BNT162b2 and mRNA-1273 were the first mRNA vaccines approved by the US Food and Drug Administration (FDA) for combatting COVID-19.13 While prior meta-analyses have suggested that non-mRNA vaccinations increase the risk of patients developing autoimmune diseases, data on the long-term effects of mRNA vaccine administration on AI-CTDs are scarce.14,15 Our study observed the impact of mRNA vaccination on the occurrence of AI-CTDs for > 1 year in a nationwide population-based cohort study. We observed a significant increase in the incidence of SLE and BP following mRNA vaccination. Although there tended to be a higher risk of developing ANCA-associated vasculitis, sarcoidosis, Sjögren’s syndrome, and dermatomyositis/polymyositis in the vaccination group, these differences were not statistically significant.
In a recent cohort study, patients diagnosed with COVID-19 had a 1.26-fold and 1.78-fold higher risk of developing CTDs than the general population in South Korea and Japan, respectively.16 Similarly, patients in the mRNA vaccination group of our study exhibited a higher risk of developing certain CTDs than patients in the historical control group, with the risk for SLE and BP being 1.14-fold and 1.53-fold, respectively. Additionally, higher incidences of SLE, Sjögren’s syndrome, and BP were observed in patients with COVID-19, which is consistent with a previous study.16 However, the risks of incident inflammatory arthritis, such as rheumatoid arthritis and ankylosing spondylitis, did not increase following mRNA vaccination. This may be attributed to differences in the demographic characteristics of the study population and observational periods across the studies.
The association between BP and mRNA vaccination was previously unclear. In the present study, we observed a higher risk of developing BP after mRNA vaccination than without vaccination. The US case series of subepidermal blistering eruptions (including BP) following mRNA vaccination reported it to be more common in women and after the age of 40.17 Consistently, our study reported a higher risk of BP in women and in patients over 40 years of age following mRNA vaccination than in historical controls. In particular, the female population had a 2.64-fold higher risk of incident BP than the male population, suggesting the need to monitor BP development in women who have received mRNA vaccines.
Although the association between mRNA vaccination and SLE remains unclear, there have been cases in which SLE has developed following mRNA vaccination.18 mRNA vaccination reportedly leads to elevated plasma anti-dsDNA antibody levels and the extracellular self-DNA influences the pathogenesis of AI-CTDs including SLE.19,20 Another study found that booster vaccinations increase circulating cell-free DNA in B cells, T cells, and monocytes.21 Therefore, it can be speculated that mRNA vaccination influences autoimmunity, contributing to SLE development. Our study found that the risk for SLE was higher in the vaccinated group regardless of sex.
Consistently, the incidence of most AI-CTDs did not increase in our sub-analyses. The observed risk of AI-CTDs varies according to the type of mRNA vaccine used. However, further studies are needed to elucidate whether factors such as mRNA dose may contribute to this difference.22,23 In the subgroup analysis according to booster vaccination, the risk of AI-CTDs tended to be higher among individuals who were not vaccinated than among those who were. This finding may be attributed to individuals who were newly diagnosed or had preexisting AI-CTDs and did not receive booster vaccinations. In other words, our analysis demonstrated that booster vaccination did not increase the incidence of AI-CTDs. Given the substantial benefits of mRNA vaccination in preventing COVID-19 and reducing disease severity, patients with autoimmune diseases should be encouraged to be vaccinated.24
This study has several strengths. First, we used the national medical data of > 10 million people, and national COVID-19 infection and vaccination profiles. Second, the risk of incident AI-CTDs was measured with a large sample size and longer observation period (median 15.7 months), than that used in previous studies.25 Third, we designed a historical control cohort to minimize selection bias and examined the reliability of the analysis by evaluating positive and negative outcome controls. Fourth, subgroup analyses were conducted according to sex, age, type of mRNA-based COVID-19 vaccine, diagnosis of COVID-19, cross-vaccination status with any non-mRNA COVID vaccine prior to mRNA vaccination, and history of booster vaccination.
However, this study has some limitations. First, the analysis was conducted on individuals belonging to a single ethnic group. Since autoimmune disease-associated single nucleotide polymorphisms vary by ethnicity, our results may not be generalizable to other populations.26 Second, the observation period may be too short to allow examination of the association between AI-CTDs and mRNA vaccination. Although our study has one of the longest follow-up periods among mRNA vaccine studies reported to date, this duration may still be considered too short given that the development of AI-CTDs can take years to decades after trigger exposure.27 Third, considering the global decline in the use of healthcare services during the COVID-19 pandemic, autoimmune diseases may have been underdiagnosed during this period.28,29 Nevertheless, we investigated negative control outcomes to address these concerns.
In conclusion, our study results suggest that mRNA vaccination does not increase the risk of developing most AI-CTDs. However, further research is needed regarding the potential association with certain conditions such as SLE and BP, especially in women and patients older than 40 years. Therefore, disease monitoring encompassing age, sex, and ethnicity is necessary after administration of mRNA-based vaccines. Our study provides clinical insights into mRNA therapeutics.30