IgG4-Related Disease

The clinical manifestations of IgG4-RD are usually tumor-like masses or organ enlargement, which result from dense tissue infiltration by immune cells and expansion of the extra-cellular matrix. One or more organs are affected; the 11 organs considered typical of IgG4-RD include the pancreas, bile ducts, lacrimal glands, orbital tissues, salivary glands, lungs, kidneys, retroperitoneal tissues, aorta, meninges, and thyroid gland.

Most patients have multiorgan involvement at the time of diagnosis but tend to have one dominant phenotype. One study identified approximately equal proportions of the following clinical phenotypes (1 Pathophysiology reference Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ).

The cause of IgG4-RD is unknown, but is thought to involve autoimmunity because of its chronic, insidious nature, the targeting of self-proteins by antibodies, and responsiveness to immunosuppression (1 Etiology reference Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ).

IgG4-RD is characterized by a dense lymphoplasmacytic infiltrate composed of CD3+ T cells, activated B cells, and plasma cells with a disproportionate number expressing IgG4 (usually > 40% of all IgG expressing cells) (1 Pathology reference Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ). Classically, inflammation progresses over time to fibrosis with a characteristic "storiform" or whorled pattern. Additional features include obliterative phlebitis and a mild eosinophilic infiltrate. Importantly, the eosinophilic component should not be more prominent than the lymphoplasmacytic infiltrate. The histopathology may differ slightly among tissues, for instance, typical storiform fibrosis is less commonly observed in lacrimal gland, parotid gland, and lung biopsies.

Common general manifestations of IgG4-RD include lymphadenopathy Lymphadenopathy Lymphadenopathy is palpable enlargement of ≥ 1 lymph nodes. Diagnosis is clinical. Treatment is of the causative disorder. (See also Overview of the Lymphatic System.) Lymph nodes are present... read more and weight loss. Weight loss is a particularly prominent symptom in patients with exocrine pancreatic insufficiency. Fever is highly uncommon in IgG4-RD and should prompt consideration of alternative diagnoses.

Other manifestations are specific to the affected organs.

Pancreatic involvement may be painless, sometimes with jaundice if there is an obstructing pancreatic mass, or may cause abdominal pain and nausea if acute pancreatitis Acute Pancreatitis Acute pancreatitis is acute inflammation of the pancreas (and, sometimes, adjacent tissues). The most common triggers are gallstones and alcohol intake. The severity of acute pancreatitis is... read more is present. Some patients, likely many more than reported, present with a more smoldering and insidious chronic pancreatitis Chronic Pancreatitis Chronic pancreatitis is persistent inflammation of the pancreas that results in permanent structural damage with fibrosis and ductal strictures, followed by a decline in exocrine and endocrine... read more and symptoms of exocrine pancreatic insufficiency (eg, flatulence, abdominal distention, steatorrhea, undernutrition, weight loss), and/or endocrine pancreatic insufficiency (eg, asymptomatic hyperglycemia or frank diabetes mellitus).

Retroperitoneal fibrosis most often manifests with flank or back pain but is often asymptomatic and identified incidentally on abdominal imaging.

Aortitis and periaortitis are usually asymptomatic and identified only incidentally by imaging or postoperatively after aortic resection done to correct an aneurysm. The thoracic aorta is more commonly involved than the abdominal aorta (1 Symptoms and signs reference Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ).

Salivary and lacrimal gland involvement usually causes painless, bilateral enlargement but may be asymmetric. Dry mouth and/or eyes is uncommon.

Orbital involvement may cause proptosis Proptosis This photo shows a woman's slightly bulging left eye (proptosis), caused by a meningioma. Proptosis is protrusion of the eyeball. Exophthalmos means the same thing, and this term is usually... read more , orbital pain, periorbital edema, or pain with extraocular movements.

Pulmonary involvement may be asymptomatic or cause cough, dyspnea, or pleurisy.

The diagnosis of IgG4-RD is suspected in patients who present with any of the clinical phenotypes described above Symptoms and Signs Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more . The following other causes of similar manifestations must be considered:

Classification criteria for IgG4-RD published in 2019 include 32 exclusion criteria that can help in making a differential diagnosis (1 Diagnosis references Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ). Although these criteria are not designed for diagnostic purposes, they offer a framework for thinking about the disease, including suggested testing and interpretation of the results.

Although the diagnosis of IgG4-RD can be made without biopsy in a subset of patients in the appropriate clinical context (eg, Mikulicz syndrome), when paired with an elevated serum IgG4 level, biopsy is usually needed to distinguish IgG4-RD from other causes of tumor-like lesions and/or lymphadenopathy. Immunostaining with IgG4 and IgG should be done only if there are at least 2 of the following 3 histopathologic findings: dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. An increased number of IgG4+ plasma cells on biopsy, on its own and even at high abundance, is non-specific and must be paired with other findings to diagnose IgG4-RD. An IgG4/IgG+ ratio on biopsy > 40% is considered mandatory for the histological diagnosis of IgG4-RD, whereas the diagnostic number of IgG4+ cells per high power field varies across organs and type of biopsy (2 Diagnosis references Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ). For instance, ≥ 100 and 10 IgG4+ cells per high power field on core biopsies of the submandibular gland and pancreas, respectively, are highly suggestive of IgG4-RD in the appropriate setting.

Cross-sectional imaging (CT, MRI) should be done of clinically affected areas (eg, of orbits, chest, abdomen and pelvis). Imaging of other areas is often done to screen for asymptomatic manifestations (eg, retroperitoneal fibrosis).

Serum IgG4 levels are elevated in 80 to 90% of patients with IgG4-RD (3 Diagnosis references Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ); elevations can range from mild (1 to 2 times the upper limit of normal) to marked elevation (> 5 times the upper limit of normal) (4 Diagnosis references Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ). However, elevations are not diagnostic and must be interpreted within the context of other clinical data. Many patients, especially those with single-organ involvement (eg, isolated retroperitoneal fibrosis), have normal levels, and serum IgG4 elevation is not specific to IgG4-RD. For example, chronic allergic conditions are a frequent cause of mild serum IgG4 elevation (ie, < 2 times the upper limit of normal).

Other testing that may be helpful includes

An elevated total IgG level (hypergammaglobulinemia) or an elevated globulin to albumin ratio indicates the activation of antibody secreting cells that is typical of but not specific to IgG4-RD. The elevation in total IgG likely reflects the accumulation of autoantibodies. Marked elevations of the total IgE level (often 5 to 10 times the upper limit of normal) are common in patients with IgG4-RD. These values are often markedly higher than the IgE level in patients with asthma or chronic atopic disease. Although high total IgE level is an independent predictor of relapsing IgG4-RD (5 Diagnosis references Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ), very few IgE expressing B cells and plasma cells are in lesional tissues, suggesting serum IgE is more likely an immunologic epiphenomenon than pathogenic itself.

Treatment of IgG4-RD aims to reduce inflammation, induce remission, and preserve organ function. Typically, tumor-like masses or organ enlargement should normalize following treatment. When organs fail to normalize in response to 1 to 2 months of high-dose corticosteroids or 3 to 4 months following B-cell-depleting therapy, this usually indicates irreversible fibrosis, which is common in patients with retroperitoneal fibrosis, longstanding organ involvement, or an incorrect diagnosis.

Initial treatment is with an oral corticosteroid (eg, prednisone 30 to 40 mg once daily), administered for 2 to 4 weeks and then tapered over the course of 2 to 3 months. Rituximab is often used as a steroid-sparing option when patients are poor candidates for corticosteroids (eg, those with uncontrolled diabetes), and can be used to induce or maintain remission when patients do not tolerate corticosteroid tapering, or experience disease recurrence within 12 months of stopping corticosteroids. Rituximab is nearly universally effective in treating active IgG4-RD, but randomized trials are lacking (1 Treatment reference Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder that often manifests with tumor-like masses and/or painless enlargement of multiple organs... read more ).

Some patients require surgical procedures, such as stenting, to relieve mechanical obstruction of the ureters or bile ducts.

Serum IgG4 levels generally decline with treatment over the course of months but often never normalize.

Like most immune-mediated conditions, there is no cure, but IgG4-RD is very treatable. When organ damage occurs, it is usually due to delays in diagnosis and insidious development of organ involvement and damage following treatment-induced remission.