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 IgG4 positive 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−CD38highCD27high. 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 IgG4 related disease. Elevated levels of IgG4 are consistent with, but not diagnostic of, IgG4-related disease because IgG4 is also elevated in other diseases such as Castleman’s disease, allergic disorders, Churg-Strauss syndrome and sarcoidosis.

Using an upper limit of normal of 135 mg/dL, sensitivity and negative predictive values of an elevated serum IgG4 concentration are high for the diagnosis of IgG4-related disease at 90% and 96%, respectively. On the other hand, specificity of elevated serum IgG4 concentrations is poor at 60% and positive predictive value is even worse at 34%. An elevated IgG4/IgG ratio cutoff of ≥0.08 does not improve test performance.

A 2016 meta-analysis of nine case-control studies found that a cutoff value of serum IgG4 ranging from 135 to 144 mg/dL conferred a sensitivity of 87 percent and a specificity of 83 percent.

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.

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