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
- Orbital tissues (tissues surrounding the eye)
- Salivary glands (glands that lie under the side of the jaw and behind the angle 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)
Measurement of serum IgG4 can aid in the diagnosis of IgG4-RD.
What is IgG4-RD?
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.
Although elevated serum IgG4 is consistent with the diagnosis of IgG4-RD, not all patients will have elevated concentrations.
IgG4 related disease (IgG4-RD) encompasses a constellation of individual organ disorders that share particular pathologic, serologic, and clinical features. These disorders were previously thought to be unrelated. They are characterized by the infiltration of IgG4+ plasma cells and an elevated serum IgG4.
Common features of IgG4-RD include:
- Elevated serum IgG4 (≥135 mg/dL)
- Clinical examination identifying swelling or masses in single or multiple organs
- Histopathological evidence of infiltrating IgG4+ plasma cells and fibrosis
- Imaging identifying narrowing of ducts and/or enlargement of organs
IgG4-RD includes disorders such as:
- Type 1 (IgG4-related) autoimmune pancreatitis (AIP)
- Salivary gland disease (Mikulicz's disease)
- Nypophysitis
- Riedel thyroiditis
- Interstitial pneumonitis
- Nephritis
- Prostatitis
- Lymphadenopathy
- Retroperitoneal fibrosis
- Inflammatory aortic aneurysm
IgG4 elevation was also found to be associated with cystic fibrosis, vasculitis, and cancer. It was also associated with auto-immune diseases and patients with repeated infections or primary-immune deficiencies. It was also shown that IgG4 elevation can be associated to hypogammaglobulinemia in few patients with other IgG subclass deficiencies.
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- 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.
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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 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 of IgG4-Related Disease:
- 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.
If diagnosed before serious organ damage has occurred, IgG4-RD typically responds well to treatment but chronic therapy and the attempts to avoid side-effects of treatment, particularly glucocorticoids, remain the rule. Glucocorticoids are typically viewed as the initial treatment of IgG4-RD, but the shortcomings of this treatment approach are widely appreciated. Although nearly all patients with IgG4-RD respond to glucocorticoids, approximately 40% of those fail to achieve complete remission or relapse within one year, even if glucocorticoids are continued at a minimum of 5 mg/day. The disease often recurs after prednisone tapering, as well.
The role of conventional DMARDs in IgG4-RD is not clear, and much evidence suggests that the impact of these drugs in the absence of prednisone is small. Rituximab, however, is frequently an excellent treatment for IgG4-RD and it is not typically associated with many of the adverse effects linked to glucocorticoids. Other treatment strategies are now being developed based on the large amount of information learned in recent years about the pathophysiology of IgG4-RD.
Please discuss diagnosis and treatment options with your medical professional.
