title: Elevated serum immunoglobulin G4 levels in patients with Graves' disease and their clinical implications.
abstract: BACKGROUND
  Immunoglobulin G4-related disease (IgG4-RD) is a new clinical entity that affects various organs with increased IgG4 positive plasmacytes and progressive fibrosis. While IgG4-RDs in association with Hashimoto's thyroiditis or Riedel's thyroiditis have been reported, the relationship between IgG4-RD and Graves' disease (GD) is yet unknown. To elucidate the relation of GD to IgG4-RD, serum IgG4 levels and their clinical implications in patients with GD were investigated.
  
  
  METHODS
  In this prospective study, serum IgG4 levels were measured in 109 patients with GD and classified into two groups according to the comprehensive diagnostic criteria of IgG4-RD previously established: (i) GD with elevated-IgG4 levels (≥ 135 mg/dL), and (ii) GD with nonelevated IgG4 (<135 mg/dL).
  
  
  RESULTS
  Seven out of 109 patients with GD (6.4%) had elevated serum IgG4 levels [mean ± standard deviation (range): 175.0 ± 44.5 (136-266) mg/dL] and elevated ratios of IgG4/IgG [12.7 ± 4.5% (7.6%-21.2%)]. The remaining patients with GD had serum IgG4 levels and IgG4/IgG ratios of 39.6 ± 27.6 (3-132) mg/dL and 3.2 ± 2.2% (0.3%-11.5%), respectively. Ages in the elevated IgG4 group were significantly higher than those of the nonelevated IgG4 group: 54.7 ± 6.2 versus 43.4 ± 15.4 years, respectively. Ultrasound examinations revealed that the elevated IgG4 group had significantly increased hypoechogenic areas in the thyroid in comparison to the nonelevated IgG4 group (low echo scoring: 1.66 ± 0.81 vs. 0.61 ± 0.89, respectively). In the correlation analysis, TSAb (rs=0.385, n=42) titers were significantly correlated with se rum IgG4 levels, while they were not significantly different between the two groups. In the elevated IgG4 group, symptoms were controllable with a small dose of antithyroidal drug (ATD; n=4), a combination treatment with ATD and L-T4 (n=1), or L-T4 administration only one year after the first visit (n=2).
  
  
  CONCLUSIONS
  A small portion of GD patients harbored elevated serum IgG4 levels. They were older, had increased hypoechoic areas in the thyroid, and appeared to be responsive or prone to be hypothyroid after ATD treatment. Thus, the present study suggests the presence of a novel subtype of GD. Measuring serum IgG4 levels may help to distinguish this new entity and provide potential therapeutic options for GD.
authors.affiliation: The First Department of Medicine, Wakayama Medical University , Wakayama, Japan .
authors.forename: Ken
authors.initials: K
authors.lastname: Takeshima
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Inaba
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamaoka
authors.forename: Waka
authors.initials: W
authors.lastname: Miyamoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ota
authors.forename: Asako
authors.initials: A
authors.lastname: Doi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kawashima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ariyasu
authors.forename: Hisao
authors.initials: H
authors.lastname: Wakasaki
authors.forename: Hiroto
authors.initials: H
authors.lastname: Furuta
authors.forename: Taisei
authors.initials: T
authors.lastname: Nakao
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Akamizu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D013956:Antithyroid Agents / Q000627:therapeutic use; D005260:Female; D006111:Graves Disease / Q000145:classification / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D018828:Immunoglobulins, Thyroid-Stimulating / Q000097:blood; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013974:Thyroxine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D013956:Antithyroid Agents; D007074:Immunoglobulin G; D018828:Immunoglobulins, Thyroid-Stimulating; D013974:Thyroxine