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IgG4-related diseases

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Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fascinating condition recognised as a systemic disease in 2003 *[1], [2]. The first link between autoimmunity affecting the pancreas, elevated serum IgG4 concentrations and large numbers of IgG4-positive plasma cells in pancreatic tissue was described only 2 years earlier [3]. Since then, many diseases that have long been viewed organ-specific are now considered within the spectrum of IgG4-RD. Practically any organ can be affected, having in common a key pathological feature consisting in dense lymphocyte and plasma cell infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and often an elevated serum IgG4 concentration. While good clinical response to steroid therapy is observed, immunosuppressive or B-cell depleting therapy can be required. It is important to distinguish the IgG4-RD from traditional organ-specific autoimmune disease to guide therapy.

Section snippets

What we know about immunoglobulin G4

Many terms have been used to describe immunoglobulin G4 related disease (IgG4-RD), including IgG4-related sclerosing disease, IgG4-related autoimmune disease, systemic IgG4 plasmacytic syndrome (SIPS), IgG4-related multiorgan lymphoproliferative syndrome (IgG4-MOLPS) and IgG4-associated multifocal systemic fibrosis [4]. IgG4 is the common factor of all these names, although its contribution as a specific pathogenic molecule is uncertain (reviewed in Refs. [5], [6], [7], *[8], *[9]). IgG4 has

Epidemiology of the IgG4-RD

IgG4-RD affects mostly middle-aged and elderly men. This marked male predominance, with the possible exception of those patients with predominantly head and neck involvement, in whom the male and female ratio is balanced, contrasts with other autoimmune diseases that mimic IgG4-RD such as Sjögren's syndrome (SS) and primary biliary cirrhosis (PBC), which have female predominance [4].

Few data exist on the incidence and prevalence of IgG4-RD. Many medical conditions that have long been viewed as

Clinical manifestations of the IgG4-RD

IgG4-RD can affect almost any organ, and its symptoms are referable to involvement of the specific target organ, often in the form of mass lesion *[4], *[12], *[13]. IgG4-RD usually presents subacutely, and most patients do not have constitutional symptoms. The condition usually comes to clinical attention due to organ swelling or damage. The disorder is also often identified incidentally through radiographic findings or unexpectedly in pathological specimens. However, sometimes IgG4-RD causes

What we know about IgG4-RD histopathology

The key morphologic features of IgG4-RD are dense lymphoplasmacytic infiltrates that are organised in a storiform pattern, obliterative phlebitis and a mild-to-moderate eosinophil infiltrate *[13], [16], *[58]. These features are modified by the microanatomy of the particular site involved and perhaps by the age of the lesion. The combination of histopathological features and immunohistochemical stain results can provide strong supportive evidence for the diagnosis of IgG4-RD. Specific criteria

Diagnostic criteria for IgG4-RD

Diagnostic criteria for IgG4-related MD, [30], IgG4-related pancreatitis [59] and IgG4-related kidney disease [60] have been established. Also, a guideline for diagnosis of IgG4-RD was recently published [4] (Table 4). However, these organ-specific criteria are not suitable for the diagnosis of patients with involvement of other organ. Recently, two IgG4-RD Japanese groups established comprehensive diagnostic criteria for IgG4-RD [61].

Diagnostic criteria for IgG4-RD are as follows:

  • a)

    Clinical

Laboratory evaluation

As initially observed in patients with autoimmune pancreatitis, the majority of patients with IgG4-RD have an elevated serum IgG4 level, although approximately 30% of patients have normal serum IgG4 concentrations, despite classic histopathological and immunohistochemical findings [62]. Although serum IgG4 level has been described to be the most sensitive and specific laboratory test for the diagnosis of IgG4-RD, an elevated serum IgG4 level can be encountered in other diseases such as

Treatment of IgG4-RD

There have been no randomised controlled studies for treatment of either IgG4-RD or IgG4-related pancreatitis. In addition, except for case reports, there are virtually few case reports on the treatment of extrapancreatic IgG4-RD and most series have limited follow-up.

Spontaneous improvement of uncertain duration occurs in a significant number of patients with IgG4-related pancreatitis [69], [70]. These IgG4-related pancreatitis patients had relatively low serum IgG4 concentrations at baseline,

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