Sjögren’s syndrome in childhood

This review presents our 10-year experience with children diagnosed with Sjögren’s syndrome (SS). Patients between the ages of 9 and 17 years had abnormalities in laboratory values consistent with but not entirely diagnostic of those required to diagnose SS in adults. The spectrum of clinical manifestations suggests that the SS clinical phenotype in children is more variable than that in adults. Here, we review manifestations of SS in children. Our patients were treated with hydroxychloroquine, despite the lack of prospective data about effects on SS progression and/or autoantibody spreading. Patients have been followed for between 3 and 6 years without substantial progression of their disease or change in autoantibody status. Longer term follow-up (10–20 years) is needed to define the natural history of SS in childhood and its treatment outcomes. Prospective validation of SS criteria in childhood could facilitate assessment of the utility of hydroxychloroquine and other therapies.     

Prevalence of alpha-fodrin antibodies in patients with chronic hepatitis C infection and Sjögren syndrome

Objective. Hepatitis C virus infection (HCV) is associated with various extrahepatic manifestations. Antibodies against alpha-fodrin are associated with sicca symptoms and may valuable diagnostic markers in patients with primary Sjögren syndrome (SS) lacking Ro antibodies. The frequency and role of alpha-fodrin antibodies in patients with chronic HCV infection are unknown. The aim of this study was to investigate the prevalence of alpha-fodrin antibodies in HCV-infected patients with SS. Material and methods. Alpha-fodrin antibodies were detected more often in hepatitis C patients (25%; n=142) than in HBV-infected individuals (8%; n=49) and healthy controls (6%; n=174) (p<0.01). Based on these findings, we investigated the frequency of sicca symptoms in a second cohort and studied other antibodies associated with SS. Results. HCV-infected individuals showed sicca symptoms in 53% of cases as determined by the Saxon and Schirmer tests, which was more frequent than in healthy controls (1%, p<0.01) but not in patients with autoimmune liver disease (51%). Antibodies specific for Ro (SS-A) were significantly more common in patients with autoimmune liver disease than in HCV-infected patients and healthy controls (16% versus 1% and 0%, p<0.003). SS was found in 18% of patients with HCV, in 15% of patients with autoimmune liver disease and in 1% of healthy controls. However, we found no correlation between sicca symptoms and the presence of antibodies against alpha-fodrin, Ro and La. Conclusions. Patients with chronic HCV infection show a high prevalence of sicca symptoms and antibodies against alpha-fodrin. However, neither the frequency nor the severity of symptoms correlated with the presence of alpha-fodrin antibodies.     

Biologic therapy in Sjögren’s syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disease with complex and diverse clinical manifestations. It is characterized by lymphocyte infiltration of exocrine glands such as the salivary gland and lacrimal gland leading to insufficient secretion of the gland, manifested as dry mouth and dry eyes. In addition, it can involve extraglandular organs and cause systemic damage. The pathogenesis of SS is still unclear. At present, symptomatic treatment is the mainstay and there is a lack of effective therapy. With the development of molecular pathways underlying the pathogenesis of SS, more and more novel biological agents are used to treat SS. We summarized and analyzed the existing evidences on the efficacy of biological treatment of SS and their targets. Analysis of the efficacy of biological therapy and improvement of treatment strategies can help to give full play to its therapeutic advantages.

     

Thyroid disease in Sjögren’s syndrome

From 1960 to 2007, an important number of patients with primary Sjögren’s syndrome (pSS) along with thyroid disease diagnosed by laboratory data and clinical presentation were reported. The most common thyroid disorder found was autoimmune thyroiditis and the most common hormonal pattern was subclinical hypothyroidism. The coexistence of SS and thyroiditis is frequent and suggests a common genetic or environmental factor predisposition with similar pathogenic mechanisms. pSS was ten times more frequent in patients with autoimmune thyroid disease and autoimmune thyroiditis was nine times more frequent in pSS. Therefore, SS should be studied in patients with thyroid disease and vice versa. Antigens are shared by both thyroid and salivary glands, which could be responsible for the association between both diseases. Immunogenetic studies had suggested that both diseases have a common genetic predisposition. pSS and thyroid disease patients were mostly women with positive antithyroglobulin, antiparietal cell and antithyroid peroxidase antibodies. Thyroid dysfunction is frequent in pSS patients and those prone to develop thyroid disorders are identified by thyroid-related autoantibodies or by rheumatoid factor and anti-Ro/SSA activity. Patients with pSS have an increased tendency to develop other autoimmune diseases. Hypothyroidism was the most common autoimmune disease developed in pSS patients during follow-up of 10.5 years. Lymphomas are also associated with SS and thyroiditis and a 67-fold increased risk for thyroid mucosa-associated lymphoid tissue (MALT) lymphoma and a 44-fold increased risk for parotid lymphoma is being attributed to autoimmune thyroiditis and pSS. It is suggested that immune mechanism deficiency is a causal factor for B cell lymphoma in pSS and autoimmune thyroid disease. Other studies are necessary to clarify the shared pathogenesis mechanism in SS and autoimmune thyroid disease and to understand this fascinating autoimmune association.     

Cricoarytenoid arthritis in Sjögren’s syndrome

We present the case of a 50-year-old female with polyarthralgias and dysphonia. Indirect laryngoscopy revealed the presence of cricoarytenoid arthritis. The patient complained of dryness of the eyes and oral mucosa and was diagnosed with Sjögrens syndrome. Treatment with prednisolone quickly brought remission of systemic and laryngeal symptoms as well as improvement in the results of video-laryngostroboscopic tests. Laryngeal involvement is uncommon in Sjögrens syndrome. One case with vocal nodules, one with lymphocytic infiltration of the larynx, and one with repeated false cord swelling have been previously reported.     

Autoantigen-targeting microRNAs in Sjögren’s syndrome

MicroRNAs are short endogenous non-coding RNAs that regulate gene expression in various physiological and pathological conditions. To characterize autoantigen-targeting microRNAs in Sjögren’s syndrome (SS), a systematic study was carried out, in which a candidate microRNA set was first identified by bioinformatics analysis and literature search. Then, their gene silencing activities were evaluated with fusion reporter gene and endogenous targets, leading to the identification of three microRNAs: TRIM21-targeting miR-1207-5p, TRIM21-targeting miR-4695-3p, and La autoantigen-targeting miR-299-5p. Compared to healthy controls, downregulation of miR-1207-5p and miR-4695-3p expression was further revealed in the minor salivary glands of primary SS (pSS) patients. This, on the one hand, characterized two autoantigen-targeting microRNAs in Sjögren’s syndrome and, on the other hand, suggested that downregulation of miR-1207-5p and miR-4695-3p expression may lead to increased TRIM21 levels in the minor salivary glands, which contributes to the development of Sjögren’s syndrome.     

A follow-up study of minimally invasive lip biopsy in the diagnosis of Sjögren’s syndrome

The aims of this study were to characterize a minimally invasive technique of minor salivary gland biopsy of the lower lip and to present a large patient material undergoing this procedure because of a suspicion of Sjögren’s syndrome (SS), as well as to assess the procedure’s short-term and long-term value as a diagnostic test and a prognostic factor. The sample consists of consecutive 191 patients undergoing lower lip biopsy in 1987–1990 in Kanta-Hame Central Hospital, Hameenlinna, Finland. The method used was the retrospective chart review. Only three (1.6%) of the biopsies were uninformative, and only one (0.5%) of the patients had a biopsy complication. In 41% of the cases, biopsy was suggestive of SS. Females and elderly patients were more likely to have a positive biopsy result. Surprisingly, a large diversity between pathologists was observed. With the use of focus score instead of older Chisholm classification as an indicator of SS, the specificity of SS diagnostics improved, and the variability between pathologists diminished. Neither SS diagnosis nor positive lip biopsy for SS predicted patients’ long-term outcome. In only three patients (1.6%) did the histological diagnosis change due to repeated biopsies. The minimal invasive lower lip biopsy technique presented in this study is a reliable and safe aid in SS diagnostics. The currently recommended histological grading system (focus score?≥?1 suggesting SS) is more specific and reproducible than older Chisholm classification. Repeated biopsy very rarely adds new information.     

Validation of different sets of criteria for the diagnosis of Sjögren’s syndrome in Japanese patients

Objective

To validate the revised Japanese Ministry of Health criteria for the diagnosis of Sjögren’s syndrome (SS) (JPN) (1999), The American-European Consensus Group classification criteria for SS (AECG) (2002), and American College of Rheumatology classification criteria for SS (ACR) (2012).

Methods

The study subjects were 694 patients with SS or suspected SS who were followed-up in June 2012 at ten hospitals that form part of the Research Team for Autoimmune Diseases, The Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare (MHLW). All patients had been checked for all four criteria of the JPN (pathology, oral, ocular, anti-SS-A/SS-B antibodies). We studied the clinical diagnosis made by the physician in charge and the satisfaction of the above criteria.

Results

Of the 694 patients, 499 patients did not have other connective tissue diseases (CTDs). SS was diagnosed in 476 patients (primary SS in 302, secondary SS in 174), whereas non-SS was diagnosed in 218 patients (without other CTDs in 197, with other CTDs in 21) by the physician in charge. The sensitivities of JPN, AECG, and ACR in the diagnosis of all forms of SS (both primary and secondary SS) were 79.6, 78.6, and 77.5 %, respectively, with respective specificities of 90.4, 90.4, and 83.5 %. The sensitivities of the same systems in the diagnosis of primary SS were 82.1, 83.1, and 79.1 %, respectively, with specificities of 90.9, 90.9, and 84.8 %, respectively. The sensitivities of the same systems in the diagnosis of secondary SS were 75.3, 70.7, and 74.7 %, respectively, with specificities of 85.7, 85.7, and 71.4 %, respectively.

Conclusion

The sensitivity of JPN to all forms of SS and secondary SS, the sensitivity of AECG to primary SS, and the specificities of JPN and AECG for all forms of SS, primary SS, and secondary SS were highest in the diagnosis of SS in Japanese patients. These results indicate that the JPN criteria for the diagnosis of SS in Japanese patients are superior to ACR and AECG.     

Lymphoproliferation in autoimmunity and Sjögren’s syndrome

Sjögren’s syndrome is a chronic inflammatory process involving primarily the exocrine glands. Its association with lymphoma is well documented. A low-grade marginal-zone lymphoma related to mucosa-associated lymphoid tissue is the most common lymphoid neoplasia in Sjögren’s syn-drome. Among all autoimmune diseases, Sjögren’s syn-drome is the best tool to clarify the multiple components of autoimmunity and lymphomatogenesis. Herewith, the authors review the literature and discuss the molecular, clinical, histopathologic, and therapeutic aspects of these tumors in Sjögren’s syndrome.     

Specific immunotherapy-induced Sjögren’s syndrome

Background: Allergen-specific immunotherapy (SIT) is a well-documented treatment for allergic rhinitis, asthma, and allergy to bee venoms. Side-effects of SIT in long-term have not been well documented yet. Herein, we report a case of Sjögrens syndrome following SIT. Case: The patient, a 25-year-old Caucasian woman, was started on subcutaneous grass-pollen immunotherapy. The patients autoantibodies before the SIT screening tests were negative. We determined that anti-extractable nuclear antigen (ENA) was positive (ENA = 98.4, normal range 0–25 U) on routine screening tests at 44 weeks of her treatment, and then SIT was discontinued. The patient complained of burning and itching in her eyes for 6 months. Schirmers and salivary flow tests were positive. Although antinuclear antigen and rheumatoid factor were negative, anti-SS-A/Ro was positive. Viral hepatitis markers were negative. Minor salivary-gland biopsy was performed, which showed grade 4 sialoadenitis. The HLA type of the patient was B55 (B22), Bw6, Cw1 for class I and DR11, DR52, DQ7 (DQ3) for class II. After the immunotherapy had been stopped, there were no changes in the symptoms and laboratory findings of the patient during the 1st year of follow-up. Conclusion: This is the first case to be reported of Sjögrens syndrome following SIT. Patients undergoing SIT must be carefully followed up for the development of autoimmunity and an autoimmune disease.     

Polymyalgia rheumatica in primary Sjögren’s syndrome

The aim of the study was to describe the clinical and laboratory aspects of primary Sjögren’s syndrome (pSS) associated with polymyalgia rheumatica (PMR). The retrospective study compares the clinical and laboratory aspects of patients with pSS associated with PMR on a relatively large cohort of patients (n=16) and pSS patients without PMR (n=531). The prevalence of PMR among pSS patients was 3%, while in the average population, the prevalence of PMR is only 0.75%. PMR developed 8.7 years after the diagnosis of pSS in the older female pSS population (over 50 years of age), and in those with only glandular features. Interestingly the pSS/PMR patients had hypo gammaglobuline levels, while in the pSS patient group hypergammaglobulinaemia presented. Furthermore, positive ANA serology was more frequent among pSS/PMR patients. Since the clinical management of pSS/PMR is different from pSS, a better understanding of this clinical entity is essential.     

Targeting primary Sjögren’s syndrome

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Hallmarks of the disease are a loss of salivary and lacrimal gland function as well as lymphocytic infiltration, elevated proinflammatory cytokines, and circulating autoantibodies. Patients often experience significant fatigue and a decrease in their quality of life. Approximately 30–50% of pSS patients develop extra-glandular manifestations including malignant lymphoma. Although therapeutic approaches for pSS target both dryness and systemic manifestations, effective treatments are limited. However, new therapies targeting specific immune pathways associated with pSS are being developed. This review describes current and future targeted therapies against pSS.     

Anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjögren’s syndrome

Sjögren’s syndrome (SS) is an autoimmune disease that affects exocrine glands including salivary and lacrimal glands. Recently, autoantibodies against muscarinic acetylcholine receptor M3 (M3R) have been detected in serum from 9 to 100 % of patients with SS in addition to anti-SS-A and anti-SS-B antibodies. These observations suggest the possibility that anti-M3R antibodies could serve as a new diagnostic test in patients with SS. Some anti-M3R antibodies are directly responsible for salivary underproduction in patients with SS. Thus, strategies designed to eliminate such pathogenic antibodies could help cure SS sufferers. In this review, we summarize the current state of knowledge of anti-M3R autoantibodies in patients with SS and the correlation between B cell epitopes and the function of anti-M3R antibodies.     

Cerebellar involvement in patients withprimary Sjögren’s syndrome: diagnosis and treatment

The aim of this study is to describe the clinical features of cerebellar involvement in patients with primary Sjögren’s syndrome (pSS). We retrospectively analyzed the manifestations, treatments, and outcomes in patients with pSS-cerebellar complication in Peking Union Medical College Hospital and cases reported in literature. Altogether 13 patients were identified. They were 2 males and 11 females with a mean age at disease onset of 45.2?±?14.6 years. Nine (69.2%) patients went to the clinic because of ataxia, and pSS was not suspected until accidental screening for autoantibodies. Dysarthria (7, 59.8%), limb tremor (4, 30.8%), and nystagmus (2, 15.4%) were the rest symptoms related to cerebellum. Of the patients, 81.8% (9/11) had abnormal cerebrospinal fluid findings, and 11 patients (84.6%) had cerebellar atrophy in the brain MRI. Dry eyes and dry mouth were detected in 9 (69.2%) and 7 (59.8%) patients, while positive objective xerostomia and ocular test in 82.5% (7/8) and 100% (10/10) of the patients, respectively. Anti-Ro/SSA antibody was positive in 12 (92.3%) and anti-La/SSB in 6 (46.2%) patients. Glucocorticoids were applied in 12 patients (92.3%). Cyclophosphamide (3, 20.1%), mycophenolatemofetil (1, 7.7%), and hydroxychloroquine (4, 30.8%) were chosen as immunosuppressants or anti-inflammatory drug. During a median follow-up of 9 months (range, 1–18 months), 8 (61.5%) patients remained stable, 3 (20.1%) patients were in remission, and 2 (15.4%) patients were in progression. Clinical cerebellar complication secondary to pSS was rare, and sometimes pSS was not suspected until accidental screening for autoantibodies. Because the onset of cerebellar manifestation is often insidious and rapid deteriorates, early diagnosis and empirical aggressive glucocorticoid treatment is warranted.     

Sjögren’s syndrome in patients with ankylosing spondylitis

There are few reports about the coexistence of Sjögren’s syndrome (SS) and ankylosing spondylitis (AS). To evaluate the frequency of SS in patients with AS. We studied 70 patients with AS presenting to the university outpatient clinic between January 2002 and November 2003. All the patients were asked about sicca symptoms by using sicca questionnaire. Rheumatoid factor, anti-nuclear antibody, anti-Ro, and anti-La antibodies were examined for each of the patients. Salivary flowmetry for the existence of xerostomia, Schirmer’s test, and break-up time for the existence of xerophtalmia were performed in all patients with AS. Minor salivary gland biopsy was performed on the patients with at least three positive responses to the sicca questionnaire and positive xerostomia/ xerophtalmia tests. Biopsies were regarded as pathological when they showed focal grade III and grade IV sialoadenitis according to Chisholm grading criteria. Among 70 AS cases, 56 (80%) were men, 14 (20%) were women, and the mean age was 42 years old. Minor salivary gland biopsy was performed on the 16 patients. Of 16 minor salivary gland biopsies, 7 were assessed as pathological—5 of them showed grade III, and 2 of them showed grade IV sialoadenitis. Of these seven patients, one was anti-Ro-positive, and two were anti-La-positive. There was no patient with normal salivary gland biopsy and anti-Ro and/or anti-La positivity. In our study group, 7 (10%) of 70 AS patients had concomitant SS. Therefore, it seems likely that AS may have pathogenetic association with SS.     

Sjögren’s syndrome,the old and the new

Sjögren’s syndrome is a chronic autoimmune disease characterised by progressive injury to exocrine glands accompanied by diverse extra-glandular manifestations. The spectrum of Sjögren’s manifestations expanded in recent years to include new symptoms and signs such as small fibre neuropathy, and also well-defined activity and prognostic indexes. Similar to other non-organ-specific autoimmune diseases, a mosaic of factors have been linked with the development and appearances of Sjögren’s syndrome. Progress has been made unravelling those factors, including susceptibility genes, immunological parameters and various environmental factors in the last decade, some of which may enable targeted therapies, biological and non-biological ones, for patients suffering from this disease.Thus, herein we review the postulated aetiologies, pathogenesis and new insights related to Sjögren’s syndrome.     

Efficacy prediction of cevimeline in patients with Sjögren’s syndrome

The objective of this study was to examine the clinical and immunological factors influencing the efficacy of cevimeline hydrochloride hydrate (cevimeline) for the treatment of xerostomia in patients with Sjögren’s syndrome (SS). Thirty primary SS patients who were medicated with cevimeline were enrolled in this study. Whole stimulated sialometry (WSS) was compared between pre- and posttreatment points (4 weeks after oral cevimeline administration) and the increment rate of WSS was calculated. Multiple regression was employed to examine the relative contributions of the clinical and immunological factors, including age, pretreatment WSS, duration of disease, sialography, minor salivary gland biopsy, anti-Ro/SS-A antibodies, anti-La/SS-B antibodies, and antibodies to muscarinic type 3 receptors to the posttreatment WSS. Patients with normal sialography findings, negative minor salivary gland biopsy, and absence of anti-La/SS-B antibodies had significantly higher increment rates of WSS compared with those with positive findings (p?=?0.042, 0.002, and 0.018, respectively). Results of the multiple regression analysis showed that sialography (coefficient = ?0.867, p?=?0.004) and minor salivary gland biopsy (coefficient = ?0.869, p?=?0.003) had significant associations with the posttreatment WSS. Our preliminary results demonstrated the relationship between the effect of cevimeline on saliva secretion and the degree of salivary gland destruction evaluated by sialography and histopathological findings in the labial minor salivary glands. These diagnostic approaches could provide useful prognostic information on the efficacy of cevimeline in SS patients.