The diagnostic utility of submandibular gland sonography and labial salivary gland biopsy in IgG4-related dacryoadenitis and sialadenitis: Its potential application to the diagnostic criteria.

Objectives: In this study, we investigated the diagnostic utility of submandibular gland (SMG) sonography and labial salivary gland (LSG) biopsy as a less invasive procedure for diagnosing IgG4-related dacryoadenitis and sialadenitis (IgG4-DS)Methods: Sixty-eight patients with suspected IgG4-DS by presenting swelling of elevated serum IgG (>1747 mg/dl) and/or swelling glands underwent SMG sonography, LSG biopsy and measurement for serum IgG4. SMG sonographic diagnosis was determined by the following characteristic changes; 'hypoechoic areas of a nodal pattern with high vascularity' and/or 'hypoechoic areas of a reticular pattern in the superficial part'.Results: Thirty-one patients were diagnosed with IgG4-DS, 5 with IgG4-RD unaccompanied by lacrimal and salivary gland lesions, 28 with Sjögren's syndrome, and 4 with malignant lymphoma. The sensitivity, specificity, and accuracy of SMG sonography and LSG biopsy were 100%, 83.8%, 91.2% and 64.5%, 73.8%, 75.0%, respectively. Moreover, those of SMG sonography and LSG biopsy combined with serum IgG4 concentration (>135 mg/dl) were 100%, 94.6%, 97.1% and 64.5%, 91.9%, 79.4%, respectively.Conclusion: LSG biopsy needs to be extremely careful to diagnose IgG4-DS because of its low sensitivity. SMG sonography is sufficient for the diagnosis of IgG4-DS, especially when combined with serologic analysis. Thus, SMG sonography could adapt to the diagnostic criteria of IgG4-DS as a non-invasive method.

Hyperglycemia and Salivary Gland Dysfunction in the Non-obese Diabetic Mouse: Caveats for Preclinical Studies in Sjögren's Syndrome.

The Non-obese Diabetic (NOD) mouse model for type I diabetes also develops some features of Sjögren's syndrome (SS). Since the source of the mice and the environment exert a strong influence on diabetes, this study investigated SS development in NOD mice obtained from two vendors. Female NOD mice from The Jackson Laboratory (JAX) and Taconic Biosciences were monitored for blood glucose and pilocarpine-induced salivation. The gut microbiome was analyzed by 16S rRNA sequencing of stool DNA. At euthanasia, serum cytokines and sialoadenitis severity were evaluated. The onset of diabetes was significantly accelerated in JAX mice compared to Taconic mice. Although the gut microbiome between the two groups was distinct, both groups developed sialoadenitis. There was no correlation between the severity of sialoadenitis and reduced saliva production. Instead, salivary gland dysfunction was associated with hyperglycemia and elevation of serum IL1ß, IL16, and CXCL13. Our data suggest that inflammatory pathways linked with hyperglycemia are confounding factors for salivary gland dysfunction in female NOD mice, and might not be representative of the mechanisms operative in SS patients. Considering that NOD mice have been used to test numerous experimental therapies for SS, caution needs to be exerted before advancing these therapeutics for human trials.

Differences and similarities between IgG4-related disease with and without dacryoadenitis and sialoadenitis: clinical manifestations and treatment efficacy.

BACKGROUND: This study aimed to compare the differences and similarities in the clinical manifestations and treatment efficacy of IgG4-related disease (IgG4-RD) in patients with and without dacryoadenitis and sialoadenitis (DS). METHODS: A total of 121 untreated IgG4-RD patients in Peking Union Medical College Hospital were enrolled in this study. The patients were divided into three groups: DS-predominant (group A), non-DS (group B), and DS with other internal organs affected (group C). The patients were followed up for at least 15 months. Baseline and follow-up data were collected. The disease activity was evaluated according to the IgG4-RD responder index. RESULTS: The mean ± SD age at disease onset was 53.2 ± 14.1 years, and 71.9% of the patients were male. The prevalence of allergies was higher in groups A (21, 61.8%) and C (32, 69.6%) than group B (14, 34.1%). More patients with DS (17, 50.0%, and 17, 37.0%) had sinonasal lesions than those without DS (5, 12.2%). Moreover, an increased number of eosinophils were more common in patients with DS than in those without, as were increased serum IgG, IgG4, and IgE levels. More patients in group B and group C (28, 68.3%, and 31, 67.4%) received a combination therapy of corticosteroid and immunosuppressant. During the 15-month follow-up, 28 (23.1%) patients had disease relapse. CONCLUSION: Results demonstrated that IgG4-RD patients with DS had distinctive clinical features compared with non-DS. Allergy and sinonasal involvement were more common in patients with DS. Patients with DS showed higher serum IgG4 levels than those without DS.

Interleukin 5-producing ST2+ memory Th2 cells in IgG4-related dacryoadenitis and sialadenitis.

Objectives: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is often complicated by allergic disorders. This study was conducted to investigate the mechanism of type 2 helper T-inflammation (Th2-inflammation) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS). Methods: We separated and analyzed the proportion of growth stimulation expressed gene 2 (ST2)+ memory Th2 cells among the peripheral blood mononuclear cells by flow cytometry in cases with IgG4-DS and healthy individuals. Finally, we identified the role of ST2+ memory Th2 cells in the involved tissues. Results: The proportion of circulating ST2+ memory Th2 cells was much higher in the patients with IgG4-DS than in the healthy controls. Abundant infiltration of ST2+ memory Th2 cells was detected in the involved salivary glands and lymph nodes, and these cells produced interleukin-5. Conclusion: We demonstrated that there is an increase of interleukin-5 producing ST2+ memory Th2 cells in the involved tissues in IgG4-DS. This subset of cells is considered to be an important player in inducing the inflammatory Th2 environment characteristic of IgG4-DS.

Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment.

OBJECTIVES: Patients with immunoglobulin-G4 related disease (IgG4-RD) diagnosed according to the comprehensive diagnostic criteria (CDC) show varied therapeutic responses and prognoses. We assumed that there are clinical stages in IgG4-RD and have verified it using serum cytokine levels in the groups classified by lesion distribution. METHODS: Definite IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) cases were divided according to the CDC for IgG4-RD into 11 cases with focal type and 30 cases with systemic type. The levels of serum interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-21, interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, and monocyte chemotactic protein (MCP)-1 were measured in healthy controls, allergic patients, probable IgG4-RD cases, and focal and systemic type cases. The cytokine environment was analyzed in each group. The 52 definite IgG4-RD cases were next classified into four groups with cluster analysis in terms of therapeutic responses and prognosis. The relationships between each cytokine level and therapeutic responses were also analyzed. RESULTS: Both serum IL-5 and IFN-α concentrations were very low in healthy controls, but they increased in the allergic cases, probable cases, and focal and systemic type cases. The level of serum IL-5 was significantly higher in definite cases than in healthy controls. The serum IL-5 level was also significantly increased in the groups with a poor prognosis than in the good prognosis group. CONCLUSION: These results suggest that there are clinical stages in IgG4-RD, and serum IL-5 play roles in the pathogenesis of IgG4-RD.

Flagellar filament structural protein induces Sjögren's syndrome-like sialadenitis in mice.

OBJECTIVE: Sjögren's syndrome (SS) is a systemic autoimmune disease that primarily affects lacrimal and salivary glands. We previously reported that FliC derived from Escherichia coli could induce autoimmune pancreatitis-like lesions. From these results, we speculated that FliC could also induce SS-like exocrinopathy. In this study, we investigated the effects of chronic exposure to FliC on lacrimal and salivary glands and the possibility that it might lead to an autoimmune response. METHODS: C57BL/6 mice were repeatedly injected with FliC and histological changes, serum levels of cytokine/chemokines and autoantibodies were evaluated at different time points after the final injection. The presence of sialadenitis was diagnosed by histological methods. RESULTS: In FliC-treated groups, 57% of subjects developed inflammatory cell infiltrates around ducts in mandibular salivary glands, but not lacrimal glands. In addition, serum levels of total IgG, IgG1, and IgG2a were significantly higher in FliC-treated groups. Intriguingly, serum anti-SSA/Ro levels were also significantly higher in FliC-treated groups. Cytokine analysis revealed that serum levels of IL-1ß, IL-12p70, IL-13, IFN-γ, IL-15, and IL-23 seemed to be higher in FliC-treated mice. CONCLUSIONS: Our data suggest that FliC-treated mice develop an SS-like phenotype. Our model may elucidate the relationship between commensal bacteria and SS.

Clinicopathology of Immunoglobulin G4-Related Chronic Sclerosing Sialadenitis: A Single-Center Study.

OBJECTIVES: To investigate the clinicopathologic characteristics of patients with immunoglobulin G4-related chronic sclerosing sialadenitis (IgG4-RCSS), a recently recognized disease. STUDY DESIGN: Case series with chart review and pathology study. SETTINGS: Tertiary care hospital. SUBJECTS AND METHODS: We evaluated chronic sialadenitis specimens obtained over 11 years using pathologic examination and IgG4 immunohistochemistry staining. The specimens were assigned a revised diagnosis of IgG4-RCSS or chronic sialadenitis not otherwise specified, and clinicopathologic data from each group were compared. RESULTS: Of the 84 patients, 21 were diagnosed with IgG4-RCSS and 63 with chronic sialadenitis not otherwise specified. IgG4-RCSS patients were older (68.2 ± 13.9 vs 54.2 ± 15.8 years, P = .001), predominantly male (85.7% vs 61.9%, P = .036), and more likely to present with painless swelling (75% vs 44.3%, P = .001) and bilateral involvement (52.4% vs 6.3%, P < .001). Ratio of IgG4-positive plasma cells to IgG-positive plasma cells in IgG4-RCSS tissues was 0.81 ± 0.14. The mean value of serum IgG4 in IgG4-RCSS patients was 918.8 mg/dL. CONCLUSION: IgG4-RCSS is more common in older male patients and frequently presents with bilateral involvement. Informing head and neck surgeons of the clinical features of IgG4-RCSS and promoting a combined approach of clinical evaluation, imaging, and biopsy can improve the accuracy of preoperative diagnoses.

Diagnostic performance of serum IgG4 level for IgG4-related disease: a meta-analysis.

An elevated serum IgG4 level is one of the most useful factors in the diagnosis of IgG4-related disease (IgG4-RD). In this study, we performed a meta-analysis of the published articles assessing the diagnostic accuracy of serum IgG4 concentrations for IgG4-RD. The databases of MEDLINE/PubMed, EMBASE and Web of Science were systematically searched for relevant studies. Sensitivities and specificities of serum IgG4 in each study were calculated, and the hierarchical summary receiver operating characteristic (HSROC) model with a random effects model were employed to obtain the individual and pooled estimates of sensitivities and specificities. In total, twenty-three studies comprising 6048 patients with IgG4-RD were included in the meta-analysis. The pooled sensitivity was 85% with a 95% confidence interval (CI) of 78-90%; the pooled specificity was 93% with a 95% CI of 90-95%. The HSROC curve for quantitative serum IgG4 lies closer to the upper left corner of the plot, and the area under the curve (AUC) was 0.95 (95% CI 0.93, 0.97), which suggested a high diagnostic accuracy of serum IgG4 for the entity of IgG4-RD. Our study suggests that serum IgG4 has high sensitivity and specificity in the diagnosis of IgG4-RD.

[Research hotspot in IgG4-related sialadenitis].

IgG4-related disease is a novel clinical entity which can affect single or multiple organs. IgG4-related sialadenitis is referred to the salivary gland involvement of IgG4-related disease, with or without other organ involvement. IgG4-related sialadenitis is characterized by painless swelling or enlargement of salivary glands, high serum IgG4 level, abundant IgG4+ plasma cells infiltration with fibrosis histologically, and good response to glucocorticoids. With review of related articles, highlight and provide an overview of the most recent and focused findings and concepts of this disease, including the most significant pathogenic process based on kinds of immunocytes, cytokines, as well as participation of epithelial-mesenchymal transition, the clinical value of elevated serum IgG4 concentration and pathological role of infiltrated IgG4+ plasma cells, the potential relationship with salivary gland malignant tumor, the applying and usefulness of positron emission tomography-CT, the diagnostic utility of lip biopsy, treatment, prognosis, and also future perspectives.

IgG4-related sialadenitis: IgG4 is helpful, but biopsies are still crucial.

IgG4-related disease is rare, but a frequent differential diagnosis for malignant and for autoimmune diseases. Li and colleagues report the largest cohort of patients with IgG4-related sialadenitis. The observations reveal that the most important diagnostic step is obtaining biopsies. In addition, the IgG4 serum concentration may be a biomarker for the disease progression.

Immunoglobulin G4-related autoimmune pancreatitis and sialadenitis: A case report.

Immunoglobulin G4 (IgG4)-related disease is a rare systemic diseases. A 67-year-old male presented at our institution with mild upper abdominal pain and jaundice for 20 d. Laboratory results revealed high levels of IgG4 (15.4 g/L, range: 0.08-1.4 g/L). Computed tomography (CT) showed significant enlargement of the entire pancreas and a capsule-like low-density rim surrounding the whole pancreas. Positron emission tomography/CT revealed increased uneven metabolism of the entire pancreas. Both magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed stenosis of the distal common bile duct and proximal main pancreatic duct, and dilation of the proximal common bile duct and extra- and intra-hepatic bile ducts. He was diagnosed with IgG4-related autoimmune pancreatitis. The patient was treated with prednisone for 14 mo. The patient responded well to prednisone but upon cessation of the corticosteroid developed enlargement of the submandibular gland. The patient's serum IgG4 was elevated at 23.9 g/L. It is important to maintain treatment, so the patient was again treated with prednisone and had a good response. Follow-up of IgG4-related disease is thus necessary.

A case of mantle cell lymphoma presenting as IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease.

BACKGROUND: Mantle cell lymphoma (MCL) is a relatively uncommon type of non-Hodgkin lymphoma. It develops in the outer edge of a lymph node called the mantle zone. In contrast, IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by elevated serum IgG4 and persistent bilateral enlargement of lacrimal glands (LGs) and salivary glands (SGs), with infiltration of IgG4-positive plasma cells. Recent studies indicated the importance of differentiation between IgG4-DS and malignant lymphoma. CASE PRESENTATION: An 82-year-old man was suspected of IgG4-DS because of a high serum IgG level (2174 mg/dL) and bilateral swelling of LGs and SGs. Lip biopsy and fine needle biopsy of submandibular gland were performed, and subsequently, MCL was diagnosed through the histopathological findings. CONCLUSIONS: MCL most commonly occurs in the Waldeyer ring, but rarely in the stomach, spleen, skin, LG, and SG. We report an unusual case of MCL involving LGs and SGs mimicking IgG4-DS, which suggests that IgG4 testing may be useful in the differentiation of IgG4-DS in the presence of bilateral swelling of LGs or SGs.

Internal Organ Involvement in IgG4-related Sialadenitis: A Systemic Review.

OBJECTIVE: To provide an overview of internal organ involvement (IOI) in immunoglobulin G4-related sialadenitis (IgG4-RS) patients, with a focus on the prevalence and clinical features of IOI, the analysis of serum IgG4 levels in patients with or without IOI, and the usefulness of positron emission tomography (PET) for examination of the whole body. METHODS: A systematic search was performed using PubMed, CNKI, Wanfang Data and CQVIP databases. RESULTS: A total of 99 articles, including 493 IgG4-RS cases, were analysed in this study. The male-to-female ratio was 1.57:1 and the mean age was 61.67 years. IOI was observed in 71.6% patients, including lesions of the pancreas (38.5%), the biliary system and liver (17.8%), distant lymphadenopathy (20.3%), the respiratory system (15.6%), the urinary system (12.0%) and retroperitoneal fibrosis (11.4%). The lesions could occur homeochronously or metachronously with IgG4-RS. The serum IgG4 levels in the IOI-positive and IOI-negative groups were 1,131 ± 952 mg/dL and 659 ± 843 mg/dL, respectively (P < 0.01). The prevalence of IOI and the number of involved internal organs between the PET and the non-PET groups showed no significant difference (P = 0.399 and P = 0.823, respectively), but were significantly higher in the PET group, amongst patients whose first symptom or chief complaint was salivary gland swelling (P = 0.002 and P = 0.001, respectively). CONCLUSION: IOI is common in IgG4-RS and almost every organ can be affected. High levels of serum IgG4 represent a potential indicator of IOI. Furthermore, PET is a useful tool for evaluation of the whole body.

A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis.

BACKGROUND: IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease, is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in glandular tissues. Recently, several studies reported both malignant lymphoma developed on the background of IgG4-associated conditions and IgG4-producing malignant lymphoma (non-IgG4-related disease). CASE PRESENTATION: We report on the case of a 70-year-old man who was strongly suspected IgG4-DS because of high serum IgG4 concentration (215 mg/dl) and bilateral swelling of parotid and submandibular glands. Biopsies of cervical lymph node and a portion of submandibular gland were performed. These histopathological findings subsequently confirmed a diagnosis of marginal zone B cell lymphoma. CONCLUSION: Differential diagnosis of IgG4-DS is necessary from other disorders, including Sjögren's syndrome, sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, and cancer. We suggest that biopsy of swollen lesions is important for a definitive diagnosis of IgG4-DS and discuss the mechanism of development in this case.

Clinical relevance of Küttner tumour and IgG4-related dacryoadenitis and sialoadenitis.

OBJECTIVES: Küttner tumour (KT), so-called chronic sclerosing sialoadenitis, is characterised by concomitant swelling of the submandibular glands secondary to strong lymphocytic infiltration and fibrosis independent of sialolith formation. However, recent studies have indicated that some patients with KT develop high serum levels of IgG4 and infiltration of IgG4-positive plasma cells, namely IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease. The aim of this study was to clarify the clinical and pathological associations between KT and IgG4-DS. MATERIALS AND METHODS: Fifty-four patients pathologically diagnosed with KT or chronic sialoadenitis were divided into two groups according to the presence or absence of sialolith (KT-S (+) or KT-S (-), respectively). RESULTS: There were no significant differences in the clinical findings, including the mean age, sex and disease duration, between the two groups. All patients in the KT-S (+) group showed unilateral swelling without infiltration of IgG4-positive plasma cells or a history of other IgG4-related diseases (IgG4-RD), while those in the KT-S (-) group showed bilateral swelling (37.5%), strong infiltration of IgG4-positive plasma cells (87.5%) and a history of other IgG4-RD (12.5%). CONCLUSIONS: These results suggest an association between the pathogeneses of KT-S (-) and IgG4-DS, but not KT-S (+).

Serum immunoglobulin G4 level is a poor predictor of immunoglobulin G4-related disease.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Roles of IL-17, Th1, and Tc1 cells in patients with IgG4-related sclerosing sialadenitis.

OBJECTIVES/HYPOTHESIS: Immunoglobulin G4 (IgG4)-related sclerosing sialadenitis is a recently recognized disease entity characterized by high serum IgG4 concentration and IgG4-producing plasma cell expansion in affected organs, which show fibrotic or sclerotic changes. However, little is known about the roles of CD4+ and CD8+ T cells or interleukin (IL)-17 in this disease. The purpose of this study was to evaluate the characteristics of CD4+ and CD8+ T cells and IL-17 in patients with IgG4-related sclerosing sialadenitis. STUDY DESIGN: A retrospective clinical study at the Yamagata University School of Medicine. METHODS: The patient group consisted of six males and four females with an average age of 57.9 years (range, 38 to 73 years). Subsets of T helper (Th)1, Th2, T cytotoxic type (Tc)1, and Tc2 cells from patients with IgG4-related sclerosing sialadenitis were examined by using intracellular cytokine flow cytometry. Expression of IL-17 in the patients' lesions was also investigated immunohistochemically. RESULTS: Six patients with IgG4-related sclerosing sialadenitis with high ratios of IgG4/IgG and prominent infiltration of IgG4-positive plasmacytes in the involved salivary glands had systemic complications, including pancreatitis, retroperitoneal fibrosis, and/or inflammatory pseudotumor of the lung after the initial swelling of the salivary glands. Populations of Th1 and Tc1 cells were significantly greater in IgG4-related sclerosing sialadenitis than in the controls (P < .05), but Th2 and Tc2 cell populations were not significantly increased. Expression of IL-17 was observed in the lesions of affected patients. CONCLUSIONS: Increases in Th1 and Tc1 cell populations and IL-17 expression might be involved in the mechanism of pathogenesis of IgG4-related sclerosing sialadenitis.

[Study of virus content of Herpes viridae family in parotid secretion of patients with inflammatory-dystrophic diseases of salivary glands].

The study is devoted to disclose the interrelation between Herpes viridae family carriage and inflammatory-dystrophic diseases of salivary glands (SG). It was shown that inflammatory and dystrophic diseases of SG in observed patients run on the background of latent and active chronic herpes-virus infection. In the case the frequency of disclosure and content of antibodies to nuclear protein of Epstein-Barr virus in the peripheral blood serum in patients with different inflammatory and dystrophic SG diseases were statistically significantly higher and antibodies to simple 1st type virus and cytomegalovirus lower than in patients with different types of maxillofacial region pathology without SG involvement. The immediate contamination of parotid secretion by virus of Herpes viridae family was detected with the help of polymerase chain reaction in 18% of patients with SG diseases.