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Published in final edited form as: Can J Ophthalmol. 2025 Jul 31;61(1):106–113. doi: 10.1016/j.jcjo.2025.06.017

Risk of developing thyroid eye disease in patients with thyroid dysfunction that received a COVID-19 vaccination

Linus Amarikwa *, Patcharaporn Chandraparnik †,§, Karen M Wai †, Ehsan Rahimy †, Benyam Kinde †, Euna Koo †, Chase Ludwig †, Chrysoula Dosiou ‡, Prithvi Mruthyunjaya †, Andrea L Kossler †
PMCID: PMC13630481  NIHMSID: NIHMS2190011  PMID: 40684801

Abstract

Objective:

To assess the risk of developing thyroid eye disease (TED) after mRNA COVID-19 vaccination in patients with thyroid dysfunction.

Design:

A retrospective cohort study.

Participants:

All patients with hyperthyroidism with no history of TED prior to March 2021 and no history of another orbital inflammatory disease.

Methods:

The rates of TED in patients that received or did not receive any type of COVID-19 vaccination were compared. TED incidence was also compared in those receiving influenza and Tdap vaccines. All patient records were identified using the TriNetX network (Cambridge, MA). Propensity score matching (PSM) was done to control for differences in baseline demographics and medical comorbidities. The primary outcome was the relative risk of developing TED after COVID-19 vaccination.

Results:

A total of 373,909 patients with hyperthyroidism and no signs of TED were identified. After matching and assessing for vaccination status, 69,378 patients were in the COVID-19 vaccine and no COVID-19 vaccine cohorts. We found that COVID-19 vaccination resulted in an increased risk of developing TED when compared with the no COVID-19 vaccine (RR = 1.49, 95% CI: 1.39–1.58), Tdap (RR = 1.80, 95% CI: 1.56–2.06), and influenza cohorts (RR = 1.68, 95% CI: 1.49–1.88).

Conclusions:

Patients with underlying hyperthyroidism demonstrated an increased risk of developing TED following COVID-19 vaccination. Although further studies are required to confirm these findings, patients with underlying autoimmune thyroid dysfunction should receive education on the signs and symptoms of TED and be monitored for the development of TED after COVID-19 vaccination.

Vaccines are powerful tools for managing infectious disease. Estimates demonstrate that COVID-19 vaccines administered in December 2020 prevented infections, hospitalizations, and deaths at rates of 83%, 92%, and 91%, respectively.1 While COVID-19 vaccines were effective, they were found to be associated with adverse events (AEs). In a recent meta-analysis, the incidence of AEs following vaccination ranged from 23% to 76%, with mRNA vaccines carrying the greatest risk of AEs, manifesting as mostly nonspecific systemic symptoms.2 Conversely, the ophthalmic literature has found that ocular AEs are relatively rare after mRNA vaccination with an incidence of 51.3 events/100,000 persons after 2 vaccine doses.3 Commonly reported ocular AEs include blurry vision, cranial nerve palsies, uveitis, scleritis, retinal vein occlusion, and optic neuritis.3–6 Notably, the development of thyroid eye disease (TED) after COVID-19 vaccination remains a relatively uncommon and poorly understood AE.7

TED or Graves’ orbitopathy is a debilitating and disfiguring autoimmune disease that usually begins with an active, inflammatory phase lasting 6–36 months, where patients can experience pain, swelling, lid retraction, proptosis, diplopia, and in severe cases optic nerve compression.8 After the active phase, patients often progress to a chronic or stable phase characterized by fibrosis and persistent soft tissue changes.9 There are several risk factors for the development of TED. The most notable examples are female sex, increased age, tobacco smoke exposure, radioactive iodine ablation, and uncontrolled thyroid dysfunction.10 Recent case reports and series have suggested that COVID-19 vaccination may be a risk factor for the development of TED; to date, there are 25 case reports of COVID-19 vaccine-related TED and a retrospective case series with 98 patients in the literature.11–22 The presentation of these cases, lack of notable risk factors, and their proximity to vaccination encounters strongly suggest a causal relationship that merits further study.23–25

However, critics have stated that COVID-19 vaccine-related AEs are overreported and may represent nocebo responses.26 Many AEs may be due to patients’ underlying concern about the new technology used in recent vaccines or their perception that vaccination is associated with AEs.27–29 As public health officials decide on whether annually reformulated vaccines will become common practice and new variants of SARS-CoV-2 occur,30 vaccine hesitancy and fear of adverse events will continue to be a major concern for patients, especially those with autoimmune diseases.31

The studies suggesting a causal relationship between TED and COVID-19 lack the power of a large epidemiologic study leaving providers and patients unclear on how vaccines may affect patients at risk of developing TED. Here, we report on the incidence of TED development in a large cohort of patients with hyperthyroidism who received COVID-19 vaccinations.

Methods

This is a retrospective cohort study using patient records acquired from the TriNetX network (Cambridge, MA), an aggregated electronic health records database that pulls deidentified patient data from several health care organizations. TriNetX adheres to the Health Insurance Portability and Accountability Act (HIPAA) and is certified to the ISO 27001:2013 standard. This study used deidentified data and does not qualify as human subjects’ research. It is exempt from institutional review board approval.

Data were collected from the TriNetX database on November 13, 2024, and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting results. At the time of our query, there were ~116,000,000 patients in the database. Patients were included in the analysis if they had a history of baseline hyperthyroidism based on ICD-10 code assessment, no history of COVID infection (U07.1), and no prior history of TED or confounding orbital pathology (Supplemental Tables S1 and S2). We looked back to the earliest records to see whether patients had pre-existing orbital pathology. This cohort of patients was then split into 6 groups: Group 1 received a COVID-19 vaccination at some point between March 2021 and November 2024. Group 2 had no documented history of COVID-19 vaccination. Group 3 received a COVID-19 vaccination at some point between March 2021 and November 2024 and had no history of influenza or Tdap vaccination. Group 4 had no history of COVID-19, influenza, or Tdap vaccination. Groups 5 and 6 received influenza and Tdap vaccines, respectively, at some point between March 2021 and November 2024, but had no history of COVID-19 vaccination (Figure 1). Patients with all types of COVID-19 vaccinations available in the United States were included in the analysis.

Fig. 1–

Fig. 1–

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Flow chart of inclusion and exclusion criteria application for groups analyzed in primary outcome analysis. TED = thyroid eye disease.

The ICD-10 codes used to find patients with baseline thyroid dysfunction included: E05.0 (thyrotoxicosis with diffuse goiter), E05.8 (other thyrotoxicosis), and E05.9 (thyrotoxicosis, unspecified). Patients with baseline thyroid dysfunction were identified as TED (+) if they developed symptoms specific to TED or underwent TED-related surgeries (Supplemental Table S1) after March 2021. Patients were excluded if they had orbital disease codes that overlapped with TED (see supplementary section for ICD-10 codes [Supplemental Table S2]). Patients with other orbital diseases or TED that occurred before vaccination were excluded.

If a patient was in one of the vaccine cohorts, they were only included in the analysis after they received their vaccine. COVID vaccination was determined using RxNorm code 2468231, CPT codes: 91303, 91301, 91300, 91301, 0011A, 0012A 0001A, 0002A, 0031A, and SNOMED 840534001.

Propensity score matching (PSM) was used to match patients according to age, gender, race, and smoking status, as these are known risk factors for TED development in patients with thyroid dysfunction. PSM was performed using the TriNetx built-in analysis platform (1:1 matching by nearest neighbor greedy matching algorithm). The primary outcome was the relative risk (RR) of developing TED after COVID-19 vaccination for up to 1 year after vaccination in Group 1 versus Group 2. Secondary outcomes included estimating the mean time to the development of TED, and the duration of elevated TED risk after vaccination. We also calculated the relative risk of TED in group 3 versus Groups 4–6. The duration of the elevated risk of developing TED was done by calculating the RR at each month following vaccination. The month where the RR was no longer significant was set as the duration of elevated risk. Significance tests were 2-sided and paired. A significance threshold of p < 0.05 was used, and 95% CIs were calculated.

Results

In total, 373,909 patients had a history of baseline hyperthyroidism, no history of COVID infection, no history of TED, and no history of other orbital pathology, with 69,380 in the COVID-vaccinated cohort (Group 1) and 304,529 in the COVID-unvaccinated cohort (Group 2) (Table 1). The mean age of patients in the vaccinated and unvaccinated groups was 58.0 ± 17.8 and 53.9 ± 18.9, respectively. Females comprised 74.9% and 74.7% of the vaccinated and unvaccinated cohorts, respectively (Table 1). Before matching, the cohorts differed significantly in age (p < 0.001), gender (p < 0.001), race (p < 0.001), radioactive iodine (RAI) exposure (p < 0.001) and smoking status (p < 0.001). After PSM, 69,378 patients from each cohort were included in the statistical analysis. After PSM, age, gender, race, ethnicity, smoking status, and history of RAI did not differ significantly.

Table 1–

Propensity score matching between the COVID-19 vaccine and no vaccine cohorts

Characteristic Before matching
 P value After matching
 P value
COVID-19 vaccine No vaccine COVID-19 vaccine No vaccine
N 69,380 304,529 69,378 69,378
Age, years (SD) 58.0 (17.8) 53.9 (18.9) <0.001 58.0 (17.8) 58.0 (17.8) 0.913
Women, n (%) 51,937 (74.9) 227,389 (74.7) <0.001 51,936 (74.9) 51,976 (74.9) 0.804
Asian, n (%) 6 300(9.1) 15,456 (5.1) <0.001 6 298 (9.1) 6 298 (9.1) 0.978
Black, n (%) 11,145 (16.1) 46,899 (15.4) <0.001 11,145 (16.1) 11,131 (16.0) 0.918
White, n (%) 43,179(62.2) 186,694 (61.3) <0.001 43,179 (62.2) 43,243 (62.3) 0.723
Unknown race, n (%) 5 104 (7.4) 39,518 (12.9) <0.001 5 104 (7.4) 5 076 (7.3) 0.773
RAI, n (%) 2,010 (2.9) 5 408 (1.8) <0.001 2 009 (2.9) 1 930 (2.8) 0.202
Tobacco use, n (%) 10,089 (14.5) 29,951 (9.8) <0.001 10,087 (14.5) 10,030 (14.5) 0.664
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SMD = standard mean difference; SD = standard deviation; RAI = radioactive iodine.

We found that 2,498 (3.6%) patients in the COVID-19 vaccine cohort (Group 1) and 1,681 (2.4%) patients in the unvaccinated cohort (Group 2) developed TED. The relative risk of developing TED after COVID-19 vaccination was 1.49 (95% CI: 1.39–1.58; p < 0.001). The mean time to development of TED after COVID-19 vaccination was 7.6 weeks (Figure 2). The relative risk of developing TED remained significantly elevated for 3 months following vaccination.

Fig. 2–

Fig. 2–

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Incidence of new thyroid eye disease cases after COVID-19 vaccination. The black bars represent the incidence. Mean onset time was 7.6 weeks.

The Tdap (Group 5) and influenza (Group 6) cohorts were compared to a cohort of patients that received a COVID-19 vaccination but no Tdap or influenza vaccine (Group 3). Prior to PSM, the Tdap (Group 5) and influenza (Group 6) cohorts had 13,527 and 22,596 patients, respectively. After PSM for age, gender, race, ethnicity, smoking status, and history of RAI, the cohorts had 15,478 and 22,242 patients, respectively. After matching, the influenza cohort was noted to be significantly younger than the COVID-19 cohort (56.1 ± 19.7 vs 56.7 ± 19.0). The Tdap cohort had significantly more patients with unknown race (12.7% vs 11.8%) and a smoking history (11.5% vs 10.6%). No other factors were found to be significantly different between groups after matching. Median follow-up was 136 weeks and 202 weeks in the Tdap and influenza cohorts, respectively.

The rates of TED development, after PSM, in the Tdap and influenza vaccine cohorts were 1.97% (548/15,478) and 2.10% (468/22,242), respectively (Tables 2 and 3). When comparing cohorts that received different vaccines (Groups 5 and 6), the COVID vaccine group (Group 3) had a significantly higher risk of developing TED in comparison to patients that received Tdap (RR = 1.80; 95% CI: 1.56–2.06) and influenza (RR= 1.68; 95% CI: 1.49–1.88) (Figure 3). The Tdap group (RR = 0.77; p = 0.005) had a significantly lower rate of TED development than the control group and the influenza group (RR = 0.97; p = 0.670) did not develop TED at a significantly higher rate than the control group (Group 4).

Table 2–

Propensity score matching between the COVID-19 vaccine and influenza cohorts

Characteristic Before matching
 P value After matching
 P value
COVID-19 vaccine Influenza vaccine COVID-19 vaccine Influenza
N 69,380 22,242 22,242 22,242
Age, years (SD) 58.0 (17.7) 56.0 (19.8) <0.001 56.7 (19.0) 56.1 (19.7) 0.001
Women, n (%) 51,885 (74.9) 15,891 (71.4) <0.001 15,840 (71.2) 15,891 (71.4) 0.593
Asian, n (%) 6 299(9.1) 873 (3.9) <0.001 851 (3.8) 873 (3.9) 0.589
Black, n (%) 11,122 (16.1) 3 567 (16.0) 0.950 3 524 (15.8) 3 567 (16.0) 0.578
White, n (%) 43,135 (62.2) 14,146 (63.6) <0.001 14,137 (63.6) 14,146 (63.6) 0.929
Unknown race, n (%) 5 103 (7.4) 2 990 (13.4) <0.001 3 084 (13.9) 2 979 (13.4) 0.147
Tobacco Use, n (%) 10,240 (14.7) 3,445 (15.5) <0.001 3 486 (15.7) 3 445 (15.7) 0.592
RAI, n (%) 2 031 (2.9) 536 (2.4) <0.001 482 (2.2) 536 (2.4) 0.087
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SMD = standard mean difference; SD = standard deviation; RAI = radioactive iodine.

Table 3–

Propensity score matching between the COVID-19 vaccine and Tdap cohorts

Characteristic Before matching
 P value After matching
 P value
COVID-19 vaccine Tdap COVID-19 vaccine Tdap
N 69,378 15,559 15,478 15,478
Age, years (SD) 58.0 (17.7) 47.4 (17.3) <0.001 47.3 (17.5) 47.4 (17.3) 0.602
Women, n (%) 51,883 (74.9) 11,413 (73.7) <0.001 11,431 (73.9) 11,413 (73.7) 0.816
Asian, n (%) 6 299 (9.1) 753 (4.9) <0.001 740 (4.8) 753 (4.9) 0.730
Black, n (%) 11,122 (16.0) 2,707 (17.5) <0.001 2 689 (17.4) 2 707 (17.5) 0.787
White, n (%) 43,133 (62.2) 9 447 (61.0) <0.001 9 593 (61.9) 9 447 (61.0) 0.088
Unknown race, n (%) 5 103 (7.4) 1 962 (12.7) <0.001 1 831 (11.8) 1 962 (12.7) 0.023
Tobacco use, n (%) 10,239 (14.8) 1 785 (11.5) <0.001 1 637 (10.6) 1 785 (11.5) 0.007
RAI, n (%) 2 031 (2.9) 204 (1.3) <0.001 179 (1.2) 204 (1.3) 0.199
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SMD = standard mean difference; SD = standard deviation; RAI = radioactive iodine.

Fig. 3–

Fig. 3–

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Forest plot demonstrating the relative risk of developing TED when comparing patients in the COVID-19 vaccine cohort (Group 1) to patients in the no vaccine (Group 2), influenza vaccine (Group 6), and Tdap vaccine (Group 5) cohorts. Solid black lines indicate the 95% confidence interval for the relative risk estimates (black squares).

Discussion

This is the first study to use a large database to assess the association between COVID-19 vaccination and TED development. In our retrospective analysis of patient records in the TrinetX database, we found that patients with thyroid dysfunction who received a COVID-19 vaccine were more likely to develop TED when compared with those that had not received a COVID-19 vaccine. Although the risk of developing TED post-vaccination was significant, the incidence of TED in the COVID-19 vaccine cohort (Group 1) was relatively low at 3.6%. In line with other studies, we found that most cases of vaccine-related TED occurred within the first few weeks after vaccination. Interestingly, patients continued to be at risk of developing TED for months after vaccination. We hypothesize that many cases presenting more than 2 months after vaccination may have developed symptoms early but presented later due to delays in patient access or diagnosis, or due to mild TED symptoms that were less urgently triaged.

We found that patients that received other vaccinations (Tdap and influenza) developed TED at lower rates than those that had not received these vaccines. Though, influenza vaccination was not significantly lower. These results are in line with previous studies that found that while vaccines may be associated with rare cases of autoimmune disease exacerbation, they tend to lower the risk.32 This is because infections carry a greater risk of autoimmune disease exacerbation than the associated vaccines.33 However, COVID vaccination in patients with Graves’ disease appears to carry a greater risk of autoimmune disease exacerbation. COVID vaccines were associated with a 1.68–1.80-fold increase in the rate of TED development in those who received Tdap or influenza vaccinations. There may be certain patients with Graves’ disease that are prone to post-vaccination autoimmunity.34 Future studies and personalized medicine strategies are needed to identify these patients.

Our study confirms the increased risk of developing TED after COVID vaccination reported by Muller et al. and the case reports12–19,21,22,35 in the literature.11 Muller et al. assessed the risk of developing COVID vaccine-related TED in a cohort of 98 patients and found that patients are 3.5 times more likely to develop TED after COVID vaccination’ which is higher than the relative risk of 1.49 found in our study. There are several factors that might explain the difference between Muller et al. and our study’ including differences in age, gender, smoking history, and RAI exposure. Notably, Muller et al. had a high rate of concurrent COVID-19 infections during their study 29.5%.11 We excluded patients with a history of COVID-19 infection. Given these findings, it seems most likely that the differences in COVID-19 infections and the difference in sample size could explain the increased risk found in Muller et al., as COVID-19 infection has been linked to the development of thyroid dysfunction and TED.12,36–38

The increased risk of TED observed following vaccination remains poorly understood and may be due to several potential mechanisms, such as molecular mimicry and adjuvant-induced autoimmunity.39–41 Molecular mimicry refers to the phenomenon where a similarity between human antigens and vaccine antigens results in cross-reactive antibodies and autoimmune disease. Several reports have identified self-antigens that cross-react with epitopes on the spike protein, especially in patients with chronic diseases.42,43 Additionally, vaccine adjuvants may trigger an autoimmune response. The term Autoimmune/inflammatory Syndrome Induced by Adjuvants, or ASIA syndrome, was coined in 2011 to describe the varied autoimmune phenomena that may occur after exposure to adjuvants; ASIA has been associated with several autoimmune diseases. However, association with thyroid disease is uncommon and limited to case reports.44 Potential adjuvants associated with COVID-19 vaccine-related autoimmunity include polyethylene glycol, polysorbate 80, and anti-spike antibodies, but additional research is needed.45,46

Providers are often asked whether COVID vaccination will worsen or induce TED. This study demonstrates that while significant, the absolute risk of TED after vaccination is low. However, our study only analyzed patients that received an mRNA vaccine, which raises the question: can these results be applied to other types of vaccines like protein subunit vaccines and inactivated virus vaccines? There are few studies directly comparing the incidence of autoimmune disease in the different types of vaccines available, but the available evidence suggests that the risk difference between vaccines for postvaccination autoimmune disease is likely small.46–50 A study by Li et al. evaluated risk of developing autoimmune disease in 1.1 million patients that received either BNT162b2 (mRNA) or CoronaVac (inactivated virus) and found no significant difference in the rate of autoimmune disease development.47 These results suggest that different types of vaccines may behave similarly and the results in our study may apply to future COVID-19 vaccines that are developed. Further studies will be needed to characterize postvaccination autoimmune disease.

There are several limitations to our study. The nature of electronic health record data means that certain items may not have been captured or coded correctly. TED is a particularly challenging disease to study in this context, as there are no standard ICD-10 codes for TED. Also, the codes used to identify patients with thyroid disease are not specific and could have also included patients with nonautoimmune thyroid dysfunction. We mitigated this weakness by exclusively looking at patients with baseline thyroid dysfunction that developed TED symptoms postvaccination and excluding patients with other orbital pathology. Given the dearth of patients that were vaccinated with non-mRNA vaccines, we elected to focus exclusively on patients treated with mRNA vaccines. This limits, but does not preclude, the application of our results to non-mRNA vaccines. Although we did exclude all patients with documented COVID-19 infection from our analysis, we may have missed several patients with mild COVID-19 infections that were never formally diagnosed51–53 Our inclusion criteria likely captured patients with moderate-to-severe TED and may have missed patients with mild TED, indicating that we likely underestimated the incidence of TED in our cohort. The focus on moderate-to-severe disease may prove more useful to providers, as patients with moderate-to-severe TED are most likely to need treatment. The challenges faced in assessing TED are not unique to our study and highlight the importance of creating an ICD-10 code for TED. Doing so would enable several currently impossible studies to be completed.

Management guidelines are needed for patients at risk of developing TED; the most recent joint guidelines on TED management from the American Thyroid Association and European Thyroid Association do not comment on the potential for TED development after vaccination.54 In the interim, the authors recommend: (1) patients with a history of hyperthyroidism should be counseled on the signs and symptoms of TED prior to vaccination; (2) patients should be given return precautions and follow up with their endocrinologist or ophthalmologist if they develop TED symptoms; (3) TED should be added to the list of adverse events of special interest that are monitored in the vaccine adverse events monitoring system (VAERS); and (4) the treatment of postvaccine TED should be carefully considered on a case-by-case basis, as studies have found that steroids and B-cell depleting therapies like rituximab blunt the response to COVID-19 vaccination, resulting in lower antibody titres;55–57 and (5) if indicated, patients with thyroid dysfunction should still receive the COVID-19 vaccine as current evidence, though limited, suggests that vaccine-related TED can be successfully treated with conventional TED therapies.

In conclusion, our study demonstrates that patients with baseline hyperthyroidism who received the COVID-19 vaccination were more likely to develop TED than those who received no vaccine, a Tdap vaccine, or an influenza vaccine in the first 3 months after vaccination. Future studies are needed to demonstrate a pathophysiological mechanism and identify whether there are other risk factors associated with post-COVID vaccination TED. We recommend the development of guidelines for the appropriate monitoring and counseling of patients with baseline thyroid dysfunction after COVID-19 vaccination.

Supplementary Material

Supplementary materials 1
Supplementary materials 2

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jcjo.2025.06.017.

Footnotes and Disclosure

The author(s) have made the following disclosures: Andrea L. Kossler reports being a consultant for Amgen (independent contractor), Genentech, Kriya, Aceylrin, Axogen, Argenx, and Lassen (independent contractor); a consultant and advisor for Immunovant, and an independent contractor for Viridian and Sling Therapeutics. CD is a consultant for Amgen, Immunovant, and Sling Therapeutics.

This work was supported by the National Institute of Health under Grant P30 026877 and by Research to Prevent Blindness under an unrestricted grant.

Footnotes

Prior presentations: This abstract was presented at the Innovate TED 2024 Multidisciplinary Symposium.

CRediT Author Statement

Linus Amarikwa: Writing – review & editing, Data curation, Formal analysis, Methodology, Writing – original draft, Conceptualization. Patcharaporn Chandraparnik: Conceptualization, Methodology, Supervision. Karen M. Wai: Conceptualization, Methodology, Supervision, Writing – review & editing. Ehsan Rahimy: Conceptualization, Methodology, Supervision, Writing – review & editing. Benyam Kinde: Conceptualization, Methodology, Supervision, Writing – review & editing. Euna Koo: Conceptualization, Methodology, Supervision, Writing – review & editing. Chase Ludwig: Conceptualization, Methodology, Supervision, Writing – review & editing. Chrysoula Dosiou: Conceptualization, Methodology, Supervision, Writing – review & editing. Prithvi Mruthyunjaya: Conceptualization, Methodology, Supervision, Writing – review & editing. Andrea L. Kossler: Writing – original draft, Conceptualization, Writing – review & editing, Formal analysis, Methodology, Supervision.

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Supplementary materials 2
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