IgG4-related disease (IgG4 - RD)

Last edited 06/2020

IgG4-related disease (IgG4-RD) is a pathological entity that can affect any organ or system

• the majority of patients with IgG4-RD have an elevated serum IgG4 level (1)
• pathological hallmark of this disease is dense lymphoplasmacytic infiltrate with IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis, and a variable amount of eosinophils
• elevated levels of serum IgG4 is frequent.
• histological criteria are: diffuse lymphoplasmacytic infiltrate, numerous IgG4 positive plasma cells in the examined tissue, storiform fibrosis (resembling the spokes of a cartwheel), eosinophils in mild to moderate quantities, obliterative phlebitis, and pseudotumoral lesions that tend to form in the affected organs (2)
• although serum IgG4 level has been described to be the most sensitive and specific laboratory test for the diagnosis of IgG4-RD, it is recognized that an elevated serum IgG4 level can be encountered in other diseases such as pancreatic cancer, atopic diseases, and infection (3)
• known now that up to 30% of the patients with IgG4-RD may have a normal serum concentration despite the histopathological criteria supporting a positive diagnosis - serum IgG4 level is elevated in up to 5% of the normal population
• most patients are males over 50 years of age with a male/ female ratio of 3:1
• pathology is very specific and looks similar in all organs. Because of this finding, it is considered to be analogous to systemic sarcoidosis. IgG4-RD affected patients are often misdiagnosed as having a malignancy since the lesions can mimic tumors, infections, or immune-mediated diseases (4)
  
  
• Laboratory investigations:
• elevated serum IgG 4 levels of more than 1.4 g/L is seen in 70% to 80% of patients
• IgG4 elevation more than two times the upper limit of normal (normal 140 mg/dL) has 99% specificity for IgG4-RD
• elevated IgG4 levels are nonspecific: five percent of persons without the disease can have elevated levels as well as 10% of patients with pancreatic-biliary malignancy, infectious, and inflammatory disorders - multi-organ involvement has been associated with higher IgG4 concentration
• nrmal levels do not exclude the disease
• elevated total IgG and IgE, peripheral eosinophilia, ESR (Erythrocyte Sedimentation Rate), and CRP (C -reactive protein) have been reported but are nonspecific findings
• serum ANA (anti-nuclear antibody) titers are positive in almost 50% of cases and elevated RF (rheumatoid factor) in 20% of patients (4)
• hypocomplementemia also has been reported and can be related to immune complex detected in the kidneys and pancreas of patients with the disease (4)
  
  
• Clinical manifestations:
• Type 1 autoimmune pancreatitis (AIP) is associated with an increased serum IgG4 level and it was the first disease included in the broad spectrum of IgG4- related disease
• the assumption that IgG4-RD is a multisystemic disease was raised from the fact that patients with autoimmune pancreatitis also express extrapancreatic manifestations
• fundamentally, IgG4-RD can affect any organ: the pancreas, bile ducts, eyes, salivary glands, lungs, heart, kidneys, skin, aorta, ganglia, meninges, prostate, breast, thyroid, retroperitoneal tissue, etc.

Management:

• patients usually have a good recovery after being treated with systemic glucocorticosteroids - response to steroids is so dramatic that it is has been suggested as one diagnostic criterion for the disease

Reference:

• Trampert DC et al. On the role of IgG4 in inflammatory conditions: lessons for IgG4-related disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2018; 1864 (4):1401-1409
• Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y et al. Consensus statement on the pathology of IgG4-related disease. Mod. Pathol. 2012;25:1181–92.
• Ryu JH et al. Spectrum of Disorders Associated with Elevated Serum IgG4 Levels Encountered in Clinical Practice.International Journal of Rheumatology Volume 2012, ID 232960, doi:10.1155/2012/232960.
• Stone JH, Zen Y, Deshpande V. IgG4-related disease. N. Engl. J. Med. 2012 Feb 09;366(6):539-51
• Nambiar S, Oliver TI. IgG4 Related Disease (IgG4-RD). StatPearls [Internet] June 2019.