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1 Introductory Remarks

IgG4-related disease (IgG4-RD) is a new disease concept first recognized in the twenty-first century [1, 2]. The condition is characterized by elevated serum IgG4 values and marked IgG4-positive plasma cell infiltration of affected lesions [1, 2]. The initial clue to its detection was contributed by Hamano et al. [3], who reported elevated serum IgG4 concentrations in patients with sclerosing pancreatitis. Following this observation, many additional reports on this disease, pertaining to clinical, pathology, radiological, and therapeutic aspects, have been supplied by investigators from Japan and beyond. IgG4-RD now attracts worldwide attention, and the formulation of a carefully considered disease concept and diagnostic criteria are both awaited eagerly.

Under the auspices of the Japanese Ministry of Health, Labor and Welfare, two research groups focusing on IgG4-RD have been organized. One is a group for research on the new disease entity of IgG4-related multiorgan lymphoproliferative syndrome (IgG4+MOLPS) (group leader: Hisanori Umehara, Department of Hematology & Immunology, Kanazawa Medical University, 66 members). The other is charged with establishing diagnostic and therapeutic approaches for IgG4-related systemic sclerosing diseases (group leader: Kazuichi Okazaki, Third Depatment of Internal Medicine, Kansai Medical University; 55 members).

Because IgG4-RD is a disease process that afflicts multiple organs, both groups are comprised of a versatile membership with representation of specialists from various clinical fields, pathologists, and basic investigators. These two cooperative groups have accomplished much in the field to date, including the achievement of a broad consensus on the disease name (IgG4-RD) and publication of a comprehensive set of diagnostic criteria. In this chapter, we outline these comprehensive diagnostic criteria for IgG4-RD [4].

2 Comprehensive Diagnostic Criteria for IgG4-RD

The establishment of diagnostic criteria for IgG4-RD was complicated by the fact that IgG4-RD is a truly multifaceted disorder that encompasses many conditions once considered to be separate but now recognized to overlap broadly. These conditions include autoimmune pancreatitis [5–8], Mikulicz’s disease [9, 10], Riedel’s thyroiditis [11], Küttner’s tumor [11, 12], retroperitoneal fibrosis [13, 14], inflammatory pseudotumor [15], interstitial nephritis [16, 17], interstitial pneumonia [18, 19], and others [1] (Fig. 6.1). In addition, accurate pathology characterization is essential to the diagnosis, as IgG4-RD is often difficult to differentiate from immune-mediated conditions such as Sjögren’s syndrome and granulomatosis with angiitis (formerly Wegener’s) and from hematological conditions such as Castleman’s disease and malignant lymphoma. These facts posed daunting challenges to the formulation of diagnostic criteria that are applicable potentially to all cases.

Fig. 6.1
figure 1

IgG4-related disease (IgG4RD)

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In approaching the task, an “All Japan IgG4 Team” comprised of representatives from both the Umehara and Okazaki groups was created to draft diagnostic criteria. The aims of this effort included:

  1. 1.

    Formulating criteria that would be useful not only to specialist clinicians devoted to the study of their respective organs but also to nonspecialist clinicians

  2. 2.

    Devising diagnostic criteria that would be consistent for all organs

  3. 3.

    Succinctness

  4. 4.

    Sufficient emphasis on the need to exclude malignancy

  5. 5.

    Rationale for not recommending trials of glucocorticoid therapy for diagnostic purposes in possible IgG4-RD

We therefore proposed the first “comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011,” attempting to encompass these concepts (Table 6.1) [4].

Table 6.1 Comprehensive diagnostic criteria for IgG4-related disease, 2011 [4]
Full size table

These criteria are comprised of three major items:

  1. 1.

    Single or multiple organs involved by diffuse or localized swelling, masses, nodules, and/or hypertrophic lesions

  2. 2.

    Elevated serum IgG4 levels(≥135 mg/dL)

  3. 3.

    Histopathological features that include

    • marked lymphocytic and plasma cell infiltration and fibrosis,

    • IgG4-positive plasma cell infiltration: IgG4/IgG-positive cell ratio ≥40 % and IgG4-positive plasma cells exceed 10/HPF

Patients can be classified into categories of definite, probable, or possible IgG4-RD, depending on how many of these diagnostic items are present.

The evaluation and diagnosis of patients with possible IgG4-RD requires the punctilious assessment of lesions in multiple organs, the interpretation of blood test findings, review of the pathology features (histopathology and immunostaining) and diagnostic imaging findings, judgment of the responsiveness to glucocorticoids, and exclusion of a lengthy list of potential mimickers (Table 6.1).

A variety of clues can be present in the blood. An elevated IgG4/IgG ratio (>8 %) in the blood may aid in the diagnosis in some cases even if the serum IgG4 concentration is <135 mg/dL, as is often the case – particularly in patients with single-organ disease. Patients with IgG4-RD typically demonstrate a polyclonal hypergammaglobulinemia with elevations of the total IgG concentration – IgG1 as well as IgG4 – though the IgG4 elevation is more impressive. The serum IgE concentration is also often elevated, and despite the putatively limited ability of IgG4 to fix complement and form immune complexes, hypocomplementemia is sometimes present, especially in those patients with renal disease.

The true role of IgG4 in the etiology and pathophysiology of IgG4 remains obscure. Elevations in serum IgG4 concentrations are by no means specific for IgG4-RD because the serum values can be elevated in a host of other diseases, as well, e.g., atopic dermatitis, pemphigus, bronchial asthma, and multicentric Castleman’s disease. Increased serum IgG4 values are also reported in some patients with malignant tumors. The likelihood of pancreatic cancer, however, is low when IgG4 values are less than twice the upper limit of normal.

Histopathology is the key to the diagnosis of IgG4-RD. Characteristic histopathological findings include a swirling, “storiform” fibrosis and obliterative phlebitis. Neutrophilic infiltrates are not typical but can be observed occasionally in some organs such as the lung, where the biopsy may be taken from tissue bordering on mucosal surfaces.

Pancreatic cancer and other malignancies are sometimes associated with a reactive IgG4-positive plasma cell infiltration and fibrosis in the peritumoral tissues. These findings represent a nonspecific, reactive phenomenon. High on the differential diagnosis of IgG4-RD, though, is malignancy, and thus it is essential to exclude malignant cells by careful histopathological evaluation and special marker studies as appropriate.

Nonmalignant conditions can also bear strong resemblance to IgG4-RD. These include Sjögren’s syndrome, primary sclerosing cholangitis, multicentric Castleman’s disease [20], idiopathic retroperitoneal fibrosis, granulomatosis with polyangiitis (formerly Wegener’s), sarcoidosis, and the Churg–Strauss syndrome [21]. Multicentric Castleman’s disease occasionally manifests elevated serum IgG4 concentrations and IgG4-positive cell proliferation in tissues and can be difficult to distinguish from IgG4-RD. However, multicentric Castleman’s disease is recognized to be a different disease.

Responses to glucocorticoids can be useful but imperfect indicators of IgG4-RD in cases in which it may be difficult to obtain diagnostic tissue, e.g., the pancreas, retroperitoneum, and pituitary gland. However, lymphoma and paraneoplastic lesions can also improve following glucocorticoid therapy, and so empiric steroid trials must not be undertaken lightly. For this reason, the response to glucocorticoid administration for diagnostic purposes has not been adopted in comprehensive diagnostic criteria for IgG4-RD, and the greatest possible effort must be made to obtain tissue samples to permit a histopathological diagnosis.

3 Algorithm for IgG4-RD Diagnosis

The diagnostic sensitivity of the comprehensive diagnostic criteria outlined above is not known for patients with lesions that are difficult to biopsy. To compensate for these limitations when applying these criteria in clinical practice, the use of detailed IgG4-RD organ-specific diagnostic criteria is helpful (Fig. 6.2). Diagnostic criteria for IgG4-related Mikulicz’s disease and type 1 (IgG4-related) autoimmune pancreatitis have already been announced [22, 23]. Diagnostic criteria for IgG4-related kidney disease have also been created in collaboration with the Japan Kidney Society [24].

Fig. 6.2
figure 2

Comprehensive diagnostic criteria for IgG4-RD

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4 Concluding Remarks

Researchers in a variety of different fields from across the world have contributed to the acquisition and distribution of knowledge regarding IgG4-RD. With enhanced recognition of this entity, interest in IgG4-RD continues to grow. An IgG4-RD International Symposium was held in the context of the 20th Annual Meeting of the Japanese Society for Sjögren’s syndrome (September 2011, Kanazawa, Japan), and an International Symposium for IgG4-RD was also held in the United States (October 2011, Boston). International consensus about nomenclature in each organ and pathology of IgG4-RD has been reached [25, 26]. As a next step, we must aim for broader recognition of IgG4-RD in daily clinical practice and promote the participation of larger numbers of physicians and other researchers in the investigation of this field.