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IgG4-related disease
Other Resources UpToDate PubMed

IgG4-related disease

Contributors: Alexandra Charrow MD, Sotonye Imadojemu MD, Mary Anne Morgan MD, Susan Burgin MD
Other Resources UpToDate PubMed


Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a rare multisystem inflammatory disease of unknown cause resulting in a collection of disorders that share pathologic, serologic, and clinical features. IgG4+ plasma cells infiltrate involved organs. Secondary organ fibrosis and accompanying high levels of circulating IgG4 are often seen. Recorded cases occur more commonly in middle- and advanced-aged individuals, and the condition has a slight male predominance. Pediatric cases of systemic IgG4-RD are noted in the literature, but few cases note cutaneous involvement.

Clinical manifestations are variable depending on the organ system involved. Most commonly, IgG4-RD is associated with autoimmune pancreatitis (see chronic pancreatitis), a rare, chronic disease with varied presentation, often mimicking pancreatic malignancy, making diagnosis challenging. Autoantibodies in the pancreas cause inflammation and enlargement. Other manifestations include lymphadenopathy, biliary obstruction (may present similarly to primary sclerosing cholangitis), membranous nephropathy, salivary dysfunction, lacrimal gland dysfunction, retroperitoneal fibrosis, coronary arteritis, cutaneous plaques on the head and neck, and atopy (asthma, eczema), etc, although nearly any organ system can be affected. Symptoms typically develop over months to years, and treatment success is variable.

Proposed diagnostic criteria include:
  1. Clinical examination shows characteristic diffuse / localized swelling or masses in single or multiple organs.
  2. Hematological examination shows elevated serum IgG4 concentrations (135 mg/dL).
  3. Histopathologic examination shows:
    • Marked lymphocyte and plasmacyte infiltration and fibrosis.
    • Infiltration of IgG4+ plasma cells: ratio of IgG4+ / IgG+ cells > 40% and > 10 IgG4+ plasma cells per high-power field.
The diagnosis is definite if all 3 criteria are present. If the first and third criteria are present, the diagnosis is probable. If the first and second criteria are present, the diagnosis is possible.


D80.3 – Selective deficiency of immunoglobulin G [IgG] subclasses

234549008 – Immunoglobulin G4 deficiency

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Differential Diagnosis & Pitfalls

Skin biopsy and IgG4 serum levels will greatly aid in the diagnosis and differentiation of IgG-RD from conditions with similar presentations such as:
  • Granuloma faciale
  • Sarcoidosis – Presents more frequently on the nose as red-brown papules or plaques. Diascopy reveals an "apple jelly" yellow-brown color. Biopsy reveals noncaseating granulomas.
  • Adult-onset asthma and periocular xanthogranuloma (AAPOX) – A rare non-Langerhans histiocytosis. Classically, presents with infiltration of the eyelids and lymphadenopathy. Biopsy typically reveals foamy histiocytes and Touton giant cells. Plasma cell infiltration may also be noted.
  • Sinus histiocytosis with massive lymphadenopathy – Differentiated on histology by the presence of emperipolesis and histiocytic infiltrate and a relative paucity or absence of IgG4+ plasma cells.
  • Angiolymphoid hyperplasia with eosinophilia – Classically, presents as dome-shaped vascular papules, often agminated, about the ears. Extracutaneous involvement is reported but rare, as opposed to IgG4-RD, where extracutaneous involvement is the rule. Biopsy reveals dermal or subcutaneous vascular proliferation and inflammatory cells.
  • Castleman disease – Shares systemic features with IgG4-RD including diffuse lymphadenopathy; however, differs in cutaneous findings. Rarely, it can be associated with xanthelasma and plane xanthomas which present as yellowish plaques about the eyes or elsewhere.

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Last Updated:06/29/2022
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IgG4-related disease
A medical illustration showing key findings of IgG4-related disease : Lymphadenopathy
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