Distinct Clinical Features of Post-COVID-19 Vaccination Early-Onset Graves' Disease

Luigi di Filippo; Laura Castellino; Agnese Allora; Stefano Frara; Roberto Lanzi; Francesca Perticone; Fanny Valsecchi; Alberto Vassallo; Raffaele Giubbini; Clifford J. Rosen; Andrea Giustina

Disclosures

J Clin Endocrinol Metab. 2023;108(1):107-113.

Abstract and Introduction

Abstract

Context: Several case reports of Graves' disease (GD) occurrence after COVID-19 vaccination that are possibly related to the autoimmune syndrome induced by adjuvants (ASIA) were published recently.

Objective: The aim of our study was to evaluate possible distinctive features in the presentation and clinical course of patients with GD occurring early (within 4 weeks) after COVID-19 vaccination who attended our Endocrine Unit in 2021.

Methods: Patients with a first episode of GD attending a tertiary endocrine center between January 1, 2021, and December 31, 2021, were included.

Results: Sixty-four patients with a first episode of GD were seen in 2021: 20 (31.2%) of them had onset within 4 weeks following vaccine administration. Compared with the other 44 patients, the 20 patients with postvaccine early-onset (PoVEO) GD were older (median age 51 years vs 35 years, P = .003) and more likely to be male (40.0% vs 13.6%, P = .018). At diagnosis, the biochemical and immune profiles were similar between the 2 groups. However, at 3 months after starting methimazole, patients with PoVEO GD had significantly lower thyrotropin receptor antibody titer and were taking lower doses of methimazole than the other patients with GD. None in the PoVEO group had sustained free triiodothyronine elevation.

Conclusion: This relatively large series suggests that in 2021 PoVEO GD may be a new nosologic entity representing one-third of patients evaluated for new-onset GD in our center. Distinctive features included older age at onset, higher male prevalence, and a better initial biochemical and immunologic response to treatment. Further studies are warranted to clinically and biochemically differentiate these cases from sporadically occurring GD.

Introduction

The Coronavirus disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has led to a dramatic impact on health systems worldwide during the last 2 years. As of March 2022, 452 201 564 confirmed cases and 6 029 852 deaths worldwide had been reported to the World Health Organization.^[1] COVID-19 was first recognized in China and then spread globally, with Italy as one of the worst affected countries with 13 214 498 cases and 156 493 deaths.^[1] Many anti-SARS-CoV-2 vaccines have been developed since the end of 2020 and the beginning of 2021, and after the emergency use authorization an extensive vaccination program has been implemented worldwide. Vaccines have strongly reduced infectious spread, clinical severity, and mortality of COVID-19.^[1] To date, 10 different formulations of vaccine have been approved by the World Health Organization and globally used in immunization programs.^[2] In Italy, during the last year, a total of 132 230 182 vaccine doses had been administered: 2 using messenger RNA (mRNA) technology containing antiviral Spike (S) protein genetic information (Comirnaty, BNT162b2 developed by Pfizer-BioNTech, commonly named "Pfizer vaccine"; and Spikevax, mRNA-1273 developed by Moderna, commonly named "Moderna vaccine"), and 1 using nonreplicating recombinant adenovirus vector systems transfectioning SARS-CoV-2 S-protein (Vaxzevria, ChAdOx1 nCoV-19 developed by Oxford-AstraZeneca, commonly named "AstraZeneca vaccine").^[3–5]

Despite an excellent safety profile in virtually all the clinical trials of these vaccines,^[3–5] rare and severe side effects following their administration have been described. One adverse effect recently reported is thyroid dysfunction. In the last year, during the global distribution of vaccines, an increasing number of clinical reports suggested a possible association between thyroid dysfunction, including subacute thyroiditis, autoimmune thyroiditis, and Graves' disease (GD), and anti-SARS-CoV-2 vaccination.^[6–10] In particular, several GD cases following both the first and second immunization dose and independent of the vaccine formulation (ie, mRNA and viral-vector vaccines) were recently reported.^[7–10] In addition, atypical GD presentations such as GD occurring in a patient with type 2 diabetes converting to type 1 diabetes^[11] have been reported as well as GD following an episode of subacute thyroiditis^[12] or presenting with a thyroid storm,^[13] and these emerging, less typical presentations of GD postvaccination supported the initiation of the current study.

The pathophysiologic mechanisms responsible for the development of GD after vaccination are uncertain but 2 theories have received the most support. The former relates to the autoimmune syndrome induced by adjuvants (ASIA), a syndrome triggered, in genetically susceptible subjects, by several vaccine adjuvants and excipients, such as polyethylene glycol lipids and polysorbate 80 oil-in-water emulsion contained in anti-COVID-19 vaccines. These can lead to a dysfunctional immune response, causing various pathologic conditions or endocrinopathies.^[14–16] The latter refers to an antigen molecular mimicry cross-reaction occurring between viral S proteins introduced with vaccines and thyroid peroxidase (TPO) antigens that, as suggested by recent studies, share a significant peptide amino acidic sequences similarity ranging from 50% to 70%.^[17–19] However, case reports or small case series of vaccination related GD do not provide causal evidence of the association.

In the present study, we analyzed the entire cohort of consecutive patients with a first diagnosis of symptomatic hyperthyroidism due to GD attending our tertiary healthcare Endocrine Unit from January 1,2021, to December 31, 2021, evaluating the presentation and clinical course of patients with GD occurring early (within 4 weeks) after COVID-19 vaccination compared with patients with GD occurring before or late (>8 weeks) after the vaccination.

1 2 3 4

Next Section

Abstract and Introduction
Patients and Methods
Results
Discussion
References

Table 1. Demographics and clinical characteristics of patients with GD at diagnosis
Patients with Graves' disease seen in 2021 (n = 64)
Variables
Age, y	38 (29–53)
Male sex, n (%)	14 (21.9)
Suppressed TSH (<0.01 μIU/mL), n (%)	64 (100)
TSH, μIU/mL	0.005 (0.004–0.009)
Elevated fT4 (>17 pg/mL), n (%)	48 (75)
fT4, pg/mL	24.6 (17.4–40.2)
Elevated fT3 (>4.4 pg/mL), n (%)	34/34 (100)
fT3, pg/mL	7.7 (5.5–10.9)
Elevated TRAbs (>1.75 IU/L), n (%)	58/59 (98.3)
TRAbs, IU/L	5.8 (2.9–14.8)
Positive TPOAbs, n (%)	30/51 (59)
Positive TgAbs, n (%)	20/51 (39)
Methimazole starting dose, mg	10 (10–20)
Graves' orbitopathy, n (%)	12 (18.7)
CAS	2 (1.25–3.75)
Active moderate-severe orbitopathy, n (%)	3/12 (25)

All continuous variables were expressed as median and interquartile range (IQR) (25th-75th percentile).
Abbreviations: CAS, Clinical Activity Score (referring to those with Graves' orbitopathy); fT3, free triiodothyronine; fT4, free thyroxine; TgAbs, thyroglobulin antibodies; TPOAbs, thyroid peroxidase antibodies; TRAbs, TSH receptor antibodies; TSH, thyroid-stimulating hormone.

Table 2. Demographics and clinical characteristics at diagnosis of PoVEO GD compared with patients developing GD before or late after vaccination
	Before vaccination (n = 35) + late onset (>8 weeks) after vaccination (n = 9) GD	PoVEO GD (within 4 weeks after vaccination) (n = 20)	P value
Age, y	35 (28–47)	51 (37–64)	.003
Male sex, n (%)	6 (13.6)	8 (40)	.018
Suppressed TSH (<0.01 μIU/mL), n (%)	44 (100)	20 (100)	NA
TSH, μIU/mL	0.005 (0.005–0.009)	0.006 (0.004–0.01)	.5
Elevated fT4 (>17 pg/mL), n (%)	35 (79)	13 (69)	.22
fT4, pg/mL	25 (18.4–45.4)	21 (15.2–31.9)	.15
Elevated fT3 (>4.4 pg/mL), n (%)	25/25 (100)	9/9 (100)	NA
fT3, pg/mL	8.7 (5.6–11.1)	5.6 (4.2–16)	.23
Elevated TRAbs (>1.75 IU/L), n (%)	41/41 (100)	17/18 (95)	.3
TRAbs, IU/L	6.9 (3.5–16.3)	4.2 (2.7–7.9)	.16
Positive TPOAbs, n (%)	21/35 (60%)	9/16 (56%)	>.99
Positive TgAbs, n (%)	11/35 (31%)	9/16 (56%)	.13
Methimazole starting dose, mg	15 (10–20)	10 (10–15)	.16
Low methimazole starting dose (≤10 mg), n (%)	22 (50)	13 (65)	.29
Graves' orbitopathy, n (%)	6 (13.6)	6 (30)	.17
CAS	2 (1.75–3.25)	2 (1-4)	.9
Active moderate-severe orbitopathy, n (%)	1/6 (16.6)	2/6 (33.3)	>.99

All continuous variables were expressed as median and interquartile range (IQR) (25th-75th percentile).
P values reported in bold are statistically significant.
Abbreviations: CAS, Clinical Activity Score; fT3, free triiodothyronine, fT4, free thyroxine; GD, Graves' disease; NA, not applicable; PoVEO, postvaccine early-onset; TRAbs, TSH receptor antibodies; TgAbs, thyroglobulin antibodies; TPOAbs, thyroid peroxidase antibodies; TSH, thyroid-stimulating hormone.

Table 3. Demographics and clinical characteristics at diagnosis of PoVEO GD compared with patients only developing GD before vaccination
	Before-vaccination (n = 35) GD	PoVEO GD (within 4 weeks after vaccination) (n = 20)	P value
Age, y	38 (29–50)	51 (37–64)	.009
Male sex, n (%)	5 (14.3)	8 (40)	.048
Suppressed TSH (<0.01 μIU/mL), n (%)	35 (100)	20 (100)	NA
TSH, μIU/mL	0.005 (0.005–0.009)	0.006 (0.004–0.01)	.52
Elevated fT4 (>17 pg/mL), n (%)	28 (80)	13 (69)	.33
fT4, pg/mL	24.8 (18.2–46.1)	21 (15.2–31.9)	.17
Elevated fT3 (>4.4 pg/mL), n (%)	18/18 (100)	9/9 (100)	NA
fT3, pg/mL	7.8 (5.6–14.3)	5.6 (4.2–16)	.27
Elevated TRAbs (>1.75 IU/L), n (%)	34/34 (100)	17/18 (95)	.35
TRAbs, IU/L	8.4 (3.3–17.8)	4.2 (2.7–7.9)	.14
Positive TPOAbs, n (%)	17/27 (63)	9/16 (56)	.45
Positive TgAbs, n (%)	10/27 (37)	10/16 (62.5)	.13
Methimazole starting dose, mg	15 (10–20)	10 (10–15)	.13
Low methimazole starting dose (≤10 mg), n (%)	18 (51.5)	13 (65)	.4
Graves' orbitopathy, n (%)	6 (17)	6 (30)	.22
CAS	2 (1.75–3.25)	2 (1–4)	.9
Active moderate-severe orbitopathy, n (%)	1/6 (16.6)	2/6 (33.3)	>.99

All continuous variables were expressed as median and interquartile range (IQR) (25th-75th percentile).
P values reported in bold are statistically significant.
Abbreviations: CAS, Clinical Activity Score; fT3, free triiodothyronine; fT4, free thyroxine; GD, Graves' disease; NA, not applicable; PoVEO, postvaccine early-onset; TgAbs, thyroglobulin antibodies; TPOAbs, thyroid peroxidase antibodies; TRAbs, TSH receptor antibodies; TSH, thyroid-stimulating hormone.

Table 4. Clinical characteristics at 3-month follow up of PoVEO GD compared with patients developing GD before or late after vaccination
	Before-vaccination (n = 35) + late onset (>8 weeks) after vaccination (n = 9) GD	PoVEO GD (within 4 weeks after vaccination) (n = 20)	P value
Suppressed TSH (<0.01 μIU/mL), n (%)	15/37 (40%)	7/19 (37%)	.78
TSH, μIU/mL	0.06 (0.005–0.81)	1.1 (0.008–4.7)	.12
Elevated fT4 (>17 pg/mL), n (%)	7/37 (19)	2/19 (10.5)	.7
fT4, pg/mL	9.78 (7.2–15.5)	10.55 (7.7–11.9)	.71
Elevated fT3 (>4.4 pg/mL), n (%)	10/32 (31.2)	0/17 (0)	.009
fT3, pg/mL	3.6 (2.7–5.5)	2.9 (2.8–3.6)	.13
Elevated TRAbs (>1.75 IU/L), n (%)	13/14 (93)	6/10 (60)	.11
TRAbs, IU/L	5.6 (2.7–27.7)	2.4 (1.4–4.1)	.016
Low methimazole dose (≤10 mg), n (%)	22/41 (53.7)	16/19 (84)	.025

All continuous variables are expressed as median and interquartile range (IQR) (25th-75th percentile).
P values reported in bold are statistically significant.
Abbreviations: fT3, free triiodothyronine; fT4, free thyroxine; GD, Graves' disease; PoVEO, postvaccine early onset; TRAbs, TSH receptor antibodies; TSH, thyroid-stimulating hormone.

Table 5. Clinical characteristics at 3-months follow up of PoVEO GD compared with patients only developing GD before vaccination
	Before-vaccination (n = 35) GD	PoVEO GD (within 4 weeks after vaccination) (n = 20)	P value
Suppressed TSH (<0.01 μIU/mL), n (%)	12/31 (39)	7/19 (37)	.76
TSH, μIU/mL	0.02 (0.005–0.34)	1.1 (0.008–4.7)	.1
Elevated fT4 (>17 pg/mL), n (%)	7/31 (22.6)	2/19 (10.5)	.45
fT4, pg/mL	9.78 (7.2–16.1)	10.55 (7.7–11.9)	.79
Elevated fT3 (>4.4 pg/mL), n (%)	9/27 (33)	0/17 (0)	.008
fT3, pg/mL	3.6 (2.7–5.8)	2.9 (2.8–3.6)	.23
Elevated TRAbs (>1.75 IU/L), n (%)	11/12 (92)	6/10 (60)	.13
TRAbs, IU/L	6.8 (3.1–27.9)	2.4 (1.4–4.1)	.015
Low methimazole dose (≤10 mg), n (%)	16/35 (46)	16/19 (84)	.009

All continuous variables are expressed as median and interquartile range (IQR) (25th-75th percentile).
P values reported in bold are statistically significant.
Abbreviations: fT3, free triiodothyronine; fT4, free thyroxine; GD, Graves' disease; PoVEO, postvaccine early-onset; TRAbs, TSH receptor antibodies; TSH, thyroid-stimulating hormone.