Subacute thyroiditis (SAT) is a thyroid inflammatory disease, whose pathogenesis and determinants of the clinical course were unclear for many decades. The last few years have brought many clinically significant new data on the epidemiology, pathogenesis and management of SAT. Several human leukocyte antigen (HLA) alleles were demonstrated not only to increase the risk of SAT, but also to correlate with SAT clinical course and determine the risk of recurrence. The world-wide epidemic of the coronavirus disease 19 (COVID-19) has provided new observations that the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can be a potent SAT-triggering factor, and that the clinical course of SAT in patients affected by COVID-19 is different from a typical one. Additionally, many new trends in the clinical course are emerging. In the last years, painless course of SAT is more and more often described, constituting a special challenge in patients hospitalized due to COVID-19. Despite an excellent availability of diagnostic methods, several difficulties in SAT differential diagnosis can be currently encountered and the proper diagnosis and treatment is frequently delayed. False positive diagnoses of SAT in patients with malignancies of poor prognosis constitute a life-threatening problem. Taking into account all the new aspects of SAT pathogenesis and of its clinical course, the new – modified – SAT diagnosis criteria have been proposed.

Subacute thyroiditis (SAT) is a thyroid inflammatory disease whose pathogenesis is still not completely defined. Previous viral infection is considered to be a triggering factor in genetically predisposed individuals. In about 70% of patients, susceptibility to SAT is associated with the HLA-B*35 allele. The correlation between SAT and other human leukocyte antigens (HLA) has not yet been unequivocally demonstrated and the genetic background is still unknown in about 30% of patients. The purpose of our study was to perform HLA genotyping using a next-generation sequencing method, to find out whether alleles other than HLA-B*35 are correlated with SAT morbidity. HLA-A, -B, -C, -DQB1, -DRB1 were genotyped using a next-generation sequencing method in 1083 subjects, including 60 SAT patients and 1023 healthy controls. Among 60 patients diagnosed with SAT, 81.7% of subjects were identified as having allele HLA-B*35, 23.3% had HLA-B*18:01, 28.3% had HLA-DRB1*01 and 75.5% had HLA-C*04:01. These alleles occurred in the control group at frequencies of 10.2%, 7.2%, 12.9% and 12.5%, respectively. The differences were statistically significant, with p < 0.05. In addition to its previously described relationship with HLA-B*35, genetic susceptibility to SAT was associated with the presence of HLA-B*18:01, DRB1*01 and C*04:01. The alleles HLA-B*18:01 and DRB1*01 were independent SAT risk factors. The assessment of these four alleles allows the confirmation of genetic predisposition in almost all patients with SAT.

The frequency of recurrence of subacute thyroiditis (SAT) is rather high, reaching 20–30%. The reason for SAT relapse is still unknown. Recently, we have demonstrated the association between SAT and the presence of HLA-B*18:01, DRB1*01, and C*04:01, apart from the previously known HLA-B*35. The aim of the present study was to evaluate the correlation between SAT-associated HLA haplotypes and the risk of SAT recurrence. HLA-A, -B, -C, -DQB1 and -DRB1 were genotyped using a next-generation sequencing method in 49 SAT patients. The patients were divided into the following HLA groups: 1. HLA-B*35 and/or HLA-C*04, but without any other of the analyzed antigens; 2. HLA-DRB1*01, regardless of the co-presence of HLA-B*35 or -C*04:01, but without HLA-B*18:01; 3. HLA-B18 only, without any other antigen; 4. HLA-B*18:01 plus -B*35, regardless of the presence of any other analyzed antigens. The recurrence rate was compared between the groups. The recurrence rate was significantly increased in patients with HLA-B*18:01 plus HLA-B*35. In conclusion, the risk of SAT recurrence was HLA-dependent and the determining factor was the co-presence of HLA-B*18:01 and -B*35. In such high-risk patients, the steroid treatment regimen should be intensified with a slower dose reduction.

The association between HLA and the risk of Graves’ disease (GD) has been analyzed for many years. However, the results were often inconsistent and mostly regarded Asian populations. The purpose of our study was to perform HLA genotyping using a next-generation sequencing (NGS) method in Caucasians, to find out which alleles are eventually correlated with GD morbidity as well as which of them can be considered protective. HLA-A, -B, -C, -DQB1, -DRB1 were genotyped using a next-generation sequencing method in 2376 persons, including 159 GD patients and 2217 healthy controls. We have demonstrated a significant association between the risk of GD and the following alleles: HLA-B*08:01, -B*39:06, -B*37:01, -C*07:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*03:01, -DRB1*11:01, -DRB1*13:03, -DRB1*01:03, -DRB1*14:01, -DQB1*03:01, DQB1*02:01. The alleles HLA-B*39:06, -B*37:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*14:01 are novel GD-associated, previously not-reported independent ones with no linkage disequilibrium with other high-risk alleles. On the other hand, the frequencies of HLA-B*07:02, -C*07:02, -C*03:04, DRB1*07:01, -DQB1*02:02, -DQB1*03:03 were significantly lower in GD compared to controls. This study demonstrated the actual relationships between HLA and GD based on the NGS method and provided a novel set of alleles as a reliable tool for an individual personalized risk assessment.