Elevated Serum IgG4 Levels Research Articles

Serum IgG subclasses in autoimmune diseases.

To characterize serum IgG subclass levels in several autoimmune diseases, including primary Sjogren syndrome (pSS), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and primary biliary cirrhosis (PBC). We aimed to analyze serum IgG subclass distribution and to test whether serum IgG4 levels are elevated in these diseases.Serum IgG subclass levels from 102 pSS, 102 SSc, 100 SLE, and 59 PBC patients, as well as 40 healthy controls (HCs), were measured using the immunonephelometric assay. The distribution of IgG subclasses among these autoimmune diseases was analyzed.In this cross-sectional study, serum IgG1 (IgG1/IgG) and/or IgG3 (IgG3/IgG) were significantly increased, compared with those in HCs. Only 6.34% of patients had levels of serum IgG4 >135 mg/dL. There were no significant differences in the frequency of elevated serum IgG4 levels between patients and HC. In pSS, serum IgG1 levels were much higher than those in other disease groups, whereas serum IgG2 and IgG3 levels were most prominently increased in PBC.A strikingly different serum IgG subclass distribution was detected in patients with autoimmune diseases compared with HCs. Serum IgG subclass levels also showed distinct characteristics among different autoimmune diseases. Serum IgG4 levels in these patients were lower or not much higher than those in HCs, which differed from IgG4-related diseases.

The prevalence of IgG4-positive plasma cell infiltrates in inflammatory bowel disease patients without autoimmune pancreatitis.

IgG4-related autoimmune disease can exist in other organs even when there is no evidence of autoimmune pancreatitis. The aim of our study was to determine the prevalence of IgG4-positive plasma cells in the histopathological evaluations of colon biopsy specimens in IBD patients. The number of IgG4-positive plasma cells with strong cytoplasmic immunoreactivity was counted in each colon biopsy from inflammatory bowel disease patients who had no evidence of autoimmune pancreatitis. Five high power fields (HPFs) in the highest density plasma cell infiltration area were counted and were then averaged. An average >10 cells/HPF was considered significant for IgG4-related disease. We detected IgG4-positive plasma cell staining in the colon of 21 of 119 patients (17.6%). Of these 21 patients, 5 had elevated serum IgG4 levels (>140 mg/dL). Of the total, 4.2% (5/119) had both IgG4-immunstaining and elevated IgG4 serum levels. The demographic features, disease type and activity, and response to treatment (especially to steroid treatment) were similar between the IgG4-negative and IgG4-positive groups. In our study, 4.2% of patients with the diagnosis of IBD had elevated IgG4 serum levels and significant IGg4 immunostaining. Together, these two parameters indicate the possible diagnosis of an IgG4-related systemic disease.

Refractory IgG4-related intracranial hypertrophic pachymeningitis responded to rituximab.

Immunoglobulin G4-related disease (IgG4-RD) is a novel clinical entity characterized by elevated serum IgG4 levels and histopathologic features of storiform fibrosis, obliterative phlebitis, tissue eosinophilia, and infiltration of IgG4-positive plasma cells. Although it can involve almost any organ, IgG4-RD rarely involves the nervous system. The principal neurologic manifestations include hypophysitis and hypertrophic pachymeningitis (HP). In some patients, previously known idiopathic HP may in fact be IgG4-related. Acknowledgment: The authors thank Dr. Suzanne Z. Powell for her assistance in IgG4 antibody staining.

Graves'-like orbitopathy: do not forget IgG4-related disease.

ultrasonographic and/or serological evidence of autoimmune thyroid disease makes diagnosis of GO even more uncertain. Thus, if in typical cases imaging is confirmatory, then in doubtful circumstances it is mandatory. Many conditions may cause exophthalmos and/or extraocular muscle enlargement mimicking GO. Table 1 offers a list of these conditions, for some of which etiology is uncertain. IgG4-related disease is a recently described fibroinflammatory multiorgan disorder characterized by tumefactive lesions, lymphoplasmacytic infiltration with abundant IgG4-positive plasma cells, storiform fibrosis and frequently (but not always) elevated serum IgG4 levels (see [4] for an excellent and exhaustive review of this disease). Initially described in the context of autoimmune pancreatitis, IgG4-related disease may indeed affect several extrapancreatic sites, including the thyroid and the orbit. Riedel’s (fibrosclerosing) thyroiditis has been shown immunohistochemically to be comprised within the spectrum of IgG4-related disease [5]. The fibrous variant of Hashimoto’s thyroiditis might also be closely related to IgG4-related disease [6]. Graves’-like orbitopathy was described in a patient with autoimmune pancreatitis and very high serum IgG4 concentrations, in the absence of thyroid autoimmune disease or related thyroid dysfunction [7]. Clinical features were similar to those of moderate-to-severe and active GO. Imaging was characterized by enlarged extraocular muscles (with tendon sparing) and lacrimal gland, and expansion of the adipose tissue; there was an excellent response of orbital changes to intravenous glucocorticoids and orbital radiotherapy [7]. An additional case was described at the Mayo Clinic: the patient had a longlasting diagnosis of “GO”, treated many times with oral glucocorticoids because of repeated recurrences [8]. The patient was eventually submitted to orbital Graves’ orbitopathy (GO) affects about 25 % of patients with hyperthyroidism due to Graves’ disease [1], is usually mild and infrequently progressive [2, 3], although moderate-to-severe or (rare) sight-threatening forms do exist and require aggressive treatments [1]. In most cases, the onset of GO is temporally related to the onset of hyperthyroidism, but in some instances the orbital disease may precede or follow the onset of hyperthyroidism by months or years [1]. In addition, it is known that GO may less frequently develop in patients with euthyroid or hypothyroid Hashimoto’s thyroiditis [1]. The diagnosis of GO is simple and straightforward in the typical patient who, in addition to signs and symptoms of hyperthyroidism, has positive TSHreceptor antibody tests, bilateral eye symptoms (lacrimation, grittiness, photophobia, diplopia) and signs (exophthalmos, periorbital soft tissue swelling, ocular dysmotility, rarely visual defects). Diagnosis is confirmed by imaging studies showing enlarged extraocular muscles (with tendon sparing) and/or expansion of the orbital fibroadipose tissue [1]. Diagnostic problems arise particularly in those patients who are not hyperthyroid and have asymmetrical or unilateral orbital involvement. The presence of euthyroid/hypothyroid chronic autoimmune thyroiditis does not guarantee that orbital disease be related to GO; the absence of thyroid

Case Series and Systematic Review of IgG4‐Related Diseases in the Head and Neck

Objectives: Immunoglobulin G4-related disease (IgG4-RD) is a poorly understood chronic inflammatory disorder affecting the middle aged and elderly that can present to the otolaryngologist. We aim to summarize the current literature by performing a systematic review as well as describe our institutional experience with 8 patients. Methods: Our search used Pubmed, Ovid, and Scopus using the keywords IgG4 related disease, head and neck, orbit, salivary glands, sialadenitis, Kuttner, angiocentric eosinophilic fibrosis, submandibular, lacrimal, thyroid, dacryoadenitis, nasal, sinus, paranasal, and Mikulicz’s. Original research and review articles published in English from 1964 to 2013 whose major topic was IgG4-RD affecting the head and neck were included. Data regarding the various presentations and management of IgG4-RD were summarized. Additionally, we present our own experience with a series of 8 patients diagnosed with this condition. Results: One hundred twenty-four articles met our inclusion criteria. IgG4-RD most often presents as a mass lesion in the head and neck region. Common diagnostic features include: (1) elevated serum IgG4 level, (2) marked infiltration of exocrine glands by IgG4-positive plasma cells with fibrosis, and (3) marked improvement with corticosteroid therapy. Early diagnosis and involvement of rheumatology is important in management. Conclusions: IgG4-RD is a challenging nonsurgical disease that has multiple manifestations in the head and neck. It must be distinguished from various mimics including malignancy, systemic diseases, and infectious. Otolaryngologists should be aware of this condition and its management.

The impact of elevated serum IgG4 levels in patients with primary sclerosing cholangitis

BackgroundElevated IgG4 levels have been reported among patients with primary sclerosing cholangitis. Epidemiological data has only been provided from tertiary centres. AimsTo investigate the prevalence of elevated IgG4 levels and to compare prognosis between patients with and without elevated IgG4 levels in serum in two European cohorts of patients with primary sclerosing cholangitis. MethodsSerum IgG4-levels were measured in a consecutive series of patients from Berlin, and retrospectively collected in a population-based cohort from Sweden (total N=345). Cox's proportional hazard analysis was used to calculate relative risks for liver-related death or liver transplantation and cholangiocarcinoma. ResultsElevated IgG4 values were demonstrated in 10% of patients. A previous history of pancreatitis, combined intra- and extrahepatic biliary involvement and jaundice were independently associated with elevated IgG4 in multivariate analysis. IgG4 status was not associated with an increased risk for the combined endpoint liver-related death or liver transplantation or cholangiocarcinoma. ConclusionThe prevalence of elevated IgG4 values among European patients with primary sclerosing cholangitis is similar to what previously has been reported from the United States. Elevated IgG4 was not associated with an increased risk of liver transplantation or liver-related death or cholangiocarcinoma.

IgG4- related disease: an orphan disease with many faces.

Immunoglobulin G4- related disease (IgG4-RD) is a rare systemic fibro-inflammatory disorder (ORPHA284264). Although patients have been described more than 100 years ago, the systemic nature of this disease has been recognized in the 21st century only. Type 1 autoimmune pancreatitis is the most frequent manifestation of IgG4-RD. However, IgG4-RD can affect any organ such as salivary glands, orbits, retroperitoneum and many others. Recent research enabled a clear clinical and histopathological description of IgG4-RD. Typically, lymphoplasmacellular inflammation, storiform fibrosis and obliterative phlebitis are found in IgG4-RD biopsies and the tissue invading plasma cells largely produce IgG4. Elevated serum IgG4 levels are found in many but not all patients. Consequently, diagnostic criteria for IgG4-RD have been proposed recently. Treatment is largely based on clinical experience and retrospective case series. Glucocorticoids are the mainstay of therapy, although adjunctive immunosuppressive agents are used in relapsing patients. This review summarizes current knowledge on clinical manifestations, pathophysiology and treatment of IgG4-RD.

Rare Thyroid Cartilage Involvement of Multiple Myeloma Visualized on F-18 FDG-PET/CT Imaging: 3 Case Reports.

Plasma cell neoplasms (PCN) are clonal proliferations of immunoglobulin producing plasma cells. Extramedullary tumors form a small percentage of plasma cell tumors. Although 80–90 % of extramedullary lesions occur in head and neck region, they account for 1 % of all head and neck tumors. Furthermore, extramedullary plasmacytoma of the endolarynx and thyroid cartilage is very rare [1]. Computerized tomography (CT) widely used to detect thyroid cartilage involvement in multipl myeloma. Previous studies have shown that Positron emission tomography (PET)/CT with F-18 fluorodeoxyglucose (FDG) is useful in detection of both osseous and extraosseous myeloma lesions. However, to our knowledge there is no thyroid cartilage involvement shown with PET/CT. Our present case reports thyroid cartilage involvement of Multiple Myeloma (MM) visualized on F-18 FDG-PET/CT imaging. Three male patients were referred to our clinic (aged 58, and 64) for detection of disease involvement and evaluation of treatment response after the appropriate medical treatment. Diagnosis of MM was made for all three patients on the basis of the presence of a markedly elevated serum IgG level, an abnormal serum and urine electrophoresis showing a monoclonal kappa cell population with an M spike, and results of a bone marrow biopsy that revealed normocellular marrow with a monoclonal kappa plasma cell population. A conventional contrast-enhanced helical CT scan revealed lytic- expansile masses originating within the thyroid cartilage and disseminated lytic-expansile bone lesions. The patients underwent PET/CT imaging 60 min after 10 mCi FDG injection. MIP image of PET/CT demonstrated multiple bone lesions with increased 18 FDG uptake. PET/CT revealed hypermetabolic lesions involving the bone in all of the patients with increased 18 FDG uptake. Active 18 FDG uptake of the thyroid cartilage (SUV-max value between 4 to 8) was also detected in all patients. Extramedullary involvement of MM as presenting mesenteric mass in one patient and hyoid bone inolvement in two patients with increased 18 FDG uptake were detected. Thyroid cartilage involvement of the cases was shown in Figs. 1, ​,22 and ​and33. Fig. 1 Diffuse involvement of cervical vertebrae and thyroid cartilage Fig. 2 Increased FDG uptake in thyroid cartilage in multiple myeloma Fig. 3 Involvement of cervical vertebrae and thyroid cartilage Extramedullary tumors form a small percentage of plasma cell tumors, 80–90 % of which occurs in head and neck [2]. Laryngeal involvement accounts for 6–18 % of all extramedullary plasmacytoma, including epiglottis, glottis, false cords, aryepiglottic folds, and subglottic structures. Involvement of the cricoid cartilage occurs in patients with overt MM as well as in patients with plasmacytoma [1, 3]. Involvement of the thyroid cartilage in PCN is exceedingly rare with only 7 previously reported cases. In 3 of these cases, the neck mass was the initial presenting feature of PCN. In 4 of the seven cases, hoarseness was a presenting feature of the thyroid cartilage lesion [4]. There are two theories explaining mechanisms of cartilaginous involvement in MM. First theory suggests that cartilage may be invaded by an adjacent plasmacytoma [2]. Second theory suggests that cartilage particularly in older patients, may undergo osseous metaplasia with formation of a true central marrow space, and plasmacytomas could originate directly within this marrow. Osseous metaplasia has been previously documented in both the cricoid and the thyroid cartilage and plasmacytoma occurring within an ossified cricoid cartilage has been confirmed pathologically [1]. Although the presence of both red marrow and plasmacytoma within a cartilage would suggest an etiologic relationship, since MM usually develops within bone marrow, documentation of this is difficult, given the rarity of cartilaginous plasmacytomas with either MM or extramedullary plasmacytoma. CT and magnetic resonance imaging (MRI) is useful for the detection of extramedullary sites of the disease. Molecular imaging modalities such as F18-FDG PET or FDG- PET/CT are whole body imaging techniques capable of furnishing merged functional and morphologic information. FDG-PET or PET/CT could detect the treatment response earlier than other imaging methods. Sensitivity and specificity of FDG-PET or PET/CT in the assessment of bone myelomatous involvement at initial diagnosis are very high, 85 and 92 %, respectively [5]. In addition, PET-FDG or PET/CT could help to identify eventual extra-medullary sites of disease not allowed by MRI: therefore, it is more sensitive than MRI for the localization of extramedullary sites of disease. Zamagni et al. have demonstrated that FDG-PET detects improvement of bone disease in more patients (65 %) than MRI does (35 %) [5]. In conclusion, FDG-PET/CT is more sensitive than conventional imaging modalities for the localization of extramedullary sites of the disease.

Serum Immunoglobulin G4 Level Is a Poor Predictor of Immunoglobulin G4–Related Disease

Immunoglobulin G4-related disease (IgG4-RD) is characterized by elevation in serum IgG4 levels, typical multiorgan involvement and dramatic response to steroid therapy. We determined the predictive value of an elevated serum IgG4 for the diagnosis of IgG4-RD. We also sought to identify novel conditions, which have characteristic features of IgG4-RD. We identified all Mayo Clinic Rochester patients with serum IgG4 levels measured between January 2008 and December 2011 (n = 6014). Those with elevated serum IgG4 levels (reference range, 121-140 mg/dL) were included in the analysis and were classified as "definite," "probable," or "no" IgG4-RD. Serum IgG4 levels were elevated in 390 subjects (6.5%) of whom only 39 (10%) had IgG4-RD (29 "definite," 10 "probable"). The positive predictive value of an elevated serum IgG4 for IgG4-RD was poor (10%). Subjects with IgG4-RD differed from those without IgG4-RD in mean age (59.6 ± 15.2 vs 54.4 ± 18.3 years, P < 0.05), % males (90% vs 58%, P < 0.05), mean serum IgG4 level (437 ± 471 vs 223 ± 194 mg/dL, P < 0.05), and presence of chronic rhinosinusitis (7/39 vs 29/351, P = 0.05). Elevated serum IgG4 levels are not specific for IgG4-RD and are likely to be a false-positive. Chronic rhinosinusitis is likely an as yet underrecognized manifestation of IgG4-RD.

IgG4‐related disease: a new kid on the block or an old aquaintance?

IgG4-related systemic disease is a recently recognized systemic condition characterized by unique pathological features that can affect a variety of organs. It includes a growing number of medical conditions which have the following features in common: diffuse organ swelling or focal mass formation, sclerosing storiforme (whirl-shaped) fibrosis with a lymphoplasmacytic infiltrate rich in IgG4-bearing plasma cells, as well as elevated levels of serum IgG4. It invariably responds to steroid treatment and is mostly diagnosed in elderly men. Well-known syndromes like Mikulicz's disease of the salivary or lacrimal gland, Küttner's tumour of the submandibular gland, Riedel's thyroiditis, or retroperitoneal fibrosis, as well as novel entities such as autoimmune pancreatitis type 1, are now regarded to be manifestations of this systemic disease. This article provides an overview of the epidemiology, concepts of pathogenesis, clinical presentation, proposed diagnostic approaches, treatment options, and differential diagnosis of IgG4-related disease.

FRI0240 Usefulness of Fdg-Pet/Ct Imaging in Igg4-Related Disease

BackgroundIgG4-related disease (IgG4-RD) is a relatively common and clinically important disease. It is very difficult to confirm the diagnosis due to the ubiquity of its lesions, which can involve the...

Elevated IgG4 serum levels among primary Sjögren's syndrome patients: do they unmask underlying IgG4-related disease?

To determine IgG4 levels in a cohort of consecutive patients with primary Sjögren's syndrome (SS) and other autoimmune diseases and explore whether they associate with distinct clinical, serologic, and histopathologic features. Serum IgG4 levels were measured in 133 primary SS patients and 49 healthy donors (HDs). Seventy-four lupus and 54 rheumatoid arthritis (RA) patients served as disease controls. Immunohistochemical IgG4 analysis was performed in paraffin-embedded minor salivary gland (MSG) tissues. Raised IgG4 serum levels (>135 mg/dl) were detected in 10 (7.5%) of 133 primary SS patients (high-IgG4 group), in 8 (10.8%) of 74 lupus patients, in 7 (12.9%) of 54 RA patients, and in 1 (2%) of 49 HDs. Compared to the normal-IgG4 (<135 mg/dl) primary SS group, high-IgG4 patients exhibited increased prevalence of IgG4-related features (autoimmune cholangitis, autoimmune pancreatitis, and interstitial nephritis), lower rates of antinuclear antibody positivity, and higher IgG2 and IgE levels. Positive staining for IgG4+ plasma cells with an IgG4:IgG ratio ≥40% was detected in 3 of 6 available MSG tissues in the high-IgG4 group. Criteria of possible or definite IgG4-related disease (IgG4-RD) were fulfilled by 10 (7.5%) of 133 of our primary SS cohort. Raised IgG4 serum levels were detected in 7.5% of primary SS patients in association with IgG4RD-reminiscent clinical, serologic, and histopathologic features. Whether this high-IgG4 primary SS group represents a misclassified IgG4-RD group or a distinct primary SS subtype remains to be further explored in future studies.

IgG4 plasma cell myeloma: new insights into the pathogenesis of IgG4-related disease

IgG4-related disease is a newly described systemic fibroinflammatory process, characterized by increase in IgG4-positive plasma cells. Its pathogenesis, including the role of IgG4, remains poorly understood. Plasma cell myeloma is typically associated with a large monoclonal serum spike, which is frequently of IgG isotype. We sought to identify and characterize a subset of IgG4-secreting myeloma, as it may provide a biological model of disease with high serum levels of IgG4. Six out of 158 bone marrow biopsies (4%) from patients with IgG myeloma expressed IgG4. Four patients were men and two were women, with a mean age of 64 (range 53–87) years. Imaging showed fullness of pancreatic head (1), small non-metabolic lymphadenopathy (1), and bone lytic lesions (6). Two patients developed necrotizing fasciitis. All had elevated serum M-protein (mean 2.4, range 0.5–4.2 g/dl), and none had definite signs or symptoms of IgG4-related disease. Four myelomas had plasmablastic morphology. Four had kappa and two had lambda light chain expression. Three cases expressed CD56. Two patients had a complex karyotype. In conclusion, the frequency of IgG4 myeloma correlates with the normal distribution of IgG4 isoform. The patients with IgG4 myeloma appear to have a high rate of plasmablastic morphology and could be predisposed to necrotizing fasciitis. Despite high serum levels of IgG4, none had evidence of IgG4-related disease. These findings suggest that the increased number of IgG4-positive plasma cells is not the primary etiologic agent in IgG4-related disease. Elevated serum levels of IgG4 is not sufficient to produce the typical disease presentation and should not be considered diagnostic of IgG4-related disease.

Bilateral Optic Nerve Involvement in Immunoglobulin G4–Related Ophthalmic Disease

To describe a presumptive case of immunoglobulin G4-related ophthalmic disease (IgG4-ROD) with bilateral optic nerve involvement and to review the clinical features of this entity. Case report. A 62-year-old man presented with bilateral blurred vision. He had a history of sinus surgery, and a biopsy specimen showed dense infiltration of IgG4-positive plasma cells. His visual acuity was 20/25, right eye, and 20/125, left eye. Serologies demonstrated elevated serum levels of IgG and IgG4, and computed tomography showed masses surrounding both optic nerves at the orbital apices and bilaterally enlarged infraorbital nerves. The patient underwent 2 cycles of intravenous pulse steroid therapy followed by a taper of oral steroids Three months later, vision was 20/20 in each eye and, while the serum level of IgG was within normal limits, the IgG4 level remained elevated. IgG4-ROD may involve the optic nerves resulting in vision loss. Although steroid administration is the primary treatment for this entity, slow tapering is essential to avoid relapse.

Elevated Serum Immunoglobulin G4 Levels in Patients with Graves' Disease and Their Clinical Implications

Immunoglobulin G4-related disease (IgG4-RD) is a new clinical entity that affects various organs with increased IgG4 positive plasmacytes and progressive fibrosis. While IgG4-RDs in association with Hashimoto's thyroiditis or Riedel's thyroiditis have been reported, the relationship between IgG4-RD and Graves' disease (GD) is yet unknown. To elucidate the relation of GD to IgG4-RD, serum IgG4 levels and their clinical implications in patients with GD were investigated. In this prospective study, serum IgG4 levels were measured in 109 patients with GD and classified into two groups according to the comprehensive diagnostic criteria of IgG4-RD previously established: (i) GD with elevated-IgG4 levels (≥ 135 mg/dL), and (ii) GD with nonelevated IgG4 (<135 mg/dL). Seven out of 109 patients with GD (6.4%) had elevated serum IgG4 levels [mean ± standard deviation (range): 175.0 ± 44.5 (136-266) mg/dL] and elevated ratios of IgG4/IgG [12.7 ± 4.5% (7.6%-21.2%)]. The remaining patients with GD had serum IgG4 levels and IgG4/IgG ratios of 39.6 ± 27.6 (3-132) mg/dL and 3.2 ± 2.2% (0.3%-11.5%), respectively. Ages in the elevated IgG4 group were significantly higher than those of the nonelevated IgG4 group: 54.7 ± 6.2 versus 43.4 ± 15.4 years, respectively. Ultrasound examinations revealed that the elevated IgG4 group had significantly increased hypoechogenic areas in the thyroid in comparison to the nonelevated IgG4 group (low echo scoring: 1.66 ± 0.81 vs. 0.61 ± 0.89, respectively). In the correlation analysis, TSAb (rs=0.385, n=42) titers were significantly correlated with se rum IgG4 levels, while they were not significantly different between the two groups. In the elevated IgG4 group, symptoms were controllable with a small dose of antithyroidal drug (ATD; n=4), a combination treatment with ATD and L-T4 (n=1), or L-T4 administration only one year after the first visit (n=2). A small portion of GD patients harbored elevated serum IgG4 levels. They were older, had increased hypoechoic areas in the thyroid, and appeared to be responsive or prone to be hypothyroid after ATD treatment. Thus, the present study suggests the presence of a novel subtype of GD. Measuring serum IgG4 levels may help to distinguish this new entity and provide potential therapeutic options for GD.

Diagnosis of immunoglobulin g4-related sclerosing cholangitis.

See Levels in Bile for Distinguishing IgG4-Associated Cholangiopathy from Other Biliary Disorders: A Single Blinded Pilot Study) by Udayakumar Navaneethan, Norma G. Gutierrez, Ramprasad Jegadeesan, et al., on page 555-559 Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is a characteristic type of SC with increased serum IgG4 levels and dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall.1 IgG4-SC is now recognized within the spectrum of systemic IgG4-related diseases. IgG4-SC is well resolved by steroid therapy, which is a characteristic feature of IgG4-related disease. IgG4-SC is frequently associated with type 1 autoimmune pancreatitis (AIP) and IgG4-related sialadenitis; retroperitoneal fibrosis can also occasionally be observed in IgG4-SC. However, some IgG4-SC cases do not involve any other organs. The cholangiographic abnormalities observed in IgG4-SC may resemble those of primary sclerosing cholangitis (PSC) and hilar cholangiocarcinoma. Since obstructive jaundice is frequently observed in IgG4-SC, and IgG4-SC is most common in elderly men, the differential diagnosis compared to that for hilar cholangiocarcinoma is sometimes very difficult. Secondary SC also should be ruled out. An elevated serum IgG4 level is a characteristic feature of IgG4-SC and can effectively detect patients with IgG4-SC.2 However, IgG4-SC patients without pancreatic involvement displayed no marked increase in serum IgG4 levels compared to patients with AIP-associated IgG4-SC. Even though an IgG4 cutoff level of 135 mg/dL is widely used as part of the diagnostic criteria for AIP, a few reports concerning the IgG4 cutoff level in the diagnosis of IgG4-SC have been published.3,4 Oseini et al.3 reported that among 126 patients with cholangiocarcinoma, 17 (13.5%) had elevated serum IgG4 levels (>140 mg/dL), while four (3.2%) had a >2-fold increase (>280 mg/dL) in serum IgG4 levels. They concluded that diagnosis using a 2-fold higher cutoff serum IgG4 level may not reliably distinguish IgG4-SC from cholangiocarcinoma, but a cutoff level 4-fold higher than the normal upper limit had 100% specificity for IgG4-SC. A recent Japanese study, which included 344 IgG4-SC patients, established a cutoff value of serum IgG4 to differentiate IgG4-SC from other diseases in nine high-volume centers in Japan.4 The cutoff obtained from receiver-operator characteristic curves displayed similar sensitivity and specificity to a cutoff of 135 mg/dL, when IgG4-SC cases were compared with controls. A cutoff of 182 mg/dL increased the specificity for distinguishing IgG4-SC from cholangiocarcinoma to 96.6%. A cutoff of 207 mg/dL might be more useful for unambiguously distinguishing IgG4-SC from all cholangiocarcinoma, but the sensitivity was only 68.4%. Only three diagnostic criteria for IgG4-SC have been proposed5,6,7 and no standard international diagnostic criteria have been defined until now. IgG4-SC should be discriminated from all three intractable diseases, namely, pancreatic cancer, PSC, and cholangiocarcinoma. The Japanese criteria were derived from a combination of characteristic clinical, serological, morphological, and histopathological features with cholangiographic classification.6,7 Recently, Navaneethan et al.8 performed a single center pilot study on the diagnostic role of biliary IgG4 in IgG4-SC. They enrolled 54 patients in total, and bile was directly aspirated from the common bile duct during endoscopic retrograde cholangiography. The median biliary IgG4 levels were markedly elevated in patients with IgG4-SC (5.5 mg/dL) compared to patients with other diseases such as PSC (1.2 mg/dL) and cholangiocarcinoma (0.9 mg/dL). A cutoff value of 3.8 mg/dL distinguished IgG4-SC from PSC and cholangiocarcinoma with a 100% and 76.9% sensitivity and specificity, respectively. However, the limitations of this study were the small number of patients enrolled (three patients with IgG4-SC and nine patients with cholangiocarcinoma) and a possibility of type II errors. Therefore, the number of patients is too small to derive a definite cutoff value at present. Another limitation was that serum IgG4 levels were not obtained from the enrolled patients. Despite these limitations, this study suggested a potential role for biliary IgG4 measurement as a diagnostic tool in patients with IgG4-SC. Thus, biliary IgG4 levels can be included in new diagnostic criteria for a prospective large multicenter study.

Immunoglobulin G4-related Disease Associated with Cutaneous Vasculitis

© 2014 The Authors. doi: 10.2340/00015555-1707 Journal Compilation © 2014 Acta Dermato-Venereologica. ISSN 0001-5555 Immunoglobulin G (IgG) is composed of 4 Ig isotypes. A new entity called IgG4-related disease has recently been established (1). This disorder is characterised by an elevated serum level of IgG4 and an infiltration of IgG4+ plasma cells, as well as lymphocyte infiltration of various organs. IgG4 is the only subclass of human IgG that is unable to activate complement by the classical pathway. In the present report, we examine two patients with IgG4related disease associated with cutaneous vasculitis.

Autoimmune pancreatitis: Multimodality non-invasive imaging diagnosis.

Autoimmune pancreatitis (AIP) is characterized by obstructive jaundice, a dramatic clinical response to steroids and pathologically by a lymphoplasmacytic infiltrate, with or without a pancreatic mass. Type 1 AIP is the pancreatic manifestation of an IgG4-related systemic disease and is characterized by elevated IgG4 serum levels, infiltration of IgG4-positive plasma cells and extrapancreatic lesions. Type 2 AIP usually has none or very few IgG4-positive plasma cells, no serum IgG4 elevation and appears to be a pancreas-specific disorder without extrapancreatic involvement. AIP is diagnosed in approximately 2%-6% of patients that undergo pancreatic resection for suspected pancreatic cancer. There are three patterns of autoimmune pancreatitis: diffuse disease is the most common type, with a diffuse, "sausage-like" pancreatic enlargement with sharp margins and loss of the lobular contours; focal disease is less common and manifests as a focal mass, often within the pancreatic head, mimicking a pancreatic malignancy. Multifocal involvement can also occur. In this paper we describe the features of AIP at ultrasonography, computed tomography, magnetic resonance and positron emission tomography/computed tomography imaging, focusing on diagnosis and differential diagnosis with pancreatic ductal adenocarcinoma. It is of utmost importance to make an early correct differential diagnosis between these two diseases in order to identify the optimal therapeutic strategy and to avoid unnecessary laparotomy or pancreatic resection in AIP patients. Non-invasive imaging plays also an important role in therapy monitoring, in follow-up and in early identification of disease recurrence.

Autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus is associated with elevated IgG4 but not with low vitamin D.

To assess levels of vitamin D and of immunoglobulin G subclasses in children and adolescents with type 1 Diabetes Mellitus with or without autoimmune thyroiditis. Among 213 patients with type 1 diabetes, the cases with thyroid-specific autoantibodies formed Group 1 [n=19, M/F: 7/12, median age 13 years (10.1-14.7)]. Nineteen age-, gender-, and diabetes duration-matched cases with type 1 diabetes without any other systemic disease were designated as controls [Group 2, M/F: 7/12, median age 12.9 years (10.5-14.9)]. Levels of thyroid hormones, vitamin D, total IgG and IgG subclasses, as well as IgG subclasses/total IgG ratios were similar between the groups. Five cases (26%) in Group 1 had IgG4 levels > + 2 SDS, whereas there were no such cases in Group 2 (p=0.046). These five patients had similar clinical features but higher median IgG4 levels and IgG4/Total IgG ratios compared to the subjects with IgG4 levels < + 2 SDS in Group 1 and Group 2. There was no difference of vitamin D levels between the groups. Only a small percentage of patients with type 1 diabetes also having autoimmune thyroiditis had elevated serum IgG4 levels, revealing the heterogeneity of autoimmune thyroiditis and existence of IgG4 thyroiditis in the pediatric age group. Total IgG, the other IgG subclasses, and vitamin D levels did not differ in patients with autoimmune thyroiditis and type 1 diabetes compared to those suffering only from type 1 diabetes.

A Case of Resected Plasma Cell Type Castleman’s Disease with Intramediastinal Lymph Nodes Spread

We report a case of resected plasma cell (PC) type Castleman's disease (CD) in a 21-year-old female who had an anterior mediastinal mass with additional surrounding nodules. She was aware of low-grade fever and fatigue for several years. From hematological and biochemical examinations, elevated inflammatory responses and levels of serum IgG (2908 mg/dL) and IL-6 (22.2 pg/mL) were observed. She was diagnosed with PC type CD by needle biopsy under computed tomography (CT) guidance. It was thought that the lesion was localized in the mediastinum. Then, mediastinal adipose tissue including the tumor, additional nodules and thymus were removed. The histological findings of PC type CD were found not only in the main tumor but also in surrounding swollen lymph nodes. Her symptoms improved and inflammatory responses decreased after the operation. No recurrence has been observed for 5 years after the operation.