Association between COVID-19 and long-term risk of autoimmune and autoinflammatory connective tissue diseases

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

In a population-based study published in JAMA Dermatology, Scientists from the Republic of Korea examined whether having coronavirus disease 2019 (COVID-19) increases the long-term risk of autoimmune and autoinflammatory connective tissue diseases.

They found a significantly higher risk of developing autoimmune and autoinflammatory diseases such as rheumatoid arthritis (RA), lupus, Crohn’s disease and alopecia among people with Covid-19, with the risk particularly increased for people with severe cases of infection with the variant Delta and those who were not vaccinated.

Background

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has not only caused immediate health problems but can also lead to long-term autoimmune and autoinflammatory diseases. While acute effects such as respiratory and cardiovascular problems are well known, the potential of Covid-19 to trigger autoimmune responses through mechanisms such as immune cross-reactivity is less understood.

Evidence suggests the virus may interfere with the immune system’s self-tolerance, producing autoantibodies linked to conditions such as arthritis and Guillain-Barré syndrome. Recent research shows an increased risk of autoimmune connective tissue diseases such as lupus, rheumatoid arthritis, Crohn’s disease and alopecia areata among Covid-19 survivors. However, previous studies were restricted by brief follow-up times, which may have missed the gradual onset of these diseases. Long-term research is indispensable to fully understand the impact of Covid-19 on autoimmune disease risk and to support with ongoing health monitoring.

Therefore, investigators in this study used an extended follow-up period to assess the long-term risk of developing autoimmune and autoinflammatory diseases after 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 this study analyzed 6,912,427 participants. Of these, 3,145,388 participants had Covid-19 and 3,767,039 were the control group, both of whom had at least 180 days of follow-up. The sample was balanced on demographic and health factors, with an average age of 53.39 years and 46.4% of participants were women.

Covid-19 was confirmed by a polymerase chain reaction test or a physician-confirmed rapid antigen test. Outcomes were measured by tracking autoimmune disease diagnoses (requiring at least three doctor visits) and assessed using codes from the tenth revision of the International Classification of Diseases (ICD-10). Inverse probability of treatment weighting (IPTW) was used to balance cohorts based on demographics, socioeconomics, lifestyle, and comorbidities.

Cox proportional hazard models adjusted for factors such as age, gender, COVID-19 virus severity, period variants (Delta or Omicron), and vaccination status were used for risk analysis. Sensitivity analyzes were performed to address any potential diagnostic issues and underreporting by comparison with a pre-pandemic historical control cohort.

Results and discussion

According to the study, patients with Covid-19 were shown to be at increased risk of a number of autoimmune diseases, including alopecia areata (adjusted Harard ratio [AHR]1.11), vitiligo (AHR, 1.11), Behçet’s disease (AHR, 1.45), Crohn’s disease (AHR, 1.35), RA (AHR, 1.09), alopecia totalis (AHR , 1.24), ulcerative colitis (AHR, 1.15), Sjögren’s 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 likely to develop alopecia areata, vitiligo and RA, while women were at increased risk of alopecia totalis, Behçet’s disease and bullous pemphigoid. Age-based analyzes showed that participants under 40 years of age had a higher risk of developing autoimmune diseases such as primary scarring alopecia and ulcerative colitis, while those over 40 years of age had a higher risk of developing diseases such as Sjögren’s syndrome, SLE and ankylosing spondylitis were higher.

It has been found that the severity of COVID-19 affects the risk of autoimmune diseases, with patients in intensive care at a much higher risk of developing sarcoidosis, Sjögren’s syndrome and bullous pemphigoid. The delta dominance period posed a greater risk of autoimmune disease than the omicron period. Vaccination appears to reduce the risk of autoimmune diseases, with unvaccinated patients being more susceptible to conditions such as RA, SLE and Crohn’s disease. Sensitivity analyzes with historical controls (pre-pandemic) confirmed similar trends, indicating the robustness of the results.

Positive control findings, such as heart failure, were consistent with known effects of COVID-19, while negative controls (e.g., epidermoid cysts) showed no significant association, strengthening the validity of the study. Overall, COVID-19 has been associated with an increased risk of various autoimmune diseases, especially among older, unvaccinated or severely affected people.

Broad surveillance enhances research that uses large-scale national data, takes into account a wide range of covariates, and uses stratified analyzes to identify risk subgroups. However, the generalizability of the study may be restricted due to single ethnicity, potential limitations related to confounding factors, selection bias based on untested or asymptomatic cases, and low incidence rates of some diseases affecting statistical significance.

Application

Overall, the study highlighted the long-term risk of autoimmune and autoinflammatory connective tissue diseases in Covid-19 patients, highlighting the importance of continued vigilance and research into the potential effects of Covid-19. Going forward, it is vital to recognize subgroup-specific disease vulnerabilities and patterns to address the lasting impact of the pandemic on global health.