A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

Abstract

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz's disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.

Fig. 1

IgG4-related conditions. Many diseases have been reported to be IgG4-related

Fig. 2

Histopathology of IgG4-related disease (IgG4RD). IgG4RD is characterized histopathologically by the infiltration of IgG4-positive plasma cells and fibrosis. However, the severity of fibrosis is dependent on the individual organs involved. For example, storiform fibrosis and obliterative phlebitis are characteristic of retroperitoneal lesions, but are very seldom observed in salivary glands (×40)

Fig. 3

Prevalence of patients with IgG4RD. An attempt was made to estimate the number of individuals with IgG4RD throughout Japan by using as an example Ishikawa Prefecture (population 1.14 million people) with little population inflow/outflow. If all new patients with IgG4RD visit Kanazawa Medical University Hospital (KMU) or Kanazawa University Hospital (KUH), the incidence of this disease throughout Japan would be 0.28–1.08/100,000 population, with 336–1,300 patients newly diagnosed per year. If life expectancy after diagnosis is 20 years, then approximately 6,700–26,000 patients in Japan would have developed IgG4RD over the past 20 years. The numbers in the table represent the numbers of patients who visited KMU or KUH each year

Fig. 4

Comparison of clinical symptoms and laboratory findings in IgG4RD and typical Sjögren’s syndrome (SS) [29]. a Clinical symptoms, b immunological findings, and c subclasses of immunoglobulins and IgG observed in patients with IgG4RD (n = 61) and typical SS (n = 31). Data are expressed as percentages. P values are for comparisons of IgG4RD with typical SS. Patients with typical SS fulfilled both Japanese and European SS criteria and were positive for both anti-SSA/Ro and anti-SSB/La antibodies

Fig. 5

Histopathological findings of minor labial salivary gland biopsies in patients with IgG4RD and typical SS. a Massive infiltration of lymphocytes and plasma cells was observed in patients with IgG4RD and those with typical SS (×200). IgG4RD, however, was characterized by lymphoid follicle formation but ducts were intact without lymphocytic infiltration. H&E staining. b IgG4RD showed scattered IgG4+ plasma cells in the periphery of the follicles (×200), whereas typical SS showed few or no IgG4+ cells. IgG4 immunostaining. c Staining for immunoglobulin κ- and λ-chains (×200)