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IgG4-Related Disease

(IgG4-RD)

By

Cory Perugino

, DO, Massachusetts General Hospital

Last full review/revision Sep 2020| Content last modified Sep 2020
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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. Serum IgG4 level is often but not always elevated. Symptoms depend on which organs are affected. Diagnosis typically requires biopsy. Treatment is with corticosteroids and sometimes rituximab.

IgG4 is the least common of the 4 subtypes of IgG. Its function likely varies with the context; in allergic disease, it is thought to have an immune-inhibitory role in preventing anaphylactic reactions to allergens. It has also been reported to have a role in autoimmunity and malignancy, but its function in these contexts is less well established. IgG4-RD has a wide range of manifestations that are unified by their histopathologic findings and response to treatment.

Most patients are middle-aged to older men, but the disorder can affect people of any age and sex.

Pathophysiology

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, parotid glands, submandibular glands, lungs, kidneys, retroperitoneal tissues, aorta, meninges, and the thyroid gland.

Most patients have multiorgan involvement at the time of diagnosis but tend to have one dominant phenotype. A 2019 study (1) identified approximately equal proportions of the following clinical phenotypes.

Pancreato-hepato-biliary disease

Pancreatic involvement commonly manifests as autoimmune pancreatitis (type 1, IgG4-related) and may take the form of

  • An obstructive pancreatic mass, with painless jaundice and diffuse pancreatic enlargement

  • Acute pancreatitis with abdominal pain and nausea

  • Smoldering and insidious chronic pancreatitis with exocrine pancreatic insufficiency and/or overt diabetes mellitus

IgG4-related sclerosing cholangitis can occur, usually in patients who also have autoimmune pancreatitis. This combination is highly suggestive of IgG4-RD.

Retroperitoneal fibrosis and/or aortitis

IgG4-RD likely accounts for most cases of idiopathic retroperitoneal fibrosis. Fibrosis is usually circumferential around the aorta (periaortitis) or over only the anterolateral portion. Fibrosis may extend inferiorly to the iliac vessels. The main complication is ureteral compression causing hydronephrosis.

IgG4-RD can also cause noninfectious aortitis of either the thoracic or abdominal aorta, which is distinguished from retroperitoneal fibrosis by the presence of circumferential mural aortic wall thickening or enhancement on imaging studies. Aortitis is occasionally complicated by aortic aneurysm.

Head- and neck-limited disease

Major salivary (eg, parotid and/or submandibular) and lacrimal glands are commonly affected. Glands are painlessly enlarged bilaterally, but usually their function is not impaired. Elevated IgG4 levels and characteristic histopathology help differentiate IgG4-RD of these organs from conditions such as Sjögren syndrome and sarcoidosis.

The orbits can be affected. IgG4-RD accounts for about 25 to 50% of cases of inflammatory orbital disease (previously called orbital pseudotumor). IgG4-RD can also cause orbital myositis.

Classic Mikulicz syndrome with systemic involvement

IgG4-related Mikulicz syndrome is combined involvement of the lacrimal, parotid, and submandibular glands. When paired with an elevated serum IgG4 level, this presentation is essentially diagnostic of IgG4-RD.

Other phenotypes

Lungs and pleura may be involved, sometimes with hilar adenopathy and lung nodules that can resemble sarcoidosis. Histopathology is essential for distinguishing these disorders. Interstitial lung disease may occur and cause significant deterioration in pulmonary function, which is uncommon in patients without interstitial lung disease.

Renal involvement most often manifests as tubulointerstitial nephritis, usually as asymptomatic impairment of kidney function, sometimes requiring dialysis. Proteinuria, sometimes in the nephrotic range, may occur, reflecting an associated glomerulopathy, but cellular casts and/or hematuria are infrequent. Multiple renal masses and hypocomplementemia are usually present.

Many other tissues may be involved, including the skin, prostate, meninges, and sinuses. There is limited evidence of involvement of the brain, luminal gastrointestinal tract, spleen, bone marrow, or peripheral nerves.

Pathophysiology reference

  • Wallace ZS, Zhang Y, Perugino CA, et al: Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis 78(3):406-412, 2019. doi:10.1136/annrheumdis-2018-214603

Etiology

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 (1), and responsiveness to immunosuppression.

Etiology reference

  • Perugino CA, AlSalem SB, Mattoo H, et al: Identification of galectin-3 as an autoantigen in patients with IgG4-related disease. J Allergy Clin Immunol 143(2):736-745.e6, 2019. doi:10.1016/j.jaci.2018.05.011

Pathology

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. Most patients also have elevated serum IgG4 levels, but some have normal levels.

Pathology reference

Symptoms and Signs

Common general manifestations of IgG4-RD include lymphadenopathy and weight loss. Weight loss is particularly common when there is multiple organ involvement and/or 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 is present. Some patients 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. Aortitis is almost always asymptomatic and identified only incidentally by imaging or postoperatively after aortic resection.

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

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

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

Diagnosis

  • Biopsy

  • Serum IgG4 level

  • Serum complement levels (C3 and C4)

  • Selective imaging

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

Recently, classification criteria for IgG4-RD have been published (1), including 32 exclusion criteria, the presence of which should remove IgG4-RD from consideration. Although these criteria are not designed for diagnostic purposes, they do 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, is non-specific and must be paired with other findings to diagnose IgG4-RD.

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 only 60 to 70% of patients with IgG4-RD; elevations are not diagnostic and must be interpreted with caution. Chronic allergic conditions are a frequent cause of mild serum IgG4 elevation.

Other testing that may be helpful includes

  • Urinalysis, complete metabolic panel: Renal involvement

  • Serum amylase and lipase, hemoglobin A1c, stool elastase: Pancreatic involvement

  • Serum C3 and C4 complement levels: Low in IgG4-related tubulointerstitial nephritis

  • Total IgG and total IgE levels

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 auto-antibodies. 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; their relationship to the pathophysiology of IgG4-RD remains unknown although high total IgE level is an independent predictor of relapsing IgG4-RD (2).

Diagnosis references

  • Wallace ZS, Naden RP, Chari S, et al: The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol 72(1):7-19, 2020. doi:10.1002/art.41120

  • Wallace ZS, Mattoo H, Mahajan VS, et al: Predictors of disease relapse in IgG4-related disease following rituximabRheumatology (Oxford) 55(6):1000-1008, 2016. doi:10.1093/rheumatology/kev438

Prognosis

Like most immune-mediated conditions, there is no cure, but IgG4-RD is very treatable. Most of the organ damage in this disease happens prior to diagnosis.

Treatment

  • Corticosteroids

  • B cell targeted therapy with rituximab

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, this usually indicates irreversible fibrosis, which is common in patients with retroperitoneal fibrosis.

Initial treatment is with an oral corticosteroid (eg, prednisone 30 to 40 mg once daily), administered for 2 to 4 weeks 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 (1).

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

Treatment reference

Key Points

  • 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, major salivary glands, lungs, kidneys, retroperitoneal tissues, and aorta.

  • 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 rituximab.

Drugs Mentioned In This Article

Drug Name Select Trade
RAYOS
RITUXAN
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