Immunoglobulin G4-Related Disease (IgG4-RD) is a chronic inflammatory disorder characterized by an abnormal immune response that results in the formation of tumor-like masses and enlargement of affected organs. While its name references the IgG4 antibody subtype, the condition is understood to be a systemic fibro-inflammatory process rather than a classical autoimmune disorder. This disease can affect multiple organ systems simultaneously or sequentially, often making its initial presentation complex. Early recognition is important because untreated inflammation progresses to irreversible scarring and organ dysfunction.
Understanding IgG4-Related Disease
The underlying mechanism of IgG4-RD involves a dense infiltration of affected tissues by lymphocytes and plasma cells. A defining pathological feature is the disproportionate number of these plasma cells that secrete the Immunoglobulin G subclass 4 (IgG4) antibody. This cellular infiltration triggers a chronic inflammatory process that leads to extensive fibrosis, or scarring, within the organ structure. This scarring is often characterized by a distinctive “storiform” pattern when viewed under a microscope.
The accumulation of inflammatory cells and resulting fibrosis causes affected organs to become enlarged, hardened, and dysfunctional, sometimes mimicking a cancerous growth. Another specific finding in the tissue is obliterative phlebitis, which is the inflammation and fibrous obliteration of small veins. Although the disease is frequently referred to as “autoimmune,” the precise role of the IgG4 antibody itself in causing tissue damage is not fully established. IgG4 is primarily considered a marker of the disease process, distinguishing it from conditions where antibodies directly attack tissue targets. The current understanding points toward an underlying immunological dysregulation driving this inflammatory and profibrotic response.
The Range of Organ Involvement
IgG4-RD is defined by its systemic nature, having the potential to involve nearly any organ system in the body. The pancreas is one of the most commonly affected organs, leading to Type 1 Autoimmune Pancreatitis (AIP). The inflammation and fibrosis cause the pancreas to swell and harden, impairing its ability to produce digestive enzymes and hormones like insulin. This pancreatic involvement often occurs alongside inflammation in the biliary system, resulting in IgG4-related sclerosing cholangitis, which can obstruct the bile ducts and cause jaundice.
In the head and neck region, the disease frequently manifests as painless, bilateral swelling of the salivary and lacrimal (tear) glands. This presentation, sometimes referred to as Mikulicz’s syndrome, can cause significant enlargement of the glands around the eyes and jaw. The resulting mass effect can cause dry eyes or dry mouth, or in the orbits, it can lead to proptosis, where the eye bulges outward.
Retroperitoneal fibrosis (RPF) involves the formation of a dense, fibrous mass in the space behind the abdominal cavity, often encasing major blood vessels like the aorta. A particular concern with RPF is the obstruction of the ureters, the tubes that carry urine from the kidneys to the bladder. This obstruction can block urine flow and cause hydronephrosis, leading to pressure damage and loss of kidney function. The kidneys themselves can also be directly affected by IgG4-related tubulointerstitial nephritis, which impairs the organ’s filtering capacity.
Confirming the Diagnosis
Diagnosing IgG4-RD requires a multi-step approach because its non-specific symptoms can easily mimic other conditions, including malignancy or other immune disorders. The process begins with clinical assessment, looking for characteristic organ swelling or dysfunction. Serology involves measuring the concentration of IgG4 in the blood, where levels above a certain threshold are highly suggestive of the disease.
However, elevated serum IgG4 is neither entirely sensitive nor specific, as a significant minority of patients (potentially 30-40%) have normal levels, and high levels can occur in other conditions. Imaging studies are used to identify characteristic findings, such as diffuse organ enlargement, mass-like lesions, or thickening of structures like the bile ducts or aortic wall. The most definitive component of diagnosis is histopathology, which requires obtaining a tissue biopsy from the affected organ.
Pathologists look for the signature triad of features: a dense infiltration of lymphocytes and plasma cells, the presence of storiform fibrosis, and often obliterative phlebitis. Crucially, the tissue must demonstrate an increased number of IgG4-positive plasma cells, defined by a specific ratio when compared to the total number of IgG-positive plasma cells, to confirm the diagnosis. This combination of clinical, imaging, serological, and pathological evidence is necessary to distinguish IgG4-RD from its many potential imitators.
Primary Treatment Approaches
The goal of treating IgG4-RD is to suppress the inflammatory process to halt the progression of fibrosis and prevent permanent organ damage. The standard first-line therapy involves the use of high-dose glucocorticoids, such as prednisone. This treatment is highly effective at inducing remission in most patients, often leading to a prompt reduction in organ swelling and the resolution of symptoms.
Following the initial high-dose induction phase, the medication dosage is gradually tapered down to a low-dose maintenance level over several months. This slow tapering is important because the disease has a high tendency to relapse if treatment is discontinued prematurely. For patients who cannot tolerate the side effects of long-term glucocorticoid use or for those who experience relapse, steroid-sparing agents are introduced.
These secondary treatments often include immunosuppressive drugs, with B-cell depletion therapy being a prominent option. Medications like Rituximab target and deplete the B cells that mature into the plasma cells producing IgG4 antibodies. While treatment can successfully resolve the inflammation and swelling, established fibrosis is often irreversible. This underscores why early diagnosis and the prompt initiation of therapy are important to prevent lasting functional impairment in affected organs.