IgG4-related disease

IgG4-related disease (IgG4-RD) is a systemic disease that is characterized by fibroinflammatory infiltration of various organs induced by plasma cells that express IgG4 (immunoglobulin G subclass 4).

Terminology

Since 2012, IgG4-related disease has become the preferred term ^9,10. However, it has been known by many other names in the past:

• IgG4-related sclerosing disease

• IgG4-related systemic disease

• IgG4-related systemic sclerosing disease

• IgG4-syndrome, IgG4-associated disease

• IgG4-related multiorgan lymphoproliferative syndrome

Epidemiology

IgG4-related diseases are more common in middle-aged or elderly males.

Clinical presentation

Clinical manifestations vary by the organ involved. These organ systems may be either synchronously or sequentially involved.

Pathology

Location

The disease spectrum is broad across organ systems:

• central nervous system

  • IgG4-related hypertrophic pachymeningitis

  • IgG4-related hypophysitis

  • chronic subdural hemorrhage

• head and neck

  • sialadenitis/chronic sclerosing sialadenitis (Küttner tumor)

  • Riedel thyroiditis

  • IgG4-related orbital disease

  • pansinusitis

• thoracic

  • interstitial pneumonia/IgG4-related lung disease

  • fibrosing mediastinitis

  • IgG4-related cardiovascular disease

    • IgG4-related coronary disease

• abdominopelvic

  • autoimmune pancreatitis

  • sclerosing cholangitis

  • sclerosing mesenteritis

  • cholecystitis 

  • IgG4-related renal diseases ¹¹

    • tubulointerstitial nephritis

  • retroperitoneal fibrosis

  • inflammatory aortic aneurysm

  • ​prostatitis

  • gastrointestinal ⁸

    • colorectal

• multisystem

  • inflammatory pseudotumors, e.g. presenting as paravertebral masses

  • lymphadenopathy

Microscopic appearance

Three major histopathologic characteristics of IgG4-related disease are ⁹: 

• dense lymphoplasmacytic infiltrate

• at least focally storiform fibrosis

• obliterative phlebitis

Two of these features are required for a confident pathologic diagnosis of IgG4-related disease, with a few organ-specific exceptions ⁹. Additional supporting features are non-obliterative phlebitis and eosinophilia ⁹.

Immunophenotype

Immunohistochemistry should demonstrate plasma cells that stain for IgG4. IgG4+ plasma cells must account for more than 40% of IgG+ plasma cells ⁹. The absolute density of IgG4+ plasma cells (number per high power field (hpf)) suggestive of the diagnosis varies by organ. For example, the cutoff is >10/hpf for pancreatic biopsy specimens and >100/hpf for lacrimal and salivary glands ⁹.

Markers

Serology is often, but not always, abnormal in IgG4-related diseases. A serum IgG4 level >135 mg/dL is supportive of the diagnosis ⁹.

Supportive are also circulating plasmablasts ¹².