Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized fibroinflammatory disorder that can result in lesions in almost any organ, can involve multiple organ systems, and can lead to organ failure. Clinical presentation varies widely and depends on the organs involved (eg, pancreas, salivary and lacrimal glands, retroperitoneum, lymph nodes, lungs, kidneys, aorta). IgG4-RD is highly treatable, but irreversible damage can occur without treatment. An accurate diagnosis is important for timely intervention, but is often delayed and can be challenging because several diseases can “mimic” IgG4-RD. No single test can be used to diagnose IgG4-RD; instead, diagnosis depends on a combination of medical information, including history, physical findings, imaging, and laboratory results, supported by histopathology. Laboratory tests used in the workup for IgG4-RD include measurement of IgG4 serum level, autoantibody tests to rule out IgG4-RD mimickers, and tests to identify affected organs, in conjunction with immunostaining and histopathologic analysis.
Quick Answers for Clinicians
The clinical presentation of IgG4-related disease (IgG4-RD) varies greatly, but patients frequently present with a mass lesion that suggests malignancy, and symptoms specific to the affected site. The organs most often involved include the pancreas, biliary tract, salivary and lacrimal glands, retroperitoneum, and lymph nodes. Symptoms may range from swelling of involved organs to obstruction (eg, pancreaticobiliary) to organ dysfunction, and can be emergent. Patients may also suffer from nonspecific constitutional effects such as weight loss or fever, whereas other patients are asymptomatic but are found to have a mass lesion during imaging for another condition.
IgG4-related disease (IgG4-RD) was first identified when increased levels of serum IgG4 were discovered in connection with pancreatitis. Type 1 autoimmune pancreatitis, now understood to be associated with IgG4, is sometimes referred to as IgG4-related pancreatitis and is thought to be the most frequent manifestation of IgG4-RD.
Identification of affected organs is important in the evaluation of IgG4-related disease (IgG4-RD). Laboratory tests can be helpful to determine whether particular organs are involved; for example, tests for complement components (eg, complement 3 [C3] and complement 4 [C4]) can be used to help identify renal involvement. A CBC with differential can be used to detect eosinophilia (500-1,500 eosinophils/µL) or hypereosinophilia (>1,500 eosinophils/µL). Increased blood eosinophils suggest a greater risk of relapse following treatment. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) test findings commonly are abnormally increased. An increased ESR is more frequently found than an increased CRP in patients with IgG4-RD and occurs due to hypergammaglobulinemia, which is common in untreated IgG4-RD. This can present as a discordance, with a high ESR and low CRP.
Several diseases are considered IgG4-related disease (IgG4-RD) mimickers. These include Sjögren syndrome, sarcoidosis, and antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis (such as eosinophilic granulomatosis with polyangiitis), giant cell arteritis, lymphoma, infection, multicentric Castlemans disease, Erdheim-Chester disease, and inflammatory myofibroblastic tumor. Clinical features and laboratory testing can be used to distinguish between the diseases; for example, parotid gland involvement and positive anti-SSA (Ro) and anti-SSB (La) antibodies support a diagnosis of Sjögren syndrome, rather than IgG4-RD. Cutaneous disease, splenomegaly, and granulomas are features that can distinguish sarcoidosis from IgG4-RD.
Indications for Testing
Testing for IgG4-RD is appropriate in patients with:
- Possible autoimmune pancreatitis
- Clinical presentation suggestive of IgG4-RD (presentation depends on affected organs)
The IgG4 serum level test is frequently used for IgG4-RD and at one time was considered essential for diagnosis. Increased serum IgG4 levels can support the diagnosis of IgG4-RD in the appropriate clinical context, and the majority of patients (~70%) have increased concentrations. However, serum IgG4 concentrations are neither highly specific nor sensitive for IgG4-RD diagnosis. A range of diseases such as biliary tract, pancreatic, liver, and lung diseases also may be attended by increased serum IgG4. Serum IgG4 concentrations do correlate with the number of organs affected, and multiorgan involvement is associated with serum concentrations >3 times the upper limit of normal. Serum IgG subclass evaluation should be performed in conjunction with serum protein electrophoresis to rule out a monoclonal paraprotein.
Patients with IgG4-RD also may have increased levels of IgE. Some investigators suggest that the presence of both increased IgG4 and IgE in serum can help to differentiate between IgG4-RD and other diseases, such as Sjögren syndrome. Increased serum IgE, in conjunction with circulating eosinophils, indicates a heightened risk of relapse following treatment. Increases in other subclasses of IgG, particularly IgG1, also are found in patients with IgG4-RD.
Autoantibodies, other than those with known disease associations, have been reported in patients with IgG4-RD. Although their pathogenic role has not been clearly established, they suggest an autoreactive etiopathogenesis. Testing for autoantibodies may not be indicated for all patients being evaluated for IgG4-RD, but is useful when patient symptoms suggest other diseases that must be excluded during the workup for IgG4-RD, such as Sjögren syndrome or another connective tissue disease. Refer to the Connective Tissue Disease ARUP Consult topic for more information about autoantibody testing for these diseases.
Serum Test for Plasmablasts
IgG4-expressing plasmablasts are found in the blood of patients with IgG4-RD (testing not currently performed at ARUP Laboratories). The proportion of circulating plasmablasts correlates with disease activity and the number of affected organs, independent of IgG4 serum concentrations; however, this testing is not widely available and is not routinely used in clinical practice.
Histopathologic analysis is essential in diagnosis of IgG4-RD. Key histopathologic features associated with IgG4-RD include dense lymphoplasmacytic infiltrate, obliterative phlebitis, and/or fibrosis in a storiform pattern, at least focally; the presence of two or more of these features is significant for diagnosis.
The detection of IgG4-positive and IgG-positive plasma cells via immunohistochemical staining also is important for diagnosis. Interpretation generally takes into account both the number of IgG4-positive cells per high power field and the ratio of IgG4-positive to IgG-positive plasma cells. The diagnostic cutoff for plasma cell quantification depends on the organ affected, but a ratio of 40% IgG4-positive to IgG-positive plasma cells is considered confirmatory for IgG4-RD.
The clinical scenario must be considered in interpreting histopathologic and immunostaining results because diseases that mimic IgG4-RD (eg, vasculitis, inflammatory bowel disease, and lymphoma) may also demonstrate a pronounced infiltrate of IgG4-expressing plasma cells.
Refer to the ARUP Immunohistochemistry Stain Offerings brochure for additional information.
There is no standard monitoring protocol for IgG4-RD. Serum IgG4 concentrations will generally decrease in response to treatment, although levels may not become normal even with disease remission. Serum IgG4 levels may be useful to monitor patients for disease relapse, but relapse can occur in patients with low serum IgG4 concentrations.
During and after treatment, patients should be monitored for disease flares, which are not uncommon. Monitoring is also recommended for complications related to glucocorticoids, which are indicated for treatment in patients with IgG4-RD.
ARUP Lab Tests
Essential test for the pathologic diagnosis of IgG4-RD
Refer to the ARUP Immunohistochemistry Stain Offerings brochure for additional information
Diagnosis and monitoring
Often increased in patients with IgG4-RD; increased levels may predict relapse
May be increased in patients with IgG4-RD
May help to identify eosinophilia in patients with suspected IgG4-RD
Automated Cell Count/Differential
Monitor rheumatologic disease
May help to identify renal involvement in patients with IgG4-RD
Preferred test to detect acute phase inflammation (eg, autoimmune disease, including rheumatoid arthritis; granulomatous disease, including sarcoidosis; infection, including sepsis and pneumonia), which is increased in malignancies and in cases of tissue damage from insufficient blood supply
Nonspecific test used to detect inflammation associated with infections, cancers, and autoimmune diseases; also increased with hypergammaglobulinemia
A high erythrocyte sedimentation rate (ESR) with low C-reactive protein can help identify IgG4-RD
Available only to the University of Utah and its clients
Wallace ZS, Perugino C, Matza M, Deshpande V, Sharma A, Stone JH. Immunoglobulin G4-related Disease. Clin Chest Med. 2019;40(3):583–597.PubMed
Weindorf SC, Frederiksen JK. IgG4-Related Disease: A Reminder for Practicing Pathologists. Arch Pathol Lab Med. 2017;141(11):1476–1483.PubMed
Abraham M, Khosroshahi A. Diagnostic and treatment workup for IgG4-related disease. Expert Rev Clin Immunol. 2017;13(9):867–875.PubMed
Ther Clin Risk Manag201612189-99PubMed
Culver EL, Sadler R, Bateman AC, et al. Increases in IgE, Eosinophils, and Mast Cells Can be Used in Diagnosis and to Predict Relapse of IgG4-Related Disease. Clin Gastroenterol Hepatol. 2017;15(9):1444–1452.e6.PubMed
Chen LYC, Mattman A, Seidman MA, Carruthers MN. IgG4-related disease: what a hematologist needs to know. Haematologica. 2019;104(3):444–455.PubMed
Ryu JH, Horie R, Sekiguchi H, Peikert T, Yi ES. Spectrum of Disorders Associated with Elevated Serum IgG4 Levels Encountered in Clinical Practice. Int J Rheumatol. 2012;2012:232960.PubMed
Ann Rheum Dis2015741190-5PubMed
Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22(1):1–14.PubMed
Du H, Shi L, Chen P, et al. Prohibitin Is Involved in Patients with IgG4 Related Disease. PLoS One. 2015;10(5):e0125331. Published 2015 May 1.PubMed
Brito-Zerón P, Bosch X, Ramos-Casals M, Stone JH. IgG4-related disease: Advances in the diagnosis and treatment. Best Pract Res Clin Rheumatol. 2016;30(2):261–278.
Lin W, Zhang P, Chen H, et al. Circulating plasmablasts/plasma cells: a potential biomarker for IgG4-related disease. Arthritis Res Ther. 2017;19(1):25. Published 2017 Feb 10.
Shenoy A, Mohandas N, Gottlieb A. Cutaneous and systemic IgG4-related disease: a review for dermatologists. Dermatol Online J. 2019;25(6):13030/qt9w91m8dz. Published 2019 Jun 15.
Eur J Intern Med
Am J Surg Pathol