IgG4-related disease

Author: Dr Anthony Yung, Dermatologist, Hamilton, New Zealand; Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, March 2014.

What is IgG4?

IgG4 is a subclass of IgG, which is the most common form of immunoglobulin (antibody proteins found throughout the body). IgG accounts for 75% of antibodies circulating in the blood. Antibodies are an important part of the body's secondary response to infection and toxins. They are made by plasma cells, a specialised type of B lymphocyte (an immune cell).

There are 4 subclasses of IgG. Subclass IgG4 is the least common of these, accounting for about 4% of IgG in serum (the non-cellular portion of blood). IgG4 has unique structure. Its specific biological role is uncertain.

What is IgG4-related disease?

IgG4-related disease is a newly-described rare syndrome consisting of many disease entities that were previously thought to be unrelated. These conditions have the common pathological features of:

  • Inflammatory pseudotumours, ie swelling of organs (organomegaly) or nodules within an organ
  • Lymphoplasmacytic infiltration of tissues with many IgG4-positive plasma cells
  • Storiform fibrosis (scarring involving cells arranged like a cartwheel on histology)
IgG4-related disease: cutaneous inflammatory pseudotumour

Elevated serum IgG4 is present in 60–70% patients.

What are the symptoms of IgG4-related disease?

IgG4-related disease presents in various ways.

  • Most people with IgG4-related disease are constitutionally well. Most are middle-aged or elderly men.
  • IgG4-related disease may be diagnosed as an incidental finding when someone undergoes a routine radiological or surgical investigation.
  • 60–90% of people with IgG4-related disease have multiple organ involvement.
  • IgG4-related disease often presents as swelling of or within an organ (such as skin, orbit and lung); this is known as an inflammatory pseudotumour.
  • IgG-related autoimmune pancreatitis is more likely than other forms of IgG-related disease to be associated with disease in other sites, eg hilar lymphadenopathy (enlarged lymph glands within the chest noted on chest X-ray), bile duct lesions, lacrimal (tear gland) and salivary gland involvement, hypothyroidism, retroperitoneal fibrosis.
  • IgG4-related lacrimal, parotid or submandibular salivary disease, pneumonitis (lung disease), kidney disease are associated with pancreatitis in <20% cases.
  • Patients with IgG4-related disease may have symptoms of allergy such as asthma.
  • Up to 40–80% of patients with IgG4-related disease have lymphadenopathy (swollen lymph glands).
  • Cutaneous manifestations include erythematous plaques, papules, and subcutaneous nodules, often itchy, and often on the face or forearm. Most have inflammatory enlargement of lacrimal or salivary glands at some point.
Organ-specific IgG4-related disease
Gastrointestinal disease
  • Pancreatitis (type 1 autoimmune pancreatitis)
  • Idiopathic retroperitoneal fibrosis (Ormond disease)
  • Sclerosing cholangiitis
  • Gastritis
  • Hepatitis
Lymph node involvement
  • Generalised lymphadenopathy
Salivary and lacrimal disease
  • Mikulicz disease of the lacrimal glands (dacroadenitis) and salivary glands (sialoadenitis)
  • Sclerosing sialoadenitis (Küttner tumour of the submandibular salivary gland)
  • Chronic sclerosing dacroadenitis of the lacrimal glands
Eye disease
  • Inflammatory pseudotumour of the orbit
Heart disease
  • Chronic sclerosing aortitis and periaortitis
  • Constrictive periaortitis
Thyroid disease
  • Riedel thryroiditis
  • Fibrosing Hashimoto thyroiditis
Lung disease
  • Inflammatory pseudotumour
  • Interstitial pneumonitis
Kidney disease
  • Tubulointerstitial nephritis
  • Membranous glomerulonephritis
  • Inflammatory pseudotumour
Skin disease
  • Inflammatory pseudotumour
  • Prostatitis
  • Hypophysitis (inflammation of pituitary gland)
  • Pachymeningitis (thickening of dura mater around the brain or spinal cord)

What is the cause of IgG4-related disease?

The cause of IgG4-related disease is unknown.

  • It may be an autoimmune disorder: antinuclear antibodies and autoantibodies to pancreatic antigens have been found in autoimmune pancreatitis.
  • It has features of an allergic disorder: abnormal high Th2 cytokines (cell messenger proteins) in tissues, raised IgE and increased T-reg lymphocytes in blood and raised eosinophil count in 40% of patients. Cytokines IL-10 (interleukin 10) and TGF-β (transforming growth factor Beta) are known to support IgG4 production and are at elevated levels in IgG4-related disease.

How is IgG4-related disease diagnosed?

Diagnosis of IgG4-related disease can be difficult, as multiple organs may be involved simultaneously. Diagnostic criteria have not been fully developed.

Investigation in suspected IgG4-related disease requires a combination of clinical, endoscopic, radiological and serological tests looking for organ involvement and end organ damage (eg hormonal abnormalities).

Tissue diagnosis requires biopsy of affected organ tissues, including skin biopsy, demonstrating:

  • Lymphoplasmacytic infiltrate
  • Storiform fibrosis pattern
  • IgG4-positive plasma cells (the number of positive cells to confirm diagnosis depends on tissue type; most >30–50 per high power field, some, such as kidney, 10 per high power field)

Blood tests are not diagnostic but may show:

  • Peripheral eosinophilia
  • Raised serum IgG4

There are specific criteria for the diagnosis of some tissue-specific disorders, eg autoimmune pancreatitis.

How is IgG4-related disease treated?

IgG4-related disease is usually treated with systemic steroids, ie prednisone 40mg per day for 2–4 weeks followed by a gradual tapering of the dose.

In patients that cannot be taken off prednisone, a steroid-sparing agent like azathioprine or mycophenolate may be used. Rituximab, a B cell-depleting monoclonal antibody, has been used with some success.

Organ-specific replacement therapy may be required:

  • Thyroxine for thyroiditis (thyroid disease) causing hypothyroidism
  • Pancreatic enzyme replacement for pancreatic insufficiency
  • Insulin for diabetes mellitus
  • Hormone replacement for hypopituitarism: hydrocortisone, thyroxine, growth hormone, desmopressin and sex hormones (testosterone for men; oestrogen and progesterone for women)

What is the prognosis of IgG4-related disease?

Prognosis of IgG4-related disease is variable. It may spontaneously resolve or persist, with remitting and relapsing symptoms.

Major causes for morbidity and mortality are major organ involvement such as:

  • Liver cirrhosis (end-stage liver disease with scarring)
  • Portal hyperte nsion
  • Biliary obstruction
  • Retroperitoneal fibrosis
  • Aortic dissection from aneurysm
  • Diabetes mellitus
  • Pancreatic insufficiency

IgG4-related disease may be associated with a possible increased risk of non-Hodgkin lymphoma. It is not known if IgG4-related disease leads to an increased risk of other forms of cancer.


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