Abstract
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.
Highlights
Human immunoglobulin G (IgG) subclasses were numbered in an order reflecting the time of their discovery, which corresponds to their prevalence in plasma [1]
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
Even though elevated serum immunoglobulin G4 (IgG4) levels and increased numbers of IgG4(+) plasma cells in tissues are considered to be a hallmark of IgG4-RD [60], recent studies suggest that IgG4 plays a role in the pathophysiology of autoimmune thyroid diseases, including Graves’ Orbitopathy (GO)
Summary
Human immunoglobulin G (IgG) subclasses were numbered in an order reflecting the time of their discovery, which corresponds to their prevalence in plasma [1]. High concentrations of clonally expanded CD4+ CTL in blood and affected organs were observed in active IgG4-RD Both B cell depletion treatment with rituximab and glucocorticoid treatment improved the symptoms and decreased CD4+ CTL levels [31, 32]. Increased T follicular regulatory cells and T follicular helper (Tfh) cells, especially Tfh, were reported in IgG4-RD patients, compared to healthy controls, and correlated positively with serum IgG4 concentration and the number of involved organs [41,42,43,44]. 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. Due to the complexity of IgG4-RD pathogenesis, the potential contribution of IgG4 in this disease remains unclear
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