024 by the Journal of Rheumatology
This is an Open Access article, which permits use, distribution, and reproduction, without modification, provided the original article is correctly cited and is not used for commercial purposes.
REFERENCES
DATA SHARING
The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification.
