A case report of Mikulicz's disease.

Mikulicz's disease is a unique condition involving the enlargement of the lacrimal and salivary glands, similar to that observed in Sjogren's syndrome; however, Mikulicz's disease is clinically characterized by infrequent autoimmune reactions and responsiveness to glucocorticoid treatment. The ultrasound features of the lacrimal and salivary glands in patients with IgG4-Mikulicz's disease were characterized by multiple hypoechoic areas of varying sizes within the enlarged glands. IgG4 serum level was also elevated, in contrast to the detection of normal levels in Sjogren's syndrome. In this article, we intended to illustrate a case of Mikulicz's disease with clinical and imaging features.

Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts.

OBJECTIVE: IgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes. METHODS: We used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis. RESULTS: In the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1-3 (316, 178 and 445 mg/dL, respectively, p<0.001). CONCLUSION: We identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

[IgG4-related disease: a case report]. / Enfermedad asociada a IgG4: reporte de un caso.

IgG4-related disease is an inflammatory condition characterized by high levels of IgG4. It affects salivary and lacrimal glands, pancreas, lymph nodes, lungs or kidney. The diagnosis is based on identifying a histological pattern with a dense lymphocyte and plasmacyte infiltration, focal fibrosis or phlebitis, finding more than 10 IgG4 positive cells per high power field and/or IgG4/IgG ratio in plasma higher than 40%. We present a patient with Mikulicz's disease who meets histological findings required for the diagnosis of IgG4 related disease.

La enfermedad relacionada con IgG4 es una condición fibroinflamatoria en la que existe elevación de IgG4, afección a nivel de glándulas salivares, lacrimales, páncreas, ganglios linfáticos y pulmón. Para su diagnóstico se requiere la identificación de un patrón histológico sugestivo que muestre infiltrado linfoplasmocitario denso, fibrosis focal o flebitis a nivel de una glándula, más de 10 células positivas para IgG4 por campo de gran aumento y relación de IgG4/IgG arriba de 40% en plasma. Describimos el caso de una paciente que presentó enfermedad de Mikulicz y cumplió con los datos histológicos para diagnóstico de enfermedad relacionada con IgG4.

Detection of IFN-γ+IL-17+ cells in salivary glands of patients with Sjögren's syndrome and Mikulicz's disease: Potential role of Th17•Th1 in the pathogenesis of autoimmune diseases.

  Objective: Th17 cells, which mainly produce interleukin (IL)-17, have been suggested to play a critical role in the pathogenesis of autoimmune diseases. The plasticity of Th17 cells, in which these cells shift to a Th1 phenotype in the presence of IL-12, has recently been reported. However, the role of IL-17 in Sjögren's syndrome (SS) and Mikulicz's disease (MD) currently remains unknown. PATIENTS AND METHODS: The submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients were collected. IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected by immunohistochemical staining. RESULTS: IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected in the submandibular salivary gland and lymph node of the MD patient and salivary glands of the 15 SS patients. DISCUSSION: IFN-γ+IL-17+cells in the salivary glands of patients were speculated to be Th1/Th17 cells in the present study. Th1/Th17 cells are known to be derived from Th17 cells and differentiate into Th1 cells, and IL-17-derived Th1 cells have been suggested to induce the deterioration of juvenile idiopathic arthritis (JIA). Thus, Th1/Th17 cells may play an important role in the pathogenesis of SS and MD. CONCLUSION: IFN-γ+, IFN-γ+IL-17+, and IL-17+ cells were detected in the submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients.

Gallium SPECT/CT in evaluation of IgG4-related disease: A case report and literature review.

BACKGROUND: The clinical picture of IgG4-related sclerosing disease (IgG4-RSD) may mimic lymphoma, and should be in the differential diagnosis of patients with this clinical picture. CASE SUMMARY: A 32-year-old female had recurrent swelling of both eyelids for more than 15 years. Examination revealed elastic, firm, swollen lacrimal glands about 2-3 cm in diameter that was not painful. Head and orbits magnetic resonance imaging (MRI) showed mass lesions over the bilateral lacrimal glands, submandibular glands, and left foramen of ovale. The differential diagnosis included lymphoid tissue, inflammatory masses, and lymphoma. Gallium single-photon emission computed tomography/computed tomography (SPECT/CT) showed uptake in the bilateral lacrimal glands, right parotid and bilateral submandibular glands, bilateral perirenal region, mediastinal, prevertebral, paraaortic, lumbar, bilateral pelvic (including internal iliac chain) lymph nodes, anterior aspect of right 3rd rib, and lateral aspect of left 6th rib. CT showed multiple enlarged lymph nodes in the mediastinum, right pulmonary hilum, prevertebral space of the thoracolumbar spine, retroperitoneal paraaortic area, bilateral parailiac areas, and bilateral perirenal spaces. Antinuclear and anti-SSA/SSB antibodies were negative, and the serum IgG4 level was 740 mg/dL (normal, 8-140 mg/dL). Right parotid gland biopsy showed abundant IgG4-positive plasma cells. Mikulicz disease (IgG4-related sclerosing disease) was diagnosed and she received glucocorticoid treatment. Follow-up CT and MRI showed with resolved eyelid swelling and perirenal mass lesions. Follow-up gallium scan was normal. CONCLUSION: Gallium SPECT/CT can be a useful tool for initial and follow-up evaluation of IgG4-RSD.

Concomitant occurrence of Mikulicz's disease and immunoglobulin G4-related chronic rhinosinusitis: a clinicopathological study of 12 cases.

AIMS: Concomitant occurrence of Mikulicz's disease (MD) and immunoglobulin (Ig)G4-related chronic rhinosinusitis (IgG4-related CRS) is extremely rare. We evaluated the clinicopathological features of MD patients with concomitant IgG4-related CRS (CRS-MD). METHODS AND RESULTS: Twelve CRS-MD patients were evaluated clinically and biopsy samples were taken from the lacrimal/salivary glands (n = 12) and nasal mucosa (n = 7) for assessment of IgG4-positive cells, using immunohistochemical techniques. Similarly, nine MD patients and 10 patients with common CRS were evaluated as controls. CRS-MD patients had higher serum IgG and IgG4 concentrations than MD patients (P < 0.05 for both). Lymphoplasmacytic infiltration, lymphoid follicle formation and sclerosis was prominent in the lacrimal/salivary glands in both groups; however, the magnitude of IgG4-positive plasma cells infiltration in the CRS-MD group was significantly higher compared to the MD group (P = 0.004). Similarly, evaluation of nasal mucosa revealed greater lymphocyte, plasma cell and eosinophil infiltration and lymphoid follicle formation, together with significantly higher IgG4-positive plasma cell infiltration in the CRS-MD group compared to the common CRS group (P = 0.004). CONCLUSIONS: Concomitant MD and IgG4-related CRS were characterized by a combination of IgG4-positive plasma cells infiltration in the lacrimal/salivary glands and the nasal mucosa and increased serum IgG4.

Case report of Mikulicz's disease: A modern concept of an old entity.

Introduction: Modern knowlegde defines Mikulicz´s disease as a part of immunoglobulin G4-related disease. The main feature is the presence of lymphoplasmacytic infiltrates, immunoglobulin G4 plasma cells positivity, distinctive storiform fibrosis and moderate eosinophilia. Case Report: A 59-years old male presented with a mild keratoconjuctivitis sicca and enlarged lacrimal and salivary glands during the last two years. Althought clinical presentation of the patient was typical, earlier testing did not pinpoint Mikulicz ´s disease. By typical clinical presentation, elevated serum immunoglobulin G4 level and histopathological finding of lacrimal glands tissue we diagnosed Mikulicz´s disease successfully treated with corticosteroid therapy. Conclusion: We reported the first case of IgG4-related Mikulicz´s disease in Serbia. Our report highlights IgG4-related Mikulicz` s disease as an important differential diagnosis with Sjögren`s syndrome and lymphoproliferative disease in rheumatological practice.

Effectiveness of imaging modalities for screening IgG4-related dacryoadenitis and sialadenitis (Mikulicz's disease) and for differentiating it from Sjögren's syndrome (SS), with an emphasis on sonography.

INTRODUCTION: The aim of this study was to clarify the effectiveness of various imaging modalities and characteristic imaging features in the screening of IgG4-related dacryoadenitis and sialadenitis (IgG4-DS), and to show the differences in the imaging features between IgG4-DS and Sjögren's syndrome (SS). METHODS: Thirty-nine patients with IgG4-DS, 51 with SS and 36 with normal salivary glands were enrolled. Images of the parotid and submandibular glands obtained using sonography, 2-[(18)F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT), computed tomography (CT) and magnetic resonance imaging (MRI) were retrospectively analyzed. Six oral and maxillofacial radiologists randomly reviewed the arranged image sets under blinded conditions. Each observer scored the confidence rating regarding the presence of the characteristic imaging findings using a 5-grade rating system. After scoring various findings, diagnosis was made as normal, IgG4-DS or SS, considering all findings for each case. RESULTS: On sonography, multiple hypoechoic areas and hyperechoic lines and/or spots in the parotid glands and obscuration of submandibular gland configuration were detected mainly in patients with SS (median scores 4, 4 and 3, respectively). Reticular and nodal patterns were observed primarily in patients with IgG4-DS (median score 5). FDG-PET/CT revealed a tendency for abnormal (18)F-FDG accumulation and swelling of both the parotid and submandibular glands in patients with IgG4-DS, particularly in the submandibular glands. On MRI, SS had a high score regarding the findings of a salt-and-pepper appearance and/or multiple cystic areas in the parotid glands (median score 4.5). Sonography showed the highest values among the four imaging modalities for sensitivity, specificity and accuracy. There were significant differences between sonography and CT (p = 0.0001) and between sonography and FDG-PET/CT (p = 0.0058) concerning accuracy. CONCLUSIONS: Changes in the submandibular glands affected by IgG4-DS could be easily detected using sonography (characteristic bilateral nodal/reticular change) and FDG-PET/CT (abnormal (18)F-FDG accumulation). Even inexperienced observers could detect these findings. In addition, sonography could also differentiate SS. Consequently, we recommend sonography as a modality for the screening of IgG4-DS, because it is easy to use, involves no radiation exposure and is an effective imaging modality.

Immunology of IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4(+) plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.

[Comparative study of clinical features between unilateral and bilateral orbital IgG4-related disease]. / Estudio comparativo de los hallazgos clínicos en la enfermedad orbitaria asociada a IgG4 con afectación unilateral vs. bilateral.

OBJECTIVE: Descriptive and comparative study of patients with orbital IgG4-related disease. MATERIAL AND METHODS: A review and analysis of the cases diagnosed with inflammatory orbital lesion related to IgG4 by the Ophthalmic Pathology Service in the Dr. Luis Sánchez Bulnes Hospital. RESULTS: A total of 9 cases were found, in which 66% were women, and with a mean age of 48 years and time to diagnosis of 2 years. Unilateral involvement was observed in 56% of cases. All the females experienced pain, and there was an optimal response to corticosteroid treatment in 100% of patients who required medical treatment (one case showed spontaneous resolution). In bilateral cases (44%), only 25% were female, and none had pain as a presenting symptom. Furthermore, 25% of these patients required a combination with immunosuppressants to control inflammation. CONCLUSIONS: Clinical presentation of patients with unilateral orbital IgG4-related disease differs from those with bilateral involvement.

Histopathological diagnostic value of the IgG4+/IgG+ ratio of plasmacytic infiltration for IgG4-related diseases: a PRISMA-compliant systematic review and meta-analysis.

This article aims to perform a meta-analysis to evaluate the diagnostic value of the immunoglobulin G (IgG)4/IgG ratio of plasmacytic infiltration for IgG4-related diseases.Four databases-EMBASE, ISI Web of Knowledge, PubMed, and the Cochrane Library-were systematically searched. Approximately 200 participants from several studies were included in this research. STATA 11.2 software (Stata Corporation, College Station, TX) and Meta-DiSc 1.4 (Unit of Clinical Biostatistics, Ramon y Cajal Hospital, Madrid, Spain) were used to perform the meta-analysis.Nine studies were included in the meta-analysis. The pooled diagnostic odds ratio was 18.94 [95% confidence interval (CI), 2.89-124.30]. The sensitivity was 58.80% (95% CI, 50.90-66.30) and the specificity was 90.20% (95% CI, 81.20-95.80). The positive and negative likelihood ratios were 3.12 (95% CI, 1.07-9.16) and 0.26 (95% CI, 0.09-0.70), respectively. The area under the curve of the summary receiver-operating characteristic was 0.88.To conclude, the IgG4/IgG ratio of plasmacytic infiltration is modestly effective in diagnosing IgG-related disease.

Possible involvement of epithelial-mesenchymal transition in fibrosis associated with IgG4-related Mikulicz's disease.

OBJECTIVE: Immunoglobulin G4 (IgG4)-related Mikulicz's disease (MD) is a fibrosis-associated inflammatory disease, often accompanied by lacrimal gland swelling. Although much attention has been paid to the inflammatory aspects of this disease, the mechanisms of the fibrotic processes are still unclear. We focused on the fibrotic changes occurring in the lacrimal glands of IgG4-related MD patients, by examining molecules involved in the epithelial-mesenchymal transition (EMT). METHODS: Lacrimal gland tissue specimens were obtained from 3 IgG4-related MD patients and 3 control patients with Sjögren's syndrome (SS). The glands were examined by immunohistochemistry and transmission electron microscopy. RESULTS: Storiform fibrosis, a characteristic of IgG4-related MD, was observed in the lacrimal glands of IgG4-related MD, but rarely in those of SS. Reduced E-cadherin expression, increased phalloidin-stained filamentous actin, and increased α-smooth muscle actin, snail, and heat-shock protein 47 levels were observed in the lacrimal glands of IgG4-related MD compared with those of SS. Transmission electron microscopy revealed an abnormal periodicity of collagen bundles, and basal membrane thickening in the IgG4-related MD compared with that in the SS tissues. CONCLUSION: EMT-like changes were frequently observed in the lacrimal gland epithelia from patients with IgG4-related MD. Thus, EMT may be involved in the pathology of IgG4-related MD fibrosis.

Diagnostic criteria for IgG4-related ophthalmic disease.

Immunoglobulin G4 (IgG4)-related disease is a novel clinical entity characterized by infiltration of IgG4-immunopositive plasmacytes and elevated serum IgG4 concentration accompanied by enlargement of and masses in various organs, including the lacrimal gland, salivary gland, and pancreas. Recent studies have clarified that conditions previously diagnosed as Mikulicz disease as well as various types of lymphoplasmacytic infiltrative disorders of the ocular adnexa are consistent with a diagnosis of IgG4-related disease. Against this background, the diagnostic criteria for IgG4-related ophthalmic disease have recently been established, based on both the clinical and the histopathologic features of the ocular lesions. This article reviews these new criteria with reference to the comprehensive diagnostic criteria for IgG4-related disease for all systemic conditions reported in 2012.

Ocular adnexal IgG4-related disease: clinical features, outcome, and factors associated with response to systemic steroids.

PURPOSE: The aim of this study was to investigate clinical characteristics, outcome, and factors associated with response to systemic administration of steroids in patients with ocular adnexal immunoglobulin G4 (IgG4)-related disease. METHODS: This was a retrospective evaluation of 11 patients with histopathologically verified ocular adnexal IgG4-related diseases at a medical center in Taiwan between January 2006 and December 2012. Clinical features and outcome, including serial change of serum IgG4 and clinical factors related to response to steroids systemically were evaluated. RESULTS: Seven men and four women, mean age 54.5 years and mean follow-up of 33.5 months, were evaluated. Elevated serum IgG4 levels (>135 mg/dl) were observed in ten patients (91%). Lacrimal gland involvement was noted in eight (72.7%), followed by orbit, extraocular muscles, and eyelids. Seven patients (63.6%) had bilateral ocular lesions and eight (72.7%) had extraorbital involvement. Eight of ten patients who underwent systemic steroid treatment responded well in the early phase. Recurrence developed in five patients (45%), requiring repeat steroid therapy and adjunctive treatment. Median serum levels of IgG4 reduced from 540 to 101 mg/dl in ten patients after systemic corticosteroid administration. Patients with lower serum IgG4 and IgG4:IgG ratio at diagnosis were associated with poor response (p = 0.037). CONCLUSIONS: Ocular adnexal IgG4-related disease predominantly involved the lacrimal glands bilaterally and was usually associated with high serum IgG4 levels and multiple organ involvement. Most patients responded well to steroid therapy, which was accompanied by a marked decrease in serum IgG4.

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 (+).