A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details
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IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.
KeywordsIgG4-related diseases Mikulicz’s disease Sjögren’s syndrome Autoimmune pancreatitis Castleman’s disease
- MHLW Japan
Ministry of Health, Labor and Welfare Japan
Lymphoplasmacytic sclerosing pancreatitis
Familial multifocal fibrosclerosis
In 1892, Dr. Johann von Mikulicz, also known as Jan Mikulicz-Radecki, published a paper describing a patient with symmetrical swelling of the lachrymal, parotid, and submandibular glands, with massive infiltration of these glands by mononuclear cells . Following reports describing similar patients, this condition was called Mikulicz’s disease (MD). In contrast, patients with similar symptoms, but with diseases such as leukemia, malignant lymphoma, and sarcoidosis, were reported to have Mikulicz’s syndrome . In 1930, Dr. Henrik Sjögren, an ophthalmologist, published a paper describing a woman with rheumatoid arthritis accompanied by keratoconjunctivitis sicca and severe swelling of the parotid glands, a condition that has been recognized as Sjögren’s syndrome (SS) . In 1953, Morgan and Castleman examined 18 patients with MD and concluded that this condition is one manifestation of SS . Since then, MD has attracted very little interest in western countries. In Japan, however, there have been many patients with MD, such that differences between MD and SS have been clarified [5, 6, 7]. For example, their gender distribution is quite different, in that MD occurs in both men and women, whereas SS occurs mainly in women. Second, patients with MD have relatively mild xerostomia and xerophthalmia, despite significant enlargement of their lachrymal and salivary glands. Further, MD is accompanied by more complications, such as autoimmune pancreatitis (AIP). Patients with MD show a better response to glucocorticoid therapy than patients with SS. Finally, it has become clear that MD is related to elevated serum IgG4 concentrations and infiltration of IgG4-positive cells [5, 6, 7, 8, 9].
Following the description of a patient with chronic pancreatitis due to an autoimmune mechanism , lymphoplasmacytic sclerosing pancreatitis (LPSP) was found to be a characteristic histopathological finding in patients with AIP . These findings led to the concept of AIP, which has characteristics similar to those of other autoimmune diseases, such as hypergammaglobulinemia, the presence of various autoantibodies, lymphocytic infiltration into pancreatic tissue, and good responsiveness to steroids . Following a report showing elevated serum IgG4 concentrations in patients with AIP , the pancreatic research team of the Ministry of Health, Labor and Welfare Japan (MHLW Japan) showed that AIP was related to IgG4 .
Unification of different nomenclatures for IgG4-related disease (IgG4RD)
Nomenclatures of IgG-related conditions
IgG4-related autoimmune disease
IgG4-associated multifocal systemic fibrosis
van der Vliet 
IgG4-related systemic disease
IgG4-related sclerosing disease
IgG4-related disease (IgG4-RD)
Systemic IgG4 plasmacytic syndrome (SIPS)
IgG4-related multi-organ lymphoproliferative syndrome (IgG4-MOLPS)
The name “IgG4-related sclerosing disease” is mainly based on the swelling of fibrous organs, such as the pancreas and retroperitoneum, whereas “SIPS” and “IgG4+MOLPS” are based on lymphoplasmacytic proliferation in glands and swollen lymph nodes without fibrosis. Although many patients with this condition (i.e., IgG4-related sclerosing disease, etc.) have lesions in several organs, either synchronously or metachronously, other patients show involvement of only a single organ. At this point, it is unclear whether the pathogenetic mechanism of this disease is systemic or whether it consists of manifestations in individual organs. In addition, several reports have described patients with IgG4-associated conditions concomitant with malignant tumors such as pancreatic [25, 26] and salivary  carcinomas, and ocular adnexal lymphoma . Therefore, using the term ‘systemic’ may lead to an incorrect diagnosis of an IgG4-related condition in a patient with malignant tumors in other organs. Based on these reasons, the members of the two MHLW Japan research teams agreed, at their second meeting in Kanazawa on February 11, 2010, to use the term “IgG4-related disease (IgG4RD)”.
General concept of IgG4RD
Prevalence of IgG4RD
Clinicopathological features of IgG4RD
Differences between IgG4-related MD and Sjögren’s syndrome
Diagnostic criteria of IgG4+ Mikulicz’s disease  (approved by the Japanese Society for Sjögren’s Syndrome 2008)
1. Symmetrical swelling of at least 2 pairs of lachrymal, parotid, or submandibular glands for at least 3 months
2. Elevated serum IgG4 (>135 mg/dl)
3. Histopathological features including lymphocyte and IgG4+ plasma cell infiltration (IgG4+ plasma cells/IgG+ plasma cells >50%) with typical tissue fibrosis or sclerosis
Differential diagnosis is necessary to distinguish IgG4+ Mikulicz’s disease from other distinct disorders, including sarcoidosis, Castleman’s disease, Wegener’s granulomatosis, lymphoma, and cancer. The diagnostic criteria for Sjögren’s syndrome (SS) may also include some patients with IgG4+ Mikulicz’s disease; however, the clinicopathological conditions of patients with typical SS and IgG4+ Mikulicz’s disease are different
Guidelines for diagnosis of IgG4RD (proposed by the Research Program for Intractable Disease Ministry of Health, Labor and Welfare Japan, G4 team)
Clinical features highly suggestive of IgG4RD
1. Symmetrical swelling of lachrymal, parotid, or submandibular glands
2. Autoimmune pancreatitis
3. Inflammatory pseudotumor
4. Retroperitoneal fibrosis
5. Suspicion of Castleman’s disease
Laboratory data highly suggestive of IgG4RD
1. Serum IgG4 >135 mg/dl
2. IgG4+ cells/IgG+ cells >40% in biopsy
Clinical features suggestive of IgG4RD
1. Unilateral swelling of at least one lachrymal, parotid, or submandibular gland
2. Orbital pseudotumor
3. Sclerosing cholangitis
5. Hypertrophic pachymeningitis
6. Interstitial pneumonitis
7. Interstitial nephritis
8. Thyroiditis/hypo-function of thyroid
10. Inflammatory aneurysm
Laboratory data suggestive of IgG4RD
1. Hypergammaglobulinemia of unknown origin
2. Hypocomplementemia or existence of immune complex
3. Increase of IgE or eosinophils
4. Tumefactive lesions or lymph node swelling detected by gallium scan or fluoro-D-glucose positron emission tomography (FDG-PET)
IgG4-related Küttner tumor
Küttner tumor, a unilateral sclerosing sialadenitis, is an IgG4RD . A common feature of MD and Küttner tumor is that both manifest sialadenitis, as in IgG4RD. Histologically, Küttner tumors are very severe fibrous sclerotic lesions containing IgG4-positive plasma cells . In contrast, fibrosis tends to be less severe in MD, although fibrosis in MD is frequently not examined extensively, because MD is generally diagnosed by the biopsy of minor labial salivary glands. Therefore, at present, it is difficult to set a strict boundary between MD and Küttner tumor.
IgG4-related autoimmune pancreatitis (IgG4-related AIP)
Subtypes of autoimmune pancreatitis (AIP) 
Subtype of AIP other nomenclatures
Type 1 AIP without GEL IgG4-related, LPSP
Type 2 AIP with GEL IgG4-unrelated IDCP
Asia > USA, Europe
Europe > USA > Asia
Male ≫ female
Male = female (NS)
Often obstructive jaundice
Often obstructive jaundice
Rare abdominal pain
Abdominal pain like acute pancreatitis
High serum IgG
High serum IgG4
Auto antibodies (+)
Auto antibodies (−)
Other organ involvement (OOI)
Unrelated to OOI
Histological examination by American and European pathologists of the resected pancreases of patients with chronic non-alcoholic pancreatitis revealed another histopathological pattern, called idiopathic duct-centric pancreatitis (IDCP) or AIP with granulocytic epithelial lesions (GELs), later called type 2 AIP [35, 36]. Type 2 AIP is characterized primarily by these GELs, often accompanied by destruction and obliteration of the pancreatic duct . Patients with type 2 AIP show swelling of the pancreas, but no or very few IgG4-positive plasma cells. Type 2 AIP has different clinicopathological features than type 1 AIP. Type 2 AIP shows no elevations in serum IgG4 or IgG, no autoantibodies, and no involvement of other organs, except for inflammatory bowel disease. Inflammatory bowel disease has been observed in approximately 30% of patients with type 2 AIP. Although type 1, or IgG4-related, AIP (LPSP type) often occurs in older men and is accompanied by a variety of extrapancreatic lesions, type 2, or neutrophil-related pancreatitis (IDCP/GEL type), has no gender bias, younger age at onset (often <40 years), and is frequently associated with inflammatory bowel disease. Thus, after a worldwide debate over the diagnostic criteria for AIP, IgG4-related pancreatitis has been defined as type 1 (LPSP type) and neutrophil-related pancreatitis has been defined as type 2 (IDCP/GEL type) .
IgG4-related sclerosing cholangitis (IgG4-related SC)
Extrapancreatic bile duct lesions are frequently associated with AIP. For example, 73% of patients with AIP have shown wall thickening or sclerosing changes in extrapancreatic bile ducts on endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS), though only 26% of patients with AIP demonstrated sclerosing changes by ERCP . However, many individuals without AIP have shown IgG4-related SC with isolated biliary tract involvement [38, 39]. In IgG4-related SC, stenosis is usually observed in the lower part of the common bile duct. The cholangiographic appearance of stenosis in the intrahepatic or hilar hepatic bile duct is very similar to that observed in PSC , a progressive disease of unknown etiology that ultimately results in liver cirrhosis. IgG4-related SC is associated with older age, male predominance, obstructive jaundice, weight loss, and abdominal discomfort . Although steroid therapy has shown mixed results in patients with PSC, IgG4-related SC responds dramatically to steroid therapy, as does IgG4RD . The histopathological features of IgG4-related SC are similar to those of AIP and include diffuse plasmacytic infiltration, marked interstitial fibrosis with a focal storiform-like pattern, and obliterative phlebitis.
IgG4-related kidney disease (IgG4-related KD)
The kidney is a frequent target organ in IgG4RD, with tubulointerstitial nephritis (TIN) and fibrosis and abundant IgG4-positive plasma cell infiltration being diagnostically important histopathological features of this disease [42, 43, 44]. Recently, the clinicopathological features of 23 patients with IgG4-related TIN were reported to be quite uniform and similar to those observed in patients with IgG4-AIP, including high serum concentrations of IgG4 and IgE, hypocomplementemia, and TIN with infiltration of large numbers of IgG4-positive plasma cells plus fibrosis .
Kidney diseases in IgG4RD include conditions other than renal parenchymal lesions, such as hydronephrosis associated with RPF and tumors of the renal pelvis and urethra. However, IgG4-related TIN is considered to be representative of IgG4 renal parenchymal lesions . Compared with other types of interstitial nephritis, IgG4-related TIN is often associated with extrarenal lesions, such as pancreatitis, sialadenitis, and lymphadenitis, and a high incidence of hypocomplementemia . Imaging often shows heterogeneous shadows in the kidneys, such as a mass or multiple nodules (findings that are not observed in other types of interstitial nephritis). Histopathologically, the renal tubulointerstitium shows the infiltration of many lymphocytes and plasmacytes, as well as fibrosis, and IgG4 immunostaining shows a number of IgG4-positive plasma cells . Although many studies have found no significant changes in the glomeruli, others have reported an association with glomerular lesions, including membranous nephropathy . In the near future, the Japanese Kidney Society expects to develop diagnostic criteria for IgG4-related KD.
IgG4-related pulmonary diseases (IgG4-related PD)
IgG4-related PD has been described as inflammatory pseudotumor, interstitial pneumonitis, organizing pneumonia, and lymphomatoid granulomatosis . Most (81%) patients with IgG4-related PD have been reported to be men, with a median age at diagnosis of 69 years , features similar to those of IgG4RD. Some patients present initially with respiratory symptoms, such as dry cough or dyspnea, whereas 75% of patients are asymptomatic and the disease is found incidentally by abnormal shadows on chest X-rays. Although IgG4-related PD is associated with a variety of radiologic abnormalities , diffuse lymphoplasmacytic infiltration has been observed in all lesions, with irregular fibrosis and obliterative vascular changes being more common in solid areas . Hilar and pancreatic accumulation of gallium-67 has been reported as characteristic of the active stage of AIP when serum IgG4 concentrations are high .
Radiographically, IgG4-related PD can be divided into two types, inflammatory pseudotumors and interstitial pneumonitis. Inflammatory pseudotumors have been described as nodular or mass lesions, or infiltration, and are characterized by radiating reticular shadows surrounding the tumor. Interstitial pneumonitis presents in most patients with reticular shadows, ground-glass opacity, and interstitial fibrosis in both lower lung fields .
Histopathologically, inflammatory pseudotumor is a plasma cell granuloma, with infiltration mainly by plasma cells and lymphocytes, irregular fibrosis, lymphoid follicle formation, findings of interstitial pneumonitis at the periphery of the nodule, obliterating phlebitis and arteritis, and eosinophilic infiltration . Interstitial pneumonitis is characterized by thickening of the alveolar septa due to infiltration by plasma cells and lymphocytes, and by diffuse fibrosis. Histopathologically, interstitial pneumonitis often shows a pattern previously classified as non-specific interstitial pneumonia (NSIP) . The diagnostic criteria for IgG4-related PD are now under consideration by the Japanese Respiratory Association.
IgG4-related Hashimoto’s thyroiditis (IgG4-related HT)
Hashimoto’s thyroiditis (HT) has been considered a well-defined clinicopathological entity, characterized by the presence of goiter and serum thyroid autoantibodies. Recently, a unique subtype of HT was described, characterized by the presence of prominent fibrosis such as storiform fibrosis and swirling fibrosis, numerous IgG4-positive plasma cells, and elevated serum IgG4 , and called IgG4-related HT . Among 23 patients with HT who underwent total thyroidectomy, 14 cases (60.8%) were IgG4-related HT, but there were no significant differences in positivity for thyroid and microsome tests between IgG4-related HT and non-IgG4 HT .
Riedel’s thyroiditis was first described in 1896 in two patients with hard goiter and tracheal compressive symptoms. One-third of patients with Riedel’s thyroiditis have multifocal fibrosclerosis, including sclerosing cholangitis, salivary gland fibrosis, RPF, or fibrotic orbital pseudotumor. Therefore, despite the lack of immunohistochemical staining for IgG4, certain proportions of Riedel’s thyroiditis were considered a type of IgG4RD. Although one patient with IgG4RD showed involvement of the lachrymal gland and pulmonary and biliary tracts as well as Riedel’s thyroiditis , it is still unclear whether Riedel’s thyroiditis is a type of IgG4RD.
IgG4-related lymphadenopathy and Castleman’s disease
Concomitant lymphadenopathy is common in patients with IgG4RD, and there have been several reports dealing with the morphological and immunohistological findings of lymph node lesions [55, 56, 57]. Although IgG4-related lymphadenopathy is occasionally characterized by systemic lymphadenopathy, polyclonal hyperimmunoglobulinemia, especially elevated IgG and IgE concentrations, and positivity for various autoantibodies, patients with IgG4RD with generalized lymphadenopathy should only be evaluated for lymphoma, sarcoidosis, multicentric Castleman’s disease, and other malignancies.
IgG4-related lymphadenopathy can be characterized into five histological subtypes: Castleman’s disease-like morphology (type I), reactive follicular hyperplasia (type II), interfollicular plasmacytosis and immunoblastosis (type III), progressive transformation of germinal center-like (type IV), and inflammatory pseudotumor-like morphology (type V) . In addition, IgG4-related lymphadenopathy can be classified into two types based on the infiltrative patterns of IgG4-positive cells: interfollicular plasmacytosis (types I, II, III, and V) and intragerminal center plasmacytosis (type IV). Patients with systemic IgG4-related lymphadenopathy were significantly older (68.8 vs. 43.3 years) and had significantly lower C-reactive protein (0.29 vs. 8.71 mg/dl) and interleukin (IL)-6 (8.45 vs. 34.82 pg/ml) concentrations than patients with multicentric Castleman’s disease .
IgG4-related retroperitoneal fibrosis (IgG4-related RPF)
RPF is a chronic inflammatory condition with marked fibrosis in retroperitoneal tissue. In patients with advanced RPF a retroperitoneal mass covers the abdominal aorta and compresses the ureters, leading to urinary obstruction. Its etiology is unknown, but it has many causes, including infection, radiation, drugs, malignant tumor, and trauma. Three patients with RPF and elevated serum IgG4 have been described , and the histology of all 12 patients with RPF was reported to be similar to that seen in AIP, including fibrosis, intense inflammatory cell infiltration with plasma cells, venulitis, and obliterative arteritis . Of 17 patients with RPF, 10 had both elevated serum IgG4 and histopathological features typical of IgG4RD, suggesting that RPF could be categorized as IgG4-related . However, in RPF, fibrosis gradually progresses during chronic inflammation, with lymphocyte infiltration predominant during the early stages and a fibroinflammatory process occurring later. Therefore, determining the stage of illness seems important for diagnosis and prediction of response to steroid treatment .
There have been several recent reports of inflammatory aneurysms in the abdominal or thoracic aorta [62, 63, 64]. For example, 40% of inflammatory abdominal aortic aneurysms (AAAs) were IgG4RD, with elevated IgG4 in serum and abundant infiltration of IgG4+ plasma cells and obliterative phlebitis . These findings suggested that inflammatory AAAs can be classified into 2 groups: IgG4-related and IgG4-unrelated . Although IgG4RD shows good response to steroid therapy, treatment with the anti-CD20 monoclonal antibody, rituximab, may result not only in clinical improvement, but in the tapering or discontinuation of steroids or other drugs .
Pathogenesis and pathophysiology of IgG4RD
At present, the pathogenetic mechanism and underlying immunological abnormalities in IgG4RD remain unclear. The elevated serum IgG4 concentration and tissue infiltration of IgG4-positive plasma cells are characteristic features of IgG4RD. Because IgG4 antibodies are dynamic molecules that can exchange Fab arms by swapping a heavy chain and attached light chain, IgG4 can form bi-specific antibodies, as well as functioning as a monovalent molecule [66, 67]. These properties may protect against type I allergy by inhibiting IgE functions, and may prevent type II and III allergy by blocking the Fc-mediated effector functions of IgG1 and inhibiting the formation of large immune complexes. The predominant expression of IgG4 under conditions of chronic antigen exposure is compatible with the clinical features of IgG4RD, including its slow progression and relatively weak immune response.
Some autoantibodies, including those to pancreatic trypsin inhibitor (PSTI), lactoferrin (LF), and carbonic anhydrase (CA), have been detected in patients with IgG4RD, especially in those with IgG4-related AIP . Although IgG4 from the patients was able to bind the normal epithelia of the pancreatic ducts, gallbladder, and salivary gland ducts , IgG4-type autoantibodies have not been detected in patients with IgG4RD.
Aberrant immunological findings have been observed in patients with IgG4RD. For example, the Th2-dominant immune response and the production of Th2-type cytokines, such as IL-4, IL-5, IL-10, and IL-13, are increased [69, 70, 71]. Furthermore, the numbers of regulatory T cells (Treg) expressing CD4+CD25+Foxp3 are significantly higher in the affected tissues and peripheral blood of patients with IgG4RD than the numbers in patients with autoimmune and nonautoimmune diseases [72, 73, 74]. Overexpression of the regulatory cytokines IL-10 and transforming growth factor β (TGF-β) has also been reported in patients with IgG4RD [74, 75]. IL-10 and TGF-β have potent activities in directing B cells to produce IgG4 and induce fibroplasia, respectively. IL-4, IL-5, and IL-13 are important for class switching to IgE production and eosinophil migration. Therefore, abnormalities in the production of these cytokines may be involved in the pathogenesis of IgG4RD.
Perspectives on IgG4RD
Clinical diagnostic criteria of autoimmune pancreatitis; revised proposal in Japan (2006) 
1. Diffuse or segmental narrowing of the main pancreatic duct with irregular wall and diffuse or localized enlargement of the pancreas on imaging modalities, such as abdominal ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI)
2. High-serum F-globulin, IgG, or IgG4, or the presence of autoantibodies, such as antinuclear antibodies and rheumatoid factor
3. Marked interlobular fibrosis and prominent infiltration of lymphocytes and plasma cells into the periductal area, with occasional lymphoid follicles in the pancreas
For diagnosis, criterion 1 must be present, together with criteria 2 and/or 3
However, it is necessary to exclude malignant diseases such as pancreatic and biliary cancers
Consensus has been reached on two diagnostic criteria for IgG4RD: (1) serum IgG4 concentration >135 mg/dl, and (2) >40% of IgG-positive plasma cells being IgG4-positive. The MHLW Japan team has proposed guidelines for the diagnosis of IgG4RD; these are shown in Table 3. The formulation of organ-specific (i.e., kidney and pulmonary) diagnostic criteria for IgG4RD requires cooperation with the relevant societies. Although IgG4RD responds well to steroid therapy, recurrence and relapse occur following the early reduction or withdrawal of prednisone. Therefore, it is necessary to develop treatment guidelines to establish initial doses of steroids, tapering procedures, and maintenance doses. The MHLW Japan team is currently pursuing a “Prospective study for creating IgG4-related disease treatment guidelines”, and unified clinical guidelines are expected in the near future.
This work was supported by the Research Program for Intractable Diseases, Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare, Japan. We sincerely thank the many contributing researchers and collaborators who participated in the MHLW Japan G4 team.
Conflict of interest
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