COVID-19 vaccine-associated autoimmune thyroid eye disease: Graves' orbitopathy

Thyroid eye disease (TED) is an autoimmune disorder commonly associated with hyperthyroidism of Graves' disease. The global outbreak of SARS-CoV-2 resulted in an unparalleled public health emergency. The rapid development and widespread administration of COVID-19 vaccines were instrumental in controlling viral transmission and decreasing severe disease outcomes and deaths. Although these vaccines have demonstrated strong safety and effective prevention, isolated cases of uncommon adverse events have been reported. Notably, instances of new-onset or worsening autoimmune disorders, including TED, after vaccination have drawn considerable research interest. In this review, we describe the common risk factors (age, sex, genetics, ethnicity, dysthyroid status, high serum cholesterol, oxidative stress, pregnancy, psychological stress, radioiodine therapy, trauma, systemic disease, and virus) of TED and outline the constituents of COVID-19 vaccines and the current global vaccination scenario. We further explain autoimmune mechanisms as central drivers of classical TED, particularly through the activation of autoreactive T-cells and the production of autoantibodies targeting shared antigens in orbital fibroblasts, leading to inflammation, tissue remodeling, and orbital expansion. Besides, we discuss molecular signaling (MAPK, PI3K/Akt, NF-κB, and JAK/STAT) implicated in TED. Moreover, we critically examine published case reports (n = 30) to identify shared features and potential factors associated with the onset of this autoimmune condition. We delineate the autoimmune-mediated molecular mechanisms in the development of COVID-19 vaccine-associated TED. The therapeutic management approaches and clinical outcomes related to COVID-19 vaccine-associated TED are also thoroughly examined and discussed. Improved understanding of these mechanisms may refine patient risk stratification, optimize clinical management, and inform vaccination strategies.