IgG4-related disease (IgG4-RD) is a chronic inflammatory condition that can affect various organs throughout the body. It is a relatively recent recognition in medical understanding, and its systemic nature means it can mimic a wide array of other diseases, including various forms of cancer.
The Role of IgG4 in the Immune System
Antibodies, also known as immunoglobulins, are proteins produced by the immune system to identify and neutralize foreign invaders. Immunoglobulin G (IgG) is the most abundant type of antibody in the bloodstream, with four distinct subclasses. Among these, IgG4 is the least common. Its normal function is often associated with immune tolerance, helping to block allergic reactions by preventing other antibodies from binding to allergens.
In IgG4-RD, there is an abnormal accumulation of IgG4-producing plasma cells within various tissues. This infiltration, often accompanied by other immune cells, leads to persistent inflammation and the development of fibrosis. While IgG4 antibodies are considered less inflammatory than other IgG subclasses, their excessive presence in tissues appears to be a hallmark of the disease. The exact trigger for this immune dysregulation and how IgG4 contributes to tissue damage and scarring are still subjects of ongoing research.
Organs Affected and Symptoms
IgG4-RD can manifest in a wide range of organs, leading to diverse symptoms depending on the affected body system. The condition frequently presents with painless swelling or mass formation in one or multiple organs. Early detection is beneficial as organ damage can occur even before symptoms become apparent.
Pancreas and Biliary Tree
The pancreas is one of the most commonly affected organs, leading to a condition known as autoimmune pancreatitis. Symptoms may include abdominal pain, weight loss, or painless jaundice if the pancreatic swelling obstructs the bile ducts.
Head and Neck
In the head and neck region, IgG4-RD can cause swelling of the salivary glands (such as the parotid or submandibular glands) and lacrimal (tear) glands, often appearing as noticeable bulges on the face or below the chin. Orbital disease, affecting the tissues around the eyes, can result in bulging eyes (proptosis) or pain with eye movement. Thyroid inflammation may also occur.
Kidneys
Kidney involvement presents as tubulointerstitial nephritis, which can lead to impaired kidney function. Imaging studies may reveal mass-like lesions within the kidneys. This can progress to chronic kidney failure if left unaddressed.
Lungs and Chest
Pulmonary manifestations of IgG4-RD include the formation of nodules or interstitial lung disease, where inflammation and scarring affect the lung tissue. Patients may experience symptoms such as a persistent cough, shortness of breath, or sharp chest pain, especially during inhalation.
Other Sites
Less common but notable sites include the retroperitoneum, the area behind the abdominal cavity, where it can cause retroperitoneal fibrosis. This may lead to flank or back pain and can compress the ureters, blocking urine flow from the kidneys and potentially causing kidney damage. The aorta, the body’s main artery, can also be affected, leading to aortitis and potentially an aortic aneurysm.
The Diagnostic Process
Diagnosing IgG4-RD is a comprehensive process that requires combining several pieces of clinical and laboratory evidence, as no single test is definitive. A thorough evaluation is necessary. Diagnosis involves clinical and radiological findings, serological testing, and histopathological examination.
Clinical and radiological findings involve observing swelling, masses, or dysfunction in one or more organs characteristic of IgG4-RD. Imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scans can help identify affected areas and assess the extent of organ involvement.
Serological testing often includes measuring serum IgG4 levels in the blood. While elevated IgG4 concentrations are frequently observed in patients with IgG4-RD, normal IgG4 levels can be present in a substantial number of affected individuals. Conversely, elevated IgG4 levels can also occur in other conditions, meaning that a high level alone is not sufficient for a diagnosis of IgG4-RD.
Histopathology, obtained through a tissue biopsy from an affected organ, is often considered the definitive method for confirming the diagnosis. Pathologists look for specific microscopic features, including a dense infiltration of lymphocytes and plasma cells within the tissue. They also identify characteristic scarring patterns, such as storiform fibrosis, which appears as a swirling arrangement of cells and collagen fibers. Another key finding is obliterative phlebitis, involving inflammation and fibrous obliteration of small veins. Immunostaining of the tissue is performed to count IgG4-positive plasma cells, which helps support the diagnosis.
Treatment and Long-Term Management
The primary goal of treating IgG4-RD is to reduce inflammation, prevent further organ damage, and induce remission of the disease. Early intervention is generally associated with a more favorable outcome, as irreversible fibrosis can develop if the condition remains untreated. Treatment plans are tailored to the individual, considering the organs involved and disease severity.
Glucocorticoids, such as prednisone, are typically the first-line therapy to induce remission. Following this initial period, the dosage is gradually tapered over several months to minimize potential side effects. Response to treatment is assessed through clinical improvement, laboratory markers, and imaging studies.
Despite initial success with glucocorticoids, relapses are common. For individuals who experience relapses, cannot tolerate steroids, or require steroid-sparing options, other medications are used. Rituximab, a monoclonal antibody that targets B cells, has shown effectiveness in inducing and maintaining remission in IgG4-RD by depleting these antibody-producing cells. Inebilizumab, another B-cell depleting agent, is also used for treating IgG4-RD, demonstrating significant reduction in flare risk.
Long-term management of IgG4-RD involves ongoing monitoring to track disease activity and detect any signs of recurrence or progressive organ damage. This typically includes regular blood tests to check inflammatory markers and IgG4 levels, along with periodic imaging studies of previously affected or at-risk organs. While IgG4-RD is considered a chronic condition, consistent treatment and careful monitoring can be highly effective in controlling the disease and preserving organ function.