IgG4 is the least common of the 4 subtypes of IgG. Its function likely varies with the context; in allergic disease, it is thought to have an immune-inhibitory role in preventing anaphylactic reactions to allergens. It has also been reported to have a role in autoimmunity and malignancy, but its function in these contexts is less well-established. IgG4-RD has a wide range of manifestations that vary by which organs are involved and are unified by their histopathologic findings and response to treatment.
Most patients are middle-aged to older men, but the disorder can affect people of any age and sex.
Pathophysiology of IgG4-Related Disease
The clinical manifestations of IgG4-RD are usually tumor-like masses or organ enlargement, which result from dense tissue infiltration by immune cells and expansion of the extra-cellular matrix. One or more organs are affected; the 11 organs considered typical of IgG4-RD include the pancreas, bile ducts, lacrimal glands, orbital tissues, salivary glands, lungs, kidneys, retroperitoneal tissues, aorta, meninges, and thyroid gland.
Most patients have multiorgan involvement at the time of diagnosis but tend to have one dominant phenotype. One study identified approximately equal proportions of the following clinical phenotypes (1).
Pancreato-hepatobiliary disease
Pancreatic involvement commonly manifests as autoimmune pancreatitis (type 1, IgG4-related) and may take the form of
An obstructive pancreatic mass, with painless jaundice and diffuse pancreatic enlargement
Acute pancreatitis with abdominal pain and nausea
Smoldering and insidious chronic pancreatitis with pancreatic atrophy, exocrine pancreatic insufficiency, and/or overt diabetes mellitus
IgG4-related sclerosing cholangitis can occur, usually in patients who also have autoimmune pancreatitis. This combination is highly suggestive of IgG4-RD.
Retroperitoneal fibrosis and/or aortitis
IgG4-RD likely accounts for most cases of idiopathic retroperitoneal fibrosis. Fibrosis is usually circumferential around the aorta (periaortitis) or over only the anterolateral portion. Fibrosis may extend inferiorly to the iliac vessels. The main complication is ureteral compression causing hydronephrosis.
IgG4-RD can also cause noninfectious aortitis of either the thoracic or abdominal aorta, which is distinguished from retroperitoneal fibrosis by the presence of circumferential mural aortic wall thickening or enhancement on imaging studies. Lack of both fever and leukocytosis, and insidious (often incidental) rather than acute presentation, help distinguish IgG4-related aortitis from infectious aortitis. Aortitis is occasionally complicated by aortic aneurysm.
Head- and neck-limited disease
Major salivary (eg, parotid and/or submandibular) and lacrimal glands are commonly affected. Glands are painlessly enlarged bilaterally, but usually their function is not impaired. Elevated IgG4 levels, characteristic histopathology, and insidious tempo of disease help differentiate IgG4-RD of these organs from conditions such as Sjögren syndrome and sarcoidosis. IgG4-RD does not manifest with abrupt onset or episodic salivary or lacrimal gland enlargement. Specific serologies (anti-Ro/SSA, anti-La/SSB antibodies) may help distinguish patients with Sjögren syndrome presenting with prominent swelling of the parotid, submandibular, and lacrimal glands. Also, well-formed noncaseating granulomas or certain organ manifestations, such as bulky hilar lymphadenopathy, anterior uveitis, inflammatory arthritis, or erythema nodosum, can help distinguish sarcoidosis from IgG4-RD.
The orbits can be affected. IgG4-RD accounts for about 25 to 50% of cases of inflammatory orbital disease (previously called orbital pseudotumor), which must be distinguished from granulomatosis with polyangiitis and malignancy. IgG4-RD can also cause orbital myositis.
Classic Mikulicz syndrome with systemic involvement
IgG4-related Mikulicz syndrome is a combined involvement of the lacrimal, parotid, and submandibular glands, typically with bilateral involvement of each set of glands. These findings, combined with a marked elevated serum IgG4 level, is essentially diagnostic of IgG4-RD; however, serum IgG4 is not always elevated in IgG4-related Mikulicz syndrome.
Other phenotypes
Lungs and pleura may be involved, sometimes with hilar adenopathy and lung nodules that can resemble sarcoidosis. Histopathology is essential for distinguishing these disorders. Interstitial lung disease may occur and cause significant deterioration in pulmonary function, which is uncommon in patients without interstitial lung disease.
Renal involvement most often manifests as tubulointerstitial nephritis, usually as asymptomatic impairment of kidney function, sometimes requiring dialysis; multiple renal masses and hypocomplementemia are often present. Proteinuria, sometimes in the nephrotic range, may occur, reflecting an associated glomerulopathy, but cellular casts and/or hematuria are infrequent.
Many other tissues may be involved, including the skin, prostate, meninges, and sinuses. There is limited evidence of involvement of the brain, luminal gastrointestinal tract, spleen, bone marrow, or peripheral nerves.
Pathophysiology reference
Wallace ZS, Zhang Y, Perugino CA, et al: Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis 78(3):406-412, 2019. doi:10.1136/annrheumdis-2018-214603
Etiology of IgG4-Related Disease
The cause of IgG4-RD is unknown, but is thought to involve autoimmunity because of its chronic, insidious nature, the targeting of self-proteins by antibodies, and responsiveness to immunosuppression (1).
Etiology reference
Perugino CA, Stone JH: IgG4-related disease: an update on pathophysiology and implications for clinical care. Nat Rev Rheumatol 16(12):702-714, 2020. doi: 10.1038/s41584-020-0500-7
