Immunoglobulin G4 Related Disease

Immunoglobulin G4-related disease is a rare immune disorder that can affect almost any organ in the body, often appearing as tumor-like masses that may be mistaken for cancer. Understanding this complex condition is essential for proper diagnosis and treatment.

Table of contents

• What Is IgG4-Related Disease?
• Who Is Affected by This Disease?
• What Causes IgG4-RD?
• Organs and Tissues Affected
• Signs and Symptoms
• How Is IgG4-RD Diagnosed?
• Treatment Options
• Living with IgG4-RD
• Outlook and Prognosis

What Is IgG4-Related Disease?

Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated condition, which means it involves disease in organs caused by an abnormally regulated immune system.^[1] This rare disorder is also known by several other names, including IgG4-related systemic disease, hyper-IgG4 disease, IgG4-related autoimmune disease, and IgG4-syndrome.^[1]

The disease is characterized as a multi-organ, fibro-inflammatory condition (a condition involving both tissue scarring and inflammation) with tumor-like masses of unknown cause.^[1] These masses result from dense tissue infiltration by immune cells and expansion of the tissue matrix.^[2] The disorder was first described in 1961 when researchers observed pancreatitis with elevated levels of gamma globulins, though it wasn’t formally recognized as a distinct disease until much later.^[1]

IgG4-related disease can affect virtually any organ in the body, making it similar to other systemic diseases like sarcoidosis.^[1] What makes this disease particularly challenging is that patients often have no signs or symptoms for months or even years, which means organ damage can occur silently before a person seeks medical attention.^[3]

IgG4-related systemic disease, hyper-IgG4 disease, IgG4-related autoimmune disease, IgG4-associated disease, IgG4-related sclerosing disease, IgG4-syndrome, IgG4-RD

Who Is Affected by This Disease?

The typical person with IgG4-related disease is a middle-aged to elderly individual, more commonly male than female.^[3] In contrast to most autoimmune diseases where females are more commonly affected, males are more likely to develop IgG4-RD and typically experience more severe disease with involvement of multiple organs, higher serum IgG4 levels, and greater internal damage.^[13]

While the average age of diagnosis is around 60 years, the disease can affect people of any age, including both children and individuals in their 90s.^[13] In rare cases, the disease also affects children.^[3] It can affect people of every race and ethnicity.^[13]

The exact prevalence of IgG4-related disease is not known, though it is estimated that fewer than 200,000 people in the United States are affected.^[1][9]

What Causes IgG4-RD?

The exact cause of IgG4-related disease is unknown, but it likely involves a problem with the immune system.^[5] Researchers believe it may be related to genetic background, bacterial infection and molecular mimicry (when structures of bacteria resemble parts of the body), and autoimmune processes.^[1]

Immunoglobulins are antibodies, which are proteins that are part of the body’s immune system defenses. They help protect against foreign or dangerous invaders, such as bacteria, viruses, and cancer cells.^[5] The body produces thousands of different immunoglobulins, which are grouped into 5 classes, some of which have subclasses.

IgG4 is the least common of the 4 subclasses of IgG.^[2] 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.^[5] The affected organs can enlarge and may eventually fill with scar tissue (fibrosis), and the damage can be permanent.^[5]

No disease-specific or unifying autoantibody has been identified that could explain all cases of IgG4-RD.^[2]

Organs and Tissues Affected

IgG4-related disease can affect virtually any organ system.^[4] The most commonly involved organs are the pancreas, kidneys, orbital structures (tissues around the eyes), salivary glands, and retroperitoneum (the area at the back of the abdomen).^[1]

Eleven organs are considered typical sites of involvement in IgG4-RD. Some patients have disease in only one organ, while others have diseases that affect multiple organs at the same time.^[3] It is not unusual for the disease to affect anywhere between two to six organs.^[3] Most patients have multi-organ involvement at the time of diagnosis but tend to have one dominant pattern.^[2]

• Meninges (layers of tissue covering the brain and spinal cord)
• Orbits (tissues surrounding the eye)
• Lacrimal glands (tear glands)
• Major salivary glands (parotid and submandibular glands)
• Thyroid gland
• Lungs
• Aorta (main blood vessel from the heart)
• Kidneys
• Pancreas
• Bile ducts
• Retroperitoneal tissues (at the back of the abdomen)

Researchers have identified approximately equal proportions of different clinical patterns of the disease based on which organs are primarily affected.^[2] These include pancreato-hepato-biliary disease (affecting the pancreas, liver, and bile ducts), retroperitoneal fibrosis and/or aortitis (affecting tissues at the back of the abdomen and the aorta), and head and neck-limited disease (affecting salivary and tear glands, orbital tissues).^[2]

Signs and Symptoms

Because IgG4-related disease can affect many organs, it can present in different ways with a wide variety of symptoms.^[3] The disease often appears as a mass that mimics cancer, which is why patients are frequently misdiagnosed.^[1] The disease progresses over the course of years, rather than months, and typically there are few symptoms despite significant inflammation.^[13]

Common general symptoms include swollen lymph nodes, weight loss, and fatigue.^[5][3] Weight loss is particularly common when multiple organs are involved or when the pancreas does not make enough enzymes needed for digestion.^[5] IgG4-RD almost never causes a fever.^[5]

Other symptoms depend on which specific organs are affected:

• Pancreas and bile ducts: IgG4-RD affecting the pancreas may cause jaundice (yellowing of the skin) if swelling blocks the flow of bile from the liver. People may develop acute pancreatitis with abdominal pain and nausea, or chronic pancreatitis with gas, feeling full, diarrhea, weight loss, and diabetes.^[5]
• Retroperitoneal tissues: People may have no symptoms, or may experience flank or back pain. Blockage of urine flow from the kidneys can cause enlarged kidneys and kidney damage.^[3][5]
• Salivary and lacrimal glands: These glands 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 or dry eyes are uncommon.^[2][5]
• Orbital tissues: People may develop bulging of the eyes, swelling and pain around the eyes, or pain when moving the eyes, as well as changes in vision.^[3][5]
• Lungs: People may have no symptoms or may develop cough, shortness of breath, or sharp pain when inhaling.^[5]
• Aorta: The walls of the aorta may be affected, which can lead to an aortic aneurysm (bulging of the blood vessel wall).^[5]

How Is IgG4-RD Diagnosed?

The diagnosis of IgG4-related disease is neither swift nor straightforward, and there is no single diagnostic test for this condition.^[13] Many patients experience delays in getting an accurate diagnosis, with some taking several months and others taking decades of consultations with multiple specialists.^[13] Until recently, the disease was not even assigned a standardized diagnostic code, and many healthcare practitioners have not heard of it.^[13]

Diagnosis is often made by combining information from clinical presentation, imaging studies, and tissue examination.^[13] It is critical to differentiate IgG4-RD from cancerous tumors and similar diseases of the affected organs to apply appropriate therapy and avoid unnecessary surgery.^[7]

A biopsy (removal of a small tissue sample for examination) is usually needed to distinguish IgG4-RD from other causes of enlarged organs.^[5] The central features seen under the microscope are a dense, polyclonal (involving many different cell types) infiltrate of lymphocytes and plasma cells enriched with IgG4-positive plasma cells, storiform fibrosis (a characteristic pattern of scarring), and obliterative phlebitis (inflammation and closure of veins).^[1][4] For a firm diagnosis, the ratio of IgG4-positive cells to total IgG-positive cells should be greater than 40%.^[4]

It’s important to note that the characteristic features of storiform fibrosis and obliterative phlebitis are seen in all tissues except bone marrow and lymph nodes, making these two sites less suitable for confirming the diagnosis.^[4]

Blood tests are also helpful as initial screening. These may include:

• Serum IgG4 level (often but not always elevated)^[2]
• Serum complement levels^[13]
• Serum protein electrophoresis (showing polyclonal increase in gamma globulins)^[4]

Imaging tests such as CT scans, MRI, ultrasound, or PET scans may be used to identify affected organs and monitor disease progression.^[13][5]

Treatment Options

If diagnosed before serious organ damage has occurred, IgG4-related disease typically responds well to treatment, but chronic therapy is usually necessary.^[3] Many patients follow an indolent course and respond well to treatment, but a significant proportion may have highly serious complications such as inflammation around the aorta, severe retroperitoneal fibrosis, or inflammation of the meninges.^[4]

Glucocorticoids (corticosteroids such as prednisone) are typically viewed as the initial treatment of IgG4-RD.^[3] The response to steroids is so dramatic that it has been suggested as one diagnostic criterion for the disease.^[1] Although nearly all patients with IgG4-RD respond to glucocorticoids, approximately 40% of those fail to achieve complete remission or relapse within one year.^[3] The disease often recurs after glucocorticoids are stopped.^[3]

Prednisone can be problematic for patients, who tend to be middle-aged or elderly at diagnosis. This is made worse by the fact that IgG4-RD patients often have pancreatic problems, and corticosteroids cause new or worsening diabetes in about 40% of patients.^[4] Other side effects associated with glucocorticoids include high blood pressure, high blood sugar, thinning bones, a weakened immune system, and muscle weakness, which are more likely to occur in older patients.^[11]

Rituximab is frequently an excellent treatment for IgG4-RD, and it is not typically associated with many of the adverse effects linked to glucocorticoids.^[3] Initial response rates to rituximab are high but durable remissions are rare.^[4] Rituximab is a medication that depletes B cells, a type of immune cell involved in the disease process.^[3]

In 2025, a new medication called inebilizumab (Uplizna) received approval in Europe for treating adult patients with active IgG4-RD.^[11] In clinical trials, inebilizumab reduced the risk of disease flares by 87% compared to placebo, and 58.8% of patients receiving inebilizumab achieved corticosteroid-free, flare-free complete remission at one year, compared to 22.4% of patients receiving placebo.^[9][11]

More intensive treatments may be required in rare cases of severe, refractory disease, and targeted therapy against certain disease markers warrant further exploration.^[4] Sometimes surgery may be needed to address complications.^[5]

Living with IgG4-RD

Patients with IgG4-related disease need to have close follow-ups with physicians who are knowledgeable about the condition.^[3] They also need to broaden their own knowledge and be aware of the symptoms and complications that can result from disease in the organs.^[3] Because of the organ damage IgG4-RD can cause, it is important to seek medical attention for symptoms early and begin treatment.^[3]

Regular check-ups can help detect relapses early and keep the disease under control.^[14] Staying consistent with the management plan is important for maintaining health.^[14]

Patients are encouraged to take an active role in their care by staying informed about their condition, asking questions during appointments, and speaking up to ensure their concerns are addressed.^[14] Tools like symptom trackers can help patients stay organized and prepared for medical visits.^[14]

Living with this chronic condition can be emotionally challenging. Patients should allow themselves to feel and process emotions like frustration or sadness, set realistic goals, recognize their limits, and take breaks when needed.^[14] Having open and honest conversations with friends and loved ones about the condition is an important form of self-care.^[15] By explaining the unpredictability of this rare and chronic condition to others, patients can better manage both their own expectations and those of others.^[15]

Many patients find it helpful to use energy management strategies, such as the “spoon theory,” which involves rationing energy throughout the day and prioritizing activities based on available energy.^[15] Flexible work arrangements and stress reduction can also be beneficial.^[15]

While there is no specific diet for IgG4-RD, making thoughtful food choices may help manage inflammation. A balanced diet with plenty of fruits, vegetables, whole grains, and lean proteins is recommended, while limiting fats and processed foods.^[14] Regular physical activity can also reduce inflammation and boost overall health.^[14] Smoking can worsen inflammation and increase complications, so quitting is one of the most effective steps patients can take.^[14]

Outlook and Prognosis

The outlook for people with IgG4-related disease varies depending on how early the diagnosis is made and how well the disease responds to treatment. If diagnosed before serious organ damage has occurred, the disease typically responds well to treatment.^[3] However, once significant fibrosis (scarring) has developed, the damage may be permanent.^[5]

The disease is considered treatable but rarely curable, and many patients require long-term management to prevent relapses.^[12] Close monitoring by healthcare professionals familiar with IgG4-RD is essential for the best outcomes.^[3]

Without treatment, IgG4-RD can lead to progressive organ damage and dysfunction. Some patients may develop highly serious or even fatal complications such as severe inflammation around the aorta, extensive retroperitoneal fibrosis, or inflammation of the meninges.^[4]