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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. IgG accounts for 75% of antibodies circulating in the blood, which are an essential part of the secondary immune response to infection and toxins. IgG is made by plasma cells, a specific type of B lymphocyte.

There are four subclasses of IgG. Subclass IgG4 is the least common of these, accounting for about 4% of IgG in serum. IgG4 has a unique structure. Its specific biological role is uncertain. However, IgG4 is known to play a role in protection against type 1 hypersensitivity reactions, for example to bee venom, and in the pathogenesis of autoimmune blistering diseases such as pemphigus vulgaris, helminth infections, and malignancy including melanoma.

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 pathological features of:

  • Inflammatory pseudotumours, that is, 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 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: abnormally high Th2 cytokines in tissues, raised IgE and increased T-reg lymphocytes in the 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.

Who gets IgG4-related disease?

Most patients described with IgG4-related disease are middle-aged or older men.

What are the clinical features of IgG4-related disease?

IgG4-related disease presents in various ways.

  • Most people with IgG4-related disease are constitutionally well. 
  • The 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.
  • The 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, such as hilar lymphadenopathy, bile duct lesions, lacrimal and salivary gland involvement, hypothyroidism, and retroperitoneal fibrosis.
  • IgG4-related lacrimal, parotid, or submandibular salivary disease, pneumonitis, and 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.
  • Cutaneous manifestations of IgG4-related disease include erythematous plaques, papules, and subcutaneous nodules, often itchy, and usually on the face or forearm. Most patients with cutaneous IgG4-related disease report inflammatory enlargement of lacrimal or salivary glands at some point.
Organ-specific IgG4-related disease
Organ Disease
Gastrointestinal disease
  • Pancreatitis (type 1 autoimmune pancreatitis)
  • Idiopathic retroperitoneal fibrosis (Ormond disease)
  • Sclerosing cholangitis
  • Gastritis
  • Hepatitis
Lymph node involvement
  • Generalised lymphadenopathy
Salivary and lacrimal disease
  • Mikulicz disease of the lacrimal glands (dacryoadenitis) and salivary glands (sialoadenitis)
  • Sclerosing sialoadenitis (Küttner tumour of the submandibular salivary gland)
  • Chronic sclerosing dacryoadenitis of the lacrimal glands
Eye disease
  • Inflammatory pseudotumour of the orbit
Heart disease
  • Chronic sclerosing aortitis and peri-aortitis
  • Constrictive peri-aortitis
Thyroid disease
  • Riedel thyroiditis
  • Fibrosing Hashimoto thyroiditis
Lung disease
  • Inflammatory pseudotumour
  • Interstitial pneumonitis
Kidney disease
  • Tubulointerstitial nephritis
  • Membranous glomerulonephritis
  • Inflammatory pseudotumour
Skin disease
  • Inflammatory pseudotumour
  • Prostatitis
  • Hypophysitis
  • Pachymeningitis

How is IgG4-related disease diagnosed?

The 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 a biopsy of affected organ tissues, including skin biopsy. See IgG4-related skin disease pathology. Features include:

  • 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, such as autoimmune pancreatitis.

How is IgG4-related disease treated?

IgG4-related disease is usually treated with systemic steroids, often prednisone 40 mg 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 significant organ involvement such as:

  • Liver cirrhosis
  • Portal hypertension
  • Biliary obstruction
  • Retroperitoneal fibrosis
  • Aortic dissection from an 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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