Clinical practice guideline for Sjögren's syndrome 2017.

OBJECTIVES: The objective of this study is to develop clinical practice guideline (CPG) for Sjögren's syndrome (SS) based on recently available clinical and therapeutic evidences. METHODS: The CPG committee for SS was organized by the Research Team for Autoimmune Diseases, Research Program for Intractable Disease of the Ministry of Health, Labor and Welfare (MHLW), Japan. The committee completed a systematic review of evidences for several clinical questions and developed CPG for SS 2017 according to the procedure proposed by the Medical Information Network Distribution Service (Minds). The recommendations and their strength were checked by the modified Delphi method. The CPG for SS 2017 has been officially approved by both Japan College of Rheumatology and the Japanese Society for SS. RESULTS: The CPG committee set 38 clinical questions for clinical symptoms, signs, treatment, and management of SS in pediatric, adult and pregnant patients, using the PICO (P: patients, problem, population, I: interventions, C: comparisons, controls, comparators, O: outcomes) format. A summary of evidence, development of recommendation, recommendation, and strength for these 38 clinical questions are presented in the CPG. CONCLUSION: The CPG for SS 2017 should contribute to improvement and standardization of diagnosis and treatment of SS.

Treatment outcomes of sialendoscopy for submandibular gland sialolithiasis: The minor axis of the sialolith is a regulative factor for the removal of sialoliths in the hilum of the submandibular gland using sialendoscopy alone.

OBJECTIVE: To assess the general guidelines for the removal of sialoliths for submandibular gland sialolithiasis using sialendoscopy alone. METHODS: We analyzed 61 sialoliths treated using sialendoscopy in 42 patients with submandibular gland sialolithiasis. We evaluated the submandibular gland sialoliths and divided each case based upon the location: the Wharton's duct or the hilum. We measured the major and minor axes of the sialoliths using a soft tissue computed-tomography (CT) scan and evaluated the removal rate of the sialoliths using sialendoscopy alone. RESULTS: The removal rate of the sialoliths in the Wharton's duct (52.6%) was significantly higher than that in the hilum of the submandibular gland (26.1%) (P=0.042). The minor axis was significantly correlated to the treatment outcome of sialendoscopy alone for all cases (P=0.030). A significant correlation was observed for cases involving the hilum of the submandibular gland and the measurement of the minor axes of the sialoliths for the treatment outcome of sialendoscopy alone (P=0.009). The major axis showed no correlation with the treatment outcomes of sialendoscopy alone. CONCLUSION: The measurement of the minor axes of the sialoliths with a soft tissue CT scan was correlated with treatment outcome of sialendoscopy alone for all cases, particularly sialoliths in the hilum. The easurement of the major axis showed no correlation with outcomes of sialendoscopy alone.

Diagnostic and treatment effects of sialendoscopy for patients with swelling of the parotid gland when sialoliths are undetected with computed tomography.

Between August 2009 and May 2016, 74 patients underwent sialoendoscopic surgery. 32 patients had parotid gland disease and 9 patients had intermittent swelling of the parotid gland and sialoliths were not detected with CT imaging. 4 patients were diagnosed with idiopathic Stensen's duct stenosis. Sialendoscopy directly confirmed Stensen's duct stenosis in 2 patients. However, the sialendoscope was unable to be inserted in the other 2 patients, who had stenosis of the orifice of the Stensen's duct. Balloon expansion of the duct was performed in these 2 patients and a steroid drug was injected into the duct in one patient. Complete remission was archived in one patient treated with sialendoscopy. Three patients had sialolithiasis. Microsialoliths and/or white floating matter was observed and removed using sialendoscopy. All patients experienced complete remission. In cases of Sjögren syndrome and recurrent parotitis, sialendoscopic surgery was performed, but the symptoms showed no improvement. For patients with microsialoliths, sialendoscopy may be most useful for diagnosis and treatment when the sialoliths are not detected with CT imaging. At present, sialendoscopic surgery have limitation in the treatment of Stensen's duct stenosis and may similarly have limitation in the treatment of Sjögren's syndrome and recurrent parotitis.

The landmark for removal of sialoliths using sialendoscopy alone in parotid gland sialolithiasis.

OBJECTIVE: To assess the general guidelines for removal of sialoliths in parotid gland sialolithiasis using sialendoscopy alone. METHODS: We analyzed 34 sialoliths treated using sialendoscopy in 26 patients with parotid gland sialolithiasis. We divided the Stensen's duct and parotid gland into for parts using computed tomography findings: (A) front of the masseter, (B) anterior and lateral to the center (anterolateral) of the masseter, (C) posterior and lateral to the center (posterolateral) of the masseter, (D) behind of the masseter. The location and size of each sialolith was assessed. RESULTS: The removal rates of sialoliths in the different locations by sialendoscopy alone were as follows: front of the masseter, 68.8%; anterolateral of the masseter, 60.0%; posterolateral of the masseter, 0%; and behind of the masseter, 33.3%. The removal rate using sialendoscopy alone was significantly higher in the sections anterior to the center of the masseter than in those posterior to the center of the masseter (66.7% [14/21] vs. 20.0% [2/10]; P=0.019). The size of the sialolith was not correlated to the removal rate by sialendoscopy alone. CONCLUSION: Sialoliths of the parotid gland located in positions anterior to the center of the masseter are significantly easier to remove by sialendoscopy alone. The center of the masseter is a general landmark for removal of sialoliths from the parotid gland using sialendoscopy alone. The size of the sialolith is not correlated with removal, except rare huge sialoliths.

Basophils are increased and express increased levels of interleukin-4 in the parotid lesions of Kimura disease.

BACKGROUND: Kimura disease (KD) is a systemic soft-tissue disease that leads to formation of painless masses in lymph nodes, with the highest predilection for the head and neck and especially the parotid gland. KD lesions are characterized by marked eosinophil infiltration, production of IgE and increased expression of T-helper type 2 (Th2) cytokines (interleukin [IL]-4, IL-5, etc.). Skewing to a Th2 inflammation is also demonstrated in the peripheral blood, with elevated eosinophils and high IgE levels. It is thought that basophils may play important roles in orchestrating this Th2 inflammation via IL-4 production leading to the induction of IgE synthesis as well as eosinophil infiltration. However, there are no reports as yet on the role of basophils in KD. OBJECTIVE: The present study was performed to investigate the potential role of basophils in the pathogenesis of KD. In this context we also examined the expression of IL-4 in basophils in the KD lesions. METHODS: By immunohistochemistry using a monoclonal antibody against a basophil marker ProMBP1 we investigated the number and distribution of basophils in the KD lesions. By double immunohistochemistry we analyzed the colocalization of IL-4 in basophils. RESULTS: There was an increased number of basophils infiltrating the KD parotid gland lesions as compared to that in normal control parotid tissue. By double-immunofluorescence we found that approximately 7% of IL-4-positive cells in KD patients' parotid glands were basophils. CONCLUSION: Basophils may also play a role in the pathogenesis of KD, leading to the induction of IgE synthesis and eosinophil infiltration.

Increased expression of thymic stromal lymphopoietin and its receptor in Kimura's disease.

OBJECTIVE: The objective of this study was to investigate the expression of thymic stromal lymphopoietin (TSLP) and TSLP receptor (TSLPR) in Kimura's disease (KD). METHODS: Using parotid gland tissues from KD patients and control subjects, we quantified the expression levels of mRNA for TSLP, interleukin (IL)-25, IL-33, and their receptors by massively parallel sequencing. We also performed immunohistochemical analysis of TSLP and TSLPR, and counted cells immunoreactive for these proteins by the polymer immunocomplex and double immunofluorescence methods. RESULTS: The levels of mRNA for TSLP, TSLPR, and IL-25R, but not IL-25, IL-33, or IL-33R, were significantly elevated in parotid gland tissues from the KD group as compared to the control group. Immunohistochemical analysis revealed that TSLP- and TSLPR-positive cells were significantly increased in number in parotid gland tissues from KD patients. Double immunofluorescence staining showed that TSLP and TSLPR were localized mainly in CD68-positive macrophages and tryptase-positive mast cells, respectively. CONCLUSIONS: Overexpression of TSLP and TSLPR might contribute to the pathogenesis of KD through interactions between macrophages and mast cells. Regulation of TSLP/TSLPR signaling may be a potential therapeutic approach for KD.

Eosinophilic otitis media is associated with asthma severity and smoking history.

PURPOSE: Eosinophilic otitis media (EOM) is an intractable otitis media characterized by an accumulation of eosinophils in the middle ear and a strong association with asthma. We investigated the relationship between EOM and asthma severity, asthma risk factors, lung function, and airway structural changes assessed by high-resolution computed tomographic (HRCT) scanning. MATERIALS AND METHODS: Forty-one asthma patients with chronic rhinosinusitis (18 men and 23 women; mean age 56 years; age range 25-82 years) were included in this study. EOM was diagnosed according to the published diagnostic criteria. Asthma severity and risk factors for asthma, such as smoking history (Brinkman index, BI), were examined. Airway wall thickness and emphysema were assessed with HRCT scanning by a blinded respiratory specialist using a validated method. Lung function was measured using standard procedures. RESULTS: EOM was diagnosed in 34% of the patients. Asthma severity, BI and airway wall thickness were each statistically greater in patients with EOM than in patients without EOM. CONCLUSION: There was a close relationship between EOM and asthma severity in asthma patients with chronic rhinosinusitis. Cessation of smoking might help prevent EOM by reducing airway wall thickness.

99mTcO4- accumulation in scintigraphy and expression of Na+/I- symporter in salivary gland tumors.

OBJECTIVE: Warthin's tumors and oncocytomas show exceptionally good (99m)TcO4(-) (Tc) accumulation images in Tc scintigraphy. However, the mechanism of Tc accumulation in these tumors remains unclear. Sodium-iodide symporter (NIS) is a plasma membrane protein expressed in the thyroid, lactating breast, stomach and salivary glands; it facilitates uptake of I(-) and Tc. We hypothesized that Warthin's tumor cells and oncocytomas may also express NIS, which would promote uptake of Tc. We examined NIS localization and the mechanism of Tc accumulation in various salivary gland tissues. METHODS: Immunohistological localization of NIS was performed for 19 tumors from 18 patients who underwent preoperative Tc scintigraphy. Expression of mRNA for NIS in the normal salivary gland, Warthin's tumors and pleomorphic adenomas was analyzed by real-time PCR. RESULTS: In normal salivary glands, striated duct cells were strongly immunostained by anti-NIS antibodies. In Warthin's tumors, eosinophilic epithelial cells exhibited positive immunostaining, but their staining was varied among the cases. Furthermore, all Tc-positive specimens were NIS-positive, and all Tc-negative specimens were NIS-negative. Real-time PCR showed that NIS mRNA expression was detectable in normal salivary glands and Warthin's tumor cells. The expression was significantly higher in normal salivary glands compared with Warthin's tumor cells and pleomorphic adenoma. CONCLUSION: Tc-positive salivary glands expressed NIS. Our findings suggest that Tc accumulation in Warthin's tumors and oncocytomas is due to poorer Tc excretory function compared with normal salivary gland tissues, in addition to active uptake of (99m)TcO4(-) via NIS.

DNA microarray analysis of labial salivary glands in IgG4-related disease: comparison with Sjögren's syndrome.

OBJECTIVE: To compare gene expression in labial salivary glands (LSGs) from patients with IgG4-related disease with that in LSGs from patients with Sjögren's syndrome (SS). METHODS: Gene expression was analyzed by DNA microarray in LSG samples from 5 patients with IgG4-related disease, 5 SS patients, and 3 healthy controls. Genes differentially expressed in IgG4-related disease and SS were identified, and gene annotation enrichment analysis of these differentially expressed genes was performed using Gene Ontology (GO) annotation. Validation of the results was performed by quantitative polymerase chain reaction (PCR) using LSG samples from 9 patients with IgG4-related disease, 10 SS patients, and 4 controls. RESULTS: Gene expression patterns in patients with IgG4-related disease, SS patients, and healthy controls were quite different from each other in hierarchical clustering as well as in principal components analysis. In IgG4-related disease compared with SS, a total of 1,771 probe sets (corresponding to 1,321 genes) were identified as up-regulated, and 1,785 probe sets (corresponding to 1,320 genes) were identified as down-regulated (false discovery rate of <5%). GO term analysis indicated that the up-regulated set of differentially expressed genes in IgG4-related disease encoded proteins that function in cell proliferation, extracellular matrix organization, and organ development. PCR validated significantly higher expression of lactotransferrin in patients with IgG4-related disease than in SS patients (P < 0.05) and significantly higher expression of CCL18 in patients with IgG4-related disease than in SS patients and controls (P < 0.05). CONCLUSION: The results clearly showed that the gene expression pattern in LSGs from patients with IgG4-related disease is different from that in LSGs from SS patients.

Anti-IgE therapy to Kimura's disease: a pilot study.

Kimura's disease is a chronic disease that is characterized by subcutaneous granuloma of soft tissues in the head and neck region, increased eosinophil counts and high serum IgE levels. It is thought to be an IgE-mediated disease. Omalizumab, a monoclonal antibody, has recently been suggested as a potential new systemic treatment for IgE-mediated diseases, based on its efficacy in treating asthma and allergic rhinitis. We report a study of three patients with Kimura's disease who received anti-IgE (omalizumab) treatment. All patients were treated with a fixed schedule of eight cycles of omalizumab 300mg, administered subcutaneously at intervals of 2 weeks. The size of tumorous regions was evaluated by MRI at base line and after 4 months of treatment. Blood samples were taken every month. In each of the patients, the size of tumorous regions and the peripheral blood eosinophil and basophil counts were all decreased after the treatment. These results suggest that omalizumab may be valuable for treatment of Kimura's disease.

Improvement of eosinophilic otitis media by optimized asthma treatment.

Eosinophilic otitis media (EOM) shows a very high rate of association with asthma, and intractable otitis media involves marked eosinophil infiltration into the middle ear. The middle ear space is connected to the nasopharynx by the Eustachian tube, and it is considered a part of the upper respiratory tract. Allergic rhinitis and asthma often coexist as chronic inflammatory diseases of the upper and lower airways, respectively, and have an impact on each other. In fact, inhaled corticosteroids reduce seasonal eosinophilia systemically in the circulation and locally in the nasal mucosa, as well as attenuate seasonal nasal symptoms. We report a case of EOM associated with adult-onset asthma that improved following optimal asthma therapy after changing the treatment from inhaled fluticasone propionate (FP) (200 µg b.i.d.) to a combination of FP/salmeterol (250/50 µg b.i.d.). This result supports the hypothesis that EOM and asthma are closely linked, presenting as different manifestations of a similar disease syndrome.

Orally inhaled fluticasone propionate improved chronic rhinosinusitis with co-morbid asthma: report of a case.

Chronic rhinosinusitis and asthma are expressions of airway inflammatory diseases that frequently coexist, especially in the case of adult-onset asthma. Both conditions have similar pathological features, while one affects the upper airways and the other the lower airways. Whether the treatment of bronchial inflammation affects the severity of sinus disease remains an unanswered question. We report a case of refractory chronic rhinosinusitis with co-morbid adult-onset asthma that effectively improved upon treatment with a daily dose of 200 µg (100 µg b.i.d.) of inhaled fluticasone propionate (FP).

A case of adenoid cystic carcinoma presenting as Garcin's syndrome without mass formation.

Adenoid cystic carcinoma (ACC) is a malignant neoplasm that commonly arises in the major or minor salivary gland and usually forms mass lesions. Here, we report a case of ACC involving a 56-year-old man, who displayed right multiple cranial nerve palsies with ipsilateral severe facial pain but not any mass formation. Right submaxillary gland biopsy after repeated challenges at last revealed the primary focus of ACC with perineural invasion and without lymph node metastasis. The neurological manifestations were considered to be attributed to the perineural spread of ACC. It is extremely rare for ACC to show Garcin's syndrome without mass formation.

Axonal projections of medullary swallowing neurons in guinea pigs.

A central pattern generator (CPG) for swallowing in the medulla oblongata generates spatially and temporally coordinated movements of the upper airway and alimentary tract. To reveal the medullary neuronal network of the swallowing CPG, we examined the cytoarchitecture of the swallowing CPG and axonal projections of its individual neurons by extracellular recording and juxtacellular labeling of swallowing-related neurons (SRNs) in the medulla in urethane-anesthetized and paralyzed guinea pigs. Three major types of neuronal discharge patterns were identified during fictive swallowing induced by stimulation of the superior laryngeal nerve: early (burst-like activation during the pharyngeal stage), late (activation after the pharyngeal stage), and inhibited (inhibition during the pharyngeal stage) types. Sixteen neurons were successfully labeled in the nucleus tractus solitarii (NTS) and in the medullary reticular formation (RF). No motoneuron was labeled. The SRNs in the NTS had axons projecting to the NTS, RF, nucleus ambiguus, nucleus hypoglossus, and dorsal motor nucleus of the vagus on the ipsilateral side. Some NTS SRNs projected only within the NTS. The axons of SRNs in the RF projected also to the NTS, RF, motor nuclei on the ipsilateral side, and to the other side RF. These findings show anatomic substrates for the neuronal network of the CPG for swallowing, which consists of complex neuronal connections among SRNs in the NTS, RF, and motor nuclei.

A relationship between mast cells and alpha-smooth muscle actin-positive cells in the nasal polyps of chronic rhinosinusitis.

CONCLUSION: These results suggest that mast cells (MCs) play a role in promoting nasal polyp (NP) formation and progression with alpha-smooth muscle actin (alpha-SMA)-positive cells. OBJECTIVES: We studied the quantification and the localization of MCs and myofibroblasts in NPs. PATIENTS AND METHODS: We examined NPs from 12 patients with chronic rhinosinusitis undergoing endoscopic sinus surgery. MCs and myofibroblasts that expressed alpha-SMA were detected immunohistochemically. The numbers of labeled cells were quantified in NPs. These cells were evaluated in the tip, central, and pedicle areas. The number of MCs was compared between low (zone 1), moderate (zone 2), and high (zone 3) zones of alpha-SMA-positive cells. RESULTS: The number of MCs was significantly higher in pedicle areas than in tip areas of NPs. The distribution of alpha-SMA-positive cells tended to be more remarkable in pedicle areas than in tip and central areas of NPs. The number of MCs was significantly higher in zone 3 than in zone 1 of alpha-SMA-positive cells.

Neuromuscular junctions of the posterior cricoarytenoid muscle in multiple system atrophy: a case study.

CONCLUSION: The present study showed a variety of stages of neurogenic degeneration of the muscle fibers and the neuromuscular junctions (NMJs) of the posterior cricoarytenoid (PCA) muscle in multiple system atrophy (MSA). These findings coincide with abductor paralysis of vocal cords. Ultrastructural features of the NMJs of the PCA muscle in MSA were different from those of previous studies on experimental resection of recurrent nerve and amyotrophic lateral sclerosis (ALS). OBJECTIVES: MSA may influence various respiratory functions. Upper airway tracts including larynx are affected without exception during its clinical course. Morphological changes of NMJs of the intrinsic laryngeal muscle in MSA were examined ultrastructurally. PATIENT AND METHODS: The patient was a 68-year-old male complaining of recurrent aspiration pneumonia, dysphagia, respiratory disturbance, and abductor paralysis of vocal cords. The motor nerve terminals of the PCA muscle in a patient with MSA were investigated electron microscopically. RESULTS: The NMJs showed varying degrees of ultrastructural changes by motor nerve degeneration. They were seen in the pre- and post-synaptic regions. Muscle fibers losing nerve terminals showed severe damage in their cytoplasm.

[A case of Mikulicz's syndrome associated with sarcoidosis].

A 29-year-old woman with symmetrical bilateral swelling of the parotid, submandibular, and lacrimal glands--also called Mikulicz's symptoms--showed skin rash and pedal erythema. Serum IgG4 was within the normal range but serum ACE and lysozome were elevated. Incisional biopsy of the parotid glands and histopathological examination indicated sarcoidosis. This was complicated by uveitis and a low-grade fever. No facial nerve palsy was observed. Based on these findings, the definitive diagnosis was Mikulicz's syndrome associated with sarcoidosis. An alternative diagnosis was incomplete Heerfordt syndrome. The administration of steroid hormones, caused parotid, submandibular, and lacrimal glands swelling to disappear.