Human Leukocyte Antigen (HLA) Subtype-Dependent Development of Myasthenia Gravis, Type-1 Diabetes Mellitus, and Hashimoto Disease: A Case Report of Autoimmune Polyendocrine Syndrome Type 3

Background

Autoimmune polyendocrine syndrome type 3 (APS3) consists of multiple autoimmune diseases, including autoimmune thyroid disorders (AITD), type-1 diabetes mellitus (T1DM), lymphocytic hypophysitis, insulin autoimmune syndrome, and pernicious anemia, all of which are related to the loss of immune tolerance [1,2]. The absence of adrenocortical dysfunction is one of the features that distinguishes APS3 from the autoimmune polyendocrine syndrome types 1 and 2 [3].

Myasthenia gravis (MG) is classified as an autoimmune disease, as are T1DM and AITD, and HLA-B46/-DR9 has been reported to be associated with early-onset ocular subtype [4]. Although APS3 accounts for 41.5% of all autoimmune polyendocrine syndromes [2], we found only 2 case reports on APS3 combined with MG [5,6] through a PubMed search. Although the patients’ clinical features, such as disease-specific HLA, typical manner of onset, and clinical types, were reported, the small number of case reports has provided limited insights on APS3 combined with MG. For example, although some cases of MG and T1DM are associated with the same HLA type, it remains unknown whether these conditions develop interdependently or whether their occurrence is not associated. In addition, it remains unknown whether measurement of anti-islet antibodies provides clues to the prognosis of T1DM and whether thymus resection can prevent the development of T1DM. Answers to these questions could provide a better understanding of the pathogenesis of APS3. This could help physicians to provide appropriate treatment for patients with this condition.

After extending our literature search to Japan Medical Abstracts Society, we found additional 7 published case reports on APS3 with MG. These additional reports were either written in Japanese or presented at conferences held in Japan [7]. The fact that we were able to identify this many additional cases by searching a localized database suggests that APS3 complicated by MG might not be as rare as current estimates suggest, leading us to investigate the clinical features and underlying pathology characterizing APS3 with MG.

This study was approved by the Institutional Review Board of Kurume University Hospital (2019–021), and all procedures were in accordance with its ethical standards, and with the principles of the 2013 Declaration of Helsinki. Written informed consent for publication of the patient’s clinical details and clinical images was obtained from the patient.

In this report, we describe a case of APS3 complicated by MG and compare the onset-type, clinical sub-types, and autoantibody-titers for each disease, and compare our patient’s case with the features of 9 other cases that have been reported previously. The objective was to gain a better understanding of the pathogenesis of APS3 in order to make recommendations about its treatment. Furthermore, having identified novel HLA subtypes during the course of our analysis, we expanded the aims of our study to include an assessment of APS3 with MG about its specific clinical features.

Case Report

CASE COMPARISONS:

The features of the 9 cases reported previously, and the present case, are summarized in Tables 2 and 3. We compared the clinical features and HLA haplotypes of the cases included in our case review to those previously described in the general Japanese population [10] and to those of other cases of MG, T1DM, and Hashimoto disease described in the literature [5–7].

The frequencies were compared using Fisher’s exact test. P-values <0.05 were considered statistically significant. All statistical analyses were performed using GraphPad Prism 7.0.4 (GraphPad Software, CA, USA).

The frequency of ocular-type MG in this case series was significantly higher than that of patients with MG described in a previous report (90% [9/10 cases] versus. 20%, P<0.001) [11]. In this study, T1DM progressed to AITD more frequently in patients with AITD and T1DM without MG (50.0% [5/10 cases] versus 7.1% [1/14 cases], P=0.028) [12]. In addition, the prevalence of slowly progressive, insulin-dependent diabetes mellitus (SPIDDM) in this study was lower than that reported in patients with AITD and T1DM without MG (30.0% [3/10 cases] versus 71.4% [10/14 cases], P=0.055) [12].

The prevalence of HLA-DR9 in APS3 patients with MG was higher than that of the general Japanese population (75.0% [6/8 cases] versus 14.283%, P<0.001) [10], although the present case was the only case with HLA-B46. In addition, the prevalence of the HLA-DQ9 type had a significantly higher prevalence among cases in our study than among of Japanese bone marrow donors (57.1% [4/7 cases] versus 16.1%, P=0.016) [13]. In contrast, the frequency of HLA-DR4, which has been reported to be associated with T1DM [14], was similar to that of the general Japanese population (37.5% [3/8 cases] versus 23.879%, P=0.29).

Discussion

We described a case who diagnosed with APS3, including T1DM, AITD, and early-onset seronegative ocular MG. HLA-B46-DR9: B*46: 01-DRB1*09: 01 represent high prevalence in early-onset ocular MG [4]. However, the present case is the first case to be described with HLA-B46/DR9: B*46: 01-DRB1*09: 01, early-onset ocular MG, T1DM, and AITD, as APS3 (Tables 2, 3).

Previously, the HLA-DR9 has been associated with the ocular type of MG, and seronegative MG [15]. In addition, HLA-DR9/DQ9 and DR4 have previously been reported to be associated with T1DM [14]. Taking account for the results of this study into account, HLA-DR9/DQ9 may be a specific HLA subtype associated with APS3 with a combination of MG, T1DM, and AITD. In contrast, the frequency of HLA-DR4, which is a sensitive HLA subtype for T1DM and was positive in the present case [14], is similar to that of the general Japanese population [13]. The findings of this study suggest that MG complicated with APS3 might be associated with the ocular-type of MG, because the frequency of ocular-type of MG in this study was significantly higher than that of all cases of MG described in a previous report [11]. Notably, HLA-B46/DR9: B*46: 01-DRB1*09: 01, which was only found in the present case, may independently associated with early-onset ocular MG [4] as APS3.

As shown by the present case, T1DM complicated with MG might be the acute onset-type. Most of the cases of T1DM and AITD, but without MG, have the SPIDDM type of T1DM [2,12] and develop after the onset of AITD. However, we found that among the cases of APS3 with MG included in this review, the diagnosis of T1DM more frequently preceded the development of AITD and was more frequently the acute-onset type, compared to patients with ordinary T1DM without MG [12]. Acute-onset T1DM and SPIDDM are both considered autoimmune conditions [12]. Furthermore, both forms of T1DM are associated with the presence of anti-islet antibodies, and a high prevalence of HLA-DR4 and -DR9 [14]. Although the mechanisms underlying the differences between the 2 forms are not understood, the conditions are distinct in terms of the age of onset, islet autoantibody titer, and residual beta-cell function at onset [16]. The acute onset of T1DM in the present case might provide clues to the pathogenesis of T1DM and its mechanism of progression.

Moreover, these new insights regarding T1DM might have consequences for recommended treatments. Thymectomy might be ineffective for preventing the development of T1DM although it has become one of the primary therapies used to improve the neurological functioning in patients with MG. Furthermore, the latest research has shown that the thymectomy is effective for generalized MG without thymoma [17]. However, the therapeutic effect of thymectomy for the ocular type and seronegative MG has not been shown yet. Immunologic tolerance is established by the central tolerance that removes autoreactive T-cells during the maturation process in the thymus, and peripheral tolerance by which regulatory T-cells in the peripheral tissues inhibit autoreactive T-cells. Dysfunction of immunologic tolerance leads to various autoimmune diseases, including T1DM [18]. T1DM has recently been reported to be associated with failure of peripheral immunologic tolerance as a result of dysfunction of the regulatory T-cells [19], but the mechanism remains to be clarified. However, there is relatively little information available on the association of T1DM with central immunologic tolerance failure, and research on the association between immunologic tolerance and T1DM has been based on animal studies in which non-obese diabetic mice were used [20,21].

The main limitation of the present study the small number of cases included in the review. The numbers are insufficient to determine whether the HLA-DR9/DQ9 serotypes are specific predictors for development of APS3 with MG. Although one previous case report of T1DM that developed after thymectomy was reported [22], further evidence is necessary to determine whether thymectomy may prevent the development of T1DM.

Conclusions

HLA-DR9/DQ9 might be specific HLA serotypes associated with the APS3 subtype with both MG and T1DM. In our patient’s case, her T1DM was the acute-onset type and developed many years after the onset of MG, which differed from the more common presentation of T1DM with AITD as SPIDDM. The examination of anti-islet antibody with ocular-type MG patients with the HLA-DR9/DQ9 serotype might help to assess the risk of developing T1DM.