Immunoglobulin G4–related disease

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Synonyms

IgG4-RD, IgG4-related systemic disease,

Overview

Immunoglobulin G4–related disease is a systemic immune-mediated fibroinflammatory disease that presents as organ dysfunction or mass lesions with lymphoplasmacytic infiltration in single or multiple organs. It can result in organ failure or death if untreated. This disease has been recognized as a distinct clinical entity since the beginning of the 21st century, when investigators in Japan reported that extrapancreatic manifestations of autoimmune sclerosing pancreatitis shared a distinct histopathologic signature with the parent disease. Since then, the histologic features of infiltrative IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis have been reported in almost every organ and share similar features with apparently unrelated pathologic entities, such as dacryoadenitis (Mikulicz disease) to retroperitoneal fibrosis (Ormond disease).

Symptoms

Common symptoms of IgG4-RD include swollen lymph nodes and weight loss. Weight loss is particularly common when multiple organs are involved and/or when the pancreas does not make enough of the enzymes needed for digestion. IgG4-RD almost never causes a fever.

Other symptoms are specific to the affected organs:

  • Pancreas and bile ducts: IgG4-RD that affects the pancreas may cause jaundice (yellowing of the skin) if swelling of the pancreas blocks the flow of bile from the liver to the digestive tract. People may also develop acute pancreatitis, which causes abdominal pain and nausea. Some people develop chronic pancreatitis and have symptoms of pancreatic insufficiency (for example, gas, feeling full, diarrhea, undernutrition, weight loss, diabetes).

  • Retroperitoneal (abdominal) tissues: People with retroperitoneal tissues affected by IgG4-RD may not have symptoms, or they may have flank or back pain. Retroperitoneal fibrosis can compress the ureters (tubes that carry urine from the kidneys to the bladder) which blocks urine flow and increases pressure in the kidneys, which can damage them. Sometimes the walls of the aorta are affected, which can lead to an aortic aneurysm.

  • Salivary and lacrimal glands: These glands, if affected, usually cause painless, noticeable swelling on one or both sides of the face, below the chin, or over the outer portion of the upper eyelids. Dry mouth and/or eyes are uncommon.

  • Orbit: People with IgG4-RD affecting the orbits, particularly the muscles controlling the eyeballs, may develop bulging of the eyes (proptosis), swelling and pain around the eyes, or pain when moving the eyes.

  • Lungs: If IgG4-RD affects the lungs, people may not have symptoms or may have a cough, shortness of breath, or sharp pain when inhaling, often due to inflammation of the pleura (the two thin layers of tissue that separate the lungs from the chest wall).

Diagnosis

A biopsy is usually needed for doctors to distinguish IgG4-RD from other causes of enlarged organs and/or swollen lymph nodes.

Doctors usually do blood tests to measure levels of IgG4 and other immunoglobulins, but even though the disease involves IgG4 producing cells, IgG4 levels are not always elevated. And other diseases can cause elevated IgG4 levels. Other blood tests are done to see what organs may be affected and to help exclude other diseases.

Doctors will usually do a CT or MRI of areas where people have symptoms (for example, of orbits, chest, abdomen, and pelvis). They may also do imaging tests of other areas to look for organs that could be affected but are not causing symptoms.

Sometimes, urine and stool tests are helpful.

Treatment

Treatment of IgG4-RD aims to reduce inflammation and stop the effects of the disorder.

Initial treatment is often with an oral corticosteroid (for example, prednisone), which is given for 2 to 4 weeks then tapered over the course of 2 to 3 months. Rituximab, a medication that modifies the immune system’s activity, is often used when corticosteroids are not appropriate (for example, in people with uncontrolled diabetes) or if the disease recurs when tapering or stopping corticosteroids. Rituximab is nearly universally effective in treating active IgG4-RD.

Typically, organ function returns to normal after treatment. However, if a lot of scar tissue had already formed in an organ, function may not fully return to normal.

Some people require surgical procedures, such as stenting, to relieve blockages of the ureters (the tubes that carry urine from the kidneys to the bladder) or bile ducts.