Long-term risk of autoimmune diseases after mRNA-based SARS-CoV2 vaccination in a Korean, nationwide, population-based cohort study – Nature.com

Study population

The primary cohort was established by combining the National Health Insurance Service (NHIS) and Korea Disease Control and Prevention Agency (KDCA) databases, which comprised the healthcare data of >99% of the entire Korean population and their COVID-19 diagnosis and vaccination profiles. In total, 9,258,803 individuals who had received at least one dose of the mRNA-based COVID-19 vaccine were included (Fig.1). As COVID-19 vaccines have been administered nationwide in South Korea, the proportion of unvaccinated individuals was minimal13. Therefore, the use of unvaccinated individuals as comparators could have resulted in improper cohort selection and potential selection bias. We consequently established a historical control cohort within mRNA-vaccinated individuals, but the observational period was shifted back 2 years from the date of the first dose of mRNA vaccination of the historical control cohort. In total, 4,445,333 and 4,444,932 patients were included in the vaccination and historical control cohorts, respectively, and all were observed for 1 year. The baseline demographic and general health characteristics of each cohort are summarised in Table1. The covariates were well-balanced after the inverse probability of treatment weighting (IPTW). The COVID-19 vaccination profiles, such as the type of mRNA vaccine or history of non-mRNA vaccination, are summarised in Supplementary Table1. The mean follow-up times for the vaccination and historical control cohorts were 471.2466.16 days and 471.2866.15 days, respectively.

This nationwide population-based cohort study combined data from the Korea Disease Control and Prevention Agency (KDCA) and the COVID-19 National Health Insurance Service (NHIS) cohort (K-COV-N cohort). The study included approximately 20% of the total South Korean population. This primary cohort comprised all individuals vaccinated with at least one dose of the mRNA-based COVID-19 vaccine (BNT162b2, Pfizer-BioNTech; mRNA-1273, Moderna) until 31 December 2022. Subsequently, half of the primary cohort was extracted to establish the vaccination cohort, and the study index was defined as the date of the first dose of the mRNA-based COVID-19 vaccine. A historical control cohort was established by extracting the other half of the primary cohort as the control, and its study index was assigned as the date of the first dose of the mRNA-based COVID-19 vaccine minus 2 years. A total of 4,445,333 vaccination and 4,444,932 control cohorts were selected and observed until 31 December 2022 and 31 December 2020, respectively. Abbreviations: COVID-19, Coronavirus 2019 disease.

Cumulative incidence plots for the AI-CTDs are shown in Fig.2, with Supplementary Fig.1 providing additional details, including cumulative incidence for positive and negative control outcomes, as well as the cumulative number of events for each time point. The risks of developing incident AI-CTDs in the vaccination and historical control cohorts are shown in Fig.3. To mitigate the risk of type I error induced by multiple comparisons, we employed a Bonferroni correction for 27 predefined outcomes and used an adjusted 99.81% confidence interval (99% CI) to determine statistical significance. Individuals who had the mRNA COVID-19 vaccine did not incur higher risks of developing most AI-CTDs such as alopecia areata (adjusted hazard ratio [aHR], 1.00; 99% CI, 0.961.04), alopecia totalis (aHR, 0.79; 99% CI, 0.680.93), psoriasis (aHR, 0.80; 99% CI, 0.770.84), vitiligo (aHR, 0.95; 99% CI, 0.881.02), anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (aHR, 1.09; 99% CI, 0.721.66), sarcoidosis (aHR, 1.06; 99% CI, 0.781.44), Behcet disease (aHR, 0.69; 99% CI, 0.580.82), Crohns disease (aHR, 0.92; 99% CI, 0.771.09), ulcerative colitis (aHR, 0.97; 99% CI, 0.871.08), rheumatoid arthritis (aHR, 0.86; 99% CI, 0.840.89), systemic sclerosis (aHR, 1.01; 99% CI, 0.731.38), Sjogrens syndrome (aHR, 1.07; 99% CI, 0.961.18), ankylosing spondylitis (aHR, 0.95; 99% CI, 0.871.04), dermato/polymyositis (aHR, 1.02; 99% CI, 0.771.35), and bullous pemphigoid (BP) (aHR, 1.53; 99% CI, 0.902.60). However, individuals in the mRNA vaccination cohort were at considerably higher risk of developing systemic lupus erythematosus (SLE) (aHR, 1.16; 99% CI, 1.021.32) than those in the historical control cohort.

The cumulative incidence plot shows the cumulative incidences of autoimmune connective tissue diseases in mRNA-based COVID-19 vaccination cohort and historical control cohort. The shaded area shows a 95% confidence interval for the cumulative incidences. Additional information, including cumulative incidence for positive and negative control outcomes, as well as the cumulative number of events for each time point, was presented in Supplementary Fig.1. Abbreviation: ANCA, anti-neutrophil cytoplasmic antibody; COVID-19, coronavirus disease 2019.

To minimise the differences in baseline characteristics between the vaccination and historical control cohorts, predefined covariates, including demographics, socioeconomic status, and comorbidities, were balanced using inverse probability of treatment weighting. Subsequently, the incidence in the vaccination cohort compared to that in the historical control cohort was estimated using multivariable Cox proportional hazards analysis after adjusting for all predefined covariates. The forest plot depicts adjusted hazard ratios (aHRs) in individuals with mRNA-based COVID-19 vaccination compared with historical controls, with the confidence interval (CI) adjusted to 99.81% for Bonferroni correction but presented as 99% CI for simplicity. The point estimate (centre) represents the aHR, and the horizontal line (error bar) shows the range of the 99% CI. The incidence rate was calculated as the number of events divided by 10,000 person-years, with the population at risk also presented. Abbreviations: aHR, adjusted hazard ratio; ANCA, antineutrophil cytoplasmic antibody; CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio.

To validate these findings, we evaluated the risks of positive and negative control outcomes associated with mRNA vaccination. For the positive control outcomes, the risk of myocarditis (aHR, 7.20; 99% CI, 4.3711.86), pericarditis (aHR, 2.75; 99% CI, 1.953.88), and GuillainBarre syndrome (aHR, 1.62; 99% CI, 1.162.25) were considerably higher in the vaccination cohort than in the historical control cohort (Fig.3). Conversely, the risk of having negative control outcomes was not considerably higher in the vaccination cohort than in the historical control cohort (benign skin tumour (aHR, 1.02; 99% CI, 1.001.05), melanoma in situ (aHR, 1.21; 99% CI, 0.642.29), and tympanic membrane perforation (aHR, 0.84; 99% CI, 0.770.91)).

In subgroup analyses, we compared the vaccination and historical control cohorts stratified by sex, age (<40 vs. 40), type of mRNA-based COVID-19 vaccine (BNT162b2, PfizerBioNTech vs. mRNA-1273, Moderna), cross-vaccination status with any history of non-mRNA COVID vaccination (ChAdOx1 nCoV-19 [AZD1222], OxfordAstraZeneca or Ad26.COV2.S, JanssenJohnson & Johnson, or others) prior to mRNA vaccination, and any history of COVID-19 diagnosis. In general, there were no significant differences between the two cohorts in the subgroup analyses for most outcomes (Figs.45), with Supplementary Figs.211 providing additional details for each stratified analysis. However, women who had received the mRNA vaccine had a significantly higher risk of developing BP (aHR, 2.67; 99% CI, 1.116.42) (Fig.4a, b). In addition, aged 40 years who had undergone mRNA vaccination tended to have a higher risk of developing BP (aHR, 1.53; 99% CI, 0.902.61) (Fig.4c, d). In the stratified analysis based on the type of mRNA vaccine received, individuals who received the BNT162b2 vaccine had a significantly higher risk of developing SLE (aHR, 1.18; 99% CI, 1.021.36) (Fig.5a, b). In addition, cross-vaccination with non-mRNA vaccines did not independently affect the incident risk of any AI-CTDs (Fig.5c, d). In analyses according to the status of COVID-19 diagnosis, the incidence was not higher for almost all AI-CTDs, except SLE in individuals with COVID-19 diagnosis (aHR, 1.23; 99% CI, 1.051.44) (Supplementary Figs.6 and 7).

The forest plot depicts adjusted hazard ratios (aHRs) and 99% confidence intervals (CIs) in individuals with mRNA-based COVID-19 vaccination compared with historical controls. The point estimate (centre) represents the aHR, and the horizontal line (error bar) shows the range of the 99% CI. The incident risks of autoimmune disorder outcomes were stratified by sex ((a) Male or (b) Female) and age ((c) <40 years or (d) 40 years). Additional details, including unadjusted HRs and population at risk, were provided in Supplementary Figures.; Male subgroup (Supplementary Fig.2), female subgroup (Supplementary Fig.3), subgroup aged <40 years (Supplementary Fig.4), and subgroup aged 40 years (Supplementary Fig.5). Abbreviations: aHR, adjusted hazard ratio; ANCA, antineutrophil cytoplasmic antibody; CI, confidence interval; COVID-19, coronavirus disease 2019.

The forest plot depicts adjusted hazard ratios (aHRs) and 99% confidence intervals (CIs) in individuals with mRNA-based COVID-19 vaccination compared with historical controls. The point estimate (centre) represents the aHR, and the horizontal line (error bar) shows the range of the 99% CI. The incident risks of autoimmune disorder outcomes were stratified by the type of mRNA vaccine ((a) BNT162b2 or (b) mRNA-1273) and the history of cross-vaccination ((c) Only mRNA vaccination or (d) Cross-vaccination with non-mRNA vaccination (AZD12222 or Ad26.COV2.S)). Additional details, including unadjusted HRs and population at risk, were provided in Supplementary Figures.; Subgroup who received the BNT162b2 vaccine (Supplementary Fig.8), subgroup who received the mRNA-1273 vaccine (Supplementary Fig.9), subgroup who received only mRNA-based vaccines (Supplementary Fig.10), and subgroup who had a history of cross-vaccination with any non-mRNA vaccines (Supplementary Fig.11). Abbreviations: aHR, adjusted hazard ratio; ANCA, antineutrophil cytoplasmic antibody; CI, confidence interval; COVID-19, coronavirus disease 2019.

In total, 2,284,342 individuals had the booster mRNA vaccination (3rd dose of mRNA vaccination) among the vaccination cohort. In extended Cox proportional hazard analyses treating booster vaccination as time-varying covariate, the risk of alopecia areata (aHR, 1.12; 99% CI, 1.051.19), psoriasis (aHR, 1.16; 99% CI, 1.061.27), and rheumatoid arthritis (aHR, 1.14; 99% CI, 1.081.21) were greater in individuals who had booster vaccination compared to those who had not (Fig.6).

The forest plot depicts adjusted hazard ratios (aHRs) with 99% confidence intervals (CIs) in individuals within the vaccination cohort according to prior history of booster vaccination, defined by the administration of 3rd additional dose of the mRNA-based COVID-19 vaccine following the completion of the two-dose primary series of the same mRNA-based COVID-19 vaccine. The point estimate (centre) represents the aHR, and the horizontal line (error bar) shows the range of the 99% CI. Among the vaccination cohort, 2,284,342 individuals were vaccinated with a booster dose and the extended Cox proportional hazard analyses treating booster vaccination as a time-varying covariate were conducted for the variability of vaccination status during the observation period. The numbers of events of autoimmune disorder outcomes and population at risk were presented for each group divided based on booster vaccination status, with the number of events specifically shown before and after the booster vaccination in the individuals with booster vaccination group. Abbreviations: aHR, adjusted hazard ratio; ANCA, antineutrophil cytoplasmic antibody; CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio.

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Long-term risk of autoimmune diseases after mRNA-based SARS-CoV2 vaccination in a Korean, nationwide, population-based cohort study - Nature.com