The most characteristic biological finding associated with the disease is serum IgG4 elevation over 1.35 g/L (or 135 mg/dL). However, this elevation is neither specific for the diagnosis of IgG4-RD nor particularly sensitive [20, 21], as false negatives are observed in a range of 20–50 % of cases [13, 15]. There is no evidence at this time that IgG4 is by itself pathogenic. This is also based on previous works showing that IgG4 is not able to activate complement [22] and has a so-called antiinflammatory activity related to a dynamic process known as “Fab arm exchange” [23].

Besides serum IgG4 elevation, an increase in other IgG subclasses is frequent [13, 24] and also contributes to the hypergammaglobulinemia observed in these patients. Abnormal k/λ ratios have also been reported [25]. IgE elevation is usual, probably resulting from the associated Th2 response, as is eosinophilia (Table 4.2). Eosinophilia is frequent with possible values over 1500 eosinophils/μL [13]. Antinuclear antibodies can be found at low titers, but usually anti-extractable nuclear antigen antibodies (and especially anti-SSA and anti-SSB) are negative. In most cases, the C-reactive protein level is normal or only moderately elevated. More recently, it has been proposed that total circulating and IgG4⁺-plasmablast counts could be specifically increased and correlate with disease activity [26, 27].

Radiological evaluation depends on clinical presentation and varies according to the affected organs [28]. Diffuse or patchy mass-forming lesions can develop in the involved organs with pseudotumoral presentation. Specific radiological abnormalities in pancreas and pancreatic ducts in IgG4-related pancreatitis and in bile ducts in IgG4-related cholangitis have been retained as diagnostic criteria for organ-specific forms [29, 30], and will be discussed in detail in Chap. 6 of this book.

For systemic and whole-body evaluation of the disease, ¹⁸F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET-CT) has been reported to be a useful tool [31, 32], especially for affected sites such as aorta/large arteries, salivary glands, and lymph nodes, with more sensitivity than conventional imaging studies for these organ lesions (Fig. 4.2). It has been suggested that this imaging modality can be useful not only for the initial disease evaluation but also during follow-up to assess response to treatment and detect relapses [31, 32]. Nevertheless, the utility of serial FDG PET-CT has not been clearly demonstrated, and the radiological follow-up must be tailored on patients’ specific clinical features [28].

The diagnosis or classification of IgG4-RD is currently based on the pathological consensus criteria [11] and general Comprehensive Diagnostic Criteria (CDC) [9]. These last criteria, based on clinical, biochemical (serum IgG4 > 1.35 g/L), and histological findings have been proposed by the Japanese IgG4 team. They include: (1) organ involvement (dysfunction, diffuse, or localized swelling); (2) serum IgG4 > 135 mg/dL; and (3) histopathological findings characteristic of IgG4-RD (e.g., lymphoplasmacytic infiltrates, storiform fibrosis, obliterative phlebitis), with immunohistochemical evidence of a high proportion of IgG4⁺ plasma cells (>40 % of total IgG⁺ plasma cells, > 10 IgG4⁺ plasma cells per hpf). If all three criteria are met, the diagnosis is considered to be definite; if 1 + 3 are met, the diagnosis is probable; finally, fulfillment of 1 + 2 makes the diagnosis of IgG4-RD possible. These criteria have been designed because former organ-specific criteria for type 1 autoimmune pancreatitis [29], IgG4-related dacryoadenitis/sialadenitis [33], and IgG4-related kidney disease [34] were unable to classify all patients with characteristic pathological findings of the disease. Pathological characteristics have been defined by a consensus of experts [11] (See Chap. 3 of this book).

It was also pointed out that several benign and malignant diseases should be systematically ruled out before a diagnosis of IgG4-RD can be made. Because serum IgG4 evaluation is associated with false negative and false positive results [20, 21], pathological documentation is highly recommended. Major differential diagnoses include: Sjögren syndrome, lymphoma and solid tumors, primary sclerosing cholangitis, ANCA-associated vasculitis, idiopathic and secondary retroperitoneal fibrosis, myofibroblastic tumors, Castleman disease, and sarcoidosis.

Currently, major unanswered questions regarding IgG4-RD definition and classification are: (1) the specificity and the weight of pathological changes and clinical/imaging of organ involvement; and (2) the nosological boundaries with other idiopathic fibroinflammatory disorders. Future collaborative classification criteria should improve these points.

The overlap with other fibroinflammatory diseases is a matter of debate. Because the pathogenesis of IgG4-RD and other idiopathic fibroinflammatory diseases is largely unknown, the nosological limit is unclear. Is the IgG4-RD pathological pattern unique to some fibroinflammatory IgG4-RD diseases or a pathological step for several yet unrelated fibroinflammatory disorders? For example, based on retrospective pathological analysis of case series, the frequency of IgG4-RD retroperitoneal fibrosis ranges between 28 % [35] and 57 % [36]. In idiopathic retractile mesenteritis, Akram et al. found that only 30 % of cases presented typical pathological findings of IgG4-RD [37]. Other retrospective studies on pathological specimens of aortitis [38] and pachymeningitis [39] have also evaluated the frequency of typical histological IgG4-RD criteria to clarify the overlap with these inflammatory diseases. For Hashimoto’s thyroiditis there are controversial reports. Some case series reported that the fibrosing variant of Hashimoto’s thyroiditis is an IgG4-RD based on pathological findings [40]. An increase in tissue IgG4⁺ plasmocytes has been reported by several studies, but the exact overlap between IgG4-related thyroiditis and Hashimoto’s thyroiditis needs to be further analyzed (see Chap. 7 of this textbook) [41].

Overlap with Rosai-Dorfman disease has also been investigated because numerous IgG4⁺ plasmocytes can be observed in nodal and extranodal disease lesions, with variable degrees of fibrosis. It has been shown that some patients with Rosai-Dorfman disease harbor pathological characteristics of IgG4-RD, but large pathological series reported that the disease does not belong to IgG4-RD [42]. Likewise, differential diagnosis between IgG4-related lymphadenopathy and multicentric Castleman disease can be difficult, because of common histopathological characteristics and possible numerous IgG4⁺ plasma cells in Castleman lymphadenopathy [43].

For these reasons, both characteristic pathological and clinical/imaging assessment are important for the diagnosis of IgG4-RD. Pathological assessment of the diseased lymph nodes can be challenging.

Most data concerning the evolution and treatment of IgG4-RD come from studies performed in (IgG4-related) type 1 autoimmune pancreatitis [44–46]. Nevertheless, further data have been published these last years, based on cohorts of patients with various types of organ involvement [13, 14, 16, 18, 19, 24]. An international consensus paper on IgG4-RD management has recently been published by a multidisciplinary team of experts [28].

Favorable evolution and spontaneous regression without treatment have been described [47, 48]. Whether IgG4-RD always needs to be treated remains questionable. However, fibrosis is associated with the risk of organ dysfunction. This has been shown for salivary glands [49], for pancreas with exocrine and endocrine insufficiency [50], and for the kidneys. Moreover, severe and sometimes life-threatening evolution is possible especially in case of aortitis [51], kidney involvement [52], or meningitis [39]. For these reasons, treatment is usually required in these patients. A “wait and see” attitude can be considered in some peculiar situations: isolated and asymptomatic lymphadenopathy or mild salivary gland involvement.

First-line treatment is represented by corticosteroids. In type 1 AIP, it has been shown that remission was obtained more frequently and more rapidly with steroids than without steroids [50]. Response to steroids is usually excellent, and has been included as a diagnostic criterion of some organ involvements [29, 30, 34]. In different series, depending on the proportion of organ-limited versus systemic disease, steroids therapy induced remission in 82–100 % of patients (Table 4.3).