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).

The cause of IgG4-RD is unknown, but it is thought to involve autoimmunity because of its chronic, insidious nature, the targeting of self-proteins by antibodies (eg, galectin-3, interleukin-1 receptor antagonist, annexin A11), and responsiveness to immunosuppression (1).

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).

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 biopsies of the lacrimal gland, parotid gland, and lung.

Common general manifestations of IgG4-RD include lymphadenopathy 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 explanations.

Other manifestations are specific to the affected organs (1).

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 is present. Some patients, likely many more than reported, present with a more smoldering and insidious chronic pancreatitis 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 (2). Pain associated with retroperitoneal fibrosis is thought to relate to local nerve encasement within the fibrotic mass and typically abates with immunosuppression.

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 (3).

Salivary and lacrimal gland involvement usually causes painless, bilateral enlargement but may be asymmetric. Dry mouth and/or dry eyes are not salient features.

Orbital involvement may cause proptosis, orbital pain, periorbital edema, or pain with extraocular movements.

Pulmonary involvement may be asymptomatic or cause cough, dyspnea, or pleuritic pain.

• Biopsy

• Serum IgG4 level

• Serum complement levels (C3 and C4)

• Selective imaging

The diagnosis of IgG4-RD should be considered in patients who present with any of the clinical phenotypes described above. The following other causes of similar manifestations must also be considered:

• Salivary and lacrimal gland involvement: Sjögren disease, sarcoidosis, HIV infection, hepatitis C infection, lymphoma, salivary gland tumors

• Lung involvement: Sarcoidosis, granulomatosis with polyangiitis, idiopathic pulmonary fibrosis, malignancy, tuberculosis

• Pancreatic involvement: Acute or chronic pancreatitis, pancreatic cancer

• Aortic involvement: Giant cell arteritis, idiopathic aortitis

• Retroperitoneal involvement: Lymphoma, sarcoma, granulomatosis with polyangiitis, Erdheim-Chester disease

• Lymphadenopathy: Sarcoidosis, lymphoma, Rosai-Dorfman disease, Erdheim-Chester disease

Classification criteria for IgG4-RD include 32 exclusion criteria that can help in making the diagnosis (1). Although these criteria are not designed for diagnostic purposes, they offer a framework for thinking about the disease, including suggested testing and interpretation of test 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

• 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 (hpf) varies across organs and type of biopsy (2). For instance, in core biopsies, ≥ 100 IgG4+ cells/hpf from the submandibular gland and ≥ 10 IgG4+ cells/hpf from the pancreas 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); 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). 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

• Urinalysis and serum creatinine to assess for kidney function. Proteinuria may be present in IgG4-related kidney involvement, whereas hematuria, red blood cell casts, and dysmorphic red blood cells suggest an alternate diagnosis (eg, granulomatosis with polyangiitis).

• Serum amylase and lipase may be elevated in active disease with pancreatic involvement, while hemoglobin A1C may be elevated, and stool elastase, serum pre-albumin, and vitamins A, E, and D may be reduced in patients with pancreatic damage and dysfunction.

• Serum C3 and C4 complement levels are low in approximately one-third of patients with IgG4-RD; this finding correlates with the number of organs involved.

• Total IgG and total IgE levels are often elevated and help predict likelihood of future relapse and tracking disease activity (5).

• Erythrocyte sedimentation rate (ESR) is often elevated secondary to hypergammaglobulinemia, whereas C-reactive protein (CRP) level is usually normal.

• Testing for anti-neutrophil cytoplasmic antibodies (ANCA), anti-nuclear antibodies (ANA), and anti-Ro/SSA and anti-La/SSB antibodies can help exclude other diagnoses depending on specific patient symptoms (eg, head and neck involvement, lung involvement).

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), 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 (6).

• Corticosteroids

• B-cell targeted therapy

Rituximab also 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 (12).

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

Serum IgG4 levels generally decline with treatment over the course of months but often do not normalize.

Like most immune-mediated conditions, there is no cure, but IgG4-RD is very treatable when intervention begins early. When organ damage occurs, it is usually due to delays in diagnosis, the insidious development of organ involvement, or iatrogenic causes (eg, Whipple procedure for suspected pancreatic cancer).

• IgG4-related disease (IgG4-RD) is a chronic, immune-mediated disorder that often manifests with multiorgan involvement and tumor-like masses most often affecting the pancreas, bile ducts, lacrimal glands, orbital tissues, salivary glands, lungs, kidneys, retroperitoneal tissues, aorta, meninges, and thyroid gland.

• IgG4-RD does not cause fever and typically manifests insidiously.

• Serum IgG4 levels are usually elevated, but this finding is neither highly sensitive nor specific.

• Diagnosis is most often based on a combination of clinical, radiologic, histopathologic, and immunostaining findings with emphasis on tissue sampling.

• Treatment includes corticosteroids and often a B-cell–depleting medication.