Are Classification Criteria for IgG4-RD Now Possible? The Concept of IgG4-Related Disease and Proposal of Comprehensive Diagnostic Criteria in Japan

Recent studies suggest simultaneous or metachronous lesions in multiorgans characterized by elevated serum levels of IgG4 and abundant infiltration of IgG4-positive plasma cells with various degrees of fibrosis. Two Japanese research committees for IgG4-RD, one from fibrosclerosis (Okazaki team) and the other from lymph proliferation (Umehara team) supported by the “Research Program for Intractable Disease” of the Ministry of Health, Labor, and Welfare of Japan, have agreed with the unified nomenclature as “IgG4-RD” and proposed the comprehensive diagnostic criteria (CDC) for IgG4-RD. Validation of the CDC demonstrated satisfactory sensitivity for the practical use of general physicians and nonspecialists but low sensitivity in the organs to be difficult in taking biopsy specimens such as type1 autoimmune pancreatitis (IgG4-related AIP), compared with IgG4-related sialadenitis/dacryoadenitis (Mikulicz's disease) and IgG4-related kidney disease. Although the diagnostic criteria covering all IgG4-RD are hard to be established, combination with the CDC and organ-specific diagnostic criteria should improve sensitivity.


Introduction
Recent studies have suggested simultaneous or metachronous lesions in multiorgans characterized by elevated serum levels of IgG4 and abundant infiltration of IgG4-positive plasma cells with various degrees of fibrosis, which lead us to propose the concept of a systemic disease [1,4,10,23,24]. However, there are many synonyms suggesting a systemic disease, such as IgG4-related autoimmune disease [1], IgG4related sclerosing disease [4], IgG4-related plasmacytic syndrome (SIPS) [23], IgG4-related multiorgan lymphoproliferative syndrome (IgG4-MOLPS) [10], and systemic IgG4related disease, all of which may refer to the same conditions [24,25] (Table 1). To simplify these conditions, members of two Japanese research committees for IgG4-related disease, one from view of fibrosclerosis (Chaired by Prof. Okazaki) [24] and the other from lymph proliferation (Chaired by Professor. Umehara H) [25], both of which are supported by the "Research for Intractable Disease" Program from the Ministry of Health, Labor, and Welfare of Japan, have agreed with unification of different nomenclatures as "IgG4related disease (IgG4-RD)" and proposed the comprehensive diagnostic criteria (CDC) for IgG4-RD [15]. As it still remains unclear whether pathogenetic mechanisms in each involved organ-are same or not, the term IgG4-RD was appointed as minimally reflecting these conditions to avoid misdiagnosis of malignancy as much as possible.

IgG4-Related Disease (IgG4-RD) as the Comprehensive Nomenclature [24, 25]
In addition to MIF, there are many synonyms, such as IgG4related autoimmune disease [1], "IgG4-related sclerosing disease" [4], IgG4-related plasmacytic disease (SIPS) [23], and "IgG4 + sMOLPS" [10], all of which may refer to the same conditions. It has been debated which one is the most appropriate. Storiform fibrosis and obliterative phlebitis are characteristic of biliopancreatic, retroperitoneal, and renal lesions, but rarely observed in lachrymal/salivary glands and lymphnodes [24,25]. Then, the nomenclature of "IgG4related sclerosing disease" is mainly based on the fibrous swollen organs, whereas those of "IgG4-SIPS" and "IgG4-MOLPS" are based on lymphoplasmacytic proliferation and swollen lymph nodes without fibrosis [24,25]. Although most patients have multiorgan lesions synchronously or metachronously, about 10-20% of the patients show a solitary organ involved without confirming other organ involvement [24,25]. Therefore, it is unclear whether the pathogenetic mechanism is same among individual organs or not. In addition to IgG4-RD, IgG4-associate conditions such as high serum levels of IgG4 or abundant infiltration of IgG4-positive cells were reported in some patients with malignancy; pancreatic [6,45], biliary [46] and salivary cancer [47], gastrointestinal sarcoma [48], and ocular adnexal lymphoma [49][50][51]. Therefore, the term "systemic" may lead us to misdiagnosis of other organ lesions showing IgG4related conditions in cases of malignancy [51]. Based on these findings, the members of Umehara and Okazaki teams have agreed that the term "IgG4-related disease" is appointed as minimally accepting these conditions at this moment.

Comprehensive Diagnostic Criteria for IgG4-RD [15, 24, 25]
The patients with IgG-4-related disease show organ enlargement or nodular/hyperplastic lesions in organs in the entire body, synchronously or metachronously, due to the prominent infiltration and fibrosis of lymphocytes and plasmacytes; however, the causes of the disease are still not clear.
The organs known to be affected include the central nervous system, lacrimal/salivary glands, thyroid gland, lungs, pancreas, biliary duct, liver, gastrointestinal tracts, kidneys, prostate gland, retroperitoneum, skin, arteries, and lymph nodes. Although it remains unclear whether this disease is the same as multifocal fibrosclerosis, that is a possibility. Clinical symptoms vary depending on the organ in which the lesions are located, which suggests that it is hard to establish criteria covering all patients with IgG4-RD. Therefore, specific diagnostic criteria are required for each involved organ such IgG4-related Mikulicz's disease (IgG4related dacryoadenitis/sialadenitis [12] (Table 2), type 1 AIP (IgG4-related pancreatitis) [13] (Table 3), and IgG4-related kidney disease [14,41] (Table 4). However, these organspecific criteria do not cover other organs or are not familiar to general clinicians and specialists. Moreover, to avoid misdiagnosis of malignancy, all physicians have to know this emerging disease entity and can make a diagnosis of IgG4-RD. Therefore, the CDC for IgG4-RD, containing three major criteria (clinical, hematological and histopathological examinations), have been proposed for practical use of general physicians and nonspecialist [15] (Table 5). Although sensitivity of the CDC for definitive IgG4-RD is low in the organs to be difficult in taking biopsy specimens, it can detect possible cases of IgG4-RD. In the probable or possible cases, organ specific criteria should be used concurrently.  [12] (approved by the Japanese Society for Sjögren's Syndrome, 2008).
(1) Symmetrical swelling of at least 2 pairs of lachrymal, parotid, and submandibular glands continuing for more than 3 months, (2) elevated serum IgG4 (>135 mg/dL), or (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 from other disorders, including sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, and cancer. Although the diagnostic criteria for Sjögren's syndrome (SS) may also include some patients with IgG4+ Mikulicz's disease, the clinicopathological conditions of patients with typical SS and IgG4+ Mikulicz's disease are different.
(1) Clinical Examination. Physical examinations and imaging on US/CT/MRI can show the characteristic diffuse/localized swelling, masses, or thickness in single or multiple organs ( Figure 1).
(2) Immunological Examination (a) Increase of Serum Levels of IgG4. 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 autoimmune pancreatitis [7] ( Table 6). In patients with single-organ involvement and serum IgG4 concentration less than 135 mg/dL, the IgG4/IgG ratio may be helpful in making a diagnosis. However, elevated IgG4 may be also observed in other diseases (e.g., atopic dermatitis, pemphigus, asthma, and multicentric Castleman's disease), especially in about 10% of malignancy, which suggests that high serum IgG4 is not necessarily specific marker of IgG4-RD [6]. Although a high cutoff value with >270 mg/dL of IgG4 increases specificity but decreased sensitivity of IgG4-RD differing from pancreatic cancer [45]. Therefore, at present, the significance of elevated IgG4 in the pathogenesis/pathophysiology of IgG4-RD still remains unknown.
(b) Other Immunological Markers. In addition to increased serum levels of IgG4, high serum levels of polyclonal γglobulin, IgG, and IgE are often, and hypocomplementemia may occur [52]. As these markers are less sensitive for IgG4-RD, they are not included as a diagnostic criterion.
(3) Histopathologic Examination. Although tissue biopsies are difficult to obtain from some organs, including the pancreas, retroperitoneum and ocular cavity, histopathological examination is important.
(a) Marked Lymphocyte and Plasmacyte Infiltration and Fibrosis. Storiform or swirling fibrosis or obliterative phlebitis is Characteristic of IgG4-RD and may be important in its diagnosis.
(b) Infiltration of IgG4-Positive Plasma Cells. IgG4/IgGpositive cells more than 40% [53] or 50% [12] have been reported in lymphnodes of the patients with IgG4-RD. On the other hand, more than 10 IgG4-positive plasma cells are recommended that in diagnosis of type 1 AIP [13]. Based on these findings, the CDC for IgG4-RD recommend both the ratio of IgG4/IgG-positive cells >40% and infiltration of >10 IgG4-positive plasma cells/HPF for the definitive diagnosis [15]. Eosinophilic infiltration is often observed along with infiltration of IgG4-positive cells. It is noted that reactive infiltration of IgG4-positive cells and fibrosis may be observed in various diseases and clinical conditions, such as rheumatoid synovitis, inflammatory oral and skin lesions, and around cancer. However, it is noted that some additional immune-mediated conditions with increased serum interleukin-6 (IL-6) such as multicentric Castleman's disease may show elevated serum IgG4 and/or IgG4+/IgG+ plasma cell ratios >40%.
(4) Prohibition of Facile Steroid Treatment in the CDC for IgG4-RD. Patients with malignant lymphoma or paraneoplastic lesions can sometimes be improved by steroid administration. Therefore, steroid trials should be strictly avoided. Efforts should be made to collect tissue samples for diagnosis. However, patients having disease in organs difficult to biopsy, such as the pancreas, retroperitoneum, and pituitary, and respond to steroids may possibly have IgG4-RD. In accordance with the guidelines for treatment of autoimmune pancreatitis, patients should be started on 0.5-0.6 mg/kg/day/prednisolone. If patients do not respond to the initial steroid therapy, the diagnosis should be reviewed again.

(5) Diseases to be Excluded or Differentiated
(a) Malignancies (e.g., Cancer, Lymphoma). In cases of malignancy in the involved organs, it is essential to determine whether malignant cells are present histopathologically.
[Concept] IgG4-related disease (IgG4-RD) shows organ enlargement or nodular/hyperplastic lesions in various organs concurrently or metachronously, due to marked infiltration of lymphocytes and IgG4-positive plasma cells, as well as fibrosis of unknown etiology. IgG4-RD affects various organs, including the pancreas, bile duct, lacrimal gland, salivary gland, central nervous system, thyroid, lung, liver, gastrointestinal tract, kidney, prostate, retroperitoneum, arteries, lymph nodes, skin, and breast. Although many patients with IgG4-RD have lesions in several organs, either synchronously or metachronously, others show involvement of a single organ. Clinical symptoms vary depending on the affected organ, and some patients may experience serious complications, such as obstruction or compression symptoms due to organomegaly or hypertrophy and organ dysfunction caused by cellular infiltration or fibrosis. Steroid therapy is often effective.
[Comprehensive clinical diagnostic criteria for IgG4- RD, 2011] (1) Clinical examination shows characteristic diffuse/localized swelling or masses in single or multiple organs.
(3) Histopathologic examination shows; (1) marked lymphocyte and plasmacyte infiltration and fibrosis (2)  However, it is important to differentiate IgG4-RD from malignant tumors of each organ (e.g. cancer, lymphoma) and similar diseases (e.g. Sjögren's syndrome, primary sclerosing cholangitis, Castleman's disease, secondary retroperitoneal fibrosis, Wegener's granulomatosis, sarcoidosis, and Churg-Strauss syndrome) by additional histopathological examination. Even when patients cannot be diagnosed using the CCD criteria, they may be diagnosed using organ-specific diagnostic criteria for IgG4RD.

Sensitivity and Specificity of the CDC Criteria and Diagnostic Algorithm for IgG4-RD
The sensitivity of CDC for definitive/probable IgG4-RD is satisfactory in IgG4-related MD [12] and IgG4-related KD [14], but not in type 1 AIP [6,13]. The major reason of low sensitivity in type 1 AIP is that enough biopsy samples of the pancreas are not easily obtained in most of these patients. In addition, endoscopic ultrasonography (EUS), guide fine needle aspiration (FNA), is available in a few of institutes in Japan, for examples only 16 of 226 (7%) board member institutes in Kink district of Japan Gastroenterological Endoscopy Society (JGES). On the other hand, the sensitivity of the CDC for possible IgG4-RD is satisfactory in type 1 AIP (Table 7). In contrast, patients with type 1 AIP could not be diagnosed by the comprehensive diagnostic criteria (0%) for definite, because biopsies could not be obtained from most of these patients. Therefore, combination of the CDC and organ-specific criteria should increase the sensitivity of diagnosis, even in the possible cases of IgG4-RD. Based on these findings, a diagnostic algorithm for IgG4-RD in combination with the CDC and other organ-specific criteria has been proposed, although they have a limitation to the utility of the criteria proposed [15] (Figure 2). In patients with (a) organ enlargement, mass or nodular lesions, or organ dysfunction, performing of both (b) measurement of serum IgG4 and (c) tissue biopsy is recommended. In the cases with >135 mg/dL of IgG4, diagnostic histopathological findings of >10 IgG4 cells/HPF and an IgG4/IgG cell ratio >40 can diagnose them as definitive AIP. In possible or probable cases fulfilling criterion (a) with (b), or (c), organ-specific criteria for each disease should be applied. It is important to differentiate IgG4-RD from malignant tumors of each organ (e.g., cancer, lymphoma) and similar diseases (e.g., Sjögren's syndrome, primary sclerosing cholangitis, Castleman's disease, secondary retroperitoneal fibrosis, Wegener's granulomatosis, sarcoidosis, and Churg-Strauss syndrome) by additional histopathological examination. Future studies including other organ diseases similar to IgG4-RD are needed to establish the diagnostic efficacy of CDC.

Conclusion
"All Japan Research Team for IgG4-RD" unified the nomenclatures as "IgG4-related disease (IgG4-RD)" and proposed the comprehensive diagnostic criteria (CDC) for IgG4-RD. The CDC for IgG4-RD was made for the practical use and for general physicians to differentiate IgG4-RD from malignancy or similar diseases as much as possible. Although sensitivity of the CDC for definitive IgG4-RD is low in the organs to 8 International Journal of Rheumatology be difficult in taking biopsy specimens, it can detect possible cases of IgG4-RD. In the probable or possible cases, organspecific criteria should be used concurrently.