key: cord-0941830-s8a914a1 authors: Chee, Ying Jie; Liew, Huiling; Hoi, Wai Han; Lee, Yingshan; Lim, Brenda; Chin, Han Xin; Lai, Ray Tian Rui; Koh, Yunqing; Tham, Michelle; Seow, Cherng Jye; Quek, Zhi Han; Chen, Abel Weiliang; Lim Quek, Timothy Peng; Tan, Alvin Wai Kit; Dalan, Rinkoo title: SARS-CoV-2 mRNA Vaccination and Graves’ Disease: a report of 12 cases and review of the literature date: 2022-03-02 journal: J Clin Endocrinol Metab DOI: 10.1210/clinem/dgac119 sha: 7231c7eb2e9ff31930a14ff4f19e5699c98bd20e doc_id: 941830 cord_uid: s8a914a1 CONTEXT AND OBJECTIVE: Thyroid autoimmunity has been reported to be associated with SARS-CoV-2 and the SARS-CoV-2 vaccination recently. We report a series of patients who presented with new onset or relapse of Graves’ disease related hyperthyroidism shortly after receiving the SARS-CoV-2 mRNA vaccine at a single tertiary institution in Singapore. METHODS AND RESULTS: We describe 12 patients who developed hyperthyroidism within a relatively short interval (median onset of 17 (range: 5 - 63) days) after receiving the SARS-CoV-2 mRNA vaccine. The majority were females (11/12) with median age of 35.5 (range: 22-74) years. Six patients had new onset hyperthyroidism, while the other six had relapse of previously well-controlled Graves’ disease. TSH Receptor antibody concentrations ranged from 2.4-32 IU/L. Majority of the patients were able to go for the second dose of the vaccine without any further exacerbations. Literature review revealed 21 other similar cases reported from across the world. CONCLUSION: Our case series provide insight into the characteristics of individuals in whom Graves’ disease was triggered by the SARS-CoV-2 vaccination. Clinicians need to be vigilant of precipitation or exacerbation of autoimmune thyroid disorders in predisposed individuals after exposure to the SARS-CoV-2 vaccination. Further epidemiological and mechanistic studies are required to elucidate the possible associations between the SARS-CoV-2 vaccines and the development of thyroid autoimmunity. M a n u s c r i p t 6 We describe a case series of 12 patients with new onset or relapsed Graves' disease related hyperthyroidism post vaccination, presenting to a single tertiary Endocrinology clinic in Singapore. We included all consecutive patients who presented with new onset or exacerbation of hyperthyroidism to our center with a temporal sequence to the vaccine between January to Table 1 . There were 11 females: 9 Chinese and 3 non-Chinese (1 Malay and 2 Filipinos). One patient was a smoker. Five patients had a family history of thyroid disorders. hyperthyroidism. There was one interesting presentation of a patient who converted to hypothyroidism from hyperthyroidism after vaccination (6) and another individual had newly diagnosed Graves' disease with concurrent subacute thyroiditis (14) . Among these cases, 9 developed symptoms after the first dose, 7 after the second dose, 4 after a dose (first or second dose was not specified) and 1 after receiving a vector-based booster dose (this patient had received inactivated whole virus vaccine 3 months prior). There was paucity of follow-up clinical and biochemical data for majority of the patients, and there was insufficient information on whether those who developed new-onset or relapsed Graves' disease were able to tolerate the second vaccine dose. The follow-up progress was described in only one patient, who was diagnosed with new onset Graves' disease shortly after the first mRNA vaccine dose and received the second dose of vaccine 71 days later with a documented thyroid function test showing no further exacerbation (11) . A c c e p t e d M a n u s c r i p t 9 Apart from Graves' disease, subacute thyroiditis is a differential diagnosis to consider in thyrotoxic individuals. It is important to distinguish both entities as the management and course of disease is different. Based on recent reports of subacute thyroiditis cases occurring after receiving the SARS-CoV-2 vaccine (10, 13-14, 21-37), majority of these patients became symptomatic within short days to weeks with neck pain being the chief complaint. The TRAb concentrations were normal in all patients upon presentation, while the erythrocyte sedimentation rate was elevated in all cases. The diagnosis of subacute thyroiditis was supported by thyroid scintigraphy findings of reduced tracer uptake. Majority of these patients responded well to a combination of non-steroidal anti-inflammatory drug, glucocorticoid and beta-blocker with full resolution of symptoms and normalization of thyroid function shortly after initiation of treatment. The RNA-based SARS-CoV-2 vaccines have been extensively administered since its approval. We report an extensive case series with temporal sequence of new-onset or relapse of Graves' disease potentially triggered by exposure to the SARS-CoV-2 mRNA vaccines. In our case series, we observed that the exacerbation of hyperthyroidism can occur after the first or subsequent doses of the vaccine. Importantly, all the patients were able to tolerate a subsequent booster dose of SARS-CoV-2 mRNA vaccine without further exacerbation of hyperthyroidism. Whether thyroid autoimmunity may develop among individuals exposed to other types of SARS-CoV-2 vaccines (e.g. DNA-based) is currently unclear. In the literature, only a handful A c c e p t e d M a n u s c r i p t 10 of similar precipitation of Graves' disease and subacute thyroiditis has been reported after influenza or H1N1 vaccination (38 -41) . These cases may be under reported as clinicians may not associate the condition with the vaccination. While in the above cases, the temporal sequence suggests that thyrotoxicosis may be related to the SARS-CoV-2 vaccination, there is currently no evidence to prove a causal relationship. The relationship can only be postulated to be at best as "probable". The vaccination may serve as a precipitating agent. Using the analogy recently published in JCEM (42) , the vaccination may at best be considered to be another rain cloud in the trajectory of Graves' disease. In an individual with pre-existing Graves' disease it may serve as a role of a sudden rain cloud which may disrupt the steady state and will need re-enforcement of an umbrella; while in a new onset Graves' disease it may be a sudden rain cloud which disrupts the baseline latency of the autoimmune problem and precipitates a full blown disease (42) . However, baseline predisposing factors would have been present in the individuals and the vaccine cannot be considered as a causative agent. Selenium supplementation and optimizing Vitamin D levels may be considered to minimize aberrant autoimmune reactions in patients known to have pre-existing autoimmune disorders (43) . There is a concern about the possible deleterious effect of the 2 nd dose in patients who present after the first dose or booster doses. This limited series shows that -for Graves' hyperthyroidism, they can go for a second dose without any significant problems if treatment is initiated before the vaccination and hyperthyroidism is controlled. These patients can be treated like we prepare patients for surgery and efforts need to be made to control free T4 and free T3 concentrations before the subsequent dose as much as possible. Johns Hopkins Coronavirus Resource Center World Health Organization (WHO). COVID World Health Organization (WHO). 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Micronutrient supplementation before COVID-19 vaccination can protect against adverse effects Detection of SARS-COV-2 receptor ACE-2 mRNA in thyroid cells: a clue for COVID-19-related subacute thyroiditis Reaction of Human Monoclonal Antibodies to SARS-CoV-2 Proteins With Tissue Antigens: Implications for Autoimmune Diseases The pathogenesis of Graves' disease Cytokines, Graves' disease, and thyroidassociated ophthalmopathy Chemokines in hyperthyroidism Delineating the autoimmune mechanisms in Graves' disease We thank all the patients who participated in this study. M a n u s c r i p t 26 A c c e p t e d M a n u s c r i p t 28 Abbreviations: GD -Graves' disease; TFT -thyroid function test; FT4 -free thyroxine (pmol) (all values converted to pmol/L); TSH -thyroid stimulating hormone (mIU/L); TRAb -TSH receptor antibody (IU/L or IU/ml); TSI -thyroid stimulating immunoglobulin (% or IU/L)