Background
Subacute thyroiditis (SAT) is an inflammatory condition of the thyroid gland with characteristic presentation that generally occurs after an upper respiratory tract infection. SAT is thought to be caused by viral infection of the thyroid gland. Many viruses such as coxsackievirus, adenovirus, paramyxovirus, morbillivirus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are involved in the onset of SAT [
1,
2]. Susceptibility to SAT has been associated with certain human leukocyte antigen (HLA) alleles including
HLA-B*35:01,
HLA-B*18:01, and
HLA-C*04:01 [
3‐
5]. Furthermore, the
HLA-DPB1*05:01 and
HLA-A2 alleles are known to be involved in the susceptibility to Graves’ disease (GD), an autoimmune disorder affecting the thyroid gland, in the Japanese population [
6]. Recently, some cases of SAT [
7] and GD after the emergence of coronavirus disease 2019 (COVID-19) have been reported in several countries. Regarding COVID-19-induced SAT, atypical SAT that frequently follows a painless course was rarely reported [
8]. Moreover, the involvement of the
HLA-B*35 allele was suggested in the pathogenesis of SAT after COVID-19 [
9]. Not only COVID-19 but also the SARS-CoV-2 vaccine was also reported to cause SAT [
10]. The co-presence of the
HLA-B*35 and
HLA-C*04 alleles can play an important role in the post-SARS-CoV-2 vaccination pathogenesis of SAT [
11,
12]. To the best of our knowledge, however, a detailed investigation of these issues has not yet been conducted. The development of SAT after other vaccinations, such as the influenza vaccine, have also been reported [
13,
14].
The systematic review of Ippolito et al. [
10] reported on 51 patients who developed SAT after SARS-CoV-2 vaccination in some countries in Europe, Asia, and North America, with predominance of females (74.5%), median age of 39.5 years, and symptoms very similar to those found in typical SAT. In addition, Jafarzadeh et al. [
15] investigated the classes of the SARS-CoV-2 vaccines inducing SAT (i.e., mRNA, inactivated, and vector-based) and found that 1) the mRNA SARS-CoV-2 vaccine was mostly responsible for SAT, as with GD after SARS-CoV-2 vaccination, 2) times from vaccination to the onset of SAT and GD were about 10 days and about 10–14 days, respectively, and 3) both SAT and GD developed after the first and second vaccinations.
We encountered two patients at our institution who developed SAT after SARS-CoV-2 vaccination. One patient, who was positive for antithyroid-stimulating antibody (TSAb), developed SAT but not GD. Another patient who was positive for antithyroid-stimulating hormone receptor antibody (TRAb), developed both SAT and GD. To date, a limited number of cases of SAT and GD after SARS-CoV-2 vaccination have been reported [
16,
17]. Herein, we report on two aforementioned patients for whom we also conducted HLA typing.
Discussion and conclusions
To the best of our knowledge, this is the first report on the HLA typing results of two Japanese patients who developed SAT and both SAT and GD after SARS-CoV-2 vaccination.
We could not completely rule out the acute exacerbation of Hashimoto’s thyroiditis (HT) in patient 1. Serum TPOAb and TgAb levels decreased to normal levels during follow-up. Nishihara et al. reported that serum TPOAb and TgAb levels may increase in SAT and decrease during follow-up [
21]. Patient 1 exhibited a similar clinical course and was highly likely to have developed SAT. HT, when exacerbated acutely, causes thyrotoxicosis that results in persisting hypothyroidism [
22]. However, patient 1 developed transient hypothyroidism with oral PSL administration and later became euthyroid, a condition that persisted thereafter. Therefore, we considered that patient 1 did not show the acute exacerbation of HT and was affected by SAT. The serum TSAb level increased slightly during the initial stage and then later decreased to normal levels during follow-up. Elevated serum levels of antithyroid antibodies in SAT patients are related mostly to antigen exposure during acute thyroid destruction [
3,
23]. We presumed that this transient increase in serum TSAb level along with increased serum TPOAb and TgAb levels were laboratory changes that occurred with the onset of SAT.
Patient 2, who sought for medical attention at our hospital for the treatment of fever (37.5–38.9 °C) and pain in the thyroid gland, was diagnosed with SAT and was treated with oral PSL alone, resulting in improved serum TH levels and thyroid gland pain resolution. Therefore, we concluded that the patient developed SAT after SARS-CoV-2 vaccination, which increased serum TRAb levels. However, serum TH levels again increased thereafter. Patient 2 was diagnosed with GD by thyroid scintigraphy with 99mTc pertechnetate during the follow-up of SAT. Notably, patient 2 had no treatment history for GD, had never shown GD symptoms (e.g., weight loss, finger tremors, and palpitations) and did not present with Graves’ orbitopathy before SARS-CoV-2 vaccination. However, patient 2 was not examined for serum TRAb and TH levels prior to SARS-CoV-2 vaccination, which impeded us to completely deny the possibility of GD development prior to vaccination. Moreover, we cannot rule out the likelihood that GD exacerbation and SARS-CoV-2 vaccination occurred in a temporal coincidence manner.
Since 2020, a number of case reports are available that reported on the onset of SAT and GD after COVID-19, both as single pathological entities. The results from a systematic review indicated that 13–64% of COVID-19 patients displayed thyroid dysfunction [
24]. Additionally, COVID-19 but also SARS-CoV-2 vaccination is now considered to be involved in the onset of SAT and GD [
10,
15]. Nevertheless, no study report is available that reported on the HLA typing outcomes and the concurrent onset of SAT and GD. SARS-CoV-2 vaccines can play a role in the pathogenesis of autoimmune diseases through various mechanisms (e.g., molecular mimicry, epitope spreading, polyclonal activation, and bystander activation) [
25]. When the antigenic content of a vaccine shares structural similarities with autoantigens, immune responses to vaccine antigens could extend to host cells that exhibit similar self-antigens. On the other hand, recent studies investigating the incidence of SAT during COVID-19 found no changes in its incidence [
26,
27]. These studies drive us to conjecture that COVID-19 and SARS-CoV-2 vaccines, when acting alone, do not trigger autoimmune diseases. However, molecular mimicry between thyroid proteins and infectious agents/vaccine antigens might trigger autoimmune responses in genetically susceptible individuals with specific HLA alleles (e.g.,
HLA-B*35 and
HLA-C*04) [
15,
28]. Additionally, not only specific HLA alleles but also other factors (e.g., tissue injury, prolonged inflammatory reaction) may be required to cause autoimmune disease [
15,
26].
The
HLA-B*35,
-B*18:01,
-DRB1*01, and -
C*04:01 alleles are known to be involved in the pathogenesis of SAT [
3]. The
HLA-B*35 allele is that is known to augment susceptibility to SAT in both the Japanese and Caucasian populations, and approximately 70% of patients with SAT reportedly harbor the
HLA-B*35 allele [
4]. Both of our patients had the
HLA-B*35:01 and -
C*04:01 alleles which are strongly inferred to be involved in the postvaccination pathogenesis of SAT. Recently, Stasiak et al. reported that four patients who had developed SAT after COVID-19 [
9] had
HLA-B*35 alleles (two had
HLA-B*35:01, one had
HLA-B*35:03, and one had
HLA-C*04:01). In addition, the
HLA-B*35 and
HLA-C*04:01 alleles were involved in the postvaccination pathogenesis of SAT in Caucasians [
11,
12]. We also verified the co-presence of the
HLA-B*35 and
HLA-C*04:01 alleles in 2 Japanese patients, thus strongly suggesting the involvement thereof in the postvaccination pathogenesis of SAT.
Dong et al. reported that the
HLA-DPB1*05:01 and
HLA-A2 HLA alleles are involved in the pathogenesis of GD in the Japanese population; harboring these two alleles is associated with increased risk for developing GD [
6]. In our patients, patient 1 developed only SAT, whereas patient 2 developed both SAT and GD. Both patients had the
HLA-DPB1*05:01 allele. Patient 1 had the
HLA-A*02:01 allele although patient 2 did not have the
HLA-A2 allele. Dong et al. reported that possessing both
HLA-DPB1*05:01 and
HLA-A2 alleles increases the risk for developing GD [
6]. Notably, patient 1 who had both HLA alleles (
HLA-DPB1*05:01 and
HLA-A2) did not develop GD, although patient 2 who had only the
HLA-DPB1*05:01 allele developed GD. We presume that GD in patient 2 was triggered after SARS-CoV-2 vaccination due to the involvement of other HLA alleles that would have intensified the GD susceptibility. Besides the
HLA-DPB1*05:01 and
HLA-A2 alleles,
HLA-B46 and
HLA-Cw11 are reportedly involved in the pathogenesis of GD in the Japanese population [
6]. Additionally, the
HLA-DRB1*04:05 and
HLA-DQB1*04:01 alleles reportedly confer susceptibility to GD in children [
29]. However, patient 2, who developed both SAT and GD, had none of the aforementioned HLA alleles. The
HLA-DRB1*03:01,
HLA-DQB1*02:01,
HLA-B*08:01,
-B*39:06,
-B*37:01,
-C*07:01,
-C*14:02,
-C*03:02,
-C*17:01,
-DRB1*11:01,
-DRB1*13:03,
-DRB1*01:03,
-DRB1*14:01, and
-DQB1*03:01 alleles are associated with GD in Caucasians [
30‐
33]. Patient 2—a Japanese female—had the
HLA-DRB1*11:01 and
HLA-DQB1*03:01 alleles among these alleles, suggesting the involvement thereof in the postvaccination pathogenesis of GD. The former allele has been reported in Caucasians [
30] but has never been reported in Asians, while the latter has been reported in Asians including the Chinese, Koreans, and Thais [
34,
35]. Nonetheless, both of the
HLA-DRB1*11:01 and
HLA-DQB1*03:01 alleles have never been reported to be associated with the postvaccination pathogenesis of GD not only in the Japanese but also Asian populations. At present, no evidence is available about 1) whether the
HLA-DRB1*11:01 and
HLA-DQB1*03:01 alleles are involved only in the postvaccination pathogenesis of GD, 2) whether these alleles are associated with the concurrence of SAT and GD, or 3) whether the combination thereof increases the risk of developing GD in the Japanese population. We intend to elucidate these issues in a larger scale clinical study.
Besides the HLA alleles, factors such as cluster of differentiation 40, cytotoxic T-lymphocyte-associated antigen 4, protein tyrosine phosphatase non-receptor type 22, Fc receptor-like protein 3, thyroglobulin, TSH receptor, zinc finger and AT-hook domain containing factor, forkhead box P3, interleukin (IL)-2 receptor alpha, IL-23 receptor, and interferon induced with helicase C domain 1 are known to be involved in the pathogenesis of GD [
36‐
38]. We could not investigate whether our patients had one or more of these factors. Additionally, noncoding single nucleotide polymorphisms (SNPs) in intron 1 of the thyroid-stimulating hormone receptor (
TSHR) gene are associated with GD [
39]. Hiratani et al. [
40] found that the SNP JST022302 and several adjacent SNPs in intron 7 of the
TSHR gene were significantly associated with GD in the Japanese population and identified 3 haplotype blocks around intron 7 by linkage disequilibrium analysis. A single SNP haplotype (AATG [CT]6[TT]AG) in the haplotype block including JST022302 showed a significant association with GD in the haplotype case-control analysis. COVID-19 reportedly causes the upregulation of TSHR, which acts as an autoantigen in GD [
41]. Presuming that such upregulation also occurs after SARS-CoV-2 vaccination, the risk for developing GD may be increased by the upregulation of TSHR autoantigen in individuals who have the
TSHR gene haplotype mentioned above [
40]. Nevertheless, we did not investigate these risk factors for GD other than the HLA alleles and therefore cannot rule out their association with the postvaccination pathogenesis of GD.
Nongenetic risk factors (e.g., iodine levels, presence of infections, psychological stress, sex susceptibility, smoking habits, thyroid damage, vitamin D levels, selenium levels, and presence of immune-modulating agents) are also involved in the pathogenesis of GD [
36]. To date, serum vitamin D and selenium concentrations have never been evaluated in our patients. However, any nongenetic risk factor(s) other than SARS-CoV-2 vaccination and female sex were not considered as risk factors for GD pathogenesis in patient 2. We also aim to investigate genetic and nongenetic risk factors that could not be investigated this time.
In conclusion, we encountered two patients who developed thyroid disease after SARS-CoV-2 vaccination; one developed SAT and another developed both SAT and GD. The HLA alleles HLA-B*35:01 and HLA-C*04:01 appeared to be involved in the pathogenesis of postvaccination SAT. Moreover, the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles were speculated to be involved in the postvaccination pathogenesis of GD. The further accumulation of genetic and nongenetic evidence is required to elucidate the pathogenesis of SAT and GD that develop after vaccination for SARS-CoV-2.
Acknowledgments
The authors thank Yumi Miyashita, Division of RI Laboratory, Biomedical Research Center, Saitama Medical University and Takahiro Ogawa, Division of Molecular Diagnostics Business Development, Wakunaga Pharmaceutical Co., Ltd., for their cooperation in conducting HLA typing and analyzing its results. The authors also thank Shigehiro Katayama, MD, PhD; Mitsuhiko Noda, MD, PhD; and Satoshi Sakima, MD for their critical review and valuable suggestions for the manuscript. Editorial support, in the form of medical writing, assembling tables, and creating high-resolution images based on authors’ detailed directions, collating author comments, copyediting, fact checking, and referencing, was provided by Editage, Cactus Communications.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.