Link between COVID-19 and long-term risk of autoimmune and autoinflammatory connective tissue disorders

By Dr. Sushama R. Chaphalkar, PhD.Reviewed by Danielle Ellis, B.Sc.Nov 8 2024

The study suggests that long-term monitoring and patient management are crucial after COVID-19. 

In a population-based study published in JAMA Dermatology, researchers from the Republic of Korea investigated whether having a history of coronavirus disease 2019 (COVID-19) increased the long-term risk of autoimmune and autoinflammatory connective tissue disorders.

They found a significantly higher risk of developing autoimmune and autoinflammatory conditions, such as rheumatoid arthritis (RA), lupus, Crohn's disease, and alopecia, among individuals who had COVID-19, with risks particularly elevated for those with severe cases, Delta variant infections, and those who were unvaccinated.

Background

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has not only resulted in immediate health issues but may also lead to long-term autoimmune and autoinflammatory diseases. While acute impacts like respiratory and cardiovascular problems are well known, COVID-19's potential to trigger autoimmune responses through mechanisms like immune cross-reactivity is less understood.

Evidence suggests the virus may disrupt self-tolerance in the immune system, producing auto-antibodies tied to conditions like inflammatory arthritis and Guillain-Barré syndrome. Recent studies indicate an increased risk of autoimmune connective tissue diseases such as lupus, rheumatoid arthritis, Crohn's disease, and alopecia areata among COVID-19 survivors. However, prior studies were limited by short follow-up times, which could miss these diseases' gradual onset. Longer-term research is essential to understand COVID-19's impact on autoimmune disease risk fully and to guide ongoing health monitoring.

Therefore, researchers in the present study used an extended observation period to assess the long-term risk of developing autoimmune and autoinflammatory diseases following COVID-19.

About the study

Using the National Health Insurance Service (NHIS) database and the Korea Disease Control and Prevention Agency's COVID-19 registry, researchers in the present study analyzed 6,912,427 participants. Of these, 3,145,388 participants had COVID-19, and 3,767,039 were controls, both with a minimum of 180 days of observation. The sample was balanced for demographic and health factors and had a mean age of 53.39 years, and 46.4% of the participants were female.

COVID-19 was confirmed via polymerase chain reaction testing or physician-confirmed rapid antigen testing. Outcomes were measured by tracking autoimmune disease diagnoses (requiring at least three medical visits) and assessed using codes from the International Classification of Disease tenth revision (ICD-10). Inverse probability of treatment weighting (IPTW) was used to balance the cohorts by demographic, socioeconomic, lifestyle, and comorbidity data.

Cox proportional hazards models were used to analyze risks, adjusted for factors such as age, sex, COVID-19 severity, variant periods (Delta or Omicron), and vaccination status. Sensitivity analyses were conducted to address any potential diagnostic and underreporting issues by comparing with a prepandemic historical control cohort.

Results and discussion

According to the study, patients with COVID-19 showed an increased risk for a range of autoimmune diseases, including alopecia areata (adjusted harard ratio [AHR], 1.11), vitiligo (AHR, 1.11), Behçet disease (AHR, 1.45), Crohn disease (AHR, 1.35), RA (AHR, 1.09), alopecia totalis (AHR, 1.24), ulcerative colitis (AHR, 1.15), Sjögren syndrome (AHR, 1.13), systemic lupus erythematosus (SLE) (AHR, 1.14), ankylosing spondylitis (AHR, 1.11), and bullous pemphigoid (AHR, 1.62).

Men with COVID-19 were more prone to developing alopecia areata, vitiligo, and RA, while women had heightened risks of alopecia totalis, Behçet disease, and bullous pemphigoid. Age-based analyses showed that participants under 40 years had higher risks of autoimmune conditions, like primary cicatricial alopecia and ulcerative colitis, while those over 40 exhibited risks for conditions such as Sjögren syndrome, SLE, and ankylosing spondylitis.

The severity of COVID-19 was found to influence autoimmune risks, with patients in intensive care having markedly higher risks for sarcoidosis, Sjögren syndrome, and bullous pemphigoid. The Delta-dominant period posed higher risks for autoimmune diseases than the Omicron period. Vaccination appeared to mitigate the autoimmune risks, with unvaccinated patients showing greater susceptibility to conditions like RA, SLE, and Crohn's disease. Sensitivity analyses with historical controls (prepandemic) confirmed similar trends, indicating the robustness of the results.

Positive control outcomes, such as heart failure, were consistent with known COVID-19 impacts, while negative controls (e.g., epidermal cysts) did not show significant association, reinforcing the study's validity. Overall, COVID-19 was linked with elevated risks for various autoimmune diseases, especially among older, unvaccinated, or severely affected individuals.

An extensive follow-up strengthens the study, which uses large-scale national data, accounts for a wide range of covariates, and uses stratified analyses to identify at-risk subgroups. However, the study's generalizability may be limited due to single ethnicity, potential confounder constraints, selection bias from untested or asymptomatic cases, and low incidence rates for some diseases affecting statistical significance.

Conclusion

In conclusion, the study highlighted the long-term risks of autoimmune and autoinflammatory connective tissue disorders in patients with COVID-19, emphasizing the importance of ongoing vigilance and research on COVID-19's potential effects. In the future, it is essential to recognize subgroup-specific vulnerabilities and disease patterns to address the pandemic's lasting impact on global health.