Introduction

Graves’ disease is the most frequent cause of hyperthyroidism due to the stimulation of the TSH-receptor on follicular thyroid cells by autoimmune antibodies which results in thyrotoxicosis, goitre and extra-thyroidal manifestations (Graves’ orbitopathy, pretibial myxoedema). Graves’ hyperthyroidism is characterized by a Th-1 response with a high number of Th-1 CD4 cells and interferon secretion but usually affects genetically predisposed patients in the presence of triggering factors (stress, smoking, infection, post-partum, radioiodine treatment). The overall prevalence of Graves’ orbitopathy (GO) among patients with Graves’ disease is up to 40%, with 3–5% going on to develop severe Graves’ ophthalmopathy [1].

An increasing number of autoimmune and inflammatory-related side effects are being reported following COVID-19 vaccination (thrombotic thrombocytopenia, Guillain–Barré syndrome, myocarditis/pericarditis, type 1 diabetes mellitus, premature ovarian failure, adrenal insufficiency). Moreover, autoimmune and inflammatory-related thyroid disorders such as Graves’ disease, subacute thyroiditis and silent (painless) thyroiditis have been described following SARS-CoV-2 vaccines [2,3,4,5] but autoimmune and inflammatory orbital adverse complications are uncommon post-COVID-19 vaccination [6].

In the present study, we describe 6 new patients with GO following SARS-CoV-2 vaccines.

Methods

The 6 patients were seen in the Tertiary Endocrinology Department with Outpatient Clinic for GO with new-onset, recurrent or worsening GO following SARS-CoV-2 vaccination. For every patient, we collected information on demographic data (sex, age), previous history of autoimmune or thyroid disease, type of administered vaccines (mRNA vaccine, inactivated virus or vector vaccine), timing of GO, onset or recurrence following vaccination, signs and symptoms at presentation, laboratory tests (TSH, free T4, anti-TSH receptor antibodies) and other diagnostic examinations (CT scan or MRI scan of the orbits), specific medical or surgical therapies and ophthalmic follow-up.

Patients

  1. (a)

    A 70-year-old female was treated with oral prednisolone (7.5 mg/day) for frozen shoulder syndrome. Her past thyroid history included Graves’ disease with total thyroidectomy and daily substitutive levothyroxine therapy (137 μg) as well as stable GO after 4 intravenous infusions of tocilizumab. Eighteen weeks after the last infusion of tocilizumab, she received the second dose of the mRNA vaccine. Sixty days later, the woman presented spontaneous and orbital pain upon eye movement, conjunctival irritation and eyelid oedema. Clinical Activity Score (CAS) was 4/7 and an orbital MRI confirmed bilateral proptosis with oedema of the medial and inferior rectus muscles which was indicative of active moderate-to-severe GO. Laboratory investigations confirmed normal thyroid function with normal TSH and free T4 concentrations during stable levothyroxine treatment, and elevated levels of anti-TSH receptor antibodies (> 40 IU/L). In the context of recurrent GO during oral glucocorticoid therapy, the woman was treated with tocilizumab (8 mg/kg monthly intravenous infusions) and reported a significant and rapid (2 weeks) clinical improvement with decreased anti-TSH receptor antibodies levels (25 IU/L) after 5 infusions of tocilizumab.

  2. (b)

    A 43-year-old male patient had a personal medical history of type-1 diabetes mellitus, psoriasis, Graves’ disease treated with carbimazole (10 mg/day) and sight-threatening GO of the right eye refractory to intravenous glucocorticoids treated by 4 IV infusions of tocilizumab (8 mg/kg) with complete recovery of the dysthyroid optic neuropathy (DON). Forty-five days after the last infusion of tocilizumab, the patient received the first dose of the Moderna mRNA vaccine. The patient reported spontaneous orbital pain and diplopia the next day then decreased visual acuity after the second dose of the COVID-19 vaccine. The CAS was 7/7 and the patient presented sight-threatening GO in relation to recurrent DON on the right eye. During carbimazole therapy, TSH levels were slightly elevated with low free T4 concentrations and absence of anti-TSH receptor antibodies. The patient was once again treated with tocilizumab (8 mg/kg). Significant improvement in inflammatory symptoms (CAS = 1/7) was observed after the first infusion of tocilizumab with recovery of visual acuity after 4 IV infusions.

  3. (c)

    A 73-year-old male patient with a personal medical history of atrial fibrillation and prostate cancer presented a Graves’ disease treated with carbimazole. Twenty-one days after the first dose of the Pfizer mRNA vaccine, he experienced conjunctival irritation and diplopia. The CAS was 3/7 and an orbital MRI showed oedema of the lower rectus muscle in the right eye favouring mild GO. TSH levels were normal and anti-TSH receptor antibodies were normal. The patient was treated with selenium as well as intravenous methylprednisolone infusions and reported an improvement in symptoms affecting the right eye after the first infusion with absence of inflammatory signs or symptoms after 6 infusions of 500 mg methylprednisolone.

  4. (d)

    A 45-year-old woman had a past medical history of hyperparathyroidism, sickle cell anaemia, total thyroidectomy in the context of Graves’ hyperthyroidism managed with substitutive levothyroxine therapy, GO treated by intravenous infusions of glucocorticoids and subsequent bilateral orbital decompression for inactive GO. During the week following the second dose of the Moderna mRNA vaccine, she presented an eyelid oedema, conjunctival irritation, spontaneous and orbital pain upon eye movement without diplopia. The CAS was 4 and the woman had active moderate-to-severe GO. On stable levothyroxine treatment, TSH levels were in the normal range and anti-TSH receptor antibodies were elevated. The woman received lubricants and reported a spontaneous improvement in orbital inflammation in 5 months.

  5. (e)

    A 48-year-old male patient with a medical history of obesity, type-2 diabetes mellitus and schizophrenia had presented Graves’ disease treated with total thyroidectomy and subsequent substitutive levothyroxine therapy as well as sight-threatening unilateral right GO with DON and total recovery after steroids and orbital decompression. Eleven months after surgical decompression, the patient received the second dose of the Moderna mRNA vaccine. One month later, the patient experienced left conjunctival irritation, orbital pain with rapid decreased visual acuity. During the ophthalmic evaluation, the CAS was 5/7 and the patient presented contralateral DON. The thyroid function test showed thyrotoxic phase with increased free T4 and low TSH concentrations justifying decreased levothyroxine dosage, and anti-TSH receptor antibodies were elevated (28 IU/L). CT scan of the orbits visualised significant and bilateral proptosis with enlargement of the extraocular muscles. In the absence of response to intravenous methylprednisolone (1 gr/day × 3), the patient underwent trans-ethmoidal and transsphenoidal orbital decompression of the left eye and subsequent intravenous infusion of teprotumumab. Ophthalmic follow-up showed normal visual acuity and absence of inflammatory signs (CAS 0/7) after the first infusion of teprotumumab [7] with a significant decrease in anti-TSH receptor antibodies (9 IU/L) three months later.

  6. (f)

    A 39-year-old woman with a family history of thyroid disease presented an oedema of the upper eyelid and proptosis of the left eye with photophobia, conjunctival irritation without diplopia 7 days after the first dose of the Pfizer mRNA vaccine. The CAS was 2/7. No aggravation after the second dose of the COVID-19 vaccine was observed. The TSH level was at the lower limit of the normal range with elevated anti-TSH receptor antibodies. The orbital MRI revealed enlargement and an inflammatory aspect of the left lower rectus muscle. The woman presented mild GO, was treated with selenium (200 μg/day) and the CAS was unchanged at 6-month follow-up.

Main clinical, hormonal and radiological data as well as treatment and ophthalmic follow-up from the 6 patients are presented in Table 1.

Table 1 Main clinical, hormonal and radiological data as well as treatment and ophthalmic follow-up in 6 new patients with GO post-SARS-CoV-2 vaccines
Full size table

At the time of writing the article, GO following SARS-CoV-2 vaccines had been previously described in 12 patients [8,9,10,11,12,13,14] and the main data are reported in Table 2.

Table 2 Main clinical, hormonal and radiological data as well as treatment and ophthalmic follow-up in 12 patients with GO post SARS-CoV-2 vaccines from literature
Full size table

Discussion

After SARS-CoV-2 vaccination, GO was observed in 6 new patients (3 men, 3 women, mean age was 53 ± 6 years, ranging from 39 to 73 years). Most patients had a past personal history of Graves’ disease (5/6) or GO (4/6). Newly diagnosed or recurrent GO were reported following mRNA COVID-19 vaccines after the first (3/6) or second (3/6) dose with the mean time from COVID-19 vaccination to onset or worsening of GO at 23.8 ± 10.4 days, ranging from 1 to 60. In one patient, thyrotoxicosis was confirmed by high free T4 and low TSH concentrations while others (5/6) had normal TSH levels during chronic levothyroxine treatment in 3 patients. Autoimmune GO was associated with the presence of anti-TSH receptor antibodies in most patients (4/6). According to the activity and severity of GO, patients were treated using selenium (n = 2), intravenous glucocorticoids (n = 2) or immunosuppressive drugs (tocilizumab n = 2), anti IGF1 receptor monoclonal antibody (teprotumumab n = 1) and orbital decompression (n = 1) with significant improvement in signs and symptoms experienced by most patients.

In all reported patients with GO following COVID-19 vaccination, no triggering events (increased TSH concentrations, changes in smoking status, pregnancy, recent surgeries, radioiodine treatment) were observed in their medical history other than COVID-19 vaccination and the timing between the new-onset or reactivation of GO and SARS-CoV-2 vaccines was similar to that stated in previous reports of autoimmune and inflammatory diseases following COVID-19 vaccination [2]. Considering the high vaccination coverage, it is possible that the relationship between the occurrence of GO and COVID-19 vaccination was coincidental. However, the temporal sequence of the new onset, recurrence or worsening of GO was potentially prompted by exposure to the SARS-CoV-2 vaccines with the COVID-19 vaccination serving as a triggered event in predisposed patients with Graves’ disease and/or GO. In the absence of reports on the total number of patients with GO following SARS-CoV-2 vaccination in a defined population, estimating the incidence of this orbital side effect is difficult.

Autoimmune hyperthyroidism can occur after several vaccines (hepatitis B, human papilloma virus, H1N1) [15,16,17,18,19] and autoimmune thyroid diseases may develop in the hyperimmune environment created after the SARS-Cov-2 immunisation. The exact pathogenetic mechanisms underlying new onset, recurrence or exacerbation of GO following SARS-CoV-2 vaccines are not fully understood and several hypotheses could be put forward:

  1. (a)

    Molecular mimicry: various SARS-CoV-2 proteins (spike proteins, nucleoproteins and membrane proteins) share a genetic similarity or homology with human proteins [20]. After polyclonal activation of B lymphocytes by COVID-19 vaccines, antibodies directed against SARS-CoV-2 proteins might cross-react with thyroid antigens located on the follicular cells of the thyroid and the cells of periorbital tissues to cause Graves’ hyperthyroidism and autoimmune GO, respectively, in rare patients.

  2. (b)

    Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is the consequence of the dysregulation of the immune system following exposure to adjuvants. Adjuvants enhance the immunogenicity of vaccines, increase both innate and adaptive immune response and can induce the formation of autoantibodies. Autoimmune thyroid diseases have been reported to be related to ASIA syndrome after human papillomavirus, influenza, hepatitis B vaccination [21,22,23,24,25,26] and most recently after COVID-19 vaccines [2, 5, 27,28,29]. In the BNT162b2 mRNA vaccine, polyethylene glycol (PEG) conjugates stabilise the lipid nanoparticles and may act as adjuvants to trigger an autoimmune reaction following SARS-CoV-2 vaccination.

  3. (c)

    Autoimmune hyperthyroidism and TED are related to stimulating anti-TSH receptor antibodies and produced secondary to a Th-1 immune response in which interferon gamma plays a key role [30]. As COVID-19 vaccines lead to a production of Th-1 cells, a similar mechanism could be involved in vaccine-induced Graves’ hyperthyroidism or orbitopathy.

    Despite a mass immunisation campaign against COVID-19 infection, autoimmune thyroid adverse effects such as Graves’ disease and GO appear to be rare, suggesting they are probably under-reported side effects of COVID-19 vaccination or usually occur with individual predisposition or genetic susceptibility. In genetically susceptible individuals, T lymphocytes are excessively sensitised to the TSH receptor antigen and vaccines activating B lymphocytes may produce autoantibodies against the TSH receptor thereby causing Graves’ hyperthyroidism and GO [31, 32]. On the other hand, inflammatory recurrence of GO in some patients is also a possibility after previous immunomodulating treatments unrelated to SARS-CoV-2 vaccination. Therefore, systematic reporting of patients with GO following COVID-19 vaccination will add information on the frequency and potential mechanism(s) between SARS-CoV-2 vaccines and autoimmune GO.

After clinical and ophthalmic assessment, all grades of severity (mild, moderate-to-severe, sight-threatening) were observed in patients with GO following SARS-CoV-2 vaccination [33]. In patients with mild GO, local (lubricants) and lifestyle measures were sufficient and 2 patients had also selenium (200 μg/day) therapy. In patients with moderate-to-severe GO, immunomodulatory therapy was indicated (intravenous glucocorticoids, tocilizumab) or anti IGF1 receptor monoclonal antibody (teprotumumab), and associated with a significant improvement in most patients. For patients with sight-threating GO, urgent treatment was instituted with close monitoring of response to immunosuppressive therapies and restoration of visual acuity. The response to immunomodulatory therapy in patients with GO following COVID-19 vaccination may be related to the rapidity of treatment in such patients with a past history of autoimmune thyroid diseases or to a possible brief autoimmune reaction following SARS-CoV-2 vaccination. Finally, vitamin D supplements inhibit Th-1 type immune activity and induce suppression of B cells while selenium supplements decrease the B cell-activating factor. Therefore, these class 2 micronutrient (vitamin D, selenium) supplements have the potential to reduce and modulate autoimmune thyroid activity as well as protect against activation or relapse of autoimmune adverse events due to SARS-CoV-2 vaccination, particularly in predisposed patients with a past history of Graves’ disease and/or GO [34].

Conclusion

All vaccinations are risky but the benefits of SARS-CoV-2 vaccines outweigh any theoretical risks of immunisation. COVID-19 vaccines may be recommended to all patients who are eligible for COVID-19 vaccination or booster doses, including those with autoimmune-mediated diseases such as Graves’ hyperthyroidism and GO. Clinicians should remain vigilant for recurrence or aggravation in patients with a known history of Graves’ disease or GO following SARS-CoV-2 vaccination. In such patients with a prior history of thyroid or orbital autoimmune diseases, a baseline pre-COVID-19 vaccine examination and ophthalmic monitoring is required to diagnose rapidly autoimmune hyperthyroidism or orbitopathy. Concomitantly, class 2 micronutrient (vitamin D, selenium) supplements can be prescribed to prevent more severe forms of GO in patients with a past history of Graves’ disease and/or orbitopathy.