IgG4-related disease: nomenclature, clinical features, and treatment

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Concepts about IgG4-related disease (IgG4-RD) are now emerging swiftly. The condition has been identified in virtually every organ system, and its features are often excellent mimickers of malignancies, infections, and other immune-mediated disorders. Recommendations for nomenclature were proposed by the Organizing Committee of the 2011 International IgG4-related disease Symposium, and guidelines for the pathologic diagnosis of this condition have been published by an international group of experts. Experience with treatment regimens is growing. Glucocorticoids and B-cell depletion strategies both appear to be effective and are the subject of ongoing studies. This article reviews the current thought and understanding of this disease with regard to nomenclature, organ system involvement, and approaches to therapy.

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Nomenclature

Names for this disorder proliferated as awareness expanded of a systemic condition associated with elevated serum IgG4 concentrations and the infiltration of IgG4-positive plasma cells. Table 1 shows a partial list of names used in the medical literature to describe this entity to date. In 2011, Japanese investigators agreed that “IgG4-related disease” is the most appropriate name for this condition, given the current state of knowledge.25 This decision was supported by the organizing committee

Unification of historic disease terms and replacement of some eponyms

Many medical conditions, long viewed as unique organ-specific conditions, are actually part of the IgG4-RD spectrum. Several eponymic conditions, some of which were first recognized in the 1800s, are now identified as part of the IgG4-RD spectrum (Table 3). These eponyms have often been applied imprecisely, leading to confusion and uncertainty about the precise clinical syndromes to which they refer. In the interest of greater clarity in the medical literature, these eponyms should be replaced

Serum IgG4 concentrations

Elevated serum concentrations of IgG4, which are helpful in suggesting IgG4-RD, are neither necessary nor sufficient for the diagnosis. Patients with IgG4-RD may have polyclonal elevations of serum IgG4 concentrations approximately 25 times the upper limit of normal or even higher27 but a significant minority of patient with this disease—at least 20% but as high as 40% in some series—have normal serum concentrations of IgG4, despite classic histopathology within involved organs.28, 29 Serum

Systemic features

Patients with IgG4-RD have a predilection for forming mass lesions within organs. The pseudotumors that frequently lead to clinical presentation are often misdiagnosed as malignancies. Pseudotumors are reported commonly in the orbital region, salivary glands, lung, kidney, lymph nodes, retroperitoneum, and other organs.1, 2, 17 Many have an indolent course, but local tissue destruction including the erosion of bone has been reported (S. Narain et al, unpublished data).33, 34 IgG4-RD also has

Salivary glands

IgG4-related sialadenitis is most likely to occur in the submandibular gland (Figure), often to the exclusion of the parotids. In contrast, the opposite pattern of salivary gland involvement is more likely in Sjögren syndrome (SjS). In fact, submandibular gland enlargement in the absence of parotid gland enlargement seldom (if ever) occurs in SjS.36 However, involvement of the parotid glands has also been described in IgG4-RD (Figure 2), and this involvement may be striking. Salivary gland

Treatment

Glucocorticoids are the first-line treatment for IgG4-RD. Many cases require aggressive and immediate treatment to prevent organ dysfunction and failure. For example, the IgG4-related sclerosing cholangitis can lead to end-stage liver disease within several months and therefore requires treatment urgently. Aortitis, pachymeningitis, and certain orbital pseudotumors also demand therapy on an urgent basis. However, other disease manifestations, for example, IgG4-related lymphadenopathy, are more

Conclusions

There still remain many unknowns about the clinicopathological definition and etiology of IgG4-RD. As our understanding continues to grow about the systemic nature of this condition, more organs are found to be involved. Ongoing clinical and immunologic investigations into the nature of IgG4-RD should provide more information about the immunopathogenesis and clinical course of the disease.

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