Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory disorder associated with fibrosis and abundant tissue lymphoplasmacytic infiltrations. It typically affects the pancreas, the salivary glands, and the retroperitoneal space. However, it might also involve multiple other organs, including the orbit and the thyroid. Recent studies have suggested that IgG4 plays a role in the pathophysiology of autoimmune thyroid diseases. This ultimately led to the establishment of new clinical entities called IgG4-related thyroid disease and thyroid disease with an elevation of IgG4. The aim of this paper is to describe the pathophysiological, histopathological, and clinical features of Graves’ Disease (GD) and Graves’ Orbitopathy (GO) with elevated IgG4 levels. Multiple studies have demonstrated higher IgG4 serum concentrations in GD patients than in healthy euthyroid controls. Depending on the studied population, elevated serum IgG4 levels occur in 6.4-23% (average: 10.3%) of all patients with GD, 8.3-37.5% (average: 17.6%) of patients with GO, and 0-9.8% (average: 5.4%) of patients with GD without GO, while GO patients comprise 37.5-100% (average: 65.8%) of all GD patients with elevated IgG4 levels. Characteristic features of GD with elevated IgG4 levels include lower echogenicity of the thyroid gland on ultrasound examination, peripheral blood eosinophilia, higher prevalence of orbitopathy, and better response to antithyroid drugs with a tendency to develop hypothyroidism when compared to patients with GD and normal levels of IgG4. Typical signs of GO accompanied by increased concentration of IgG4 include younger age at diagnosis, and more severe course of the disease with a higher Clinical Activity Score (CAS).. We strongly recommend considering the diagnosis of GO with elevated IgG4 in patients with an established diagnosis of GD, elevated serum IgG4 levels, and clinical features of ophthalmic disease overlapping with those of IgG4-related orbital disease.
Human immunoglobulin G (IgG) subclasses were numbered in an order reflecting the time of their discovery, which also corresponds to their prevalence in plasma [
Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory disorder associated with fibrosis and abundant lymphoplasmacytic infiltrations, often with obliterative phlebitis and storiform fibrosis within the affected tissues. IgG4-RD appears to underlie several fibroinflammatory disorders earlier regarded as idiopathic or isolated [
The symptoms depend on the affected organ. On histopathology, this fibroinflammatory disease is characterized with specific findings such as lymphoplasmacytic infiltration of IgG4-positive plasma cells, obliterative phlebitis, and storiform fibrosis, in most cases accompanied by increased levels of serum IgG4 [
To date, an association between IgG4 and various other diseases like allergies, cancer, or rheumatoid arthritis has been revealed [
The aim of this paper is to summarize current knowledge on the role of IgG4 as a biomarker of Graves’ Disease and Graves’ Orbitopathy.
Increased immunoglobulin G4 (IgG4) concentration is a common, though nonspecific, finding observed in most IgG4-RD patients [
IgG4 is the least abundant class of IgG. Due to the specific structural features, IgG4 exerts a unique ability of Fab arm exchange [
The direct cause of IgG4-RD remains unknown. Growing evidence suggests an autoimmune basis for the disease. Potential best-studied autoantigens include annexin A11, laminin 511, and galectin-3; however, their role requires clarification [
Exposure to foreign antigens activates circulating monocytes and basophils. In consequence, they produce the B cell-activating factor (BAFF) that induces B cell proliferation and differentiation towards IgG4-producing plasmablasts and plasma cells [
T cells predominate in IgG4-RD tissue infiltrates and play an important role in its pathogenesis [
Other T cell subsets are also involved in IgG-RD pathogenesis. Both T helper type 2 cells and regulatory T cells (Treg) were reported to increase in IgG4-RD [
In IgG4-RD, the B cell subpopulations and their regulatory cytokines are altered. The aforementioned mechanisms result in the development of IgG4-producing plasma cells and their short-lived precursors—plasmablasts. Clonally expanded CD19+20-27+38hi plasmablasts, producing IgG4, were found to increase in circulation and tissue infiltrates, compared to healthy individuals, and to correlate with the IgG4-RD activity and extension (number of affected organs) irrespective of IgG4 concentration. Plasmablasts declined after B cell depletion treatment with rituximab and glucocorticoid treatment, which resulted in clinical improvement, while in relapse, they reemerged [
In several disorders, including myasthenia or pemphigus, the pathogenic role of IgG4 is well defined. Due to the complexity of IgG4-RD pathogenesis, the potential contribution of IgG4 in this disease remains unclear.
Graves’ Disease (GD) is an autoimmune thyroid disease, where the most important clinical feature is hyperthyroidism [
The pathophysiology of GO is very complex and still not fully understood. It involves complex interactions between a variety of immune cells, cytokines, interleukins, adhesion molecules, and growth factors and increased oxidative stress. A key role is being assigned to abnormally activated orbital fibroblasts, overexpression of the human leukocyte antigen-DR (HLA-DR), and autoimmunity against the thyrotropin receptor (TSH-R) and insulin growth factor 1 receptor (IGF-1R) [
The orbital tissue in GO is infiltrated by a variety of mononuclear inflammatory cells like CD4+ T cells, CD8+ cells, B cells, and macrophages [
The TSH receptor antibodies (TRAb) play a key role in GD and GO pathogenesis. Elevated TRAb serum concentrations are associated with the development of GO as well as the activity and severity of the disease [
Recent
Studies evaluating the presence of histological features of IgG4-RD in GD patients are very scarce and deliver contradictory results. According to a study by Nishihara et al., only 11 out of 1484 thyroid glands resected from GD patients had a diffuse lymphoplasmacytic infiltration in the stroma, which is a characteristic feature of IgG4-RD and IgG4 thyroiditis. Only 5 of those 11 had IgG4-positive plasma cells in the thyroid, only one showed fibrosis, and none of the 11 specimens had obliterative phlebitis [
While thyroid biopsies cannot be used to diagnose IgG4-RTD, the biopsy procedure is the gold standard of IgG4-ROD. It is usually obtained from the extraocular muscle, lacrimal gland, orbital mass lesion, and infraorbital nerve or a combination of these [
Diagnostic criteria for IgG4-related ophthalmic disease, based on the criteria established in 2014 by the Japanese Ophthalmological Society [
(A) Imaging studies: enlargement of the lacrimal gland, trigeminal nerve, or extraocular muscle; masses, enlargement, or hypertrophic lesions in various ophthalmic tissues |
Based on the fulfillment of the criteria mentioned above, the probability of the diagnosis is defined as follows: |
A study by Wong et al. reported no significant IgG4 staining in 26 orbital biopsies of GO patients. This needs to be interpreted with caution as the study analyzed mostly specimens obtained from orbital fat, while only four biopsies were obtained from the lacrimal gland and none from extraorbital muscles [
There are currently a handful of case reports describing patients with GO, and the biopsy procedure confirmed IgG4(+) plasma cell infiltration of the orbital tissue [
There are only a few studies, often with ambiguous outcomes, assessing the role of IgG4 in Graves’ Disease and even less in Graves’ Orbitopathy. We summarized data from those studies in Table
Summary of clinical studies on the role of IgG4 in Graves’ Disease and Graves’ Orbitopathy.
Study author, year of publication | Prevalence of elevated IgG4 in GD patients overall | Prevalence of elevated IgG4 in GD patients without GO | Prevalence of elevated IgG4 in GO patients | Prevalence of GO in the GD group with elevated IgG4 | Age in the nonelevated IgG4 group ( | Age in the elevated IgG4 group ( | Sex distribution in the nonelevated IgG4 group (M/F ( | Sex distribution in the elevated IgG4 group (M/F ( | Average IgG4 levels in the nonelevated IgG4 group (mg/dl) | Average IgG4 levels in the elevated IgG4 group (mg/dl) | Criteria used to define elevated IgG4 | IgG4/IgG ratio in the nonelevated IgG4 group (%) | IgG4/IgG ratio in the elevated IgG4 group ( |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Takeshima et al. 2014 [ | 7/109 (6.4%) | 4/80 (5%) | 3/29 (10.3%) | 3/7 (42.3%) | 14/88 (15.9%) | 1/6 (14.2%) | >135 mg/d | ||||||
Bozkirli et al. 2015 [ | 15/65 (23%) | 3/33 (9.1%) | 12/32 (37.5%) | 12/15 (80%) | n.a. | n.a. | n.a. | n.a. | n.a. | n.a. | >135 mg/d | n.a. | n.a. |
Sy and Silkiss | n.a. | n.a. | 2/24 (8.3%) | n.a. | 5/22 (22.7%) | 0/2 (0%) | >135 mg/dl | ||||||
Torimoto et al. 2017 [ | 5/72 (6.9%) | n.a. | n.a. | n.a. | 16/67 (23.9%) | 4/1 (80%) | >135 mg/dl | ||||||
Martin et al. 2017 [ | 8/80 (10%) | 5/51 (9.8%) | 3/29 (10.3%) | 3/8 (37.5%) | 12/72 (16.7%) | 3/8 (37.5%) | >90th percentile | n.a. | n.a. | ||||
Yu et al. 2017 [ | 6/64 (9.4%) | 0/58 (0%) | 6/22 (27.7%) | 6/6 (100%) | 16/62 (25.8) | 2/6 (33.3%) | >86.4 mg/dl | ||||||
Hiratsuka et al. 2020 [ | 2/28 (7.1%) | n.a. | n.a. | 1/2 (50%) | 66 and 70 | 5/23 (17.8%) | 0/2 (0%) | n.a. | 163.5 and 214.4 | >135 mg/dl | n.a. | 15 and 14.8 | |
Luo et al. | n.a. | n.a. | 8/57 (14%) | n.a. | 19/39 (38.78%) | 1/6 (16.67%) | >135 mg/dl | n.a. | |||||
Summary | 43/418 (10.3%) | 12/222 (5.4%) | 34/193 (17.6%) | 25/38 (65.7%) | — | — | 87/373 (18.9%) | 11/31 (26.2%) | — | — | — | — | — |
Multiple studies showed higher serum IgG4 concentrations in GD patients than in healthy euthyroid controls [
Elevated serum IgG4 levels occur in 6.4-23% (average: 10.3%) of all patients with GD, 8.3-37.5% (average: 17.6%) of patients with GO, and 0-9.8% (average: 5.4%) of patients with GD without GO, while GO patients comprise 37.5-100% (average: 65.8%) of all GD patients with elevated IgG4 levels (Table
According to the first and largest (109 patients) study on this subject published in 2014 by Takeshima et al., patients with GD and elevated IgG4 were older than those with normal IgG4 levels (
In a study by Yu et al., female sex, smoking history, and levels of IgG, IgG4, triiodothyronine (T3), free thyroxine (FT4), TRAb, and antithyroglobulin antibodies (TgAb) were associated with GO development in univariate analysis. However, the serum IgG4 concentration was found to be the only independent factor associated with GO development in multivariate analysis (
In another study, IgG4 levels were observed to increase in concordance with CAS and IgG4 levels and were also higher in the GO group compared with GD patients without GO (101.5, range: 15-366 vs. 51, range: 13-203 mg/dl;
GD affects mostly women, but thyroid eye disease in general tends to be more severe in older patients and men. In a study by Perros et al., the female to male ratio was 9.3 in patients with mild orbitopathy, 3.2 in those with moderate orbitopathy, and only 1.4 in those with severe orbitopathy. This was often related to the fact that men tend to be heavy smokers [
Another thing indirectly linking GD to IgG4-RD is the peripheral blood eosinophilia. Approximately 40% of patients with IgG4-RD have eosinophilia [
In one study, patients with immunoglobulin G4 levels above the 75th percentile were reported to have higher concentrations of antithyroid peroxidase antibodies (TPOAb) (
Regarding GD treatment with antithyroid drugs, patients with IgG4 levels above the 75th percentile require a shorter duration of the first methimazole treatment cycle than patients with immunoglobulin G4 below the 75th percentile. At diagnosis, patients with immunoglobulin G4 levels above the 90th percentile tend to have lower total T3 (
Data on time-dependent and treatment-dependent changes of IgG4 levels in GD and GO patients are incredibly scarce. In spite of some case reports, to date, there is only one longitudinal study, which followed 9 patients with GD (two with elevated IgG4 and 7 with normal values at the start of the study) for a mean of
According to a study by Luo et al., patients with GO with an elevation of IgG4 present most commonly with bilateral muscle thickening (in 7/8 cases), which affects the medial rectus muscle, the inferior rectus muscle, and relatively often the lateral rectus muscle (in 7/8, 6/8, and 5/8 cases, respectively). Infraorbital nerve thickening and lacrimal gland involvement, which are key features of IgG4-ROD, were less prevalent (1/8 and 2/8 cases, respectively) [
The diagnostic dilemma of distinguishing between GO and IgG4-ROD was described in a very detailed and informative case series by Tooley et al. [
To date, no trials assessing response to standard or potentially different treatment regimens in GO with elevated IgG4 have been conducted. However, based on studies on IgG4-RD, IgG4-ROD, GO in general, and some case reports, treatment with glucocorticoids is the first line of therapy. However, the disease has a relatively high risk of recurrence when the dose is tapered, and in these cases, other immunosuppressive regimens might be helpful. Currently, also, rituximab is considered a primary therapeutic strategy, which allows steroid discontinuation and relieves signs and symptoms [
Symptoms of IgG4-ROD may overlap those seen in other diseases, though in most patients, both eyes are affected. Likewise, CT or MRI scans of the orbital region also present unspecific features [
In the study by Wong et al., they collected orbital biopsies from patients diagnosed with nonspecific orbital inflammation (NSOI;
Lymphoma is the most common malignancy of the ocular adnexa [
Peng et al. reported a similar case of lymphoma in a 44-year-old patient who complained of bilateral proptosis for several years. Before admission to the hospital, he experienced rapid loss of vision in the right eye. During hospitalization, the patient underwent right eye exenteration and tumor resection for the left eye. Based on the chronic history, serum IgG4 concentrations, IgG4 plasma cell infiltration, and acute deterioration, the authors supposed transformation of IgG4-ROD to diffuse large B cell lymphoma [
In summary, it should be noted that IgG4+ plasma cells can be found in the histopathological examination of various diseases. Even though the histopathological examination is the gold standard in the diagnostic process of IgG4-ROD, its results should always be interpreted together with the patient’s clinical symptoms, comorbidities, and outcomes of other tests in order to avoid misdiagnosis.
In this review, we described the pathophysiological, histopathological, and clinical features of Graves’ Disease and Graves’ Orbitopathy with elevated IgG4 levels, which show many distinct characteristics compared to the classic forms of Graves’ Disease and Orbitopathy.
Based on current research, characteristic features of Graves’ Disease with elevated IgG4 levels are lower echogenicity of the thyroid gland on ultrasound examination, peripheral blood eosinophilia, higher prevalence of orbitopathy, and better response to antithyroid drugs with a tendency to develop hypothyroidism.
Characteristic features of Graves’ Orbitopathy with elevated IgG4 levels include younger age at orbitopathy diagnosis, and more severe course of the disease with higher CAS. Such patients should also have a good response to rituximab therapy, but this has not yet been studied in clinical trials.
It is prudent to remember that GO patients with elevated IgG4 can also present with an overlap of classical GO and IgG4-ROD features. Systemic manifestations of IgG4-RD are, however, not typical.
At the moment, there is not enough evidence to call this entity “IgG4-related Graves’ Disease”; thus, the term “Graves’ Disease/Graves’ Orbitopathy with elevated IgG4 levels” seems more appropriate.
Future research should focus on developing longitudinal prospective studies, especially assessing responses to different treatment regimens. More studies assessing histopathological features of orbital biopsies (especially extraorbital muscle biopsies) and resected thyroid samples are also needed.
We strongly recommend considering the diagnosis of Graves’ Orbitopathy with elevated IgG4 in patients with an established diagnosis of Graves’ Disease, elevated serum IgG4 levels, and clinical features of ophthalmic disease overlapping with those of IgG4-related orbital disease.
All data were obtained from published articles, which are cited in the bibliography.
The authors declare no conflict of interest.