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.
- People with persistently low levels of one or two IgG subclasses and a normal total IgG level have a selective IgG subclass deficiency.
- People with IgG subclass deficiency require more extensive diagnostic evaluation including the demonstration of a poor antibody response to vaccine challenge before one is diagnosed with a clinically significant IgG subclass deficiency necessitating specific treatment that may include Ig replacement therapy.
- IgG subclass deficiencies may be associated with other immunoglobulin abnormalities. One common pattern is IgG2 and IgG4 subclass deficiency associated with IgA deficiency.
- IgG subclass deficiencies are also an integral component of other well-known primary immunodeficiency diseases, such as Wiskott-Aldrich Syndrome and Ataxia-Telangiectasia.
- IgG subclass deficiencies are sometimes associated with poor or partial responses to pneumococcal polysaccharides, specifically IgG2 deficiency with or without IgG4 deficiency.
IgG1 deficiency:
Selective IgG1 deficiency is very rare, as it is usually associated with deficiency of either IgG3, or other immunoglobulin classes, such as in common variable immunodeficiency. Isolated IgG1 deficiency has been reported in chronic fatigue syndrome. As IgG1 is the most abundant IgG subclass, its deficiency often results in hypogammaglobulinemia.
IgG1 and IgG3 deficiency:
People with this combination are commonly present with infections of the lower airways, which can progress to chronic lung disease.
IgG2 and IgG4 deficiency:
Conversely, IgG2 and IgG4 deficiencies manifest in the form of otitis media and sinusitis. IgG2 deficiency is the most common type of IgG subclass deficiency, either as an isolated finding or together with IgG4 deficiency. People with this defect have recurrent infections with encapsulated bacteria such as Streptococcus pneumonia and/or Haemophilus influenza type B. IgG2 deficiency often results in infectious complications, such as bronchiectasis, bronchopneumonia, bronchitis, obstructive lung disease, and asthma. It has also been associated with ataxia telangiectasia and systemic lupus erythematosus (SLE). Children with SLE and IgG2 and IgG4 deficiency may present with cardiac tamponade, instead of the more common nephropathy and arthritis. The impact of decreased concentration of IgG4 cannot be easily assessed, since IgG4 may be present in low concentrations in healthy children. Nevertheless, it was shown that low concentrations of IgG4 are present in a large percentage of patients with recurrent respiratory tract infections.
Possible symptoms:
People with any form of IgG subclass deficiency occasionally suffer from recurrent respiratory infections similar to the ones seen in other antibody deficiency syndromes, chiefly infections with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. An increased frequency of viral upper respiratory infections may not be an indication of antibody deficiency. Therefore, it is critical to distinguish between infections caused by respiratory viruses from those due to bacterial pathogens.
A few people with IgG subclass deficiency may appear very similar to patients with severe immunoglobulin deficiencies. Rarely, IgG subclass deficient patients may have recurrent episodes of bacterial meningitis or infections of the bloodstream (sepsis).
Diagnosis:
The finding of an IgG subclass deficiency should prompt reevaluation over a period of months before determining that the patient is truly immunodeficient. Subclass deficiencies need to be carefully interpreted taking into account the clinical status of the patient as well as the person’s ability to produce specific antibodies in response to vaccines.
Measurement of IgG subclasses can be recommended in the presence of known associated abnormalities, particularly if recurrent infections are also present.
These circumstances include:
- IgA deficient patients with recurrent infections to determine if there is an associated IgG2 and IgG4 subclass deficiency
- Wiskott-Aldrich and Ataxia-Telangiectasia patients at the onset of recurrent infections
- Specific Antibody Deficiency patients with normal total immunoglobulins
Possible treatment:
- Recurrent or chronic infections of the ears, sinuses and lungs need comprehensive treatment to prevent permanent damage that might result in hearing loss or chronic lung disease. It is also important to encourage patients to continue normal activities of daily living, such as school or work.
- The mainstay of treatment includes appropriate use of antibiotics to treat and prevent infections. The type and severity of infection usually determines the type of antibiotic used and the length of treatment.
- Ig therapy is an option for selected symptomatic patients that have persistent IgG subclass deficiencies, documented poor responses to polysaccharide vaccines and who fail prophylactic antibiotic therapy. The decision to begin Ig replacement therapy needs to be carefully discussed with the healthcare provider
- People with frequent infections and persistent IgG subclass deficiencies with normal anti-polysaccharide antibodies should also be treated using adequate prevention, vaccine and antibiotic therapy, perhaps even considering the use of Ig replacement if other treatment fails.
IgG, Subclass 4
