Download Current approach to the diagnosis of IgG4

Current approach to the diagnosis of IgG4-related disease- Combination of
Comprehensive Diagnostic and Organ-Specific CriteriaHisanori Umehara1), Kazuichi Okazaki2), Takuji Nakamura1), Tomomi Satoh-Nakamura1),
Akio Nakajima3), Mitsuhiro Kawano4), Tsuneyo Mimori5) and Tsutomu Chiba6)
1
Division of RA and Autoimmune Diseases, Nagahama City Hospital, Shiga, Japan.
2
The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology,
Kansai Medical University, Osaka, Japan,
3
Division of Rheumatology, Kudo General Hospital, Ishikawa, Japan.
4
Division of Rheumatology, Department of Internal Medicine, Graduate School of Medical
Science, Kanazawa University, Ishikawa, Japan.
5
Department of Clinical Immunology, 6Department of Gastroenterology and Hepatology,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
* Corresponding
author: Hisanori Umehara, M.D., Ph.D.
Division of Rheumatology and Immunology, Nagahama City Hospital,
313, Oinuicho Nagahama, Shiga 526-0043, Japan
E mail:[email protected]
Running title:
How to diagnose IgG4-RD
Key words: IgG4-RD, diagnostic criteria, Mikulicz’s disease, autoimmune pancreatitis,
sclerosing cholangitis, orbital disease.
Total pages, body 22 pages
Total words: 5974 words
Total Tables, 6 tables
Total figures: 3 figures
Abbreviations:IgG4-RD, IgG4-related disease; MD, Mikulicz’s disease; AIP, autoimmune
pancreatitis; KD, kidney disease; TIN, tubulointerstitial nephritis; SS, Sjögren's syndrome;
RPF, retroperitoneal fibrosis; TIN, tubulointerstitial nephritis; LSG, labial salivary glands.
Summary
IgG4-related disease (IgG4-RD) is a fascinating clinical entity proposed by Japanese
investigators, and includes a wide variety of diseases, formerly diagnosed as Mikulicz's
disease
(MD),
autoimmune
retroperitoneal fibrosis, etc.
pancreatitis
(AIP),
interstitial
nephritis,
prostatitis,
Although all clinicians in every field of medicine may
encounter this new disease, a unifying diagnostic criteria has not been established.
In 2011, the Japanese IgG4 team, organized by the Ministry of Health, Labor and
Welfare (MHLW) of Japan, published comprehensive diagnostic criteria for IgG4-RD.
Several problems with these criteria have arisen in clinical practice, however, including the
difficulty obtaining biopsy samples from some patients, and the sensitivity and specificity
of techniques used to measure serum IgG4 concentrations.
Although serum IgG4 concentration is an important clinical marker for IgG4-RD, its
diagnostic utility in differentiating IgG4-RD from other diseases, called IgG4-RD
mimickers, remains unclear.
This review describes the current optimal approach for the diagnosis of IgG4-RD, based
on both comprehensive and organ-specific diagnostic criteria, in patients with diseases such
as IgG4-related pancreatitis (AIP), sclerosing cholangitis, and renal, lung and orbital
diseases.
1. Introduction
IgG4 related disease (IgG4-RD) was first described in patients with sclerosing
cholangitis who had elevated serum IgG4 levels {Hamano, 2001 #1}. Subsequently, a wide
variety of diseases characterized by high serum IgG4 concentrations and infiltration of
IgG4-positive plasma cells have been reported (1, 2), formerly diagnosed as Mikulicz's
disease (MD) (3), autoimmune pancreatitis (AIP) (4), hypophysitis (5), Riedel thyroiditis
(6), Küttner tumor (7), interstitial pneumonitis (8, 9), interstitial nephritis (10), prostatitis
(11), lymphadenopathy (12, 13), retroperitoneal fibrosis (14, 15), inflammatory aortic
aneurysm and aortitis (16, 17) and inflammatory pseudotumor (18) (Figure 1).
IgG4-RD is characterized by increased serum IgG4 concentrations and organomegaly
or nodular/hyperplastic lesions in various organs, including the pancreas, bile ducts,
lacrimal glands, salivary glands, thyroid, lungs, liver, and kidneys, either concurrently or
metachronously. Clinical symptoms vary depending on the affected organ(s), with some
patients experiencing serious complications, such as obstruction or compression symptoms
due to organomegaly or hypertrophy, or organ dysfunction caused by cellular infiltration or
fibrosis. Although pathological examination usually reveals marked infiltration of IgG4positive plasma cells and characteristic fibrosis called storiform fibrosis (1, 2, 19), it may
be impossible to formulate a single set of diagnostic criteria that covers every affected
organ. Furthermore, American College of Rheumatology (ACR) has not approved any of
the current diagnostic criteria, since these criteria are insufficiently sensitive and specific
(20).
The all Japan IgG4-RD group was organized in 2008 by the Ministry of Health, Labor
and Welfare (MHLW) of Japan. This group consists of two teams, the Umehara team (66
members) and the Okazaki team (55 members), each of which contains physicians and
researchers in various fields, including rheumatology, gastroenterology, nephrology,
pulmonology, ophthalmology, hematology, odontology, pathology, statistics, and basic and
molecular immunology. These teams started investigating this new disease by analyzing
every related clinical condition (1). They found that this complex multisystem disease
represented a single pathogenetic disorder manifesting in a variety of target organs. The
nomenclature of IgG4-RD was accepted at the first international symposium of IgG4-RD
held in Boston in 2011 (21). Subsequently, the Japanese IgG4-RD team established
comprehensive diagnostic criteria encompassing as many aspects of the symptoms of IgG4RD as possible (22).
2. Components of the diagnosis of IgG4-RD (Figure 2)
2.1. Clinical features
IgG4-RD usually affects middle to older aged individuals, with 90% of patients aged
50–80 years and median ages in various studies ranging from 58–67 years (1, 2, 23). IgG4RD, especially IgG4-related AIP pancreatitis, shows male dominance, with an M:F ratio of
4:1 to 3:1 (19, 24, 25). However, IgG4-related sialadenitis and dacryoadenitis may occur
more frequently among women (26, 27).
Patients with IgG4-RD frequently present with simultaneous or metachronous lesions in
multiple organs, along with elevated serum IgG4 and/or abundant infiltration by IgG4positive cells. Although organ distribution varies among studies, the pancreas and salivary
glands are the most frequently involved organs (25, 28). Nearly 50% of patients show
multiple organ involvement, with the remainder having isolated lesions, especially of the
pancreas (25).
2.2. Serum IgG4 levels
Elevated serum IgG4 was initially reported in patients with sclerosing pancreatitis, now
called IgG4-AIP (1). Elevated IgG4, however, is not a specific marker for IgG4-RD, as it is
increased in some patients with cancer and non-IgG4-RD, including allergic diseases,
primary sclerosing cholangitis (PSC) and autoimmune diseases (28-30). Comprehensive
diagnostic (CD) criteria for IgG4-RD were met in only 5.1% of patients in whom serum
IgG4 was measured to distinguish IgG4-RD from other conditions (29). Nevertheless,
serum IgG4 concentration was shown useful for the diagnosis of IgG4-RD in a metaanalysis comparing serum IgG4 concentration in patients with AIP and those with
pancreatic cancer and other autoimmune diseases, with mean ± SE areas under the curve
(AUC) of 0.92+0.073, 0.914+0.191, and 0.949+0.024, respectively (31). Moreover, recent
large cohort studies from the United Kingdom (UK), Taiwan, and Japan showed that IgG4
concentration had an overall sensitivity of 82.8%, 86% and 88%, respectively (25, 29, 32).
A serum IgG4 cutoff level of >135 mg/dl is considered a unique and reliable marker
predictive of IgG4-RD and is included in the diagnostic criteria for IgG4-AIP (33, 34) and
other organ-specific diseases (35-39), as well as in the CD criteria for IgG4-RD (22).
Several recent studies, however, have questioned the diagnostic utility of serum IgG4
concentration, as it showed both low sensitivity of 51% (28) and low specificity of 60%
(40). The methods used to measure IgG4 concentrations, such as nephelometry and radial
immunodiffusion, may be relatively insensitive or non-specific. In addition, differences
have been observed among commercially available kits to measure IgG4, and the methods
used may show a prozone effect, underestimating IgG4 concentrations. The most important
aspect is the difference in patients studied due to the lack of a gold standard for IgG4-RD.
In addition, IgG4 levels increase during disease progression, and are higher in patients with
multi-organ than with single organ involvement (25, 28).
Conversely, use of a serum IgG4 cut off value of >135mg/dl can yield false positive
results in some patients. For example, prospective studies of patients with non IgG4-RD,
including those with malignancy, PSC, and autoimmune diseases found that 16.1% of 1510
patients in the UK and 23% of 2740 in China had serum IgG4 >135 mg/dl (29, 32).
Although histopathological findings are more specific and important hallmarks of IgG4-RD,
tissue biopsies are difficult to obtain from some organs, including the pancreas,
retroperitoneum, and ocular cavity. Therefore, serum IgG4 remains a characteristic and
predictive marker for the diagnosis of IgG4-RD. Future studies are needed to determine
ranges of serum IgG4 that are more specific and predictive for IgG4-RD, or whether
diagnostic criteria using a weighted scoring system for serum IgG4 is more accurate
diagnostically.
2.3. Number of IgG4-positive plasma cells and pathological features
Histopathology is the key component and is indispensable for the diagnosis of IgG4-RD.
IgG4-RD diagnosis is strongly based on biopsy results showing enriched infiltration of
IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis and moderate
eosinophilia, all of which are frequently observed in the affected tissues of these patients
(2, 41). However, there are some pathological differences among organs. For example,
storiform fibrosis and obliterative phlebitis are rare within lacrimal glands, salivary glands
and lymph nodes (22, 41, 42).
High numbers of IgG4-positive plasma cells are a
characteristic marker of IgG4-RD, even in patients with serum IgG4 concentrations below
the cut off level. However, the numbers of IgG4-positive plasma cells differ among organs.
Abundant IgG4-positive cells are observed more frequent in lymph nodes, lacrimal and
salivary glands and skin than in pancreas, lungs, bile ducts, kidneys, aorta and
retroperitoneum (42). In addition, the ratio of IgG4- to IgG-positive cells is as important as
the numbers of IgG4-positive cells (43). Cut off numbers required for the diagnosis of
IgG4-RD have been reported for IgG4-positive plasma cells in various organs (42). Overall,
the diagnosis of IgG4-RD should be based on clinical features and serum characteristics, as
well as pathological findings such as the number of IgG4-positive cells.
3. How to diagnosis IgG4-RD
3.1. Comprehensive Diagnostic Criteria for IgG4-RD (CD-criteria) (22, 41, 44)
CD criteria for IgG4-RD were formulated in 2011 (Table 1). The aims of establishing
these criteria included: 1) formulating criteria that would be useful not only to specialists in
the field but also to general clinicians; 2) devising criteria that would be comprehensive for
all organs; 3) making the criteria as succinct as possible, 4) weighting of histopathological
findings to exclude malignancy; and 5) not recommending trials of corticosteroid therapy
for diagnostic purposes in patients with possible IgG4-RD.
The CD-criteria for IgG4-RD are comprised of three major items (Table 1), enabling
patients to be classified as having definite, probable, or possible IgG4-RD, according to an
algorithm of how many of these diagnostic items are present (Figure 3). A diagnosis of
IgG4-RD is possible in patients who fulfill criteria ① and ②, but with negative results on
histopathology or without histopathologic examination (categories 2 and 3), whereas a
diagnosis of IgG4-RD is probable in patients with organ involvement ① and who fulfilled
histopathologic criteria, but without increased serum IgG4 concentration ② (category 4).
Patients with organ symptoms without satisfying the serologic or histopathologic criteria
are considered unlikely to have IgG4-RD (category 5 and 6). Application of these CDcriteria to patients previously reported to have IgG4-related MD (26, 45), IgG4-related
kidney disease (36, 46) and IgG4-related AIP (47, 48, 49) found that these criteria had a
sensitivity of 83% or 70% in patients with IgG4-related MD and 87% and 85% in patients
with IgG4-related kidney disease. In contrast, these CD-criteria could not be used to
diagnose patients with IgG4-related AIP, because of the difficulty of obtaining biopsies
from most of these patients. Thus, the diagnostic sensitivity of the CD-criteria is not
sufficient for patients with lesions that are difficult to biopsy, such as those of the pancreas,
retroperitoneum, and ocular cavity. To resolve this problem, additional criteria may be
required for each organ with clinical symptoms, involving serological and histological
findings and radiological images.
3.2. Organ-specific criteria for IgG4-RD
Although CD-criteria have been established for easy use by general physicians (20), these
criteria may be inapplicable, especially in patients with lesions that are difficult to biopsy.
To overcome these problems, specific Japanese societies for various organs and medical
fields, including gastroenterology, pancreas, biliary tract, rheumatology, ophthalmology
and respiratology have established diagnostic criteria for the IgG4-RD of these individual
organs.
3.2.1. Criteria for IgG4-related pancreatitis (type I autoimmune pancreatitis: AIP)
(33) (Table 2)
AIP has been classified into two distinct subtypes, types 1 and 2. Histological
examination by American and European pathologists of the resected pancreases of patients
with chronic non-alcoholic pancreatitis revealed two distinct subtypes. Type 1, or
lymphoplasmacytic sclerosing pancreatitis (LPSP), is characterized by abundant infiltration
of lymphocytes and IgG4-positive plasmacytes, fibrosis, and obliterative phlebitis; whereas
Type 2, or idiopathic duct-centric pancreatitis (IDCP), is characterized by AIP with
granulocytic epithelial lesions (GELs).
Clinically, type 1 AIP seems to be the pancreatic manifestation of IgG4-RD,
characterized by 1) mild abdominal symptoms, usually without acute attacks of
pancreatitis; 2) occasional occurrence of obstructive jaundice; 3) increased serum IgG
and/or IgG4 concentrations; 4) diffuse, segmental or focal enlargement of the pancreas with
a capsule-like low-density rim on dynamic CT/MRI images; 5) irregular narrowing of the
main pancreatic duct on endoscopic retrograde cholangiopancreatography (ERCP) images;
6) occasional association with extrapancreatic lesions such as sclerosing cholangitis similar
to primary sclerosing cholangitis (PSC), cholecystitis, sialoadenitis, retroperitoneal fibrosis,
interstitial renal tubular disorders, enlarged abdominal and mediastinal lymph nodes,
chronic thyroiditis, and pseudotumor of the pancreas, liver, or lung; and 7) responsiveness
to steroid therapy.
Although pancreas images are similar in patients with types 1 and 2 AIP, the
clinicopathological features of type 2 differ from those of type 1 AIP, with the former
showing no elevation of serum IgG4, are infiltration of IgG4-positive plasma cells, and no
involvement of other organs except for inflammatory bowel disease (50, 51). Thus, the
LPSP type of AIP has been defined as type 1 (IgG4-related pancreatitis) and IDCP/AIP
with GEL has been defined as type 2 (33). International Consensus Diagnostic Criteria
(ICDC) for AIP have been formulated by collaboration among researchers from Japan, the
US and Korea (34). On diagnostic imaging, some patients show diffuse pancreatic swelling,
whereas others show localized swelling or pancreatic mass formation, with the latter
sometimes difficult to differentiate from pancreatic cancer (52). Diffuse pancreatic swelling
(capsule-like rim) on CT or MRI is considered diagnostic for type 1 AIP (34).
However, patients who present with localized swelling or mass formation are
recommended to undergo histopathological evaluation by endoscopic ultrasonography-
guided fine-needle aspiration (EUS-FNA) or a similar method to exclude the possibility of
pancreatic cancer. Pancreatic head swelling of type 1 AIP is typically accompanied by
lower bile duct stenosis. Extrapancreatic bile duct stenosis, such as intrahepatic or hilar bile
duct stenosis, is another feature of IgG4-RD, with these lesions collectively named IgG4related sclerosing cholangitis (IgG4-SC) (37). Differential diagnoses in patients with
apparent IgG4-SC and lower bile duct stenosis include bile duct cancer and pancreatic head
cancer.
3.2.2. Criteria for IgG4-related sclerosing cholangitis (IgG4-SC) (37) (Table 3)
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), although only
26% of patients with AIP demonstrated sclerosing changes on ERCP (53).
However, many individuals without AIP have been diagnosed with IgG4-related SC with
isolated biliary tract involvement (54, 55). Stenosis in patients with IgG4-related SC 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 in these patients is very
similar to that observed in PSC (56), 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 (56).
Although steroid therapy has shown mixed results in patients with PSC, IgG4-related SC
responds dramatically to steroid therapy, as does IgG4-RD (57). The histopathological
features of IgG4-related SC are similar to those of type I AIP and include diffuse
plasmacytic infiltration, marked interstitial fibrosis with a focal storiform-like pattern, and
obliterative phlebitis.Characteristic radiological findings in IgG4-SC include sclerosing
changes in the intra- and extra-pancreatic bile ducts. Therefore, important diagnostic
criteria for IgG4-SC include diffuse or localized narrowing of the bile ducts. Wall
thickening is frequently detected along the bile ducts and is not limited to stenotic lesions.
Diagnostic criteria also include the presence of other lesions of IgG4-RD, including IgG4-
related dacryoadenitis and sialoadenitis and IgG4-related retroperitoneal fibrosis as critical
items. Clinically obstructive jaundice is often observed in patients with IgG4-SC. However,
secondary bile duct stenosis caused by malignancy should be ruled out. In addition,
empirical steroid treatment should be avoided, although steroids can be administered for
diagnostic purposes (37).
3.2.3. Criteria for IgG4-related dacryoadenitis (DA) and sialoadenitis (SA); formerly
called Mikulicz’s disease
Mikulicz’s disease, which is characterized by symmetrical swelling of the lacrimal and
salivary glands, is now considered IgG4-related dacryoadenitis and sialoadenitis (IgG4DA/SA) (21). In contrast to IgG4-RD involving other organs, IgG4-DA/SA shows no
gender predominance (58).
IgG4-related SA, once considered a subset of Sjögren’s syndrome (SS), consists of IgG4related parotitis and IgG4-related submandibular gland disease of the salivary glands. A
similar condition, Küttner tumor, or enlargement of a unilateral submandibular gland
usually associated with IgG4-RD, has been renamed IgG4-related submandibular gland
disease (21). A clinical comparison of patients with IgG4-RD and those with typical SS
showed that 1) fewer patients with IgG4-RD than with SS had symptoms of xerophthalmia,
xerostomia, or arthralgia, whereas many had coexisting AIP, interstitial nephritis, allergic
rhinitis, and/or bronchial asthma; 2) most patients with IgG4-RD are negative for anti-SS-A
and anti-SS-B antibodies, as well as for rheumatoid factor (RF) and anti-nuclear antibody
(ANA); 3) serum IgG4 and IgE concentrations are significantly higher in IgG4-RD than in
SS patients; and 4) steroid therapy is extremely effective in patients with IgG4-RD but had
limited effect in patients with SS. The most important difference between IgG4-RD and SS
is that the former is characterized by marked infiltration of IgG4-positive plasma cells, with
a ratio of IgG4-positive to IgG-positive cells of >40%, a finding almost never seen in
patients with SS (26). Despite their similarities in organ involvement, IgG4-MD and SS are
quite different conditions, with distinct clinical and pathological characteristics (1).
Since tissue biopsies are difficult to obtain from some organs, including the pancreas,
retroperitoneum, and ocular cavity, the sensitivity of CD criteria for the diagnosis of IgG4RD in these organs is not very high. Nevertheless, histopathological examination is
essential for the diagnosis of IgG4-RD. Biopsy samples can be easily obtained from
patients with suspected IgG4-related DA and (SA). Therefore, the CD criteria for IgG4-RD
are usually applied to diagnose IgG4-DA/SA without loss of sensitivity or specificity (22,
59).
3.2.4. IgG4-related kidney disease (IgG4-RKD) (36) (Table 4)
IgG4-RKD is primarily characterized by tubulointerstitial nephritis (TIN), but
membranous glomerulonephritis (MGN) may also be observed. IgG4-RKD shows
abundant infiltration of lymphocytes and IgG4-positive plasmacytes into the kidneys, as
well as fibrosis (46, 60). Clinicopathologically, patients with TIN and/or MGN associated
IgG4-RKD usually show proteinuria and/or microhematuria, high serum concentrations of
IgG4 and IgE, and hypocomplementemia, characteristics somewhat different from those of
patients with IgG4-RD lesions in other organs. IgG4-RKD can include conditions other
than renal parenchymal lesions, such as hydronephrosis due to retroperitoneal fibrosis
(RPF) and tumors of the renal pelvis and urethra. Imaging often shows heterogeneous
shadows in the kidneys, such as a mass or multiple nodules, which are not observed in
other types of interstitial or membranous nephritis.
Criteria for IgG4-RKD were established by cooperation with the Japanese Society of
Nephrology in 2012 (61). Urinalysis for urinary protein and assays of renal function may be
diagnostic. Contrast-enhanced CT is the recommended imaging modality in IgG4-TIN (62).
The most representative findings are multiple round or wedge-shaped low-density lesions.
Rarely, IgG4-RKD presents as a solitary lesion, making the differential diagnosis from
malignancy more difficult. A rim-like lesion of the kidney is occasionally seen along part
of the renal capsule. Finally, renal pelvic lesions are sometimes encountered as diffuse
thickening of the renal pelvis with smooth intra-luminal surfaces (62). Renal tissues usually
reveal interstitial nephritis, sometimes with glomerulus lesions (membranous nephropathy).
3.2.5. IgG4-related ophthalmic diseases (IgG4-OD) (38) (Table 5)
IgG4-OD involves not only the lacrimal glands but other ocular adnexa, such as the
extraocular muscles and orbital nerves (38). In addition, IgG4-OD involves IgG4-related
inflammation of orbital soft tissue (orbital inflammatory pseudotumor), IgG4-related orbital
myositis in extraocular muscle disease and IgG4-related pan-orbital inflammation in
multiple anatomic structures (21). Because the most prominent pathological feature of
IgG4-OD is lymphoplasmacytic cell infiltration, the differential diagnosis should include
MALT (mucosa-associated lymphoid tissue) lymphoma, diffuse large B-cell lymphoma
(DLBCL) and follicular lymphoma (38).
IgG4-OD can involve three major sites of orbital lesions, the lachrymal glands, the
trigeminal nerves and the extraocular muscles, with >50 plasmacytic cells per high powered
field (HPF) is considered pathologically diagnostic (38).
3.2.6. IgG4-related pulmonary diseases (IgG4-PD) (39) (Table 6)
The clinical features of IgG4-related PD vary widely and can include inflammatory
pseudotumor, interstitial pneumonitis, organizing pneumonia, and lymphomatoid
granulomatosis (8). Although some patients present initially with respiratory symptoms,
such as dry cough or dyspnea, about 75% of patients are asymptomatic and incidentally
identified by abnormal shadows on chest X-rays. Frequent CT findings are mediastinal and
hilar lymph node swelling, thickening of bronchovascular bundles and interlobular septa,
and ground-glass opacities (GGO), similar to multicentric Castleman’s disease or
sarcoidosis (9, 49). 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
as reticular shadows, GGO and interstitial fibrosis in both lower lung fields (18).
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 (18). Interstitial pneumonitis is
characterized by thickening of the alveolar septa due to infiltration by plasma cells and
lymphocytes, and by diffuse fibrosis.
Rarely, IgG4-PD may occur independent from IgG4-RD of other organs. Therefore, the
diagnostic criteria of IgG4-PD include the presence of other lesions outside the thorax. A
definitive diagnosis of IgG4-PD requires the co-occurrence of obliterative phlebitis and/or
storiform or swirling fibrosis as well as the number of IgG4 plasma cells (39). Aggressive
surgery, such as a pulmonary biopsy, may be required to distinguish IgG4-PD from
malignancies or other pulmonary diseases, such as sarcoidosis and Castleman’s disease.
4. Discussion
Although IgG4-RD has been recognized as a new clinical entity worldwide, uniform
international criteria for diagnosing IgG4-RD have not yet been established. The presence
of many clinical mimics of IgG4-RD may result in the over-diagnosis of this new disease.
In contrast, patients with low IgG4 titers may be missed. Because IgG4-RD typically
responds to steroid or immunosuppressive therapy, with improvement and resolution of
symptoms, it is important to distinguish IgG4-RD from other inflammatory, infectious, and
neoplastic condition to avoid unnecessary aggressive therapies. The most cited criteria at
present are those made by pathologists (42) and by the all Japan IgG4-RD team (22).
However, each set of criteria has drawbacks. Although the pathological criteria have
defined diagnostic cut off numbers of IgG4-positive plasma cells in various organs (42),
these findings have not been verified. Moreover, these criteria do not include any clinical
features or laboratory findings. Although the infiltration of IgG4-positive cells is
characteristic of IgG4-RD, it is also observed in various other diseases and clinical
conditions, such as rheumatoid synovitis, inflammatory oral and skin lesions, and
carcinomas with a peritumoral inflammatory response (63). Therefore, diagnosis of IgG4RD should also be based on clinical features and laboratory findings, including serum IgG4
concentrations and pathologic examination of a tissue biopsy.
The CD criteria also have drawbacks, because of the low specificity of serum IgG4
concentrations and the low sensitivity due to difficulty in obtaining biopsy samples.
Increased serum IgG4 is not specific for IgG4-RD and has been observed in several other
diseases, such as autoimmune diseases, atopic diseases and cancers (29, 30, 40, 64). The all
Japan IgG4-RD group, consisting of the Umehara and Okazaki teams, started a nationwide
study in 2007, and established the general concepts and clinical features of IgG4-RD in
2011 (1). Although the infiltration of IgG4-positive cells and fibrosis are common features
of IgG4RD, the number of IgG4-positive cells and the severity of fibrosis are dependent on
the individual organs involved. For example, storiform fibrosis and obliterative phlebitis
are characteristic of pancreatic, biliary tract, and retroperitoneal lesions, but are very
seldom found in lesions of the salivary glands and lymph nodes. Conversely, IgG4-positive
cells are scattered throughout the fibrotic lesions of the pancreas and retroperitoneum (1, 43,
65). The cutoff value for serum IgG4 concentration, 135 mg/dl, was based on receiver
operating characteristic (ROC) curves, and its validity was confirmed in patients with AIP.
As clinical symptoms and pathological features depend on the lesion involved, detailed
diagnostic criteria for each organ are needed. Findings required for accurate diagnosis
include serological and histological findings, radiological images, and clinical symptoms.
However, too detailed criteria are not suitable for practical use by general clinicians.
Therefore, the all Japan IgG4-RD team established CD criteria based on two major
characteristics of IgG4-RD: increased serum concentrations of IgG4 and infiltration of
IgG4-positive cells (22).
IgG4-RD can be definitively diagnosed in patients with (1) organ enlargement or
dysfunction (2), a serum IgG4 concentration > 135 mg/dl, and (3) histopathological
findings of >10 IgG4 cells/HPF and an IgG4-positive/IgG-positive cell ratio > 40 % (20).
Patients who could not be diagnosed by these CD criteria could be re-diagnosed by organspecific criteria, including those for IgG4-type I AIP (34), IgG4-SC (37), IgG4-RKD (36),
IgG4-OD (38) and IgG4-PD (39), by specialists in each field.
5. Perspective
Following the first international Symposium for IgG4-RD in Boston, chaired by Prof.
Stone in 2011, the second international symposium was held in Hawaii in 2014 and was cochaired by Prof. Chiba (Kyoto University) and Prof. Stone (Harvard University). Through
international collaboration, a general consensus was achieved in the nomenclature (21),
pathological judgment (42), responder index and management (66) of IgG4-RD.
However, universal criteria for IgG4-RD have not yet been established. Therefore, the
diagnosis of IgG4-RD may be ambiguous, and many IgG4-RD mimickers have been
reported. The next step should include the development of international criteria for IgG4RD. A world-wide research committee has been organized to develop universal
classification criteria of IgG4-RD and has started analyzing patients with IgG4-RD from
around the world. We hope that the international classification criteria for IgG4-RD will be
established at the third international symposium for IgG4-RD in Hawaii in February 2017.
Acknowledgments
This work was supported by Intractable Diseases, the Health and Labor Sciences
Research Grants from Ministry of Health, Labor and Welfare, Japan. We sincerely thank
the many contributing researchers and collaborators who participated in all Japan IgG4
team.
Conflict of interest
None
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