Individuals suffering from thyroid eye disease, commonly referred to as TED, demonstrate a significantly elevated rate of low-risk human papillomavirus, or HPV, infections that were identified prior to the development of their autoimmune hyperthyroidism condition when compared to carefully matched control groups, as detailed in a concise research letter released online on February 12 in the esteemed journal JAMA Ophthalmology.
Moshe I. Weber, affiliated with the Albert Einstein College of Medicine located in Bronx, New York, along with his team of collaborators, conducted a thorough investigation into the potential relationship between HPV infections and the occurrence of TED. For this study, they drew upon a vast dataset of deidentified electronic health records sourced from the comprehensive TriNetX Live Research Network. This network encompassed data from 26,823 precisely matched patient cases, each involving individuals diagnosed with both autoimmune hyperthyroidism and TED.
Through their detailed analysis, the research team discovered that the occurrence of low-risk HPV was markedly higher among those patients diagnosed with TED in contrast to the matched control participants. Specifically, the odds ratio stood at 1.55, accompanied by a 95% confidence interval ranging from 1.16 to 2.03, with a statistically significant P-value of 0.003. This finding underscores a clear and robust association between prior low-risk HPV presence and the development of TED.
Importantly, the study revealed no notable differences in the rates of new-onset HPV infections that emerged after the diagnosis of autoimmune hyperthyroidism. In this regard, only 38 patients with TED developed such infections, compared to 31 individuals in the matched control group. The corresponding odds ratio was 1.23, with a 95% confidence interval of 0.76 to 1.97 and a P-value of 0.40, indicating no statistically significant disparity between the two cohorts.
Furthermore, the investigators observed that the incidence of low-risk HPV infections prior to the onset of autoimmune hyperthyroidism was substantially higher than those occurring afterward. To quantify this, there were 205 cases before diagnosis versus just 69 cases post-diagnosis, yielding an odds ratio of 2.97, a 95% confidence interval from 2.26 to 3.90, and a highly significant P-value less than 0.001. This temporal pattern suggests that low-risk HPV may play a predisposing role in the disease process.
In contrast, the analysis uncovered no meaningful connection between high-risk HPV and the status of TED, whether examined before or after the onset of autoimmune hyperthyroidism. For infections prior to diagnosis, the odds ratio was 1.02, with a 95% confidence interval of 0.80 to 1.30 and a P-value of 0.85. Post-diagnosis, the odds ratio dropped to 0.91, with a 95% confidence interval from 0.72 to 1.14 and a P-value of 0.41. These results effectively rule out high-risk HPV as a contributing factor in TED pathogenesis.
To delve deeper into the clinical implications, the researchers compared outcomes between 201 patients who had TED along with low-risk HPV and a matched set of TED controls without HPV. Those individuals with low-risk HPV exhibited considerably higher rates of requiring orbital decompression surgery, at 13.43% compared to 5.47% in the control group. This translated to a risk ratio of 2.46, with a 95% confidence interval spanning 1.25 to 4.81 and a P-value of 0.006, highlighting a significant clinical burden.
Notably, the two groups showed no substantial differences in other key clinical metrics, including the utilization of corticosteroids, instances of vision loss, occurrences of eyelid retraction, or cases of strabismus. This selective increase in surgical intervention needs points to a specific pathway influenced by low-risk HPV in TED progression.
The authors of the study propose that these compelling findings indicate the involvement of molecular mimicry triggered by HPV in the underlying mechanisms driving TED. Molecular mimicry refers to a process where immune responses initially directed against a viral pathogen inadvertently target similar proteins in the host’s own tissues, thereby initiating autoimmune reactions. In the context of TED, which often accompanies Graves’ disease—an autoimmune hyperthyroidism disorder—this mechanism could explain how prior HPV exposure heightens susceptibility.
Thyroid eye disease manifests through inflammation and swelling of the tissues surrounding the eyes, leading to symptoms such as bulging eyes (proptosis), double vision, pain, and potential vision impairment if untreated. It predominantly affects individuals with Graves’ disease but can occur independently. The higher prevalence of low-risk HPV prior to disease onset suggests that this viral infection might serve as an environmental trigger, interacting with genetic predispositions to provoke the autoimmune response characteristic of TED.
Low-risk HPV strains, unlike their high-risk counterparts associated with cancers such as cervical carcinoma, typically cause benign conditions like genital warts. However, their role in autoimmune disorders is an emerging area of research. The absence of association with high-risk HPV in this study further refines our understanding, implying that specific viral proteins from low-risk types may cross-react with ocular or thyroid-related antigens.
The utilization of the TriNetX Live Research Network in this investigation merits attention. This platform aggregates deidentified data from numerous healthcare organizations across the United States, enabling large-scale, real-world evidence studies with high statistical power. By matching cases on variables such as age, sex, comorbidities, and timing of diagnoses, the researchers minimized confounding factors, thereby strengthening the validity of their conclusions.
From a clinical perspective, these results advocate for increased vigilance in screening TED patients for prior HPV history, particularly low-risk types. While causation cannot be definitively established from observational data alone, the temporal precedence of HPV and the dose-response-like increase in surgical needs provide circumstantial evidence supporting a causal link. Future prospective cohort studies or mechanistic investigations in animal models could further elucidate this relationship.
Moreover, the findings contribute to the broader discourse on viral triggers in autoimmunity. Conditions like rheumatoid arthritis, multiple sclerosis, and type 1 diabetes have similarly been linked to antecedent viral infections via molecular mimicry. For TED, this study adds HPV to the list of potential culprits, alongside known associations with smoking and radioactive iodine therapy.
Publication details for the original research include Moshe I. Weber and colleagues, titled Thyroid Eye Disease and the Prevalence of Human Papillomavirus, published in JAMA Ophthalmology in 2026, with DOI: 10.1001/jamaophthalmol.2025.6244. JAMA Ophthalmology is a leading peer-reviewed journal dedicated to advancing knowledge in eye and vision science through rigorous clinical and basic research.
