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.

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.

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 (+).

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.

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.

IgG4-related dacryoadenitis in a 13-year-old girl.

IgG4-related disease is a recently described fibroinflammatory condition, often with systemic involvement. Several authors have reported IgG4-related orbital inflammation in adults. Pediatric cases of IgG4-related disease have been reported in the literature involving other areas of the body, with only 1 recent report of probable orbital involvement. The first case of probable IgG4-related dacryoadenitis is reported in a child.

Spontaneous regression of IgG4-related dacryoadenitis.

This is the first report showing the clinical course of a patient with bilateral IgG4-related dacryoadenitis, which spontaneously regressed after excision of the left lacrimal gland. A 65-year-old female had been aware of bilateral eyelid swelling without pain for 5 years. Magnetic resonance imaging revealed enlargement of bilateral lacrimal gland. Laboratory tests showed high IgG4 concentrations, measuring 394 mg/dl. The biopsied specimen of the left lacrimal gland revealed marked lymphoplasmacytic infiltration with mild fibrosis. Marked IgG and IgG4-positive plasma cells surrounded the lymphoid follicles. Although the patient did not wish to undergo any treatments, lacrimal gland lesions showed gradual remission. This case highlights the potential of spontaneous improvement in IgG4-related dacryoadenitis, indicating that careful observation may be one of the therapeutic options for such patients.

Anticyclic-citrullinated protein antibodies in the diagnosis of ophthalmic inflammatory disease.

While rheumatoid factor (RF) testing has been previously used in the detection of rheumatoid arthritis (RA), its effectiveness has been limited by poor rates of sensitivity and specificity and its positivity in multiple other disease states. Given its enhanced specificity, quantification of anticyclic-citrullinated protein (anti-CCP) antibodies has emerged as a standard in molecular testing for RA. Despite the importance of this test in clinical rheumatology, we are unaware of any reports of its use in the detection of uveitis or orbital disease. In this report, we characterize the first use of anti-CCP in the diagnosis of orbital disease.

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.

IgG4-related disease: review of the histopathologic features, differential diagnosis, and therapeutic approach.

Immunoglobulin G4-related disease (IgG4-RD) is an uncommon disorder that demonstrates characteristic clinicopathologic features including sclerosing lesions with storiform fibrosis, increased IgG4+ plasma cells with an increased IgG4+/IgG+ plasma cell ratio, obliterative phlebitis, and often an increased serum IgG4 level. This review summarizes the characteristic histopathologic and clinical features of IgG4-RD with detailed discussion of the histopathologic characteristics of the most commonly involved anatomic sites. We also present recent advances in our understanding of the pathophysiologic mechanisms of IgG4-RD and discuss updates on the treatment, prognosis, and outcomes of this rare disease, including discussion of the possible association between IgG4-RD and malignancy.

[Rationale for a diagnostic approach in non-Graves' orbital inflammation--Report of 61 patients]. / Établissement d'un arbre décisionnel diagnostique dans les orbitopathies inflammatoires non basedowiennes chroniques--à propos de 61 patients.

INTRODUCTION: Orbital inflammatory syndromes include a wide variety of inflammatory intraorbital processes which are very different in terms of clinical presentation and prognosis. We currently prefer to differentiate so-called "specific" inflammations, for which an etiology is able to be identified, from idiopathic orbital inflammatory syndromes (IOIS), for which the etiology remains unknown and the histology is nonspecific. PURPOSE: To propose an efficient diagnostic approach for clinicians managing patients with non-Graves' orbital inflammations. MATERIALS AND METHODS: This is a retrospective and prospective study concerning 61 patients managed by the medical team for non-Graves' orbital inflammations between May, 1999 and May, 2013 in the ophthalmology departments of Nice and Limoges university hospitals in France. Seventeen specific inflammations, 19 orbital lymphomas and 25 idiopathic orbital inflammatory syndromes were included. Patients were divided into two groups. Thirty-six patients (group 1) underwent primary biopsy, while for the other 25 (group 2), therapy was begun empirically without biopsy. We could therefore compare both approaches in terms of diagnostic efficiency and time until identification of a specific etiology. RESULTS: Our statistical results show that an approach without primary biopsy leads to a number of specific diagnoses statistically much lower than that obtained by the approach with primary biopsy. Also, the risk of missing a specific inflammation (with as a consequence an inappropriate treatment and a risk of functional sequelae as well as a fatal risk of missing a lymphoproliferative pathology) is very clearly higher in the case of not performing primary biopsy. Finally, the average time elapsed between the initial consultation with the ophthalmologist and a specific diagnosis was one month in the case of the first approach, while this delay was almost three times higher with the second approach, with a mean of 2.91 months (P<0.01). DISCUSSION: Our study shows that biopsy should be the mainstay of diagnostic management. A trial of empiric treatment is only performed first in myositis or in locations where biopsy could jeopardize functional prognosis. It should only be done after biopsy in all other cases. Of course, in all cases of relapse or recurrence after treatment, biopsy should be performed or repeated. CONCLUSION: The diagnostic work-up of a patient with an orbital inflammatory process must of course include blood testing and orbital imaging, but also a systematic primary biopsy for histological examination in the vast majority of cases. It must be repeated at least in the case of any doubt about the diagnosis or in the case of any recurrence or resistance to treatment.

Treatment of experimental autoimmune dacryoadenitis with cyclosporin A.

Experimental autoimmune dacryoadenitis (EAD) was induced in SJL/J mice by a single injection of purified lacrimal gland antigen (LG-Ag) in complete Freund's adjuvant. The disease is characterized by lymphocytic infiltration of the lacrimal gland and production of lacrimal gland-specific antibodies. We examined the effects of cyclosporin A (CsA) on the development and progression of this inflammatory disease. CsA (100 mg/kg/day), given from the time of immunization for 14 days, completely blocked the development of EAD in all treated mice. Both cellular and humoral immune responses to LG-Ag were markedly reduced by the administration of CsA as evidenced by the near absence of lymphocyte proliferative response and the reduced production of circulating anti-LG-Ag antibodies. Delayed CsA treatment beginning on Day 7 after immunization totally abrogated the development of lacrimal histological lesions and lymphocyte proliferative response to LG-Ag. However, serum anti-LG-Ag titers were only marginally decreased in CsA-treated animals. Treatment with CsA was found effective even when daily injections were started 14 days after immunization with LG-Ag. CsA prevented the inflammatory cell response in 5 of 10 mice when the disease was established. The lymphocyte proliferative response to LG-Ag was moderately depressed in CsA-treated animals, but antibody titers were the same as those in the oil-treated control. These studies demonstrate that CsA has a therapeutic effect in this murine model of dacryoadenitis and suggest a critical role for T lymphocytes in the pathogenesis of EAD.

[Cefmenoxime penetration in human lacrimal sac mucosa after systemic administration]. / Cefmenoxim-Penetration in die menschliche Tränensackschleimhaut nach systemischer Applikation.

Access to microbiological, pharmacokinetic and toxicological information is necessary for useful, controlled application of antibiotics in intraocular and periocular infections. It is important to know whether the antibiotic is effective against ophthalmologically relevant bacteria and if suprathreshold concentrations of the antibiotic can be achieved in the contaminated tissue. In the study presented we investigated the usefulness of cefmenoxime in cases of dacryocystitis. Lacrimal sac tissue--and serum specimens were obtained from 15 patients who underwent dacryocystorhinostomy 0.5 to 13 h after intravenous injection of 25 mg cefmenoxime kg. The usual Toti procedure was performed in 7 patients, whereas the other 8 underwent endonasal surgery. Out of the 15 patients 12 suffered from recurrent dacryocystitis. Before application of the antibiotic a serum control sample was obtained in all patients. The highest cefmenoxime levels in the lacrimal sac (72 mg/kg) were measured 30 min after injection. Thirteen hours after the injection, the cefmenoxime levels were too low to be measured. The levels of cefmenoxime in the lacrimal sac tissue were compared with the minimal inhibitory concentrations for the frequent occurrence of bacteria in lacrimal sac infections.