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Immunoglobulin G (IgG) is comprised of 4 subclasses designated IgG1 through IgG4. Approximately 65% of the total IgG is IgG1, 25% is IgG2, 6% is IgG3, and 4% is IgG4.


IgG4 related disease is a syndrome of unknown etiology most often occurring in middle-aged and older men. Two major presentations of this condition are type 1 autoimmune pancreatitis and sclerosing sialadenitis. IgG4 related disease can involve one or several organs and may initially be mistaken for Sjögren’s syndrome.


Many other previously described diseases are now considered to be IgG4 related disease including inflammatory orbital psuedotumor, sclerosing cholangitis, chronic sclerosing aortitis, Riedel thyroiditis, IgG4 related interstitial pneumonitis, retroperitoneal fibrosis, IgG4 related hypophysitis, IgG4 related pachymeningitis and IgG4 related tubulointerstitial nephritis. Each of these entities is characterized by tumorlike swelling of the involved organs due to infiltration of IgG4positive plasma cells and T lymphocytes with accompanying storiform fibrosis. Definitive diagnosis of IgG4-related disease requires tissue biopsy of the affected organ.


The peripheral blood of patients with active IgG4-related disease typically have increased numbers of B cell plasmablasts with the following immunophenotype; CD19+, CD20−, CD38 bright, and CD27 bright. These cells are also present within the inflammatory infiltrate of affected tissues.

Serum concentrations of IgG4 are elevated in 60% to 70% of patients with biopsy proven IgG related disease. Using an upper limit of normal of 135 mg/dL, sensitivity of elevated IgG4 for diagnosing IgG4 related disease is 70% and specificity is 85%. Because the prevalence of IgG4 related disease is low, the positive predictive value of IgG4 elevation is only 36%. Elevated levels of IgG4 are also found in Castleman’s disease, allergic disorders, Churg-Strauss syndrome and sarcoidosis. An elevated IgG4/IgG ratio cutoff of ≥0.08 does not improve test performance.

IgG4 levels are unreliable for assessing response to treatment. Levels can rebound above normal in up to 70% of patients after withdrawal of steroid therapy. Repeat imaging and biomarkers specific for the organ most affected are the best indicators of response to treatment.

Reference range is age dependent. Specimen is a red top tube of blood.


Carruthers Molly et al. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis 2015; DOI: 10.1136/annrheumdis-2013-204907.

Nagpal SJS and Chari ST. Immunoglobulin IgG4 Levels. JAMA 2019;321:202-203.

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