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IgG4-Related Diseases

                                

========== Summary =============

  • A distinctive group of fibroinflammatory diseases
  • May occurs in virtually any organ
  • Mass-forming fibroproliferation
  • Inflammation rich in IgG4+ plasma cells (or increased IgG4:IgG ratio)
  • Lymphoplasmacytic Phlebitis
  • Often high level of serum IgG4
  • Prompt response to steroid therapy
  • Prominent members include:
  • Autoimmune pancreatitis
  • Autoimmune hepatitis
  • IgG4-associated cholangitis
  • Idiopathic sclerosing retroperitoneal fibrosis 


       IgG4-related disease, also known as IgG4-associated systemic sclerosing disease, is a group of distinct clinical entity.  They are characterized by a constellation of marked elevation of serum level of IgG4, infiltration of involved tissue by IgG4-positive plasma cells, various mass-forming fibroinflammatory changes developing in a temporal and spatial manner, and the prompt resolution in response to corticosteroids. 

       At an international symposium on IgG4-related disease in October 2011, the expert panel reached the consensus on the definition, terminology and diagnostic criteria for IgG4-related diseases. Histologically, storiform fibrosclerosing change, increased numbers of tissue IgG4+ plasma cells (or an increased IgG4:IgG ratio) and lymphoplasmacytic phlebitis are considered three key findings in all IgG4-related disease. It is important to remember that variably high numbers of IgG4-positive plasma cells are found in diverse non-specific inflammatory conditions, indicating that high IgG4-positive plasma cell counts and high IgG4 : IgG ratios per se do not reliably distinguish IgG4-associated systemic disease from non-specific conditions.  Therefore, IgG4 counts must be cautiously interpreted in the context of appropriate clinical and histopathologic features.

       IgG4-related diseases affect predominantly middle-aged and elderly patients, with male predominance.  IgG4-related disease has been reported in a wide variety of organs or tissue types. Regardless of the anatomic site, the histological changes are strikingly similar. Notable members of this disease include autoimmune chronic pancreatitis, sclerosing cholangitis and retroperitoneal fibrosis. They are outlined in this podcast. In addition, Riedel's thyroiditis, fibrotic pseudotumor of the orbit and fibrosis of the salivary glands have all been reported to be part of this disease spectrum.

Autoimmune pancreatitis: Autoimmune pancreatitis is a unique form of chronic pancreatitis characterized by a high serum IgG4 concentration and various extrapancreatic manifestations.  Mayor Clinic group propose that diagnosis of autoimmune pancreatitis can be made with one or more of the following criteria: (1) diagnostic histology, (2) characteristic imaging on computed tomography and pancreatography with elevated serum IgG4 level, or (3) response to steroid therapy of pancreatic or extrapancreatic manifestations of autoimmune pancreatitis. 

IgG4-associated cholangitis: IgG4-associated cholangitis is a steroid-responsive hepatobiliary inflammatory condition associated with autoimmune pancreatitis that clinically and radiologically mimics primary sclerosing cholangitis.  On a liver biopsy, the histological features of IgG4-associated cholangitis may be distinctive, and in conjunction with IgG4 immunohistochemical stain, may help distinguish this disease from primary sclerosing cholangitis (i.e. PSC).  Identification of coexistence of autoimmune pancreatitis is reportedly the most useful finding.  

Autoimmune hepatitis: Autoimmune hepatitis may be classified into either an IgG4-associated type or an IgG4 non-associated type with the former showing a marked response to prednisolone treatment. Many cases of serum autoantiboy-negative but with histologic features of autoimmune hepatitis that respond to steroid treatment well may be IgG4 related.

Tubulointerstitial nephritis: Tubulointerstitial nephritis is typically characterized by a mass-like lesion consisting of a lymphoplasmacytic infiltrate with eosinophils and prominent IgG4-positive plasma cells and immune-complex deposits in the tubular basement membrane, may be part of a systemic IgG4-related disease.

Idiopathic sclerosing retroperitoneal fibrosis: Idiopathic sclerosing retroperitoneal fibrosis is also found to exist in IgG4-associated and non-IgG4-associated group. The only tests that reliably distinguish the 2 groups were serum IgG4 levels or IgG4 to IgG ratio in the plasma cells in a tissue biopsy. The only major clinical difference was the striking male predominance in IgG4-related group.  Steroid therapy was effective irrespective of IgG4.

Reference / Suggested Readings

J. H. Stone et al.: IgG4-Related Disease.  N Engl J Med  366:539-551, 2012.

J. H. Ryu et al.: Spectrum of Disorders Associated with Elevated Serum IgG4 Levels Encountered in Clinical Practice. Intl J Rheum vol. 2012, Article ID 232960, 6 pages, 2012.

V. Deshpande et al.: Consensus statement on the pathology of IgG4-related disease. Modern Pathol. 25 (9):1181–1192, 2012.

W. Cheuk & J.K.C. Chan: Advances in anatomic pathology. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol. 17(5):303-32, 2010.

T.C. Smyrk: Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol. 23(1):74-9, 2011.