IgG4-related autoimmune diseases: Polymorphous presentation complicates diagnosis and treatment

Abstract

Background: IgG4-associated autoimmune diseases are systemic diseases affecting multiple organs of the body. Autoimmune pancreatitis, with a prevalence of 2.2 per 100,000 people, is one such disease. Because these multi-organ diseases present in highly variable ways, they were long thought just to affect individual organ systems. This only underscores the importance of familiarity with these diseases for routine clinical practice.

Methods: This review is based on pertinent articles retrieved by a selective search in PubMed, and on the published conclusions of international consensus conferences.

Results: The current scientific understanding of this group of diseases is based largely on case reports and small case series; there have not been any randomized controlled trials (RCTs) to date. Any organ system can be affected, including (for example) the biliary pathways, salivary glands, kidneys, lymph nodes, thyroid gland, and blood vessels. Macroscopically, these diseases cause diffuse organ swelling and the formation of pseudotumorous masses. Histopathologically, they are characterized by a lymphoplasmacytic infiltrate with IgG4-positive plasma cells, which leads via an autoimmune mechanism to the typical histologic findings--storiform fibrosis ("storiform" = whorled, like a straw mat) and obliterative, i.e., vessel-occluding, phlebitis. A mixed Th1 and Th2 immune response seems to play an important role in pathogenesis, while the role of IgG4 antibodies, which are not pathogenic in themselves, is still unclear. Glucocorticoid treatment leads to remission in 98% of cases and is usually continued for 12 months as maintenance therapy. Most patients undergo remission even if untreated. Steroid-resistant disease can be treated with immune modulators.

Conclusion: IgG4-associated autoimmune diseases are becoming more common, but adequate, systematically obtained data are now available only from certain Asian countries. Interdisciplinary collaboration is a prerequisite to proper diagnosis and treatment. Treatment algorithms and RCTs are needed to point the way to organ-specific treatment in the future.

Figure 1

Diagnostic algorithm corresponding to the diagnostic criteria proposed by the Japanese study group for IgG4-related disease (modified from Okazaki et al. [10]) IgG4+: IgG4-positive HPF: high power field

Figure 2

Imaging in autoimmune pancreatitis (AIP): a) MRI shows a sausage-shaped, swollen pancreas with the main finding in the area of the body and tail. b) MRCP shows the AIP-typical variations in the caliber of the pancreatic duct without prestenotic dilatation and with a classic double duct sign, i.e., localized stenosis in both the bile duct and the pancreatic duct. MRI, magnetic resonance imaging; CHD, common hepatic duct; MRCP, magnetic resonance cholangiopancreatography

Figure 3

Scheme for treatment of IgG4-related disease according to the Japanese guidelines. The recommendations relate mainly to autoimmune pancreatitis, but can probably be applied to other forms of IgG4-related disease. BW, body weight

eFigure 1

Histopathological findings in type 1 autoimmune pancreatitis: a) hematoxylin–eosin (HE) staining. Inset: vascular involvement in the inflammatory process. b) Immunohistochemical evidence of IgG4-positive plasma cells

eFigure 2

Imaging in IgG4-related cholangitis (IAC): a) MR image of a stenosis close to the hilum with evidence of an inflammatory pseudotumor (arrows). b) Endoscopic ultrasound shows circular wall thickening with distal common hepatic duct stenosis