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Clinical manifestations and diagnosis of IgG4-related disease

Clinical manifestations and diagnosis of IgG4-related disease
Literature review current through: Jan 2024.
This topic last updated: Jan 29, 2024.

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

Organs affected by IgG4-RD share pathologic, serologic, and clinical features. Before its recognition as a unified disease in the early 2000s, the diseases discussed in this topic had been presumed to be unrelated, single-organ disorders [4-6].

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

Type 1 autoimmune pancreatitis (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).

EPIDEMIOLOGY — In a 2023 study, the overall incidence of IgG4-RD was estimated to be 0.78 to 1.39 per 100,000 person-years [7]. The epidemiology of specific forms of IgG4-RD is discussed below.

CLINICAL FEATURES

Spectrum of disease — Immunoglobulin G4-related disease (IgG4-RD) can involve one or multiple organs, and manifestations of this disease have been demonstrated in nearly every organ system [1,2,8,9]. Patients often present with subacute development of a mass in the affected organ or diffuse enlargement of an organ [1,5,10].

Patients often feel well at the time of diagnosis. Lymphadenopathy is common, but patients are generally afebrile [11]. However, symptoms of asthma or allergy are present in approximately 40 percent of patients. Additionally, patients with multiorgan disease often lose substantial amounts of weight (eg, 20 to 30 pounds), which may be due to IgG4-related autoimmune pancreatitis (AIP). (See 'Autoimmune pancreatitis' below.)

IgG4-RD is often recognized incidentally based on a radiologic finding or histopathologic examination of a tissue specimen. Imaging studies (eg, computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]) may demonstrate diffuse or focal organ lesions (usually a mass or swelling).

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

Autoimmune pancreatitis — The salient issues regarding IgG4-related AIP are briefly outlined here. An overview of AIP is provided elsewhere. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis".)

Nomenclature – Two types of AIP have been defined. Type 1 AIP (which is associated with IgG4-RD) is also called lymphoplasmacytic sclerosing pancreatitis [12]. Type 2 AIP (which is not associated with IgG4-RD) is sometimes called either idiopathic duct-centric chronic pancreatitis (IDCP) or granulocyte-positive epithelial pancreatitis [13,14]. 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 [14,15]. AIP is discussed in detail separately. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis", section on 'Clinical features'.)

Epidemiology – AIP has been estimated to account for 2 percent of patients with chronic pancreatitis [16].

The prevalence of type 1 AIP in Japan has been estimated to be 0.82 per 100,000 persons. However, this is likely to be an underestimate because the study was performed when IgG4-RD was a newly described condition [16,17].

Type 2 AIP (which is not associated with IgG4-RD) appears to be much less common than type 1 AIP and is sometimes associated with inflammatory bowel disease [18].

Clinical features – Type 1 AIP often presents as a pancreatic mass or as painless obstructive jaundice and can be mistaken for pancreatic cancer. Patients with type 1 AIP may exhibit acute, recurrent, or chronic pancreatitis. 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, IgG4-related salivary gland involvement, or other disease manifestations. These disease manifestations are discussed in greater detail below.

Imaging features – Radiologic features of 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. The radiologic findings in types 1 and 2 AIP are similar, and the two entities cannot be distinguished on the basis of their imaging features. Other imaging features of AIP are discussed elsewhere. (See "Autoimmune pancreatitis: Clinical manifestations and diagnosis", section on 'Imaging findings'.)

IgG4-related sclerosing cholangitis

Epidemiology – IgG4-related sclerosing cholangitis is present in more than 70 percent of patients with IgG4-related AIP but sometimes occurs as isolated cholangitis in the absence of pancreatic disease [5]. (See 'Autoimmune pancreatitis' above.)

Clinical features – IgG4-related sclerosing cholangitis and primary sclerosing cholangitis have similar clinical presentations, which include abdominal discomfort, diarrhea, malaise, jaundice, and pruritus. However, many patients with IgG4-related sclerosing cholangitis are asymptomatic at the time of diagnosis.

Patients with IgG4-related sclerosing cholangitis often have extrabiliary manifestations of IgG4-RD [19,20]. The combination of biliary tract and pancreatic disease is nearly diagnostic of IgG4-RD.

Imaging features – Biliary tract imaging of IgG4-related sclerosing cholangitis is characterized by diffuse or segmental narrowing of the intrahepatic and/or extrahepatic bile duct, associated with thickening of the bile duct wall, but these features may not be present in all cases [21].

Lymphadenopathy

Epidemiology – Asymptomatic IgG4-related lymphadenopathy is common, occurring in 41 to 80 percent of patients with AIP [22,23].

Clinical features – The lymphadenopathy is generally non-tender and the nodes themselves are rubbery rather than hard. The lymphadenopathy is often asymptomatic at the time of diagnosis. However, it may also present with symptoms due to impingement on other organs. The mediastinal, hilar, intraabdominal, and axillary lymph nodes are most commonly involved; multiple groups of lymph nodes are often involved simultaneously [24]. Individual nodes are typically no more than 2 centimeters in diameter but may range up to 5 centimeters [25]. IgG4-related lymphadenopathy may be the initial or only manifestation of IgG4-RD in a given patient [26].

Imaging features – Multiple imaging studies (eg, ultrasound, CT, MRI, gallium-67) may be used to detect IgG4 lymphadenopathy. However, IgG4-related lymphadenopathy may not enhance, and the radiologic characteristics are not specific for this diagnosis.

Salivary gland involvement

Nomenclature – Various combinations of the salivary glands can be involved in IgG4-RD. Mikulicz disease refers to the simultaneous enlargement of the lacrimal, parotid, and submandibular glands. Küttner tumor refers to bilateral sclerosing sialadenitis of the submandibular glands [26].

Epidemiology – Nearly 40 percent of patients with IgG4-related pancreatitis also have salivary or lacrimal gland involvement. Unlike AIP and other forms of IgG4-RD, IgG4-RD of the salivary glands affects males and females equally [23,27]

Clinical features – Major salivary gland (parotid or submandibular) involvement is a common feature of IgG4-RD.

Parotiditis and submandibular sialadenitis present with bilaterally symmetric, tender masses between the ear and jaw (ie, parotid gland) or beneath the jaw (ie, submandibular gland). The sublingual glands may also be affected, although their enlargement is often more difficult to detect on physical examination.

AIP is detected in approximately 17 percent of patients presenting with IgG4-related sialadenitis [22,27]. Sialadenitis often presents prior to AIP in patients who develop both conditions [28]. (See 'IgG4-related sclerosing cholangitis' above.)

Imaging features – Ultrasound may identify abnormalities associated with IgG4 salivary gland disease, such as masses and decreased echogenicity [29]. Other imaging studies (eg, CT, MRI) may be useful for identifying salivary gland enlargement, which may not enhance. MRI of an involved gland may be hypointense on T2 imaging, although this finding is not specific for IgG4-RD [30].

Ultrasound may be useful to distinguish salivary gland enlargement due to Sjögren’s disease versus IgG4-RD [31]. On ultrasound, diffuse inhomogeneity of the salivary gland with anechoic or hypoechoic areas is more characteristic of Sjögren’s disease than other causes. Other imaging modalities (eg, CT, MRI) may detect enlargement of the salivary glands consistent with IgG4-RD. However, findings from these other imaging modalities are not specific for IgG4-RD.

Dacroadenitis and ocular and orbital inflammatory disease

Nomenclature – Many patients diagnosed as having idiopathic orbital inflammation, orbital benign lymphoid hyperplasia, or idiopathic orbital myositis would now be diagnosed as having a form of IgG4-RD.

Epidemiology – IgG4-related ophthalmic disease is encountered in approximately 17 to 23 percent of patients with IgG4-RD and may involve the orbital and periorbital tissues, including the extraocular muscles [32-34]. IgG4-RD appears to account for 25 to 50 percent of orbital pseudotumors. Depending upon the diagnostic criteria used, IgG4-RD accounts for approximately 5 to 25 percent of cases originally diagnosed as nongranulomatous idiopathic orbital inflammation [35].

Clinical features – IgG4-related ophthalmologic disease presents clinically as proptosis and periocular swelling [36,37]. IgG4-related dacryoadenitis may also lead to dry eyes and is typically bilateral, 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 patients with IgG4-related salivary disease [32-34]. (See 'Salivary gland involvement' above.)

IgG4-related ophthalmologic disease may present concurrently with lymphoma of the head and neck. It is not certain whether IgG4-RD predisposes to the development of ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphomas or other lymphomas [38-40]. 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 [41]. However, 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) [42].

Imaging features – Both CT and MRI may identify enlargement of the extraocular structures, although these findings are not diagnostic of IgG4-RD. In a study of 27 patients with IgG4-RD affecting the orbits, bilateral enlargement of the extraocular muscles, especially the lateral rectus, was the most common finding, although a minority of patients also had an infiltrative process affecting the orbital fat (44 percent) or optic nerve (30 percent) [43].

Retroperitoneal fibrosis and related disorders

Nomenclature – Sclerosing mesenteritis, sclerosing mediastinitis, and multifocal fibrosclerosis are all forms of retroperitoneal fibrosis (RPF), which are often due to IgG4-RD [44-46].

Epidemiology – IgG4-RD is responsible for approximately 30 to 60 percent of all RPF cases [47]. Retroperitoneal fibrosis is one of the most commonly encountered subsets of IgG4-RD, affecting 3 to 19 percent of these patients [47].

Clinical features – IgG4-related RPF generally involves the infrarenal aorta and the iliac arteries simultaneously. Extraperitoneal involvement (eg, obstructive uropathy) concurs in most cases [47-49]. Clinically, patients with RPF may present with flank pain due to obstructive uropathy and hydronephrosis. Other manifestations of obstructive uropathy are discussed elsewhere. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis", section on 'Clinical features'.)

IgG4-related RPF can also present with nonspecific symptoms such as low back or abdominal pain. Acute phase reactants and IgG4 serum levels are often normal (or lower on average than the levels usually observed in other patients with IgG4-RD) [47,50].

Imaging features – CT and MRI may identify a soft tissue density around the aorta and iliac arteries, which may not enhance. Both modalities may be used to evaluate for ureteral obstruction, but MRI has the advantage of not requiring intravenous contrast. MRI of the mass may be hypointense on T2 imaging, unless there is active inflammation, in which case the T2 images may be hyperintense [51].

Vascular involvement — IgG4-RD vascular involvement is seen in approximately 15 to 25 percent of patients with IgG4-RD [52-55].

Patients with IgG4-related periaortitis and aortitis generally have nonspecific symptoms caused by the aneurysm (when present) or by the impingement of adjacent tissues (eg, ureters, leading to hydronephrosis) [47,52]. Acute phase reactants and IgG4 serum levels are usually but not always elevated [47].

IgG4-related periaortitis – Periaortitis, which may include RPF, is encountered in approximately 20 to 36 percent of patients with IgG4-RD [47,56]. IgG4-related periaortitis typically involves the infrarenal abdominal aorta and the iliac vessels [47]. The thoracic aorta may be involved in approximately 12 percent of patients [56]. Inflammatory abdominal aortitis is associated with RPF and may be discovered incidentally during an evaluation for RPF [57]. (See 'Retroperitoneal fibrosis and related disorders' above.)

IgG4-related aortitis – IgG4-related aortitis is present in approximately 8 percent of patients with IgG4-RD and represents between 2 and 9 percent of all patients with noninfectious aortitis [58,59]. IgG4-related aortitis has been reported to affect males between the ages of 65 and 74 [57].

Patients with IgG4-related aortitis may have prominent aortic atherosclerosis [57,59] (see 'Other organ involvement and multisystem disease' below). The thoracic aorta is more commonly affected than the abdominal aorta [47]. The iliac, carotid, and coronary arteries can also be involved [55,60]. Arterial wall thickening is typical of IgG4-related vascular disease, but aneurysms and stenoses have also been described [55,61].

The imaging characteristics of IgG4-related aortitis are similar to the aortitis of Takayasu arteritis. Imaging of aortitis is discussed elsewhere. (See "Clinical features and diagnosis of Takayasu arteritis" and "Clinical features and diagnosis of Takayasu arteritis", section on 'Imaging'.)

Other manifestations — IgG4-RD may also affect the thyroid, lung, kidneys, and other organs.

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 [62]. On biopsy, storiform fibrosis, presence of obliterative phlebitis, and an elevated IgG4 to IgG ratio are suggestive of Riedel's thyroiditis. Other forms of thyroiditis, such as chronic autoimmune (Hashimoto's) thyroiditis, may also exhibit some of these features but are not considered to be part of the IgG4-RD spectrum. Riedel's thyroiditis is discussed in detail elsewhere. (See "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.

Four patterns of lung involvement have been described [63,64]:

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

Visceral or parietal pleural thickening may also occur.

Sclerosing mediastinitis, mediastinal adenopathy, and 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 [65,66]. However, tracheobronchial stenosis has also been described in patients without lymph node enlargement [67,68].

Kidney disease – There are no imaging findings specific to IgG4-related kidney disease, although extrarenal manifestations may help establish the diagnosis.

Tubulointerstitial nephritis – The most common manifestation of IgG4-related kidney disease is tubulointerstitial nephritis (TIN) [69-72]. IgG4-related interstitial nephritis most often presents with signs of acute or chronic kidney injury, mass lesion(s) in the kidney (potentially mimicking renal cell carcinoma), or both. Patients with IgG4-related kidney disease tend to be middle-aged (or older) males. Other clinical manifestations of acute interstitial nephritis is described in greater detail elsewhere. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Clinical features'.)

In a retrospective study of 153 patients with suspected IgG4-RD, 15 percent had TIN secondary to IgG4-RD, almost all of whom (96 percent) had other organ involvement, including sialadenitis, lymphadenopathy, AIP, dacryoadenitis, and lung lesions [72]. Symptoms were usually associated with the extrarenal manifestations rather than the kidney abnormalities.

Urinalysis is not useful for establishing a diagnosis of IgG4-related TIN. However, IgG4-related TIN may present with hypocomplementemia, which is a risk factor for relapse [8,73].

The histopathology and other laboratory characteristics of IgG4-related TIN are similar to those observed in patients with type 1 AIP [72]. (See 'Autoimmune pancreatitis' above.).

IgG4-related membranous nephropathy – IgG4-related membranous nephropathy is much less common than IgG4-related TIN, but these two kidney complications sometimes occur together [74]. In a series of nine patients with IgG4-related membranous glomerulonephritis (GN), five patients had concurrent IgG4-related TIN, and seven exhibited extrarenal involvement with IgG4-RD [74,75]. None of the patients with IgG4-RD was positive for the presence of anti-phospholipase A2 receptor (anti-PLA2R) antibodies on kidney biopsy tissues, in contrast to the majority (70 percent) of patients with primary membranous GN.

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 [76-78]. Papules, plaques, and nodules are common cutaneous manifestations, while macules and bullae are rarely seen [79].

IgG4-hepatopathy, resembling autoimmune hepatitis, and hepatic inflammatory pseudotumor [80,81].

Lymphoplasmacytic gastritis [82].

Sclerosing mastitis and inflammatory pseudotumors of the breast [83,84].

Central nervous system (CNS) involvement, with hypopituitarism associated with IgG4-related hypophysitis [85,86] and pachymeningitis being the most common manifestations [87].

Prostatitis [88].

IgG4-RD of the ovary [89].

Constrictive pericarditis [5,90,91].

Nasopharyngeal disease [92,93].

Midline-destructive lesion of the nose [94].

Amyloidosis, described in a patient who developed renal amyloidosis in the context of IgG4-RD [95].

Coronary artery disease with aneurysm formation [60,96-98].

Fasciitis [99].

EVALUATION

In whom to suspect — The possibility of immunoglobulin G4-related disease (IgG4-RD) should be suspected in patients with one of the characteristic patterns of organ or tissue involvement. (See 'Clinical features' above.)

In particular, IgG4-RD should be suspected in individuals 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 an otherwise unexplained mass lesion in any of the following organs: pancreas, biliary tree, orbits, lungs, kidneys, major salivary gland, or lacrimal gland

The combination of biliary tract and pancreatic disease, or isolated involvement of the bilateral submandibular glands, is nearly diagnostic of IgG4-RD.

For other presentations, 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. (See 'Serum IgG4' below.).

In some cases, a serum IgG4 is tested as part of a broad evaluation for evidence of autoimmunity. While we do not suggest this approach, finding a serum IgG4 concentration greater than five times the upper limit of normal should prompt consideration of IgG4-RD. However, an elevated serum IgG4 by itself is inadequate to establish a diagnosis of IgG4-RD.

History and physical — In general, the history and physical examination are not diagnostic of IgG4-RD. The goal of the history and physical is to identify manifestations that are potentially consistent with specific forms of IgG4-RD. These manifestations may assist with identifying the appropriate diagnostic tests to establish the diagnosis and to track the patient’s response to therapy over time. The history and physical should also be used to identify other potential sites of IgG4-RD involvement. (See 'Clinical features' above.)

The clinical features of IgG4-RD are subacute, typically developing over several months. Examples of IgG4-RD manifestations that can be detected on history and physical examination include the following:

Enlargement of the salivary glands on examination may be indicative of IgG4-RD. The salivary glands are typically nontender on examination. Bilateral involvement is most common, although patients may present with unilateral disease. (See 'Salivary gland involvement' above.)

Painless swelling in the superolateral orbit or eyelid swelling may be indicative of dacryoadenitis of the lacrimal glands, which is commonly associated with IgG4-RD. Involvement may be unilateral or bilateral. (See 'Dacroadenitis and ocular and orbital inflammatory disease' above.)

Ocular pain, diplopia, and proptosis may be the result of IgG4-related orbital disease, either through the development of an orbital pseudotumor or involvement of the extraocular muscles. Any diplopia associated with IgG4-RD should resolve when either eye is closed. (See 'Dacroadenitis and ocular and orbital inflammatory disease' above.)

Pruritus and jaundice may be late findings of autoimmune pancreatitis (AIP) type 1 or sclerosing cholangitis. (See 'Autoimmune pancreatitis' above.)

Other forms of IgG4-RD are discovered incidentally on imaging or as part of an evaluation of organ dysfunction. (See 'Clinical features' above.)

Laboratory evaluation

Serum IgG4 — We suggest measuring serum IgG4 levels in all patients suspected of IgG4-RD. Serum IgG4 is above the upper limit of normal in approximately two-thirds of patients with IgG4-RD and in the correct clinical setting may be strongly suggestive of a diagnosis of IgG4-RD. However, an elevated serum IgG4 in isolation cannot establish the diagnosis because of the following limitations:

High serum IgG4 is not diagnostic for IgG4-RD – An IgG4 level by itself is never adequate to establish the diagnosis of IgG4-RD in the absence of clinical and histopathologic confirmation.

Very high levels of serum IgG4 do not exclude alternative diagnoses. In a study examining 32,206 cases, 191 patients had IgG4 serum levels >5 times the upper normal limit; 25 percent had alternative diagnoses, such as malignancies, other autoimmune diseases, and infections [100].

Normal IgG4 does not rule out IgG4-RD – Serum IgG4 is normal in approximately 30 percent of patients who are ultimately diagnosed with IgG4-RD. A normal serum IgG4 level does not exclude this diagnosis [8,11,101,102].

Prozone effect may lead to false-negative IgG4 assays – The prozone effect describes false-negative IgG4 assays that occur in patients with very high levels of IgG4. The prozone effect may be corrected by dilution of the serum sample to reduce the antibody concentration.

This affect may explain some false-negative results in patients with a definite diagnosis of IgG4-RD. In one study, 10 of 38 patients with IgG4-RD had falsely low serum IgG4 levels because of the prozone effect [103].

Optimal IgG4 threshold for diagnosis unclear – A single cutoff is inadequate to evaluate serum IgG4 among patients with IgG4-RD. One study of serum IgG4 concentration measurements at a single institution over a 10-year period (2001 to 2011) compared 190 patients who had elevated serum IgG4 concentrations (mean: 234 mg/dL; range 135 to 1180 mg/dL) with 190 patients with normal IgG4 concentrations [101]. The study found the following:

The sensitivity of elevated serum IgG4 for a diagnosis of IgG4-RD was 90 percent. 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).

The specificity of elevated serum IgG4 for a diagnosis of IgG4-RD was 60 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.

-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.

-Analysis of the serum IgG4 to total IgG ratio did not improve these test characteristics.

Doubling the cutoff for IgG4 improved the specificity (91 percent) but decreased the sensitivity to only 35 percent.

Other laboratory tests — For patients with suspected IgG4, we check:

Total IgG

IgG subclasses

IgE

C3

C4

Serum protein electrophoresis (SPEP)

Patients with IgG4-RD often have elevated serum IgG4, IgG1, IgE, and hypocomplementemia. Large studies for the latter are lacking, but its frequency at the time of IgG4-RD diagnosis seems to be between 20 and 40 percent. Of note, there are data suggesting that hypocomplementemia at the time of diagnosis is linked with more active disease [104,105].

Additionally, IgG4-RD patients have polyclonal hypergammaglobulinemia with beta-gamma bridging, indicative of an inflammatory state [106]. Thus, an SPEP or total immunoglobulins can be useful in the initial evaluation of patients with possible IgG4-RD. However, serial monitoring is generally not indicated.

Other laboratory tests should be guided by the clinical manifestations. We do not test all patients suspected of IgG4-RD for every serologic abnormality that could potentially be associated with this diagnosis. However, some abnormalities may be identified as part of a broad clinical investigation that eventually leads to a diagnosis of IgG4-RD (see 'Clinical features' above). For example:

Cholestasis (including an elevated bilirubin and alkaline phosphatase) may be indicative of either AIP or IgG4-related sclerosing cholangitis. (See 'Autoimmune pancreatitis' above and 'IgG4-related sclerosing cholangitis' above.)

An elevated serum creatinine may be indicative of post-obstructive kidney disease, which can be caused by retroperitoneal fibrosis (RPF) occluding the ureter. (See 'Retroperitoneal fibrosis and related disorders' above.)

Other laboratory tests may be more useful to exclude alternate diagnoses. (See 'Differential diagnosis' below.)

Imaging — Identification of a mass or organ enlargement on imaging often raises suspicion for IgG4-RD. In patients who have not yet undergone imaging, we obtain imaging of the specific area of suspected involvement.

We use CT in most cases, although it cannot distinguish active inflammation from fibrosis, even with the use of contrast.

Positron emission tomography (PET) is a reasonable alternative, particularly when vascular involvement is suspected, although it may not be widely available. Additionally, masses associated with IgG4-RD may not be PET avid.

No imaging findings are diagnostic of IgG4-RD, and imaging findings may not distinguish IgG4-RD from other diagnoses.

Issues regarding the imaging of specific manifestations of IgG4-RD are discussed above. (See 'Clinical features' above.)

Biopsy

Role and performance of biopsy — We strongly prefer confirmation of the diagnosis by biopsy of an involved organ whenever possible. However, although histopathology findings are important to the diagnosis of IgG4-RD, such findings alone are never diagnostic of IgG4-RD. Diagnosing IgG4-RD requires consideration of the clinical, serological, radiologic, and pathologic data and exclusion of potential mimickers (eg, malignancy). (See 'Differential diagnosis' below.)

Core needle biopsy adequate for most patients – How to perform the biopsy 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 [11,23].

In a study reevaluating 72 biopsies from patients with IgG4-RD, core needle biopsies were comparable to surgical biopsies with regards to demonstrating features of IgG4-RD [107]. However, surgical biopsies displayed higher numbers of IgG4+ cells per high-power field (HPF).

Selection of biopsy site – In patients with multi-organ involvement, we do not biopsy all involved organs. Instead, we select a single organ to biopsy based on practical considerations (eg, accessibility of organ). We also do not use lip, lymph node, or gastrointestinal tract biopsies to establish the diagnosis for the following reasons:

In patients with IgG4-RD with salivary gland involvement, a lip biopsy (ie, biopsy of labial minor salivary glands) is helpful mainly to exclude other diseases such as Sjögren’s disease and lymphomas, but its sensitivity is quite low in diagnosing IgG4-RD. Biopsy of submandibular glands is more sensitive for diagnosing IgG4-RD in patients with swelling of these glands [108,109].

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 'Lymph node pathology' below.)

Biopsies of the intestinal tract 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.

IgG4 staining – IgG4 staining should be performed on all biopsies in patients suspected of IgG4-RD, although IgG4+ plasma cells may be seen in a wide range of diagnoses other than IgG4-RD.

Staining of previously obtained tissues for IgG4 may provide useful information [110]. 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.

Solid organ pathology — Biopsies of involved organs frequently demonstrate characteristic histopathologic features and immunohistochemical staining (picture 1). These findings include:

Lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and lymphocytes

Storiform fibrosis

Obliterative phlebitis

Tissue eosinophilia

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), Castleman disease, and other conditions [110]. Consequently, the diagnosis cannot be predicated entirely upon pathology findings, regardless of the intensity of IgG4-positive plasma cell infiltration.

For establishing a diagnosis of IgG4-RD, the histopathologic features are more important than tissue IgG4-positive cell counts and the ratios of IgG4- to IgG-positive cells [5,11,23,111,112]. The diagnosis of IgG4-RD cannot be predicated entirely upon the number of IgG4-positive plasma cells for the following reasons:

Many diseases are associated with large numbers of IgG4-positive plasma cells.

The number of IgG4-positive plasma cells per high-power field (HPF) that is regarded as consistent with or suggestive of IgG4-RD varies somewhat from tissue to tissue.

Generally, the minimum for making the diagnosis for most tissues is from 30 to 50 IgG4-positive cells per HPF.

However, in some organs or tissues (eg, kidney) only 10 IgG4-positive plasma cells per HPF may be sufficient.

Lymph node pathology — 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. (See 'Role and performance of biopsy' above.)

Although we do not recommend lymph node biopsy for establishing the diagnosis of IgG4-RD, lymph node biopsy may be important to exclude other conditions (eg, lymphoma, sarcoidosis, and Castleman disease). (See 'Differential diagnosis' below.)

Lymph node biopsies have been categorized into five histologic patterns, all of which feature abundant IgG4-positive cells. The patterns include:

Multicentric Castleman disease-like

Follicular hyperplasia

Interfollicular expansion

Progressive transformation of germinal center-like

Nodal inflammatory pseudotumor-like

IgG4-related lymphadenopathy generally demonstrates eosinophil infiltration but lacks fibrosis or phlebitis (which are common features of solid organ pathology in IgG4-RD) [11,113-115]. (See 'Solid organ pathology' above.)

DIAGNOSIS

Establishing the diagnosis — The diagnosis of immunoglobulin G4-related disease (IgG4-RD) is made when a patient meets both of the following criteria:

Clinical or radiologic evidence of tumor-like swelling of an involved organ.

Biopsy of the involved organ that demonstrates:

Lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells

Storiform fibrosis (typified by a cartwheel appearance of the arranged fibroblasts and inflammatory cells)

Obliterative phlebitis

The presence of these histologic findings (picture 2 and picture 3), often together with mild tissue eosinophilia (picture 4), is strongly suggestive of IgG4-RD (picture 2) [11,116].

The number of IgG4-positive plasma cells per high-power field (HPF) that is regarded as consistent with or suggestive of IgG4-RD varies somewhat from tissue to tissue. (See 'Solid organ pathology' above.)

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), developed the 2019 ACR/EULAR classification criteria for IgG4-related disease [117]. Classification is based on a three-step process as follows [117]:

Clinical, radiologic involvement and/or compatible histopathological findings in 1 of 11 organs.

Absence of exclusion criteria (32 clinical, serological, radiologic and pathological features).

Scoring ≥20 in eight weighted domains. The cutoff of 20 points offers a specificity and sensitivity of more than 97 and 82 percent when used to distinguish IgG4-RD from mimics of IgG4-RD.

However, these classification criteria may not identify all patients with IgG4-RD and should not be used as a substitute for a through clinicopathologic evaluation, as described above. (See 'Evaluation' above.)

Features that suggest alternate diagnoses — We are cautious in making a diagnosis in a patient who has one of the following features, which may be indicative of infection, malignancy, or another autoimmune disease [117]:

Persistent fever in the absence of infection

No objective response of the mass to glucocorticoids (eg, oral methylprednisolone 32 mg daily for two weeks)

Specific hematologic abnormalities (eg, simultaneous leukopenia and thrombocytopenia or substantial hypereosinophilia consistent with an idiopathic hypereosinophilic syndrome) (see "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis')

Autoantibodies suggestive of another autoimmune diagnosis (eg, antineutrophil cytoplasmic antibody, serum cryoglobulins, anti-Ro, La, Sm, ribonucleoprotein, or double-stranded deoxyribonucleic acid [dsDNA] antibodies) (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Diagnosis' and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Diagnosis')

Radiologic features suspicious for malignancy or infection

Rapid radiologic progression (ie, significant worsening in four to six weeks)

Long bone abnormalities consistent with Erdheim-Chester disease (see "Erdheim-Chester disease", section on 'Initial evaluation')

Splenomegaly [11,23,107,110]

Postdiagnostic evaluation — We do not perform total-body CT scans to detect asymptomatic or subclinical disease manifestations. Instead, we conduct a careful clinical assessment to look for evidence of additional organ involvement, followed by selected radiologic studies. If the radiologic studies identify a mass that is not clearly related to IgG4-RD, biopsy of the relevant organ may help confirm the diagnosis. (See "Treatment and prognosis of IgG4-related disease", section on 'Pretreatment evaluation'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of immunoglobulin G4-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 [118,119].

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

Pancreatic cancer – Autoimmune pancreatitis (AIP) may be difficult to distinguish clinically from adenocarcinoma of the pancreas. Painless jaundice may be seen with either condition, and both conditions may have elevated levels of serum IgG4 and IgG4-positive plasma cells in the affected tissue [120]. (See 'Autoimmune pancreatitis' above.)

Biopsy, either intraoperatively or obtained by endoscopic ultrasound, is the gold standard for distinguishing AIP from pancreatic cancer. However, 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.

When biopsy is nondiagnostic or unavailable, CT scan may be useful to rule out pancreatic cancer. Radiologic features of type 1 AIP that can help differentiate this diagnosis 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 [121,122].

When the diagnosis is still not clear, we treat empirically with glucocorticoids (eg, oral methylprednisolone 32 mg daily for two weeks). Patients with type 1 AIP usually exhibit substantial radiologic and clinical improvement following such a trial.

Adenocarcinoma of the pancreas is discussed elsewhere. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Diagnostic approach'.)

Primary sclerosing cholangitis – Distinguishing primary sclerosing cholangitis from IgG4-related sclerosing cholangitis is crucial because of the drastically different prognoses associated with these conditions. (See 'IgG4-related sclerosing cholangitis' above.)

Both entities present with cholestatic liver function tests, elevated serum IgG4, and narrowing of the intra- and extrahepatic bile ducts [123]. The clinical presentations and radiologic features of these conditions may be very similar. Additionally, biopsies performed via endoscopic retrograde cholangiopancreatography are seldom sufficiently deep to define the histopathologic features of IgG4-RD [124,125].

The following features may help distinguish primary sclerosing cholangitis from IgG4-related sclerosing cholangitis:

The simultaneous presence of bile duct involvement and pancreatic disease is nearly diagnostic of IgG4-RD. Isolated bile duct involvement sparing the pancreas can occur in IgG4-RD but is unusual [19,20].

Serum IgG4 concentrations greater than four to five times the upper limit of normal strongly favor IgG4-RD.

When the diagnosis is still not clear, we treat empirically with glucocorticoids (eg, oral methylprednisolone 32 mg daily for two weeks); patients who fail to improve symptomatically on this regimen are unlikely to have IgG4-related sclerosing cholangitis.

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 [126].

Primary sclerosing cholangitis is discussed elsewhere. (See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Cholangiocarcinoma – Cholangiocarcinoma and IgG4-related sclerosing cholangitis share multiple clinical and radiologic features, which may make these diagnoses difficult to distinguish. (See 'IgG4-related sclerosing cholangitis' above.)

The following features are more characteristic of cholangiocarcinoma rather than IgG4-related sclerosing cholangitis:

Obstructive jaundice

An enlarged pancreas

Lymphadenopathy

High serum bilirubin

High serum cancer antigen 19-9

Complete obstruction of the hilar or bile ducts as demonstrated by endoscopic retrograde cholangiopancreatography

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 [127].

Cholangiocarcinoma is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of cholangiocarcinoma", section on 'Diagnostic approach'.)

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 – Most patients diagnosed with idiopathic RPF actually have IgG4-RD [57,128-131]. (See 'Retroperitoneal fibrosis and related disorders' above.)

RPF related to IgG4-RD may be differentiated from other causes of RPF based 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.

However, confirmation of the diagnosis of IgG4-RD in this setting is often challenging because diagnostic pathology is often unavailable; when it is available, it often demonstrates nonspecific fibrotic changes.

When pathology is unavailable or nondiagnostic, the following features may help distinguish IgG4-related RPF from idiopathic RPF:

Extraperitoneal manifestations are present in more than half of patients with IgG4-related RPF [48].

Infrarenal periaortitis extending inferiorly to involve the iliac vessels is strongly suggestive of IgG4-related RPF.

Idiopathic RPF is discussed elsewhere. (See "Clinical manifestations and diagnosis of retroperitoneal fibrosis", section on 'Distinguishing between primary and secondary disease'.)

Aortitis and periaortitis – Both IgG4-RD and a number of noninfectious and infectious disorders can cause aortitis and periaortitis. (See 'Vascular involvement' above.)

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 [132].

When histopathology is unavailable or non-diagnostic, elevated serum IgG4, serum IgE, or antinuclear antibodies favors a diagnosis of IgG4-related aortitis over other diseases [133]. Additionally, various epidemiologic, clinical, and histopathologic features serve to differentiate IgG4-RD from other diseases. For example, patients with IgG4-related aortitis are typically older than those with Takayasu arteritis or Behçet syndrome [134]. (See "Clinical features and diagnosis of Takayasu arteritis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Diagnosis'.)

Fevers are extremely unusual in IgG4-RD. In patients with aortitis or periaortitis who present with fever, infection and malignancies, particularly unusual presentations of lymphoma, should be considered [135,136].

However, infections, with the possible exception of syphilis (now vanishingly rare as a cause of aortitis), seldom cause diffuse aortic disease. (See "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Cardiovascular'.)

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 disease and orbital inflammatory disease:

Sjögren's disease – Both Sjögren's disease and IgG4-related sialoadenitis and dacryoadenitis can exhibit prominent swelling of the parotid, submandibular, and lacrimal glands. (See 'Salivary gland involvement' above and 'Dacroadenitis and ocular and orbital inflammatory disease' above.)

These diagnoses can generally be distinguished based upon respective characteristic histopathologic and laboratory findings, as well as associated clinical features. For example, unlike Sjögren's disease, IgG4-related sialadenitis is less commonly associated with dry eyes, dry mouth, arthralgias, or autoantibodies (ie, rheumatoid factor, antinuclear antibodies, anti-Ro/SSA antibody, anti-La/SSB antibody) [111].

However, compared with Sjögren’s disease, IgG4-related sialadenitis is more commonly associated with allergic rhinitis, bronchial asthma, AIP, and interstitial nephritis.

Patients who fulfill criteria for both Sjögren's disease and IgG4-RD have been identified, although most of these patients would be clinically classified as having IgG4-RD [137].

Sjögren’s disease is discussed in detail elsewhere. (See "Diagnosis and classification of Sjögren’s disease", section on 'Diagnosis'.)

Orbital pseudotumor – 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 is a common manifestation of IgG4-RD [138]. However, the possibility of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis as a cause of orbital pseudotumor should be considered. (See 'Other manifestations' above and 'Other organ involvement and multisystem disease' below.)

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, kidney disease, and ANCA-associated vasculitis:

Lung disease – IgG4-RD of the lungs can exhibit many different and often overlapping patterns. Pulmonary involvement in IgG4-RD can mimic (and be mimicked by) several conditions, including sarcoidosis, neoplasms, ANCA-associated vasculitis, and interstitial lung disease associated with autoimmune diseases. (See 'Other manifestations' above.)

Features that can help distinguish IgG4-RD from other disorders include an association with other (nonpulmonary) manifestations of IgG4-RD and histopathologic characteristics on biopsy. In IgG4-RD of the lung:

IgG4+ plasma cells are frequent, although storiform fibrosis is not always present in lung biopsies [139,140].

Neutrophilic aggregates are sometimes observed in the lung in IgG4-RD, unlike in other tissues in IgG4-RD [139].

The disease extends along the bronchovascular bundle, leading to the thickening of bronchial walls and surrounding tissue [140].

Generalized lymphadenopathy – IgG4 lymphadenopathy may be difficult to distinguish from lymphadenopathy from other causes (eg, multicentric Castleman disease, Rosai-Dorfman disease, inflammatory myofibroblastic tumor), since the pathologic findings of IgG4 lymphadenopathy may be nonspecific. (See 'Lymphadenopathy' above.)

Unlike other forms of generalized lymphadenopathy, IgG4 lymphadenopathy generally:

Presents with other clinical or laboratory manifestations of IgG4-RD [25]

Has modest lymph node enlargement

Lacks constitutional features

Responds to treatment with glucocorticoids [11]

Patients with bilateral hilar lymphadenopathy due to IgG4-RD may be incorrectly diagnosed with sarcoidosis [141,142]. In one study of patients suspected of having sarcoid, a final diagnosis of IgG4-RD was more common among patients with an elevated serum IgG4. Patients with IgG4-RD also had significantly higher IgG4, IgG4/IgG ratio, and IgG4/IgG3 ratio in their bronchoalveolar lavage fluid [141].

Pulmonary sarcoid is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Initial evaluation'.)

Goiter – The fibrosing variant of chronic autoimmune (Hashimoto's) thyroiditis and Riedel's thyroiditis may be difficult to distinguish from IgG4-related autoimmune (Hashimoto's) thyroiditis [62,143-145]. (See 'Other manifestations' above.)

These diagnoses share some histopathologic characteristics, including an increased IgG4+ to IgG+ ratio in the thyroid gland. Some authors have hypothesized that the fibrosing variant of Hashimoto's thyroiditis might be an early form of Riedel's thyroiditis [144]. The presence of other organ involvement may help distinguish IgG4-related autoimmune thyroiditis from these other diagnoses.

Riedel's and Hashimoto's thyroiditis are discussed in detail elsewhere. (See "Infiltrative thyroid disease", section on 'Riedel's thyroiditis' and "Disorders that cause hypothyroidism", section on 'Chronic autoimmune (Hashimoto's) thyroiditis'.)

Kidney disease

Tubulointerstitial nephritis – Other forms of interstitial nephritis can mimic IgG4-related tubulointerstitial nephritis (TIN). (See 'Other manifestations' above.)

These include drug-related interstitial nephritis, chronic pyelonephritis, multicentric Castleman disease, and interstitial nephritis related to other autoimmune diseases (eg, Sjögren's disease, GPA).

On biopsy, there is an abundance of IgG4+ plasmacytes and storiform fibrosis, with tubular basement membrane immune complex deposition, but granulomatous inflammation, marked neutrophilic infiltration, and karyorrhexis are absent [146].

Interstitial nephritis is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Diagnosis'.)

Membranous glomerulonephritis – Idiopathic membranous glomerulonephritis (GN) may be difficult to distinguish from IgG4-associated membranous GN. However, immunostaining of the kidney tissue for the presence of anti-phospholipase A2 receptor (anti-PLA2R) antibodies may help distinguish these diagnoses.

In a series of nine patients with IgG4-related membranous GN, none of the patients with IgG4-RD had evidence of anti-PLA2R on kidney biopsy, although it is present in a majority of patients with primary membranous GN [74,75]. The presence of extrarenal manifestations of IgG4-RD may also help confirm the diagnosis of IgG4-associated membranous GN.

Granulomatosis with polyangiitis IgG4-RD sometimes presents as GPA with atypical features, such as pachymeningitis, orbital mass, or chronic periaortitis [147,148] (see 'Dacroadenitis and ocular and orbital inflammatory disease' above and 'Vascular involvement' above and 'Other manifestations' above). Moreover, tissue biopsies from patients with GPA can have substantial infiltrates of IgG4-positive plasma cells.

The pattern of organ involvement and signs of inflammation may help distinguish these entities. The ears, nose, throat, lungs, and kidneys are more commonly affected in GPA, 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 GPA [149].

Granulomatosis with polyangiitis is discussed in detail elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Vascular disease – Some patients diagnosed with an inflammatory abdominal aortic aneurysm actually have IgG4-RD [150]. An inflammatory abdominal aortic aneurysm is a form of chronic periaortitis that is associated with atherosclerotic disease and often presents with retroperitoneal fibrosis and acute phase reactant elevation.

In a study of 114 patients with abdominal aortic aneurysms who required surgery, 7 patients (6 percent) had pathologic findings consistent with IgG4-RD [151]. Only two of these patients had elevated serum IgG4 levels (ie, more than 1.35 g/L).

Because atherosclerotic inflammatory abdominal aortic aneurysms and IgG4-related periaortitis share many features, these diagnoses may be difficult to distinguish clinically. However, both diagnoses are treated with glucocorticoids, which may decrease the importance of differentiating these two diagnoses [152]. In a series of five patients with inflammatory abdominal aortic aneurysms treated with prednisone 5 mg twice daily, all patients experienced pain relief within a few weeks and radiographic improvement over 18 months [153]. However, the optimal dose and duration of glucocorticoid therapy for inflammatory abdominal aortic aneurysms is unclear.

The diagnosis and management of abdominal aortic aneurysms is discussed in detail elsewhere. (See "Management of symptomatic (non-ruptured) and ruptured abdominal aortic aneurysm", section on 'Symptomatic (non-ruptured) AAA' and "Clinical features and diagnosis of abdominal aortic aneurysm", section on '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

Clinical manifestations – Patients often present with subacute development of a mass or diffuse enlargement of the affected organ. Patients may be asymptomatic.

Autoimmune pancreatitis – Type 1 autoimmune pancreatitis (AIP; ie, lymphoplasmacytic sclerosing pancreatitis) is associated with immunoglobulin G4 (IgG4-RD). It can present as a pancreatic mass, painless obstructive jaundice, or pancreatitis. On CT, the pancreas is diffusely enlarged and surrounded by a halo of edema. However, radiologic studies do not distinguish type 1 AIP from type 2 AIP (which is not associated with IgG4-RD). (See 'Autoimmune pancreatitis' above.)

IgG4-related sclerosing cholangitis – IgG4-related sclerosing cholangitis may present with abdominal discomfort, diarrhea, malaise, jaundice, and pruritus. Biliary tract imaging of IgG4-related sclerosing cholangitis demonstrates diffuse or segmental narrowing of the intra- and/or extrahepatic bile duct, associated with thickening of the bile duct wall. However, radiologic studies may not distinguish IgG4-related sclerosing cholangitis from primary sclerosing cholangitis, pancreatic cancer, or cholangiocarcinoma. (See 'IgG4-related sclerosing cholangitis' above.)

Lymphadenopathy – Lymphadenopathy may be observed in the mediastinal, hilar, intrabdominal, or axillary regions and is commonly asymptomatic at the time of presentation. Lymph node biopsies are nonspecific, since increased numbers of IgG4 cells may be seen in lymph nodes for a variety of reasons. (See 'Lymphadenopathy' above and 'Lymph node pathology' above.)

Other manifestations – IgG4-RD may present as sialadenitis, dacryoadenitis, orbital pseudotumor, orbital myositis, retroperitoneal fibrosis (RPF), aortitis, and periaortitis. IgG4-RD may also involve the thyroid, lung, kidney, and other organ systems. (See 'Salivary gland involvement' above and 'Dacroadenitis and ocular and orbital inflammatory disease' above and 'Retroperitoneal fibrosis and related disorders' above and 'Vascular involvement' above and 'Other manifestations' above.)

Evaluation – IgG4-RD should be suspected in any patient presenting with any of the following (see 'In whom to suspect' above):

Pancreatitis of unknown origin

Sclerosing cholangitis

Bilateral salivary and/or lacrimal gland enlargement

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

Diagnosis – The diagnosis of IgG4-RD requires clinical or radiologic evidence of tumor-like swelling of an involved organ and a biopsy that demonstrates a lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells (eg, 30 to 50 per high-power field [HPF]), storiform fibrosis, and obliterative phlebitis. Serum IgG4 is elevated in two-thirds of patients. Some patients with IgG4-RD have hypocomplementemia and elevated serum IgG1 and IgE. However, IgG4-RD is a clinical diagnosis; serum, histologic, and radiologic studies are not diagnostic in isolation. (See 'Diagnosis' above and 'Biopsy' above and 'Laboratory evaluation' above and 'Imaging' above.)

The following features make IgG4-RD less likely:

Persistent fever

No response to glucocorticoids

Simultaneous leukopenia and thrombocytopenia

Hypereosinophilia

Autoantibodies suggestive of another autoimmune diagnosis (eg, antineutrophil cytoplasmic antibody [ANCA], serum cryoglobulins, anti-Ro, La, Sm, ribonucleoprotein, or dsDNA antibodies)

Radiologic features suspicious for malignancy or infection

Rapid radiologic progression (ie, significant worsening in four to six weeks)

Long bone abnormalities consistent with Erdheim-Chester disease

Splenomegaly

Differential diagnosis – The differential diagnosis of 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 and may be found in a wide range of unrelated disorders (table 1). Clinical assessment, radiologic studies, histology, and response to empiric courses of glucocorticoids (eg, methylprednisolone 32 mg daily for two weeks) may all play a role in distinguishing IgG4-RD from other causes. (See 'Differential diagnosis' above.)

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Topic 121220 Version 11.0

References

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