Diagnosis and differential diagnosis of IgG4-related disease

INTRODUCTION — Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that is capable of affecting multiple organs [1-3]. Common forms of presentation include:

●Type 1 (IgG4-related) autoimmune pancreatitis (AIP).

●Sclerosing cholangitis – IgG4-related sclerosing cholangitis typically occurs together with type 1 AIP; it is distinct from primary sclerosing cholangitis in histology, treatment, and prognosis.

●Salivary gland disease – Salivary gland involvement can present as major salivary gland enlargement or as sclerosing sialadenitis. The lacrimal gland, parotid gland, and submandibular gland are all affected commonly together in different combinations. The combination of lacrimal, parotid, and submandibular gland enlargement is termed "IgG4-related Mikulicz disease."

●Orbital disease – Orbital disease is often complicated by proptosis because of involvement of the extraocular muscles or the presence of an orbital pseudotumor.

●Retroperitoneal fibrosis – Retroperitoneal fibrosis (RPF) frequently occurs in the larger context of chronic periaortitis and can often affect the ureters, leading to hydronephrosis and renal injury.

The involved organs share a number of core pathologic features and striking clinical and serologic similarities. Before its recognition as a unified disease in the early 2000s, the seemingly disparate manifestations had been presumed to be unrelated, single-organ disorders [4-6]. (See "Pathogenesis and clinical manifestations of IgG4-related disease".)

The diagnosis and differential diagnosis of IgG4-RD are presented here. The pathogenesis, clinical manifestations, and treatment of IgG4-RD are described separately. (See "Pathogenesis and clinical manifestations of IgG4-related disease" and "Treatment and prognosis of IgG4-related disease".)

Type 1 AIP (IgG4-related pancreatitis) and IgG4-related sclerosing cholangitis are also discussed in more detail elsewhere (see "Autoimmune pancreatitis: Clinical manifestations and diagnosis"), as are several of the other conditions associated with this disorder (see appropriate topic reviews).

DIAGNOSIS — The diagnosis of IgG4-related disease (IgG4-RD) is based upon the combination of characteristic histopathologic, clinical, serologic, and radiologic findings. The commonly shared features of this multiorgan disorder, which may present in a range of clinical patterns, include tumor-like swelling of involved organs, a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, and a variable degree of fibrosis that has a characteristic "storiform" pattern (picture 1). In addition, elevated serum concentrations of IgG4 are found in 60 to 70 percent of patients with IgG4-RD. (See "Pathogenesis and clinical manifestations of IgG4-related disease" and 'Diagnostic features' below and 'Diagnostic testing' below and 'Diagnostic criteria' below.)

Indications for diagnostic evaluation — The possibility of IgG4-RD should be suspected in patients with one of the characteristic patterns of organ or tissue involvement. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Overview of manifestations'.)

The major examples of patients at high risk for having IgG4-RD are those with any of the following:

●Pancreatitis of unknown origin

●Sclerosing cholangitis

●Bilateral salivary and/or lacrimal gland enlargement

●Retroperitoneal fibrosis (RPF)

●Orbital pseudotumor or proptosis

●Development of a mass lesion in any of the following organs: pancreas, biliary tree, orbits, lungs, kidneys, major salivary gland, or lacrimal gland

●Finding of a serum IgG4 concentration greater than five times the upper limit of normal

The likelihood of IgG4-RD for patients presenting with at least one of these conditions is significantly increased if the serum concentration of IgG4 is substantially elevated.

Diagnostic features — We strongly prefer confirmation of the diagnosis by biopsy of an involved organ whenever possible. Although histopathology findings are important to the diagnosis of IgG4-RD, such findings are never diagnostic alone of IgG4-RD. Pathology findings must always be interpreted in the context of clinical, serologic, and radiologic data. Confident diagnoses of IgG4-RD can only be made by considering data from these four realms of evidence and by the exclusion of potential mimickers. (See 'Differential diagnosis' below.)

Biopsies of involved organs frequently demonstrate characteristic histopathologic features and immunohistochemical staining. These findings include lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and lymphocytes, accompanied by fibrosis that has storiform features (image 1). Many biopsies also demonstrate obliterative phlebitis and modest tissue eosinophilia. The histopathologic and immunohistochemical staining features of IgG4-RD are strikingly similar in different tissues, regardless of the organ or tissue involved (see 'Diagnostic criteria' below). However, IgG4 lymphoplasmacytic infiltrates and even storiform fibrosis can also be observed in conditions mimicking IgG4-RD. Such conditions include a variety of malignancies, granulomatosis with polyangiitis (GPA; Churg-Strauss), Castleman disease, and other conditions [7]. Consequently, the diagnosis cannot be predicated entirely upon pathology findings, regardless of the intensity of IgG4-positive plasma cell infiltration.

Serum IgG4 levels should be measured and are a valuable adjunct to diagnosis. However, as with the number of IgG4-positive plasma cells in tissue, the concentration of IgG4 in serum can never be high enough to suffice by itself in establishing the diagnosis of IgG4-RD. Correlation with other data (clinical features, radiologic findings, and pathology results) is always required because serum IgG4 concentrations are neither sufficiently sensitive nor specific for IgG4-RD. Similarly, blood plasmablast concentration measurements, particularly those for IgG4+ plasmablasts, can be helpful but also have poor specificity and are not widely available. (See 'Diagnostic testing' below.)

Diagnostic testing — Certain tests are useful as part of the initial diagnostic evaluation. Laboratory tests that are helpful include IgG subclasses, IgE, and serum complement measurements. None of these tests alone has high diagnostic specificity, but the combination of elevations of serum IgG4, IgG1, and IgE in addition to hypocomplementemia of C3 and C4 should heighten concern for this diagnosis. The diagnosis of IgG4-RD requires the identification of characteristic findings upon biopsy of affected tissue, but additional organ involvement may be suspected based upon the comprehensive history and physical examination and the routine laboratory testing and imaging performed to make the diagnosis. Additional laboratory studies and selection of imaging depends upon the clinical findings and range of considerations in the differential diagnosis in a given patient. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Clinical manifestations' and 'Diagnosis' above and 'Differential diagnosis' below.)

The extent of disease should be established by further laboratory testing and selected imaging studies, even if the diagnosis has already been confirmed in one or more organs. As an example, if a patient has biopsy-confirmed disease in the lacrimal glands and extraocular muscles, it is still important to know if pulmonary, pancreatic, or renal disease is present. Cross-sectional imaging, particularly computed tomographic (CT) scanning, is helpful in this regard. (See "Treatment and prognosis of IgG4-related disease", section on 'Pretreatment evaluation'.)

We obtain the following testing for establishing the initial diagnosis:

●Tissue biopsy – The specific procedure depends upon which target organ will be biopsied and whether a discrete mass is present. A core needle biopsy is often adequate, but fine-needle aspirates do not provide adequate tissue [8,9]. In a study re-evaluating 72 biopsies from patients with IgG4-RD, it was found that surgical, compared with needle, biopsies displayed higher numbers of IgG4+ cells per high-power field (HPF) [10]. No statistically significant differences were seen in IgG4+/IgG+ cells ratio, in the frequency of storiform fibrosis, or in the frequency of obliterative phlebitis. We agree with the expert consensus that confirmation of the diagnosis by biopsy is important for the exclusion of malignancy and other disorders that may mimic IgG4-RD [7]. Following the identification of abnormal histopathology characteristic of IgG4-RD within one organ (and in the setting of clinical features compatible with the diagnosis of IgG4-RD), we generally do not perform additional biopsies of other organs. This is particularly true if the other ostensibly affected organs begin to improve with glucocorticoid treatment. (See 'Diagnostic criteria' below.)

The diagnosis of IgG4-RD should not be predicated only upon a lymph node biopsy. Many conditions can be associated with elevated numbers of IgG4-positive plasma cells in lymph nodes, and the specificity of this finding is poor. Although the authors do not recommend lymph node biopsy for establishing the diagnosis of IgG4-RD, such procedures are often performed and may be important for the exclusion other conditions (eg, lymphoma, sarcoidosis, and Castleman disease) (see 'Differential diagnosis' below). Biopsies of the intestinal tract also often have a high concentration of IgG4+ plasma cells. Because the gastrointestinal tract is seldom affected in IgG4-RD, biopsies from the gastrointestinal tract should not be relied upon to establish the diagnosis of IgG4-RD.

Staining of previously obtained tissues (eg, salivary glands) for IgG4 may provide useful information [7]. Even pathology samples archived for years in paraffin can still yield important diagnostic information. Review of previous biopsies and the performance of appropriate immunostains may obviate the need for a new biopsy.

●Serum IgG4 – Serum IgG4 levels should be measured, although elevated levels are not specific for IgG4-RD (see 'Differential diagnosis' below). Serum IgG4 levels are elevated (defined as >135 mg/dL, >121 mg/dL, or >86 mg/dL, depending upon the laboratory) in approximately two-thirds of the patients [8,11]. In addition, a sizeable minority of patients [12] have normal serum IgG4 concentrations even before treatment, despite the presence of the typical histopathologic changes in tissue [13].

The serum IgG4 level was elevated above the upper limit of normal in 86 percent of 114 patients in one study [9]. The degree of IgG4 elevation correlates imperfectly with the degree of disease activity, but is often a useful parameter to follow in individual patients – particularly if the serum IgG4 concentration is elevated substantially at baseline. The serum IgG4 concentration tends to increase with the number of organs involved and usually decreases after treatment with glucocorticoids [8,14].

The prozone effect may lead to underestimation of serum IgG4 levels and might explain some false-negative results in patients with definite diagnosis of IgG4-RD. With the prozone effect, the usual pattern observed is that a completely normal serum IgG4 concentration is reported despite the fact that the patient appears to have clinical features compatible with active IgG4-RD in multiple organs. In one study, 10 of 38 patients had falsely low serum IgG4 levels because of the prozone effect [15]. The prozone effect may be corrected by further dilution of the serum sample.

One study of serum IgG4 concentration measurements at a single institution over a 10-year period (2001 to 2011) reported the test characteristics for this assay [11]. During that time period, 190 unique patients had elevated serum IgG4 concentrations. The comparison population consisted of 190 other randomly selected patients with normal IgG4 concentrations. The study found the following:

•Sixty-five of the 72 patients with either definite or probable IgG4-RD had elevated serum IgG4 concentrations (mean: 405 mg/dL; range: 140 to 2000 mg/dL), for a sensitivity of 90 percent.

•Among the 308 subjects without IgG4-RD, 125 had elevated IgG4 levels (mean: 234 mg/dL; range: 135 to 1180 mg/dL) and 183 had normal IgG4 concentrations, for a specificity of 60 percent.

•The negative predictive value of a serum IgG4 assay in these particular groups who were tested was 96 percent, but the positive predictive value was only 34 percent.

•Doubling the cutoff for IgG4 improved the specificity (91 percent) but decreased the sensitivity to only 35 percent, viewed as unacceptably low. Analysis of the serum IgG4 to total IgG ratio did not improve these test characteristics.

A 2016 meta-analysis of nine case-control studies found that a cutoff value of serum IgG4 ranging from 135 to 144 mg/dL conferred a sensitivity of 87 percent and a specificity of 83 percent [16]. It should be clear that increased IgG4 serum levels are not sufficient to establish a diagnosis of IgG4-RD. Such antibody levels can also be increased in numerous other conditions. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Pathogenesis'.)

●Blood plasmablast concentrations – Measurement of the blood plasmablast concentration has some utility in assessing the likelihood of an IgG4-RD diagnosis. Elevated blood plasmablast concentrations are not, however, diagnostic of IgG4-RD. They are known to occur in many types of immune-mediated diseases (eg, systemic lupus erythematosus). Before patients with IgG4-RD have undergone treatment, elevated blood plasmablast concentrations may have a higher sensitivity for this diagnosis than even serum IgG4 concentrations [17,18]. Following the start of treatment, however, the utility of blood plasmablast measurements as a disease biomarker declines substantially. For longitudinal assessments of disease activity, serum IgG4 concentrations are usually superior. Another disadvantage of attempting to use plasmablasts for the assessment of IgG4-RD is that routine plasmablast assays, particularly those for IgG4 plasmablasts, are not widely available.

Patients with IgG4-RD who were untreated at the time their blood was sampled were found to have dramatic elevations of blood plasmablast concentrations. Plasmablasts were identified through flow cytometry of peripheral blood, gating on cells that were CD19^lowCD38+CD20-CD27+ [17]. The investigators evaluated 37 untreated patients with IgG4-RD and a total of 35 controls, including both healthy individuals (n = 14) and patients with other active inflammatory diseases who had not yet received treatment (n = 21). The results are summarized below:

•The IgG4-RD patients had significantly elevated total plasmablast counts (median: 4698/mL; range: 610 to 79,524/mL) compared with both untreated disease (median: 592/mL; range: 19 to 4294/mL) and healthy controls (median: 94/mL; range: 1 to 653/mL).

•Thirteen IgG4-RD patients (36 percent) had normal serum IgG4 concentrations (mean: 60 mg/dL; range: 5 to 123 mg/dL; normal: <135 mg/dL). However, the median plasmablast count was not significantly lower in that subset with normal serum IgG4 concentrations compared with those with elevated serum IgG4: 3784/mL versus 5155/mL, respectively (p = 0.24).

•Among the 12 rituximab (RTX)-treated patients, the median plasmablast level during disease flare was 6356/mL (range: 1123 to 41,589/mL), declining to 1419/ml (range: 386/mL to 4150/mL) during remission.

These studies of circulating plasmablasts confirm that these cells are elevated to high levels in patients with active IgG4-RD, even in patients with normal serum IgG4 concentrations. Plasmablast counts therefore are a potentially useful biomarker for diagnosis, assessing response to treatment, and determining the appropriate time for retreatment. Additional studies of plasmablasts, IgG4+ plasmablasts, and other B cell subsets are required to understand the value in clinical use. They may be most useful in patients who have not been previously treated. It remains unclear at the moment whether any B cell subset studied in the peripheral blood adds information more useful than serum IgG4 concentrations in establishing the diagnosis of IgG4-RD, following treatment response, or predicting disease recurrence.

Diagnostic criteria — Consensus statements from a multinational, multidisciplinary group of experts on IgG4-RD describe guidelines for the diagnosis of the disease and the histopathologic findings important in making the diagnosis [7,19]. Well-defined diagnostic criteria had previously been proposed only for AIP. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis", section on 'Diagnostic approach'.)

According to this consensus, the histopathologic findings of a dense lymphoplasmacytic infiltrate, storiform fibrosis (typified by a cartwheel appearance of the arranged fibroblasts and inflammatory cells), and obliterative phlebitis are critical features for establishing the diagnosis (picture 1 and picture 2) [8,20]. The presence of these findings, often together with mild tissue eosinophilia (image 2), is strongly suggestive if accompanied by increased numbers of IgG4-positive plasma cells in the affected tissue.

The number of IgG4-positive plasma cells per HPF that is regarded as consistent with or suggestive of IgG4-RD varies somewhat from tissue to tissue. Tissue IgG4-positive cell counts and the ratios of IgG4- to IgG-positive cells are considered secondary in importance to the histopathologic appearance of the tissue [5,8,9,19,21]. Generally, the minimum for making the diagnosis for most tissues is from 30 to 50 IgG4-positive cells/HPF. However, in some organs or tissues, including the kidney and others, only 10 IgG4-positive plasma cells/HPF may be sufficient.

The diagnosis cannot be predicated entirely upon the number of IgG4-positive plasma cells, because a large number of other entities can have such cells. Similarly, the diagnosis of IgG4-RD cannot be based upon serum concentrations of IgG4 alone, because serum IgG4 concentrations are neither sufficiently sensitive nor specific for this disease.

A group of IgG4-RD experts from around the globe, under the auspices of American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) developed the 2019 ACR/EULAR classification criteria for IgG4-RD [22]. Classification is based on a three-step process as follows: (1) clinical, radiologic involvement and/or compatible histopathologic findings in 1 of 11 possible organs, (2) absence of exclusion criteria (32 clinical, serologic, radiologic, and pathologic features), and (3) scoring ≥20 in 8 weighted domains [22]. The threshold of 20 points resulted in a specificity and sensitivity of more than 97 and 82 percent, respectively. The performance of these criteria was excellent in a validation study for Japanese patients with IgG4 kidney disease [23].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of IgG4-related disease (IgG4-RD) is broad and usually depends upon the specific site of involvement and clinical presentation.

Elevations in serum and tissue IgG4 concentrations are not specific to IgG4-RD; they are also found in other disorders (table 1), some of which have similarities to IgG4-RD clinically, including multicentric Castleman disease, allergic disorders, eosinophilic granulomatosis with polyangiitis (GPA), and sarcoidosis; and are elevated in a large number of other conditions [24,25].

Pancreato-hepato-biliary disease — Important mimics of IgG4-related pancreato-hepato-biliary disease included pancreatic cancer, primary sclerosing cholangitis, and cholangiocarcinoma:

●Pancreatic cancer – The differentiation of autoimmune pancreatitis (AIP) from adenocarcinoma of the pancreas is sometimes difficult on the basis of clinical presentation. Painless jaundice may be seen with either condition, and many patients have undergone modified Whipple procedures out of concern for pancreatic cancer. IgG4-positive plasma cells can also be found in the diseased pancreatic tissue in both conditions, although to a lesser degree in pancreatic cancer. As in AIP, elevated serum IgG4 levels can also be seen in some patients with pancreatic cancer, although they are usually less than twice the upper limit of normal; thus, increased IgG4 serum levels alone cannot be used to exclude a diagnosis of pancreatic malignancy with certainty [26].

Radiologic features of type 1 AIP that can help in the differentiation from pancreatic cancer include: diffuse enlargement of the pancreas ("sausage-shaped" pancreas), a halo of edema surrounding the organ, and delayed homogenous enhancement during the portal and venous phases [27,28]. Both of these features are appreciated most readily on abdominal CT scanning. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Autoimmune pancreatitis' and "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer".)

Biopsy, either intraoperatively or obtained by endoscopic ultrasound, is the gold standard for distinguishing AIP from pancreatic cancer. Biopsies obtained by endoscopy generally provide relatively small samples. These can be useful in establishing the diagnosis of malignancy but are not entirely reassuring if negative. A short trial of glucocorticoids (eg, one month of prednisone 40 mg/day) is reasonable when definitive confirmation by biopsy is difficult. Patients with type 1 AIP usually exhibit substantial radiologic and clinical improvement following such a trial.

●Primary sclerosing cholangitis – Distinctions between primary sclerosing cholangitis and IgG4-related sclerosing cholangitis are crucial because of the drastically different prognoses in these conditions. Both entities present with cholestatic liver biochemistry and strictures in the cholangiogram [29]. The clinical presentations and radiologic features of these conditions may be very similar. Both can present with narrowing of the intra- and extrahepatic bile ducts. However, the simultaneous presence of bile duct involvement and pancreatic disease, which is typical of type 1 AIP, makes IgG4-RD much more likely. Isolated bile duct involvement sparing the pancreas can occur in IgG4-RD, but is unusual.

Defined diagnostic criteria for IgG4-related sclerosing cholangitis are lacking; the differentiation from primary sclerosing cholangitis is based upon tissue biopsy with the demonstration of infiltrates of IgG4+ plasma cells and severe interstitial fibrosis, increased IgG4 serum levels, and characteristic responsiveness to glucocorticoids in the IgG4-RD.

The presence of clinical manifestations of IgG4-RD in extrabiliary organs can also be an important clue to the presence of IgG4-RD [30,31]. One study has suggested that a composite score, based upon age, other organ involvement, and beaded appearance of the bile duct, is able to differentiate sufficiently between IgG4-related cholangitis and primary sclerosing cholangitis, but this tool needs further validation [32]. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis", section on 'Clinical manifestations' and "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Differential diagnosis' and "Clinical manifestations and diagnosis of cholangiocarcinoma" and "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'IgG4-related sclerosing cholangitis' and "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis".)

●Cholangiocarcinoma – One study has suggested that patients with cholangiocarcinoma, unlike patients with IgG4-related sclerosing cholangitis, are more likely to present with obstructive jaundice, an enlarged pancreas, and lymphadenopathy, although these can be features of both. Cholangiocarcinoma patients also generally have higher serum bilirubin concentrations, higher levels of cancer antigen 19-9 (CA 19-9), and complete obstruction of the hilar or bile ducts as demonstrated by endoscopic retrograde cholangiopancreatography (ERCP). A cutoff higher than the standard upper limit of normal for serum IgG4 concentrations (ie, >135 mg/dL) may also be useful in distinguishing IgG4-RD from cholangiocarcinoma; the higher the serum IgG4 concentration, the greater the likelihood that the patient has IgG4-RD rather than a biliary tract malignancy [33]. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'IgG4-related sclerosing cholangitis' and "Clinical manifestations and diagnosis of cholangiocarcinoma".)

Retroperitoneal fibrosis and/or aortitis — IgG4-related retroperitoneal fibrosis (RPF), aortitis, and periaortitis need to be differentiated from other causes of RPF and of noninfectious and infectious disorders that may cause aortitis and periaortitis:

●Retroperitoneal fibrosis – The differentiation of RPF related to IgG4-RD from other causes of RPF is based mainly on the histopathologic and clinical findings. Biopsy findings in IgG4-related RPF, in contrast to RPF from other causes, usually have a tissue IgG4+ to IgG+ ratio >40 percent. In addition, extraperitoneal lesions are present in more than half of these patients [34]. The finding of infrarenal periaortitis extending inferiorly to involve the iliac vessels is a radiologic pattern strongly suggestive of IgG4-related RPF. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis".)

●Aortitis and periaortitis – Both IgG4-RD and a number of noninfectious and infectious disorders can cause aortitis and periaortitis. Infections, with the possible exception of syphilis (now vanishingly rare as a cause of aortitis), seldom cause diffuse aortic disease but can cause focal lesions. These are usually associated with classic symptoms of infections such as fevers if caused by bacterial disease. In contrast, fevers are extremely unusual in IgG4-RD. Malignancies, particularly unusual presentations of lymphoma, should also be excluded [35,36].

Various epidemiologic, clinical, and histopathologic features serve to differentiate IgG4-RD from other diseases. Patients with IgG4-related aortitis are typically older than those with Takayasu arteritis or Behçet syndrome [37]. In one study, patients with IgG4-RD inflammatory abdominal aortic aneurysms had higher IgG4 and IgE serum levels and increased rates of positive antinuclear antibodies compared with patients with non-IgG4-related inflammatory abdominal aortic aneurysms [38].

Histopathologic characteristics are most useful for distinguishing IgG4-related and unrelated disease. High numbers of IgG4+ plasmacytes are seen in IgG4-related aortitis, although these can be seen in other aortitis as well. Additional histologic features favoring a diagnosis of IgG4-RD include the presence of storiform fibrosis, lymphoid follicles, and obliterative phlebitis. Granulomatous inflammation, the presence of either epithelioid granulomas or multinucleated giant cells, intense neutrophilic infiltration, and the finding of necrosis all argue strongly against IgG4-RD [39].

Head and neck disease — Several conditions that share some features with IgG4-related head and neck disease should be differentiated from IgG4-RD, including Sjögren's syndrome (SS) and orbital inflammatory disease:

●Sjögren's syndrome – Both SS and IgG4-related sialoadenitis and dacryoadenitis can exhibit prominent swelling of the parotid, submandibular, and lacrimal glands. These diagnoses can generally be distinguished, however, based upon respective characteristic histopathologic and laboratory findings, as well as associated clinical features. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Salivary and lacrimal gland involvement' and "Diagnosis and classification of Sjögren's syndrome" and "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease" and "Clinical manifestations of Sjögren's syndrome: Extraglandular disease".)

In SS, unlike IgG4-RD, there is a female predominance; IgG4 serum levels are usually within normal limits; and in salivary gland biopsies, IgG4+ plasmacytes, storiform fibrosis, and obliterative phlebitis are usually absent. Clinical and laboratory features that characterize IgG4-related sialadenitis and also help to distinguish it from SS include fewer patients with dry mouth, dry eyes, or arthralgias, and relatively mild dryness of the eyes and of the mouth; a higher frequency of allergic rhinitis and bronchial asthma; a higher frequency of type 1 AIP and interstitial nephritis; and low frequencies of autoantibodies, including rheumatoid factor, antinuclear antibodies, anti-Ro/SSA, and anti-La/SSB [39].

However, patients who fulfill criteria for both SS and IgG4-RD have been identified. In a cohort of 133 patients with well-defined primary SS, increased IgG4 serum levels (>135 mg/dL) were present in 10 patients (7.5 percent) [40]. In a few of them, in whom labial minor salivary gland biopsies were available, increased numbers of IgG4+ plasmacytes were detected. The patients with elevated levels of IgG4 displayed a higher frequency of IgG4-RD clinical features (AIP, autoimmune cholangitis, and interstitial nephritis); and lower rates of antinuclear, anti-Ro/SSA, and anti-La/SSB autoantibodies. Most of these 10 patients were thought to probably represent IgG4-RD patients misclassified as having SS. Patients with strongly positive serum assays for anti-Ro/SSA antibodies most likely have Sjögren's syndrome and not IgG4-RD, even though the clinical features of these conditions overlap.

●Orbital pseudotumor – IgG4-RD is a major cause of orbital inflammatory disease and appears to account for 25 to 50 percent of orbital pseudotumors, including those originally diagnosed before recognition of IgG4-RD as orbital benign lymphoid hyperplasia or idiopathic orbital inflammation. Depending upon the diagnostic criteria used, IgG4-RD accounts for between approximately 5 and 25 percent of cases originally diagnosed as nongranulomatous idiopathic orbital inflammation [41]. The emergence of IgG4-RD as an important cause of orbital inflammation underscores the importance of performing biopsies in cases of orbital inflammation in which the diagnosis is not completely clear. In children, orbital pseudotumor seems to be a common manifestation of IgG4-RD [42].

Other organ involvement and multisystem disease — A range of conditions affecting various organs individually or as multisystem disorders can resemble IgG4-RD, including lung disease, generalized lymphadenopathy, goiter, renal disease, and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV):

●Lung disease – IgG4-RD of the lungs can exhibit many different and often overlapping patterns (see "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Lung and pleural disease'). Pulmonary involvement in IgG4-RD can mimic (and be mimicked by) several conditions, including sarcoidosis, neoplasms, AAV, and interstitial lung disease associated with autoimmune diseases. Features that can help distinguish IgG4-RD from other disorders include an association with other (non-pulmonary) manifestations of IgG4-RD and histopathologic characteristics on biopsy. In IgG4-RD, IgG4+ plasma cells are frequent, although storiform fibrosis is not always present in lung biopsies [43,44]. Neutrophilic aggregates are sometimes observed in the lung in IgG4-RD, unlike in other tissues in IgG4-RD [43]. Another feature described in IgG4-RD of the lungs is the tendency of the disease to extend along the bronchovascular bundle, perhaps tracking along the lymphatic tissue, leading to the thickening of bronchial walls and surrounding tissue [44].

●Generalized lymphadenopathy – The differential diagnosis in patients with generalized lymphadenopathy includes sarcoidosis, multicentric Castleman disease, infection (eg, tuberculosis), and lymphoma or other malignancy. IgG4-related lymphadenopathy is distinguished from these conditions by the modest lymph node enlargement, histologic distinctions on biopsy, lack of constitutional features, and the usually striking clinical response of IgG4-RD to glucocorticoids [8]. Patients with bilateral hilar adenopathy may mimic sarcoidosis. (See "Evaluation of peripheral lymphadenopathy in adults" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Hodgkin lymphoma: Epidemiology and risk factors" and "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Lung and pleural disease' and "HHV-8/KSHV-associated multicentric Castleman disease".)

●Goiter – There are some forms of thyroiditis that can appear similar to and may be related to Riedel's thyroiditis. These include the fibrosing variant of chronic autoimmune (Hashimoto) thyroiditis and the IgG4-related Hashimoto thyroiditis [45-48]. These share some histopathologic characteristics with Riedel's thyroiditis, including an increased IgG4+ to IgG+ ratio in the thyroid gland, but they do not affect adjacent organs. Some authors have hypothesized that the fibrosing variant of Hashimoto thyroiditis might be an early form of Riedel's thyroiditis [47]. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Thyroid disease' and "Infiltrative thyroid disease", section on 'Riedel's thyroiditis' and "Clinical presentation and evaluation of goiter in adults".)

●Renal disease – Other forms of interstitial nephritis can also mimic IgG4-RD. These include drug-related interstitial nephritis, chronic pyelonephritis, multicentric Castleman disease, and interstitial nephritis related to other autoimmune diseases, the most common of which are SS and granulomatosis with polyangiitis. Clinical features suggesting IgG4-RD rather than features associated with other conditions, together with histopathologic characteristics, will help distinguish IgG4-RD from these conditions. In patients with IgG4-related interstitial nephritis, which most often presents with signs of acute or chronic kidney injury, mass lesion(s) in the kidney, or both, there is an abundance of IgG4+ plasmacytes and storiform fibrosis, with tubular basement membrane immune complex deposition often present, while granulomatous inflammation, marked neutrophilic infiltration, and karyorrhexis are absent [49]. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Kidney disease' and "Clinical manifestations and diagnosis of acute interstitial nephritis" and "Kidney disease in primary Sjögren syndrome".)

●ANCA-associated vasculitis – IgG4-RD can mimic systemic vasculitic disorders, including GPA. The pattern of organ involvement and signs of inflammation may help to distinguish these entities. Ear/nose/throat, lungs, and kidneys are more commonly affected in AAV, while pancreatitis, RPF, and salivary and lacrimal gland involvement are more commonly encountered in IgG4-RD. In IgG4-RD, fever is less common and levels of C-reactive protein are lower compared with AAV [50]. Histologic findings can help distinguish these conditions, together with associated clinical features and serologic characteristics. However, on occasion, AAV and IgG4-RD have been reported to overlap, sometimes presenting as AAV with atypical features, such as pachymeningitis, orbital mass, or chronic periaortitis [51,52]. Tissue biopsies from patients with AAV can have substantial infiltrates of IgG4-positive plasma cells, underscoring the perils of relying upon the concentration of such cells for the purpose of diagnosis.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: IgG4-related disease".)

SUMMARY AND RECOMMENDATIONS

●Immunoglobulin G4-related disease (IgG4-RD) should be suspected in patients with one of the characteristic patterns of organ or tissue involvement, major examples of which include pancreatitis of unknown origin, sclerosing cholangitis, bilateral salivary and/or lacrimal gland enlargement, retroperitoneal fibrosis (RPF), and orbital pseudotumor or proptosis. The likelihood of IgG4-RD for patients presenting with at least one of these conditions is significantly increased if high serum levels of IgG4, allergic symptoms, and/or other fibrotic processes are also present. (See 'Indications for diagnostic evaluation' above.)

●The diagnosis should be confirmed by biopsy of an involved organ whenever this is possible, but histopathology findings are never diagnostic alone of IgG4-RD and must be interpreted in the context of clinical, serologic, and radiologic data. Characteristic findings, which are usually strikingly similar in different tissues, include lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and lymphocytes, which is accompanied by fibrosis that has storiform features and often by obliterative phlebitis and modest tissue eosinophilia (image 1). However, similar findings can be seen in other conditions, and the diagnosis cannot be predicated entirely upon the number of IgG4-positive plasma cells. (See 'Diagnostic features' above and 'Diagnostic criteria' above.)

●Patients should undergo a thorough history, physical examination, and tissue biopsy, but the specific procedure depends upon the target organ and whether a mass is present. Serum IgG4 levels should be measured, and isolated elevated levels are a significant aid in diagnosis, although they are not diagnostic. Additional organ involvement may be identified through the history, physical examination, routine laboratory testing, and selected imaging studies. (See 'Diagnostic testing' above and 'Diagnostic features' above.)

●The major disorders that should be distinguished from IgG4-RD include pancreatic cancer, cholangiocarcinoma, primary sclerosing cholangitis, Sjögren's syndrome (SS), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Castleman disease, idiopathic RPF, and infectious aortitis. Some of these conditions may also exhibit increased levels of serum IgG4 (table 1). (See 'Differential diagnosis' above.)