In this prospective Brazilian multicentric study with RA adults, we found no new safety signals with a two-dose schedule of both Chadox1 and Coronavac vaccines. However, adverse events, either local or systemic, were more often reported with Chadox1 vaccine than with Coronavac vaccine. Of note, none of the RA patients primed with Chadox1 had adverse events leading to discontinuation of vaccination. As another major finding of our study, the COVID-19 vaccines studied did not associate with worsening of RA disease activity level.
In the present study, most patients with RA were female, brown, with a mean age of 45, data similar to other previously puplished studies.18,19,20 In our sample, the average age in the 45-year-old range is justified by the low inclusion of elderly people, most of whom had already been vaccinated when the project started, in May 2021, making their participation in this cohort unfeasible.
In patients with RA, comorbidities are frequent 22,23 and increase the risk of complications and death related to COVID 19. They were also essential to establish the order of priority for vaccination. In our study, the most frequent were arterial hypertension and obesity.The high frequency of cardiovascular diseases in general, and especially of arterial hypertension, is common data in RA studies24,25, regardless of the population. Such finding reflects the chronic effects of pro-inflammatory cytokines and corticosteroids on the cardiovascular system, especially on the endothelium, resulting in accelerated atherosclerosis and increased peripheral vascular resistance,26 which can increase the risk of complications in COVID 19.
In the present analysis, the most frequent AEFI were local reactions, headache and musculoskeletal symptoms, data compatible with other studies in the population with IMRDs.27,28,29,30 Medeiros-Ribeiro and collaborators, in their study, followed 910 individuals with IMRDs who were vaccinated with two doses of CoronaVac, including 256 patients with RA. No moderate/serious adverse events were reported. The most reported vaccine reactions were pain at the injection site (19.8%), headache (20.2%) and drowsiness (13.6%).27
In an Indian cohort, Cherian et al followed 724 patients with IMRDs, including 225 with RA, who used ChAdOx1 (87.13%) as the main immunizer. The main AEFI reported were pain at the injection site (24.95%), fever (18.32%), fatigue (17.93%) and headache (13.84%). By determination of the local health authorities, patients received a prescription for paracetamol to be used three hours after vaccination which may have impacted the frequency of adverse reactions described.28
In the COVAX registry, 4604 patients with IMRDs were followed, including 1686 patients with rheumatoid arthritis. The m-RNA platforms were the most used, with ChAdOx1 being used in 17% of the cases. The main adverse events reported were pain at the injection site (19%), fatigue (12%), myalgia (7%) and fever (7%). Seventeen serious adverse events were recorded, most with the BNT162b2 platform. Six of these patients required hospitalization.29
In a meta-analysis, Tang et al analyzed 4,433 patients with IMRDs vaccinated against COVID-19 with the different immunizers approved by the WHO. Local pain was the most prevalent symptom (30–55%), followed by fatigue (19–28%). Only two serious adverse events were reported.30
In line with previously published data, this cohort reinforces the safety of ChAdOx1 and CoronaVac vaccines against SARS-CoV-2 in the RA population with only mild adverse events occurring. A variable frequency of AEFIs is observed among the different studies, which can be justified by the analysis encompassing, simultaneously, different inflammatory diseases and distinct immunizers. More studies are needed to clarify possible differences in the frequency of adverse events following immunization among different immune-mediated rheumatic diseases.
In the monitoring of our group, AEFI were more frequent after the first dose of immunizers, corroborating data previously published in studies with the general population and in cohorts including patients with IMRDs.27,30,31 In the meta-analysis by Tang et al, AEFI were more common after the first dose of the non-replicating viral vector platform, especially pain at the site of injection, myalgia and fever.30 In the study by Gopaul et al, adverse effects were milder and shorter in duration after the second dose of ChAdOx1.31 Medeiros et al observed a lower frequency of pain at the injection site, fever, myalgia and arthralgia after the second dose of CoronoVac.27 Such findings may be related to the mechanism of action and immunogenicity of each platform, considering that published data with m-RNA vaccines show the exact opposite, with more intense reactions after the second dose.32
AEFIs were more frequent with ChAdOx1 in comparison to CoronaVac, similar to data observed in the analysis of population studies with the two immunizers in healthy individuals. In the study by Riad et al, with the immunizer Coronavac, the frequency of local AEFI was 41%.33 In a multicenter study, in which the immunizer was ChAdOx1, Falsey et al found 74% of adverse events following immunization.34 In the study by Esquivel et al, 60% of patients who received ChAdOx1 immunization and 36% of patients who received CoronaVac immunization had pain at the injection site.35 These results support the hypothesis that the greater immunogenicity of the non-replicating viral vector platform, compared to that of inactivated virus, would be related to a higher frequency of AEFI.36
In line with our data, prior studies in RA and other IMRDs populations have not shown significant flare-up of disease activity following immunization with different types of COVID-19 vaccines. In the COVAX registry, 5% of patients with inflammatory arthropathy had reactivation of the underlying disease after immunization.29 Li et al analyzed 5,493 patients with RA, of which 671 were vaccinated with CoronaVac, and found no association between the immunizer and the worsening of disease activity.37 Bixio et al observed worsening of pain and joint swelling in 7.8% of patients after vaccination.38 In analyzes involving other immune-mediated rheumatic diseases, no worsening of disease activity was observed after vaccination against SARS-CoV-2.39,40 Connolly et al. described that vaccine platforms with mRNA mechanism of action did not influence the evolution of diffuse connective tissue diseases.39 Pinte et al observed a similar incidence of IMRD reactivation in vaccinated and unvaccinated groups (6% versus 8%, p = 0.302). Furthermore, the two groups did not show any significant difference, not even in the duration of symptoms.40
RA patients may hesitate to be vaccinated mainly due to safety concerns, especially the risk of relapse after vaccination.41 It is discussed whether SARS-CoV-2 could trigger cross-reactivity through molecular mimicry, leading to autoimmunity, and whether immunizers containing the antigens of this agent could induce similar effects. Studies with chronic immune-mediated inflammatory diseases, in general, have refuted this hypothesis, reaffirming that the immunization of these patients is safe. Such findings are essential to overcome vaccine hesitancy and increase protection rates in this group.39,40
Over the last few years, several immunizers have been studied without any significant risk of worsening symptoms related to IMRDs being observed. In distinct scenarios where reactivation is observed, it is generally of mild intensity, short duration and does not require an increase in the degree of immunosuppression.42,43,44 Systematic vaccination of patients with RA is recommended by the BSR and reaffirmed in international guidelines such as the EULAR.12,45
Although immunosuppressed patients were excluded from phase 3 clinical trials of the efficacy and safety of immunizers against SARS-CoV-2, their vaccination was considered a priority due to the increased risk of hospitalization and death from COVID-19. In this study, both immunizers had a good safety profile.
Our cohort has limitations regarding its sample, with low representation of elderly people and the observational design, making it impossible to control the formation of the groups studied. Also noteworthy is the complex scenario where the vaccination schedule for patients with comorbidities was not standardized in all regions of Brazil, in addition to local differences in the speed of processing documents in the respective Ethics Committees, limiting the inclusion of patients in some centers. Our data cannot be generalized due to convenience sampling and the relatively small number of patients, however, the baseline demographic and clinical characteristics of our population were similar to that in the literature.