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Pathogenesis and clinical manifestations of IgG4-related disease

Pathogenesis and clinical manifestations of IgG4-related disease
Literature review current through: Sep 2023.
This topic last updated: Aug 28, 2023.

INTRODUCTION — Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that is capable of affecting multiple organs [1,2]. Common forms of presentation include:

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

IgG4-related sclerosing cholangitis, typically occurring together with type 1 AIP

Major salivary gland enlargement or sclerosing sialadenitis; termed IgG4-related Mikulicz disease, when presenting with the combination of lacrimal, parotid, and submandibular gland enlargement

Orbital disease, often with proptosis

Retroperitoneal fibrosis, frequently with chronic periaortitis and often affecting the ureters, leading to hydronephrosis and renal injury

The involved organs share a number of core pathologic features and striking clinical and serologic similarities, including 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). Elevated serum concentrations of IgG4 are common. Before its recognition as a unified disease in the early 2000s, the seemingly disparate manifestations had been presumed to be single-organ disorders that bore little or no relationship to each other [3-5].

The pathogenesis, epidemiology, and clinical manifestations of IgG4-RD are presented here. The diagnosis and treatment of IgG4-RD are described separately (see "Diagnosis and differential diagnosis 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 separately (see "Autoimmune pancreatitis: Clinical manifestations and diagnosis"), as are several of the other conditions associated with this disorder (see appropriate topic reviews).

TERMINOLOGY — IgG4-related disease (IgG4-RD) is the preferred name for the overall condition [6,7]. The medical literature from the years following the disease's first recognition was rife with multiple other names, including [4,5]:

IgG4-related disease

IgG4-related systemic disease

IgG4 syndrome

IgG4-associated disease

IgG4-related sclerosing disease

IgG4-related systemic sclerosing disease

IgG4-related autoimmune disease

IgG4-positive multiorgan lymphoproliferative syndrome

Hyper-IgG4 disease

Systemic IgG4-related plasmacytic syndrome

Systemic IgG4-related sclerosing syndrome

Multifocal fibrosclerosis

Multifocal idiopathic fibrosclerosis

DEFINITION AND HISTOPATHOLOGY — The hallmarks of IgG4-related disease (IgG4-RD) are dense lymphoplasmacytic infiltrations with a predominance of IgG4-positive plasma cells in the affected tissue, usually accompanied by some degree of fibrosis and often by obliterative phlebitis and an increased number of eosinophils [8]. 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 patients [9,10]. A sizeable minority of patients have normal serum IgG4 concentrations even before treatment, however, despite the presence of the typical histopathologic changes in tissue [11,12]. A good initial therapeutic response to glucocorticoids is characteristic, particularly if tissue fibrosis does not dominate the histologic picture [13].

The fibrosis associated with IgG4-RD usually has a characteristic "storiform" pattern (storiform is from the Latin word "storea," meaning "woven mat"), typified by a cartwheel appearance of the arranged fibroblasts and inflammatory cells (picture 1 and picture 2) [9,14]. Modest tissue eosinophilia is also common (image 1).

PATHOGENESIS — There is growing evidence that the pathogenesis of IgG4-related disease (IgG4-RD) has an autoimmune basis, with important roles for both B and T cells, especially CD4+ and T-follicular helper cells (Tfh). The IgG4 antibodies do not appear to be pathogenic themselves.

Several candidate autoantigens have been reported, and it is likely that more than one autoantigen can trigger this condition. Compelling cases have been made thus far for galectin-3, for laminin 111, and for annexin A11 as autoantigens [15-17], but all proposed target autoantigens require additional confirmatory studies and none of these autoantigens by themselves offers a sufficient explanation for disease causality. The mechanisms behind the loss of tolerance to these antigens remain obscure.

An emerging consensus is that the IgG4 antibodies in this disease are not pathogenic, but rather represent an epiphenomenon, possibly having an antiinflammatory role. These seem to be produced in response to cytokines (eg, interleukin 4 [IL-4]) produced as part of immune response [18]. Elevations in serum and tissue IgG4 concentrations are not specific to IgG4-RD; they are also found in disorders such as multicentric Castleman disease, allergic disorders, eosinophilic granulomatosis with polyangiitis, sarcoidosis, and a large number of other conditions [19,20]. (See "IgG subclass deficiency", section on 'IgG4 deficiency' and "IgG subclasses: Physical properties, genetics, and biologic functions", section on 'Properties of IgG subclasses' and "Diagnostic evaluation of IgE-mediated food allergy", section on 'Unvalidated methods' and "IgG subclasses: Physical properties, genetics, and biologic functions", section on 'Disorders with elevated subclass levels'.)

Immune complex deposition in the pancreas, kidneys, and certain other affected tissues has been reported [21]. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis".)

The past suggestion that IgG4-RD is a T helper cell (Th) 2-mediated condition has now been roundly debunked. Circulating Th2 memory cells in IgG4-RD have been shown to be restricted to a defined subset of subjects who have concomitant atopy [22,23]. Consequently, Th2 pathways are no longer believed to be central to disease pathophysiology.

The identification of a CD4+ cytotoxic T cell in IgG4-RD appears to be an important step forward in understanding disease pathophysiology. CD4+ T cells, the most abundant cells within affected tissues, are dispersed throughout IgG4-RD lesions. A clonally expanded population of CD4+ cytotoxic T lymphocytes in both the peripheral blood and fibrotic lesions of IgG4-RD patients suggest that these cells are central to the disease [24]. These cytotoxic T cells make products such as granzyme B and perforin. Moreover, the IL-1, transforming growth factor (TGF)-beta, and interferon-gamma elaborated by these cells are all potentially important mediators of the fibrosis that forms such a dominant part of histopathology in IgG4-RD. The CD4+ cytotoxic T cells express signaling lymphocytic activation module F7 (SLAMF7), a molecule not previously described on CD4+ T cells, on their surface. This population of CD4+ cytotoxic T lymphocytes contracts after glucocorticoid-induced remission in patients with IgG4-RD [25]. It is possible that CD4+ cytotoxic lymphocytes induce apoptosis in nonendothelial, nonimmune cells in the affected tissues [26].

The role of other T-cell subsets is also becoming evident. Tfh cells, which reside mainly within and around lymph node germinal centers, have also been found to be increased in the peripheral blood and in affected tissue from patients with IgG4-RD [27]. Circulating Tfh cells from IgG4-RD patients are more capable of facilitating B-cell proliferation and differentiation than are Tfh cells from healthy individuals [27]. Furthermore, T-follicular regulatory cells, along with Tfh cells, regulate germinal center formation and B-cell class switching [28].

The innate immune system might also play a role in the pathogenesis of IgG4-RD. A study reported altered frequency of innate lymphoid cells and their subtypes in patients with IgG4-RD compared with healthy individuals [29]. Data from both animal models and human studies suggest a role for the CCL8-CCR8 axis [30,31].

Taken together, this information suggests the hypothesis that CD4+ cytotoxic T cells orchestrate the disease and that they are sustained by continuous antigen presentation by cells of the B lymphocyte lineage, including but not limited to plasmablasts [24]. A Tfh response that is separate from the CD4+ cytotoxic T lymphocytes is likely to be responsible for the development of germinal centers within lymph nodes (and involved organs) and the production of cytokines (eg, IL-4) that drive the IgG4 class-switch, culminating in the creation of IgG4-secreting plasmablasts and long-lived plasma cells. B-cell depletion often does not lead to the complete normalization of serum IgG4 concentrations even after clinical remission, implying that long-lived plasma cells continue to make this immunoglobulin. The persistence of high albeit declining IgG4 concentrations following the achievement of disease control supports the concept that IgG4 itself does not drive the disease.

EPIDEMIOLOGY — The exact prevalence of IgG4-related disease (IgG4-RD) is unknown, in part because recognition of the disease continues to grow, and the condition does not have its own unique International Statistical Classification of Diseases and Related Health Problems (ICD)-10 code. This makes the performance of rigorous epidemiologic studies challenging. In Japan, the incidence of the disease has been reported to be approximately 0.28 to 1.08 per 100,000 of population [7], but this estimate almost certainly constitutes a substantial underestimate of the true disease prevalence. Increasing recognition of this entity and availability of widely accepted classification criteria for IgG4-RD will enable more precise epidemiologic studies [32].

IgG4-RD cohorts generally have a slight predominance of middle-aged and older males. A predilection for older males is clear for conditions such as type 1 (IgG4-related) autoimmune pancreatitis (AIP), retroperitoneal fibrosis, IgG4-related tubulointerstitial nephritis (TIN), and many other organ manifestations. However, the sex distribution differs somewhat with regard to patients with involvement of the head and neck. In a prospective study of 403 IgG4-RD patients, sialadenitis and dacryoadenitis, as well as thyroiditis, were more common in females [33]. Other risk factors have not been identified. However, a case-control study examining 234 patients with IgG4-RD and 1170 controls found that smoking was associated with increased risk of having IgG4-RD, especially in patients with retroperitoneal involvement [34].

IgG4-RD also occurs in children. In the IgG4-RD described in the pediatric population, general disease characteristics appear to be similar to those observed in the IgG4-RD of the adults [35]. However, eye manifestations, expressed mainly as orbital mass and, to a lesser extent, as dacryoadenitis [36], are thought to be more common [35,36].

Whether disease extent and severity are similar in males and females remains uncertain. In a series of 125 patients with biopsy-proven IgG4-RD, the number of organs involved, the degree of serum IgG4 elevation, and damage from IgG4-RD did not differ between male and female patients [11]. By contrast, in another study, males had higher IgG4-RD responder index scores at months 6 and 12 and a higher risk for relapse compared with females with the disorder [33].

In a study of 114 patients with IgG4-RD, those with involvement limited to one of several regions (head and neck, thoracic, hepatopancreatobiliary, and retroperitoneal) and those with systemic involvement (more than one region) were compared with respect to various demographic and clinical features [37]. The ages of patients in all groups were similar, with means from 59 to 68 years (ranges 42 to 79) [37]. All the groups, other than the patients with head and neck involvement, were predominantly males (75 to 86 percent), but the group with only head and neck disease was divided nearly equally between the sexes (48 percent males) [11].

In a worldwide study using two cohorts of IgG4-RD patients, four phenotypic groups of the disease were identified (see 'Clinical manifestations' below). The biologic underpinnings of the differences between these groups remain unclear, and further studies of the possibility of disease phenotypes within IgG4-RD are required before firm conclusions can be drawn. Of the 493 patients of the primary cohort, the majority (65.3 percent) were males, and the mean ages at symptom onset for patients from Asian and non-Asian countries were 57.7 and 59.5 years, respectively [38]. The pattern of female predominance in head and neck disease was also confirmed in these patients. Patients of Asian origin had substantially higher serum concentrations of IgG4 compared with their counterparts from the West [7].

CLINICAL MANIFESTATIONS

Overview of manifestations — IgG4-related disease (IgG4-RD) can involve one or multiple organs, and manifestations of this disease have been demonstrated in nearly every organ system [1,2,11,39]. Patients often present with subacute development of a mass in the affected organ (eg, an orbital pseudotumor, a renal mass resembling renal cell carcinoma, nodular lesions in the lung) or diffuse enlargement of an organ (eg, the pancreas) [1,4,40]. Multiple organs are affected in 60 to 90 percent of patients with IgG4-RD [5,41]. The affected tissues share particular pathologic features, although some of them, such as storiform fibrosis, are not encountered frequently in certain tissues, including salivary glands and lymph nodes [8].

Lymphadenopathy is common, and symptoms of asthma or allergy are present in approximately 40 percent of patients. Patients often feel well at the time of diagnosis and generally lack fever [9]. However, patients with multiorgan disease often lose substantial amounts of weight – 20 to 30 pounds (approximately 9 to 14 kg) over months – before the correct diagnosis is identified. This weight loss may be a strong clue to the presence of exocrine pancreatic insufficiency, caused by IgG4-related autoimmune pancreatitis (AIP). The damaged pancreas fails to produce sufficient quantities of digestive enzymes, with the result that patients are unable to absorb adequate nutrition and calories from their food.

IgG4-RD is also often recognized incidentally based upon a radiologic finding or histopathologic examination of a tissue specimen. Characteristic imaging findings on computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scanning include diffuse or focal organ lesions (usually mass/swelling). Such lesions are characterized histopathologically by IgG4+ plasma-cells infiltrates and the presence of fibrosis in most cases, regardless of the stage of the disease [42].

Clinicians should be alert to the possibility that IgG4-RD can mimic some autoimmune rheumatic diseases such as Sjögren's disease, systemic lupus erythematosus (SLE), and granulomatosis with polyangiitis, as well as a number of other conditions. (See "Diagnosis and differential diagnosis of IgG4-related disease", section on 'Differential diagnosis'.)

Many of the initial observations regarding this condition were made in patients with AIP, which often presents as a pancreatic mass or as painless obstructive jaundice and can be mistaken for pancreatic cancer. Additional reports have focused on patients with lacrimal and salivary gland involvement (IgG4-related Mikulicz disease), which was once thought to be a subset of Sjögren's disease (picture 3) [4,40]. Such patients present with prominent parotid or submandibular gland enlargement.

Four phenotypes (ie, patterns of organ involvement) were identified using latent class analysis, a form of cluster analysis, to categorize 765 patients from two large cross-sectional cohorts, which included patients with IgG4-RD from many different centers [38]. Each group, which comprised approximately 20 to 30 percent of all the patients in the cohorts, was identified and named based upon the most common manifestations and involved organs in the group.

These four phenotypes included the following groups:

Group 1 – Pancreato-hepato-biliary disease

Group 2 – Retroperitoneal fibrosis and/or aortitis

Group 3 – Head- and neck-limited disease

Group 4 – Classic Mikulicz syndrome with systemic involvement

As noted above, the molecular biologic correlates of these clinical phenotypes remain to be described and further studies of the possibility of disease phenotypes within IgG4-RD are required before firm conclusions can be drawn. Notably, however, striking differences can be observed across these phenotypes. (See 'Epidemiology' above.)

Previously described conditions that represent manifestations of IgG4-RD and the nomenclature, when not otherwise indicated, include [4-6]:

Type 1 (IgG4-related) AIP

IgG4-related sclerosing cholangitis

Mikulicz disease (IgG4-related dacryoadenitis and sialadenitis)

Sclerosing sialadenitis (Küttner tumor, IgG4-related submandibular gland disease)

Inflammatory orbital pseudotumor (IgG4-related orbital inflammation or orbital inflammatory pseudotumor)

Chronic sclerosing dacryoadenitis (lacrimal gland enlargement, IgG4-related dacryoadenitis)

A subset of patients with "idiopathic" retroperitoneal fibrosis (Ormond disease) and related disorders (IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis)

Chronic sclerosing aortitis and periaortitis (IgG4-related aortitis or periaortitis)

Riedel's thyroiditis (IgG4-related thyroid disease)

IgG4-related interstitial pneumonitis and pulmonary inflammatory pseudotumors (IgG4-related respiratory disease)

IgG4-related kidney disease (including tubulointerstitial nephritis [TIN] and membranous glomerulonephritis [GN] secondary to IgG4-RD)

IgG4-related hypophysitis

IgG4-related pachymeningitis

IgG4-related midline destructive disease

Estimates of the relative frequency of different manifestations depend upon the particular perspective of the index illness being studied. As an example, a study of patients with AIP found frequent extrapancreatic involvement, including hilar lymphadenopathy (80 percent), extrapancreatic bile duct lesions (74 percent), lacrimal and salivary gland lesions (39 percent), hypothyroidism (22 percent), and retroperitoneal fibrosis (13 percent) [43]. By contrast, AIP was found in only 17 percent of patients studied with IgG4-related lacrimal, parotid, or submandibular gland disease, and interstitial nephritis (17 percent) and interstitial pneumonitis (9 percent) were also seen among this group [44].

Lymphadenopathy — Asymptomatic IgG4-related lymphadenopathy is common, occurring in 80 percent of patients with AIP [43]. Lymphadenopathy is usually observed together with other clinical or laboratory manifestations of IgG4-RD but may be the initial or only manifestation [45]. Biopsies of lymph nodes are often problematic to interpret with regard to the diagnosis of IgG4-RD because they seldom undergo the storiform fibrosis that is so highly characteristic of IgG4-RD, and large numbers of IgG4+ plasma cells can be found in multiple diseases in which IgG4-RD is not the diagnosis, resulting in poor specificity of this finding. (See "Diagnosis and differential diagnosis of IgG4-related disease".)

In a study of 114 patients with varied organ involvement, lymphadenopathy was present in 41 percent [37]. Symptoms occasionally occur due to mass effect of the enlarging nodes; individual nodes are typically no more than 2 centimeters in diameter but may range up to 5 centimeters [45]. Multiple groups of lymph nodes are usually involved; the mediastinal, hilar, intraabdominal, and axillary are most common and can be readily seen upon scanning with gallium-67 [46]. The lymphadenopathy is generally non-tender and the nodes themselves are rubbery rather than hard.

Five histologic patterns have been reported, all of which feature abundant IgG4-positive cells. Most cases also have eosinophil infiltration [9,47-49]. The histopathology is similar to other affected tissues, except that unlike most other tissues, there is usually no fibrosis or phlebitis. The patterns include:

Type I – Multicentric Castleman disease-like

Type II – Follicular hyperplasia

Type III – Interfollicular expansion

Type IV – Progressive transformation of germinal center-like

Type V – Nodal inflammatory pseudotumor-like

Patients with lymphadenopathy may exhibit elevated serum IgG4, serum IgG and IgE, polyclonal hypergammaglobulinemia, and elevations in the erythrocyte sedimentation rate (ESR).

Autoimmune pancreatitis — Type 1 (IgG4-related) AIP is the prototypical form of IgG4-RD. The prevalence of this condition in Japan has been estimated to be 0.82 per 100,000 persons, but this is likely to be an underestimate for the reasons mentioned above [50,51]. Two types of AIP have been distinguished; the form associated with IgG4-RD is type 1 AIP, also denoted as lymphoplasmacytic sclerosing pancreatitis [41]. A second form, unassociated with IgG4-RD, is termed type 2 AIP; this latter type of pancreatitis is also known as idiopathic duct-centric chronic pancreatitis (IDCP) or granulocyte-positive epithelial pancreatitis [52,53]. Type 2 AIP appears to be much rarer than type 1 AIP and is sometimes associated with inflammatory bowel disease [54]. Some experts have proposed that the term AIP should be reserved for type 1 AIP and that the term IDCP be used for type 2 AIP [53,55]. AIP is discussed in detail separately. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis".)

AIP has been estimated to account for 2 percent of patients with chronic pancreatitis [50]. It often presents as a pancreatic mass or as painless obstructive jaundice and can be mistaken for pancreatic cancer. Some patients with type 1 AIP exhibit acute, recurrent, or chronic pancreatitis, and complications of AIP frequently include glucose intolerance or frank type 2 diabetes mellitus and, more frequently, exocrine pancreatic insufficiency. Most patients with type 1 AIP have another concomitant IgG4-related condition such as IgG4-related sclerosing cholangitis, lymphadenopathy, IgG4-related tubulointerstitial nephritis, major salivary gland involvement, and other features. (See 'Clinical manifestations' above and "Autoimmune pancreatitis: Clinical manifestations and diagnosis".)

The differentiation of AIP from adenocarcinoma of the pancreas is sometimes difficult on the basis of clinical presentations. Painless jaundice, for example, is a presentation common to both, and many patients with AIP have undergone modified Whipple procedures out of concern for pancreatic cancer. Elevated IgG4 levels can be seen in both conditions. (See "Diagnosis and differential diagnosis of IgG4-related disease", section on 'Differential diagnosis'.)

Radiologic features of type 1 AIP include diffuse enlargement of the pancreas, leading to the descriptor "sausage-shaped" pancreas, and a halo of edema surrounding the organ. Both of these features are appreciated most readily on abdominal CT scanning.

IgG4-related sclerosing cholangitis — A form of sclerosing cholangitis that is clinically and pathologically distinct from primary sclerosing cholangitis may occur in IgG4-RD. This IgG4-related sclerosing cholangitis is present in more than 70 percent of patients with IgG4-related AIP and sometimes occurs as isolated cholangitis in the absence of pancreatic disease [4]. The combination of biliary tract and pancreatic disease is nearly diagnostic of IgG4-RD. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis", section on 'Type 1 AIP'.)

Unlike primary sclerosing cholangitis, tissue biopsy in IgG4-related cholangitis demonstrates infiltrates of IgG4+ plasma cells and severe interstitial fibrosis. Patients with IgG4-related cholangitis also have increased serum concentrations of IgG4 and responsiveness to glucocorticoids that is uncharacteristic of primary sclerosing cholangitis. The presence of clinical manifestations of IgG4-RD in extrabiliary organs occurs concomitantly with IgG4-related cholangitis [56,57]. The clinical distinction between primary sclerosing cholangitis and IgG4-related sclerosing cholangitis is important but can be difficult because biopsies performed via endoscopic retrograde cholangiopancreatography (ERCP) are seldom deep enough to define the histopathologic features of IgG4-RD [58,59]. The differentiation between cholangiocarcinoma and IgG4-related sclerosing cholangitis also may be challenging. (See "Diagnosis and differential diagnosis of IgG4-related disease", section on 'Differential diagnosis'.)

Salivary and lacrimal gland involvement — Major salivary gland (parotid or submandibular) involvement is a common feature of IgG4-RD. Patients may present with lacrimal gland, parotid gland, and submandibular gland enlargement, a triad once termed "Mikulicz disease." Isolated involvement of the submandibular gland, a feature that is strongly suggestive of IgG4-RD if the glandular involvement is bilateral, was once often referred to as either a "Küttner tumor" or sclerosing sialadenitis [60]. Various combinations of these glands can be involved in IgG4-RD, and the sublingual glands may also be affected. IgG4-RD usually affects the lacrimal and major salivary glands in a symmetrical fashion.

Involvement of these glands in a manner typical of IgG4-RD was once considered erroneously to be a variant of Sjögren's disease (picture 3) [44,60-67], but these conditions are now known to be different diseases. Many of the patients previously described as having Sjögren's disease in association with pancreatic or renal disease likely had IgG4-RD rather than Sjögren's disease. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging" and "Diagnosis and classification of Sjögren’s disease", section on 'Nomenclature'.)

Nearly 40 percent of patients with IgG4-related pancreatitis also have salivary or lacrimal gland involvement. Conversely, AIP is detected in approximately 17 percent of patients presenting with sialadenitis [43,44]. Sialadenitis often presents prior to AIP in patients who develop both conditions [68]. Unlike AIP and other forms of IgG4-RD, patients with salivary and lacrimal gland involvement include comparable numbers of both males and females [37,44].

The pathologic findings in IgG4-related sialoadenitis and dacryoadenitis are typical of those in other patients with IgG4-RD, including the lymphoplasmacytic infiltrate with IgG4-positive cells. Fibrosis and obliterative phlebitis are sometimes present in tissue samples derived from submandibular glands but are uncommon in biopsies of the labial minor salivary glands (picture 4 and picture 5 and image 2 and image 3 and image 4 and image 5) [37,69]. Increased IgG4 and IgE serum levels are also present. Low complement levels may be seen and are particularly common among patients with concomitant renal involvement in IgG4-RD [11].

Patients who fulfill criteria for both Sjögren's disease and IgG4-RD have been identified. Increased IgG4 serum levels (>135 mg/dL) were present in 7.5 percent of a cohort of 133 patients with well-defined primary Sjögren's disease [70]. 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. In addition, 2.3 percent of patients studied had increased numbers of IgG4+ plasma cells in labial minor salivary gland biopsies. Most of the patients with elevated IgG4 serum levels probably represent IgG4-RD patients misclassified as having Sjögren's disease. Minor salivary gland biopsy has also been used to diagnose IgG4-RD [71].

The clinical and laboratory features that characterize IgG4-related sialadenitis and also help to distinguish it from Sjögren's disease include [63]:

Fewer patients with dry mouth, dry eyes, or arthralgias (38, 33, and 16 percent versus 87, 94, and 48 percent, respectively). Despite marked lacrimal and salivary gland enlargement, these patients experience relatively mild dryness of the eyes and of the mouth.

A higher frequency of allergic rhinitis and bronchial asthma (41 and 14 percent versus 7 and 3 percent, respectively).

A higher frequency of AIP and interstitial nephritis (17 and 17 percent versus 0 and 7 percent, respectively).

Low frequencies of autoantibodies, including rheumatoid factor, antinuclear antibodies, anti-Ro/SSA, and anti-La/SSB (27, 23, 2, and 0 percent versus 87, 90, 100, and 100 percent, respectively).

Dacryoadenitis and ocular and orbital inflammatory disease — Patients with IgG4-related ophthalmic disease, primarily involving the lacrimal gland (IgG4-related dacryoadenitis), have also been identified [72,73]. IgG4-related ophthalmic disease is encountered in approximately 17 to 23 percent of patients with IgG4-RD [74-76]. Bilateral lacrimal gland involvement is typical, even though the onset of clinical disease in the two glands may be asynchronous. Concurrent salivary gland involvement is common, and extra-ophthalmic manifestations are seen in approximately 70 to 80 percent of the patients [74-76].

IgG4-RD appears to account for 25 to 50 percent of orbital pseudotumors, including those originally diagnosed before recognition of IgG4-RD as "idiopathic orbital inflammation" or "orbital benign lymphoid hyperplasia." 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 [77].

IgG4-RD is also recognized as a cause of orbital myositis (IgG4-related orbital myositis), and it is orbital myositis that leads most often to proptosis among patients with this disease [78,79]. The orbital myositis associated with IgG4-RD is typically painless and is not associated with elevations in serum creatine kinase levels, but it can lead to substantial and sometimes permanent difficulties with extraocular muscle movements, eg, diplopia in certain fields of vision. Histologic and serologic findings are similar to those seen in patients with sialadenitis and in other tissues. Storiform fibrosis is not a consistent finding among different studies, and it seems to be more pronounced in samples obtained from dacryoadenitis rather than from orbital pseudotumors. Obliterative phlebitis is usually absent [74-76].

It is not certain whether IgG4-RD predisposes to the development of ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphomas or other lymphomas. Several such cases have been reported, but additional studies are required [80-82]. One study has indicated that a history of malignancy may itself be a risk factor for the development of IgG4-RD, rather than the converse [83]. On the other hand, a meta-analysis of 10 studies found that the standardized incidence ratio (SIR) for lymphoma in IgG4-RD patients was higher in patients with IgG4-RD compared with the general population (SIR 69.2, 95% CI 3.9-1223.0) [84].

Retroperitoneal fibrosis and related disorders — Retroperitoneal fibrosis is one of the most commonly encountered subsets of IgG4-RD, affecting 3 to 19 percent of these patients [85]. Several small case series suggest that IgG4-RD is responsible for a majority of cases of retroperitoneal fibrosis previously regarded as "idiopathic" [86-90]. It is estimated that IgG4-RD is responsible for approximately 30 to 60 percent of the total retroperitoneal fibrosis cases [85]. IgG4-related retroperitoneal fibrosis is particularly likely to involve the infrarenal aorta and to affect the iliac arteries simultaneously. Extraperitoneal involvement concurs in most but not all cases [85,91,92]. Chronic inflammatory and fibrotic change can involve regional tissues, such as the ureters, leading to obstructive uropathy. In some cases, the syndrome is responsive to glucocorticoids. The diagnosis of IgG4-RD in this setting can be challenging because of the advanced fibrotic changes typically observed in this condition. Acute phase reactants and IgG4 serum levels are often but not always normal or at least lower on average than the levels usually observed in other patients with IgG4-RD [85,93]. Retroperitoneal fibrosis is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis" and "Treatment of retroperitoneal fibrosis".)

Cases of patients with sclerosing mesenteritis, sclerosing mediastinitis, and multifocal fibrosclerosis have also been reported associated with IgG4-RD [94-96]. (See "Sclerosing mesenteritis", section on 'Etiology and pathogenesis'.)

Vascular involvement — IgG4-RD vascular involvement is seen in approximately 15 to 25 percent of patients with IgG4-RD [97-100]. The aorta is most commonly affected. However, the iliac, the carotid, and the coronary arteries can also be involved [100]. It is usually expressed as arterial wall thickening, but aneurysms and stenoses have also been described [100,101].

Aortitis and periaortitis — IgG4-RD has been recognized as one of the causes of noninfectious aortitis [89]. A series of patients with thoracic lymphoplasmacytic aortitis or with inflammatory abdominal aortic aneurysms and abdominal periaortitis has been identified in retrospective pathologic studies of patients who had undergone aortic resections [89,102,103]. Patients with IgG4-related aortitis and periaortitis do not have any specific symptomatology, other than that produced by the concurring aneurysms when present or by the involvement of adjacent tissues (eg, ureters) [85,97]. Acute phase reactants and IgG4 serum levels are usually but not always elevated [85]. (See "Epidemiology, risk factors, pathogenesis, and natural history of abdominal aortic aneurysm", section on 'Inflammation and the Th2 response'.)

IgG4-related aortitis – IgG4-related aortitis is present in approximately 8 percent of patients with IgG4-RD, with the thoracic being affected more commonly compared with the abdominal aorta [85]. In a study of 638 patients who underwent thoracic aortic resection over a five-year period in a North American hospital, three of four patients with lymphoplasmacytic aortitis exhibited histology characteristic of IgG4-RD [102]. These three patients represented 9 percent of the 33 cases identified in the study with noninfectious aortitis, or 0.5 percent of the entire series of thoracic aortic resections. These three patients and three other reported patients were all males between the ages of 65 and 74 [89].

Similarly, in a series of 125 patients reported from a hospital in Japan, two patients with IgG4-related aortitis were identified among 120 patients with thoracic aortic resections (1.6 percent) [104]. Three additional patients with atherosclerotic changes and without extra-aortic involvement by IgG4-RD also had similar infiltrates of IgG4-positive plasma cells. Whether patients with prominent atherosclerotic changes should also be included among patients with IgG4-RD remains uncertain [89,104].

IgG4-related periaortitis – Periaortitis is encountered in approximately 20 to 36 percent of patients with IgG4-RD [85,105]. The abdominal aorta is involved more commonly than the thoracic aorta [85]. Four of 10 patients with inflammatory abdominal aortic aneurysms identified at a medical center in Japan over a 15-year period had findings consistent with IgG4-RD, including infiltration with IgG4-positive plasma cells and elevated serum levels of IgG4 [103]. Patients ranged in age from 58 to 72 years. Inflammatory abdominal aortitis may be associated with retroperitoneal fibrosis [89]. In another study from Japan, periaortitis/periarteritis was identified in 36 percent of patients with IgG4-RD. Four types have been identified. In all of them, the infrarenal artery portion of the abdominal aorta was involved. Iliac arteries and ascending thoracic aorta were also affected in approximately 20 and 12.3 percent of the patients, respectively. Patients responded well to treatment with glucocorticoids. However, approximately 20 percent of the patients experienced worsening of luminal dilatation [105].

In a study in which the radiographic studies performed in 160 IgG4-RD patients from a single center were reviewed, primary large blood vessel disease, with inflammation of the vessel wall and secondary vascular involvement characterized by the presence of perivascular soft tissue, were found in 8.1 and 14.3 percent of the patients, respectively [97].

Thyroid disease — Riedel's thyroiditis is IgG4-RD of the thyroid gland. It is a rare form of thyroiditis that presents as a hard goiter that can produce symptoms related to pressure on adjacent tissues (eg, dyspnea, dysphagia, hoarseness). Cytology is not always diagnostic, and the diagnosis is usually made after thyroid resection, which is often performed to rule out malignancy and to alleviate clinical symptoms [106]. On biopsy, storiform fibrosis, presence of obliterative phlebitis, and an elevated IgG4 to IgG ratio are suggestive of Riedel's thyroiditis. However, other forms of thyroiditis, such as chronic autoimmune (Hashimoto's) thyroiditis, may also exhibit some of these features (see "Diagnosis and differential diagnosis of IgG4-related disease", section on 'Differential diagnosis'). Riedel's thyroiditis is discussed in detail elsewhere. (See "Infiltrative thyroid disease", section on 'Association with chronic autoimmune thyroiditis (Hashimoto's thyroiditis)' and "Infiltrative thyroid disease", section on 'Riedel's thyroiditis'.)

Lung and pleural disease — Multiple reports have demonstrated IgG4-related respiratory disease, which may be asymptomatic or present with cough, hemoptysis, dyspnea, pleurisy, or chest pain; pseudotumors and interstitial pneumonia have been associated with type 1 AIP [107-111]. Visceral or parietal pleural thickening may also occur. The affected tissues exhibit characteristic lymphoplasmacytic infiltrates enriched in IgG4-positive plasma cells, interspersed – usually but not always – with abundant storiform fibrosis (image 6). Four patterns of lung involvement have been described [111,112]:

Solid nodular

Bronchovascular (with thickening of bronchovascular bundles and interlobular septa)

Alveolar interstitial (with honeycombing, bronchiectasis, and diffuse ground-glass opacities)

Round-shaped, ground-glass opacities

Sclerosing mediastinitis, mediastinal adenopathy, or hilar adenopathy have been described in patients with IgG4-RD and may lead to airway narrowing from lymph node enlargement or mediastinal fibrosis with airway entrapment [113,114]. However, tracheobronchial stenosis has also been described in cases without lymph node enlargement [115,116].

The pulmonary manifestations of IgG4-RD may mimic sarcoidosis [117,118]. In one study of patients suspected of having sarcoid with bilateral hilar adenopathy and/or lung nodules on CT of the chest, patients with IgG4-RD were identified among a subset with elevated serum IgG4; they exhibited significantly higher levels of bronchoalveolar lavage IgG4, IgG4/IgG, and IgG4/IgG3 compared with those with normal serum IgG4 levels [117].

Specific criteria have been proposed for the diagnosis of IgG4-related respiratory disease [119].

Interstitial pneumonitis associated with IgG4-RD is discussed separately. (See "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'IgG4-related disease'.)

Kidney disease — The most common manifestation of IgG4-related kidney disease is TIN [120-123]. Affected patients tend to be males, middle-aged and older. The histopathology and other laboratory characteristics are similar to those observed in patients with type 1 AIP [123]. The histologic findings include lymphoplasmacytic infiltration of the kidney interstitium and the presence of storiform fibrosis (image 7). Immunohistochemistry of kidney biopsy tissue demonstrates increased numbers of IgG4-positive plasma cells (image 8). Nodular lesions mimicking renal cell carcinoma may be seen.

In a study of 153 patients with suspected IgG4-RD, retrospectively collected from multiple medical centers in Japan, 23 patients (15 percent) were identified with TIN secondary to IgG4-RD, all but one of whom (96 percent of TIN patients) exhibited involvement of other organs [123]. These extrarenal manifestations included sialadenitis (83 percent), lymphadenopathy (44 percent), AIP (39 percent), dacryoadenitis (30 percent), lung lesions (26 percent), and others in individual patients. In addition to TIN, 3 of the 23 patients also had mild mesangioproliferative GN, and one each had findings of membranous nephropathy and of focal segmental endocapillary hypercellularity.

Symptoms were usually associated with the extrarenal manifestations, rather than the kidney abnormalities, although edema was seen in two patients. Kidney changes were recognized due to urinary abnormalities, kidney dysfunction, and/or imaging abnormalities, including renal parenchymal lesions on CT and increased kidney uptake with gallium citrate scintigraphy.

Patients with IgG4-related TIN are often profoundly hypocomplementemic, with levels of serum C3 and C4 hypocomplementemia that resemble those seen in SLE and mixed cryoglobulinemia [11]. The basis of hypocomplementemia in IgG4-RD is not entirely clear, as IgG4 itself binds complement poorly. It is possible that other IgG subclasses (eg, IgG1 or IgG3) are responsible for complement activation in this setting. It is also true that a significant minority of patients with IgG4-related TIN have normal serum complement levels. The role of the complement system in IgG4-RD remains to be elucidated.

In another retrospective study from Australia, it was shown that IgG4-related TIN represented 1 percent of the total kidney biopsies performed over a 10-year period and 13 percent of all biopsies exhibiting TIN that was independent of glomerular disease [124].

IgG4-related membranous nephropathy is much less common than IgG4-related TIN, but these two kidney complications sometimes occur together [125]. In a series of nine patients with IgG4-related membranous GN, five of the patients had concurrent IgG4-related TIN, and seven exhibited extrarenal involvement by IgG4-RD [125,126]. None of the patients with IgG4-RD were positive for phospholipase A2 receptor on biopsy, although it is present in a majority of patients with primary membranous GN. (See "Membranous nephropathy: Pathogenesis and etiology", section on 'Systemic lupus erythematosus and other autoimmune disorders'.)

Other involved organs and tissues — Involvement of other organs and tissues by IgG4-RD, which has been described in additional case reports and small case series, includes:

Skin disease, including a subset of cutaneous pseudolymphoma. The lesions typically appear on the scalp, face, neck, and pinna of the ear [127-129]. Papules, plaques, and nodules are common cutaneous manifestations, while macules and bullae are rarely seen [130].

IgG4-hepatopathy, resembling autoimmune hepatitis, and hepatic inflammatory pseudotumor [131,132].

Lymphoplasmacytic gastritis associated with AIP [133].

Sclerosing mastitis and inflammatory pseudotumors of the breast [134,135].

Central nervous system (CNS) involvement, with hypopituitarism associated with IgG4-related hypophysitis [136,137] and pachymeningitis being the most common manifestations [138].

Prostatitis [139].

IgG4-related disease of the ovary [140].

Constrictive pericarditis [4,141,142].

Nasopharyngeal disease [143,144].

Midline-destructive lesion [145].

Amyloidosis, described in a patient who developed renal amyloidosis in the context of IgG4-RD [146].

Coronary artery disease with aneurysm formation [147-149].

Fasciitis [150].

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) is an increasingly recognized syndrome of unknown etiology, which is comprised of a collection of disorders that share specific pathologic, serologic, and clinical features. Patients often present with subacute development of a mass in the affected organ or diffuse enlargement of an organ. It is more common in middle-aged and older males, is also seen in females, and has been reported in children. Lymphadenopathy is common, and symptoms of asthma or allergy may be present. A good initial therapeutic response to glucocorticoids is also characteristic. (See 'Pathogenesis' above and 'Lymphadenopathy' above and 'Epidemiology' above and 'Clinical manifestations' above and 'Overview of manifestations' above and "Diagnosis and differential diagnosis of IgG4-related disease".)

The hallmarks of IgG4-RD are lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and small lymphocytes, which may be accompanied by fibrosis, obliterative phlebitis, and modestly increased tissue eosinophils. The fibrosis associated with IgG4-RD usually has a characteristic "storiform" pattern, typified by a cartwheeling appearance of the arranged fibroblasts and inflammatory cells (picture 1 and picture 2). The majority of patients have elevated serum levels of IgG4. (See 'Definition and histopathology' above.)

The pathogenesis of IgG4-RD remains incompletely understood, but there is growing evidence that the disease is autoimmune, with an important role for T cells, especially CD4+ and T-follicular helper cells (Tfh), and that the IgG4 antibodies are not themselves pathogenic. (See 'Pathogenesis' above.)

It is typical for several disease manifestations to occur in the same patient. Common manifestations of IgG4-RD include the following (see 'Clinical manifestations' above and 'Overview of manifestations' above and "Diagnosis and differential diagnosis of IgG4-related disease"):

Type 1 autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (see 'Autoimmune pancreatitis' above and 'IgG4-related sclerosing cholangitis' above and "Autoimmune pancreatitis: Clinical manifestations and diagnosis")

Mikulicz disease (or Mikulicz syndrome) and sclerosing sialadenitis (Küttner tumor), inflammatory orbital pseudotumor, and chronic sclerosing dacryoadenitis (see 'Salivary and lacrimal gland involvement' above)

A subset of idiopathic retroperitoneal fibrosis and related disorders (see 'Retroperitoneal fibrosis and related disorders' above)

Chronic sclerosing aortitis and periaortitis (see 'Aortitis and periaortitis' above)

Riedel's thyroiditis and a subset of Hashimoto's thyroiditis (see 'Thyroid disease' above)

IgG4-related interstitial pneumonitis and pulmonary inflammatory pseudotumors (see 'Lung and pleural disease' above)

IgG4-related kidney disease, particularly tubulointerstitial nephritis (TIN) (see 'Kidney disease' above)

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Topic 16155 Version 26.0

References

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