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IgG4-Related Disease

(IgG4-RD)

By

Cory Perugino

, DO, Massachusetts General Hospital

Last full review/revision Nov 2020| Content last modified Nov 2020
Click here for the Professional Version

Immunoglobulin G4-related disease (IgG4-RD) is an uncommon immune disorder that usually affects multiple tissues and organs with tumor-like masses and/or painless enlargement.

  • Symptoms depend on which organs are affected.

  • Most people with IgG4-RD are middle-aged to older men, but the disorder can affect people of any age and sex.

  • The exact cause of IgG4-RD is unknown, but it likely involves a problem with the immune system.

  • IgG4-RD can damage organs before people notice symptoms and seek medical care.

  • Organ enlargement may cause concern about a cancer until the diagnosis is made. 

  • Diagnosis typically requires biopsy.

  • Treatment is with corticosteroids and rituximab, drugs that modify the immune system's activity, and sometimes surgery.

Immunoglobulins are antibodies, which are proteins that are part of the body's immune system defenses. Immunoglobulins help protect against foreign or dangerous invaders, such as bacteria, viruses and cancer cells. The body produces thousands of different immunoglobulins, which are grouped into 5 classes (IgM, IgG, IgA, IgE, and IgD), some of which (eg, IgA and IgG) have subclasses.

IgG4 is the least common of the 4 subclasses of IgG. It has various normal functions in the body, but in IgG4-related disease, immune cells that produce IgG4, along with other related cells, accumulate abnormally in certain organs and damage them. The affected organs can enlarge and may eventually fill with scar tissue (fibrosis) and the damage can be permanent.

One or more organs are affected; the 11 organs considered typical of IgG4-RD include

  • Pancreas (organ that secretes digestive juices and hormones such as insulin)

  • Bile ducts (small tubes that carry bile, a fluid that aids in digestion)

  • Lacrimal (tear) glands

  • Parotid glands (salivary glands that lie just behind the angle of the jaw, below and in front of the ears)

  • Submandibular glands (salivary glands that lie under the side of the jaw)

  • Lungs

  • Kidneys

  • Retroperitoneal tissues (at the back of the abdomen)

  • Aorta (the main blood vessel bringing blood from the heart to the body)

  • Meninges (layers of tissue that cover the brain and spinal cord)

  • Thyroid gland (gland in the front of the neck that controls many body activities)

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 does not cause 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. 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 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

  • Biopsy

  • Blood tests

  • Imaging

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.

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

  • Corticosteroids

  • Rituximab

  • Sometimes, surgery

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 drug that modifies the immune system's activity, is often used when corticosteroids are not appropriate (for example, in people with uncontrolled diabetes). 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.

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