Long-Term Risk of Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19

Abstract

Importance: Few studies have investigated the association between COVID-19 and autoimmune and autoinflammatory connective tissue disorders; however, research with long-term observation remains insufficient.

Objective: To investigate the long-term risk of autoimmune and autoinflammatory diseases after COVID-19 over an extended observation period.

Design, setting, and participants: This retrospective nationwide population-based study investigated the Korea Disease Control and Prevention Agency-COVID-19-National Health Insurance Service (K-COV-N) cohort. Individuals with confirmed COVID-19 from October 8, 2020, to December 31, 2022, and controls identified among individuals who participated in the general health examination in 2018 were included in the analysis.

Exposures: Confirmed COVID-19.

Main outcomes and measures: Incidence and risk of autoimmune and autoinflammatory connective tissue disorders in patients after COVID-19. Various covariates, such as demographic characteristics, general health data, socioeconomic status, and comorbidity profiles, were balanced using inverse probability weighting.

Results: A total of 6 912 427 participants (53.6% male; mean [SD] age, 53.39 [20.13] years) consisting of 3 145 388 with COVID-19 and 3 767 039 controls with an observational period of more than 180 days were included. Alopecia areata (adjusted hazard ratio [AHR], 1.11 [95% CI, 1.07-1.15]), alopecia totalis (AHR, 1.24 [95% CI, 1.09-1.42]), vitiligo (AHR, 1.11 [95% CI, 1.04-1.19]), Behçet disease (AHR, 1.45 [95% CI, 1.20-1.74]), Crohn disease (AHR, 1.35 [95% CI, 1.14-1.60]), ulcerative colitis (AHR, 1.15 [95% CI, 1.04-1.28]), rheumatoid arthritis (AHR, 1.09 [95% CI, 1.06-1.12]), systemic lupus erythematosus (AHR, 1.14 [95% CI, 1.01-1.28]), Sjögren syndrome (AHR, 1.13 [95% CI, 1.03-1.25]), ankylosing spondylitis (AHR, 1.11 [95% CI, 1.02-1.20]), and bullous pemphigoid (AHR, 1.62 [95% CI, 1.07-2.45]) were associated with higher risk in the COVID-19 group. Subgroup analyses revealed that demographic factors, including male and female sex, age younger than 40 years, and age 40 years and older, exhibited diverse associations with the risk of autoimmune and autoinflammatory outcomes. In addition, severe COVID-19 infection requiring intensive care unit admission, the Delta period, and not being vaccinated were associated with higher risk.

Conclusions and relevance: This retrospective cohort study with an extended follow-up period found associations between COVID-19 and the long-term risk of various autoimmune and autoinflammatory connective tissue disorders. Long-term monitoring and care of patients is crucial after COVID-19, considering demographic factors, disease severity, and vaccination status, to mitigate these risks.

Figure 1.. Study Population Selection

Figure 2.. Comparison of Autoimmune and Autoinflammatory Disease Incidence Risks Between the COVID-19 and Control Cohorts

Hazard estimates were adjusted for all 27 covariates used in the inverse probability of treatment weighting. AHR indicates adjusted hazard ratio.

Figure 3.. Autoimmune and Autoinflammatory Disease Risk by Age and Sex in the COVID-19 and Control Cohorts

Hazard estimates were adjusted for all 27 covariates used in the inverse probability of treatment weighting. AHR indicates adjusted hazard ratio.

Figure 4.. Autoimmune and Autoinflammatory Disease Risk in the COVID-19 Cohort by COVID-19 Severity and Period

Hazard estimates were adjusted for all 27 covariates used in the inverse probability of treatment weighting. The absence of the adjusted hazard ratio (AHR) and 95% CIs for bullous pemphigoid in panel C is not due to missing data but is a result of low sample size and insufficient events in this subgroup. ICU indicates intensive care unit.