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Primary Sjögren's Syndrome (primary + sjogren_syndrome)
Selected AbstractsHealth-related quality of life in patients with Primary Sjögren's Syndrome and Xerostomia: a comparative studyGERODONTOLOGY, Issue 1 2002Jocelyne Rostron Abstract Objective: To compare the health status of groups of Primary Sjögren's and Xerostomia patients, using the Medical Outcomes Short Form 36 (SF-36). The SF-36 is a generic measure, divided into eight domains, used in the assessment of health-related quality of life. Patients and methods: The SF-36 was given to 2 groups: Group 1 comprised 43 patients diagnosed with Primary Sjögren's Syndrome (1SS) and an unstimulated whole salivary flow rate (UFR) of <0.1 ml/min). Group 2 (n = 40) reported Xerosiomia but had an UFR >0.2 ml/min. Sub groups of patients in Groups 1 and 2 were compared with community normative data, for the SF-36 Results: There were trends to suggest lower SF36 scores for 1SS patients but there were no significant differences between the mean domain scores of Groups 1 and 2. 1SS and Xerostomia patients registered lower mean scores across all 8 domains, compared with normative community data. Conclusion: The SF-36 was unable to detect significant differences between subjects with 1SS and Xerostomia but a larger sample size is required to confirm these findings. The results of this limited study suggest that a disease-specific measure is required to assess the impact 1SS on health-related Quality of life (QOL). [source] Gene expression profile in the salivary glands of primary Sjögren's syndrome patients before and after treatment with rituximabARTHRITIS & RHEUMATISM, Issue 8 2010Valérie Devauchelle-Pensec Objective Primary Sjögren's syndrome (SS) is a complex disorder, in part due to B cell abnormalities. Although anti,B cell therapy is promising in primary SS, no treatment has yet been demonstrated to modify the disease course. This open-label study was undertaken to evaluate the efficacy of rituximab in primary SS and to investigate whether expression of specific genes is associated with efficacy of this treatment. Methods Fifteen patients with primary SS were treated in an open-label trial. Salivary gland biopsy specimens were obtained, and total RNA was extracted and amplified. Microarray analysis with the Affymetrix Human Genome U133 Plus 2.0 Array was used to analyze >54,000 transcripts, and potential pathways were identified. Results With gene expression data obtained before treatment, patients could be correctly classified in terms of whether they would be responders or nonresponders to rituximab. Gene pathway analysis demonstrated that the B cell signaling pathway was the most profoundly differentially expressed before treatment in the responders compared with nonresponders. Subclassification of patients based on the level of infiltration also demonstrated differential expression of genes belonging to the interferon (IFN) pathway between responders and nonresponders. Furthermore, unsupervised analysis based on gene expression modification before and after treatment allowed identification of 8 genes that were differentially expressed between responders and nonresponders, with the difference remaining significant after Bonferroni correction. Conclusion Our results demonstrate the ability to elaborate a set of genes predictive of rituximab efficacy and highlight the importance of studying the differential expression of B cell and IFN pathway signaling molecules in relation to the response to anti-CD20 treatment. A randomized controlled study is currently ongoing to confirm these results. [source] Activation of AMP-activated protein kinase by adiponectin rescues salivary gland epithelial cells from spontaneous and interferon-,,induced apoptosisARTHRITIS & RHEUMATISM, Issue 2 2010Stergios Katsiougiannis Objective Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltrates associated with destruction of salivary gland epithelial cells (SGECs) induced mainly by apoptosis. Adiponectin is an immunoregulatory hormone. We have previously shown that SGECs from patients with primary SS as well as from controls differentially express adiponectin. SGECs derived from patients with primary SS constitutively produce and secrete adiponectin in higher quantities. The aim of this study was to investigate the effect of adiponectin on the proliferation and apoptosis of SGECs. Methods Cultured, non-neoplastic SGECs were treated with recombinant human adiponectin, and the rate of cell proliferation was assessed. Spontaneous and interferon-, (IFN,),induced apoptosis was evaluated with a specific single-stranded DNA enzyme-linked immunosorbent assay. The AMP-activated protein kinase (AMPK) inhibitor Compound C was used to test the involvement of AMPK in adiponectin effects. Western blotting was applied to detect the phosphorylation levels of AMPK after adiponectin treatment. Results Adiponectin treatment resulted in a dose-dependent suppression of proliferation of SGECs from patients with primary SS and control donors. Adiponectin protected cells from spontaneous as well as from IFN,-induced apoptosis. Furthermore, the antiapoptotic effects of adiponectin were dependent upon AMPK phosphorylation at Thr172, since pretreatment of SGECs with Compound C abolished the adiponectin protective effect. Conclusion Adiponectin exerted antiproliferative effects on SGECs without inducing apoptosis and protected SGECs from spontaneous as well as from IFN,-induced apoptosis through an AMPK-dependent pathway. Our observations suggest that adiponectin may protect SGECs in this specific inflammatory milieu, providing a potential pathway through which AMPK may regulate cell survival under energy stress conditions such as autoimmune inflammation. [source] Is there progressive cognitive dysfunction in Sjögren Syndrome?ACTA NEUROLOGICA SCANDINAVICA, Issue 3 2010A preliminary study Martínez S, Cáceres C, Mataró M, Escudero D, Latorre P, Dávalos A. Is there progressive cognitive dysfunction in Sjögren Syndrome? A preliminary study. Acta Neurol Scand: 122: 182,188. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objective,,, The aim of this study was to determine the progression of cognitive dysfunction in primary Sjögren Syndrome (SS). Methods,,, Twelve subjects with SS were compared with ten subjects with migraine and ten healthy controls on neuropsychological, mood and fatigue tests at baseline and 8 years later. Results,,, At follow-up, SS subjects performed below subjects with migraine on the Continuous Performance Test (CPT) but did not differ on other tasks. Compared with controls, both clinical groups obtained lower scores on simple reaction time, patients with SS obtained lower scores on the Wisconsin Card Sorting Test (WCST) and patients with migraine performed below controls on the Benton's Judgment of Line Orientation Test (JOLO). Clinical groups did not differ on cognitive changes over time, except that migraine subjects improved on verbal fluency. Compared with baseline, both SS and migraine patients were more impaired on simple reaction time, Trail Making Test part B, Stroop and JOLO. However, they showed higher scores on verbal and visual memory, WCST and CPT reaction time. SS also showed higher levels of depression and fatigue than migraine and controls, with no significant changes over time. Discussion,,, Preliminary evidence indicates some cognitive deficits in both SS and migraine following a pattern of fronto-subcortical dysfunction without a significant cognitive decline over time. [source] Preferential recognition of the phosphorylated major linear B-cell epitope of La/SSB 349,368aa by anti-La/SSB autoantibodies from patients with systemic autoimmune diseasesCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 3 2006A. G. Terzoglou Summary Sera from patients with primary Sjögren Syndrome (pSS) or Systemic Lupus Erythematosus (SLE) often contain autoantibodies directed against La/SSB. The sequence 349,368aa represents the major B-cell epitope of La/SSB, also it contains, at position 366, a serine aminoacid residue which constitutes the main phosphorylation site of the protein. In this study we investigated the differential recognition of the 349,368aa epitope and its phosphorylated form by antibodies found in sera from patients with systemic autoimmune diseases. Peptides corresponding to the sequence of the unphosphorylated (pep349,368aa) and the phosphorylated form (pep349,368aaPh) of the La/SSB epitope 349,368aa, as well as to a truncated form spanning the sequence 349,364aa and lacking the phosphorylation site (pep349,364aa), were synthesized. Sera from 53 patients with pSS and SLE with anti-La/SSB specificity, 30 patients with pSS and SLE without anti-La/SSB antibodies, 25 patients with rheumatoid arthritis and 32 healthy individuals were investigated by ELISA experiments. Autoantibodies to pep349,368aaPh were detected in sera of anti-La/SSB positive patients with a higher prevalence compared to the pep349,368aa (66%versus 45%). Pep349,368aaPh inhibited the antibody binding almost completely (92%), while pep349,368aa inhibited the binding only partially (45%). Anti-La/SSB antibodies presented a higher relative avidity for the phosphorylated than the unphosphorylated peptide. Immunoadsorbent experiments using the truncated peptide pep349,364aa indicated that the flowthrough showed a selective specificity for pep349,368aaPh, while the eluted antibodies reacted with both peptide analogues of the La/SSB epitope. These data suggest that sera from pSS and SLE patients with anti-La/SSB reactivity possess autoantibodies that bind more frequently and with a higher avidity to the phosphorylated major B-cell epitope of the molecule. [source] Evaluation of a new automated enzyme fluoroimmunoassay using recombinant plasmid dsDNA for the detection of anti-dsDNA antibodies in SLEJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 5 2002D. Villalta Abstract ELISA methods to detect anti-double-stranded DNA (anti-dsDNA) antibodies are highly sensitive, but are less specific for the diagnosis of SLE than the immunofluorescence test on Crithidia luciliae (CLIFT) and the Farr assay because they also detect low-avidity antibodies. This study evaluated the specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of a new automated fluoroimmunoassay (EliA dsDNA; Pharmacia, Freiburg, Germany). We compared the results with those obtained using a commercial CLIFT and an in-house anti-dsDNA IgG ELISA method, and verified its putative ability to detect only high-avidity anti-dsDNA antibodies. Sera from 100 SLE patients and 120 controls were studied. The control group included 20 healthy donors, 70 patients with other rheumatic diseases (32 systemic sclerosis (SSc); 18 primary Sjögren syndrome (pSS), 20 rheumatoid arthritis (RA)), and 30 patients with various infectious diseases (ID). Anti-dsDNA avidity was estimated using an ELISA method based upon the law of mass action, and a simplified Scatchard plot analysis for data elaboration; the apparent affinity constant (Kaa) was calculated and expressed as arbitrary units (L/U). Sensitivity, specificity, PPV, and NPV for SLE were 64%, 95.8%, 93.8% and 72.7%, respectively, for the EliA anti-dsDNA assay; 55%, 99.2%, 98.5%, and 68.8%, respectively, for the CLIFT; and 64%, 93.3%, 90.6%, and 72.3%, respectively, for the in-house ELISA. Although EliA anti-dsDNA was positive mainly in SLE patients with high- (Kaa>80 L/U) and intermediate- (Kaa 30,80 L/U) avidity antibodies (45.3% and 49.9%, respectively), it was also positive in five (7.8%) SLE patients with low-avidity anti-dsDNA antibodies, and five controls (three SSc, one pSS, and one ID) (mean Kaa = 16.4 ± 9.04 L/U). In conclusion, EliA anti-dsDNA assay showed a higher sensitivity than the CLIFT, and a good specificity and PPV for SLE. Its putative ability to detect only high-avidity anti-dsDNA antibodies remains questionable. J. Clin. Lab. Anal. 16:227,232, 2002. © 2002 Wiley-Liss, Inc. [source] Systemic increase in type,I interferon activity in Sjögren's syndrome: A putative role for plasmacytoid dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Manon Abstract In the salivary glands of primary Sjögren's syndrome (pSjS) patients, type,I IFN activity is increased, but systemic levels of type,I IFN proteins are rarely detected. This study focused on the systemic activity of type,I IFN in pSjS, as well as the role of peripheral plasmacytoid dendritic cells (pDC). Monocytes obtained from pSjS patients showed an increased expression of 40,genes. Twenty-three of these genes (58%), including IFI27, IFITM1, IFIT3 and IFI44, were inducible by type,I IFN. pSjS serum had an enhanced capability of inducing IFI27, IFITM1, IFIT3 and IFI44 in the monocytic cell line THP-1, likely due to the action of IFN-,. This effect could be inhibited by blocking the type,I IFN receptor, supporting a high type,I IFN bioactivity in pSjS serum. In addition, circulatory pDC showed increased expression of CD40. This expression was correlated to the expression level of the type,I IFN-regulated genes IFI27 and IFITM1 in monocytes of the same individual. This study indicates that the increased type,I IFN activity observed in pSjS patients is not only a local but also a systemic phenomenon and points to pDC as a possible source of this activity. [source] The health status burden of people with fibromyalgia: a review of studies that assessed health status with the SF-36 or the SF-12INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 1 2008D. L. Hoffman Summary Objective:, The current review describes how the health status profile of people with fibromyalgia (FM) compares to that of people in the general population and patients with other health conditions. Methods:, A review of 37 studies of FM that measured health status with the 36-item Medical Outcomes Study Short-Form Health Survey (SF-36) or the 12-item Short-Form Health Survey (SF-12). Results:, Studies performed worldwide showed that FM groups were significantly more impaired than people in the general population on all eight health status domains assessed. These domains include physical functioning, role functioning difficulties caused by physical problems, bodily pain, general health, vitality (energy vs. fatigue), social functioning, role functioning difficulties caused by emotional problems and mental health. FM groups had mental health summary scores that fell 1 standard deviation (SD) below the general population mean, and physical health summary scores that fell 2 SD below the general population mean. FM groups also had a poorer overall health status compared to those with other specific pain conditions. FM groups had similar or significantly lower (poorer) physical and mental health status scores compared to those with rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, myofacial pain syndrome, primary Sjögren's syndrome and others. FM groups scored significantly lower than the pain condition groups mentioned above on domains of bodily pain and vitality. Health status impairments in pain and vitality are consistent with core features of FM. Conclusions:, People with FM had an overall health status burden that was greater in magnitude compared to people with other specific pain conditions that are widely accepted as impairing. [source] Livedoid vasculopathy and hypercoagulability in a patient with primary Sjögren's syndromeINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 4 2007Raquel Cardoso MD Background, A 31-year-old woman presented with a 5-year history of painful ulcerations, palpable purpura, porcelain-white atrophic scars of the malleolar region and dorsal aspect of the feet, livedo reticularis on the limbs, arthralgia, xerophthalmia, and xerostomia. Methods, Skin biopsy revealed vessel wall hyalinization and thrombosis of the microvasculature with a very scarce dermal inflammatory infiltrate. Biopsy of the oral mucosa showed mononuclear infiltration of an intralobular duct of a salivary gland. Results, Laboratory studies, including autoantibodies and inflammation markers, were normal, except for a positive rheumatoid factor. Coagulation screening revealed C677T methylenetetrahydrofolate reductase (MTHFR) mutation, with a normal serum homocysteine. The patient was treated with oral methylprednisolone (32 mg/day with progressive reduction) and enoxaparin (20 mg/day subcutaneously), with complete ulcer healing within 4 months. Conclusion, Livedoid vasculitis or vasculopathy has not been referred to previously in association with Sjögren's syndrome, but may be associated with other autoimmune disorders and anomalies of coagulation, namely factor V Leiden mutation, protein C deficiency, and MTHFR mutation, associated or not with hyperhomocysteinemia, a condition that seems to confer an increased risk of recurrent arterial and venous thrombosis. We stress the importance of anticoagulant therapy for ulcer healing and for the prevention of other thrombotic events. [source] Follicular dendritic cells confirm lymphoid organization in the minor salivary glands of primary Sjögren's syndromeJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 9 2008Malin V. Jonsson Background:, Sjögren's syndrome (SS) is an autoimmune chronic inflammatory disorder affecting the salivary and lacrimal glands. The aim of this study was to explore immunophenotypic features of chronic inflammatory reactions in the minor salivary glands in patients with primary SS (pSS). Methods:, Formalin-fixed, paraffin-embedded labial minor salivary gland tissue sections from randomly selected patients with pSS (n = 60) were investigated for the expression of CD21, CD23, CD35 and IgD by immunohistochemistry. Results:, Based on the distribution and staining pattern of CD21, CD23, CD35 and IgD in lymphoid aggregates, several stages of chronic inflammatory reactions were observed. In 12/60 (20%) patients, lymphoid infiltrates with germinal centre (GC)-like features such as extensive networks of CD21-, CD23- and CD35-positive cells were observed in the minor salivary gland tissue. Smaller networks and,/or focal infiltrates with scattered CD21+, CD23+ and CD35+ cells were observed in the remaining 48/60 (80,%) cases. When dividing patients according to the presence (GC+) or the absence (GC,) of GC in the minor salivary glands, the mean focus score was significantly higher in the GC+ patients (P < 0.05). Double staining of the minor salivary glands revealed focal infiltrates with follicular dentritic cell networks and B cells resembling normal GCs in tonsillar tissue. Conclusion:, A particular cellular profile was demonstrated in a sub-group of patients with pSS and could be linked to serological aberrations. These findings warrant further prospective studies. [source] Innervation pattern and Ca2+ signalling in labial salivary glands of healthy individuals and patients with primary Sjögren's syndrome (pSS)JOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 3 2000Anne Marie Pedersen Abstract: We have characterised the innervation pattern and intracellular Ca2+ -signalling in labial salivary glands (LSG) of 16 patients with primary Sjögren's syndrome (pSS) and 27 healthy controls. Numerous immunoreactive nerve fibers (IRF) containing vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP) were found around acini, ducts and blood vessels. Substance P (SP)-, neuropeptide Y-, tyrosine hydroxylase- and nitric oxide synthase-IRF were mainly surrounding ducts and blood vessels. The majority of pSS patients had inflamed LSG and the presence of focal lymphocytic infiltrates (FI) were more frequent and pronounced as compared with healthy controls. In areas with normal or diffusely inflamed LSG tissue, pSS patients demonstrated the same distribution of IRF as healthy controls with similar histology. However, IRF were absent in central areas of FI both in pSS and age-matched healthy controls. Although all pSS patients had hyposalivation, stimulation with acetylcholine, norepinephrine, phenylephrine, isoproterenol, VIP, PACAP, SP, adenosine 5,-triphosphate and uridine 5,-triphosphate induced the same increase in the intracellular free Ca2+ concentration in LSG acini from both pSS patients and healthy controls, indicating the presence of functional receptor systems in vitro. [source] A histopathological study of lymphoepithelial island formation in labial salivary glands in patients with primary Sjögren's syndromeJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 3 2000Yukiko Yamamura Abstract: The proliferative status of lymphoepithelial islands in the labial salivary glands of primary Sjögren's syndrome (pSS) patients was investigated by counting the number of argyrophilic nucleolar organizer regions (AgNORs) in epithelial cells constituting the islands. The islands were classified into four groups and evaluated in terms of total area and three discrete zones of the islands. In each pSS group, the mean AgNOR number per total island epithelial cell nucleus was significantly higher than in control ductal epithelial cells. The zonal AgNOR number fluctuated during the process of island formation but became more uniform as the islands developed. Furthermore, statistically significant trends among the four pSS groups were observed in the ratio of T lymphocytes, B lymphocytes and plasma cells surrounding the islands. The results indicated that the islands are highly proliferative once island formation begins and that zonal island cell proliferation may be associated with the inflammatory cells. [source] Current issues in Sjögren's syndromeORAL DISEASES, Issue 3 2002Roland Jonsson Sjögren's syndrome is a chronic autoimmune and rheumatic disorder with prominent sicca complaints from the mucous membranes because of lack of proper exocrine secretions. There is no straightforward and simple diagnostic test for Sjögren's syndrome, although several classification criteria have been designed including several oral diagnostic tests. A new set of classification criteria in a joint effort by research groups in Europe and USA has recently been presented. A large number of autoantibodies have been reported in Sjögren's syndrome where, in some cases, the antibodies are correlated with the extent and severity of disease. The finding of serum autoantibodies directed against the muscarinic M3 receptor is an important advance in understanding the pathogenesis of not only the impaired glandular function but also associated features of autonomic dysfunction in some patients. The treatment of primary Sjögren's syndrome is still mainly symptomatic. [source] Iron and vitamin deficiencies, endocrine and immune status in patients with primary Sjögren's syndromeORAL DISEASES, Issue 3 2001IMC Lundström OBJECTIVES: To study the prevalence of iron and vitamin deficiencies, endocrine disorders and immunological parameters in patients with primary Sjögren's syndrome (1°SS). DESIGN AND SUBJECTS: At the time of the establishment of the diagnosis of 1°SS in 43 consecutive patients, a clinical examination including haematological analyses was performed. The patients' medical records were also reviewed. SETTING: Patients referred for diagnosis to The University Hospital, Linköping, a secondary or tertiary referral hospital serving the middle part of southern Sweden. RESULTS: In total, current or previously treated iron and vitamin deficiencies were registered for 63% of the 1°SS patients (iron 51%, vitamin B12 25%, folate 9%). Current low ferritin was noted in 24%, low iron saturation in 37%, decreased vitamin B12 in 13% and folate in 9%. Thyroid disease was found in a total of 33% and 30% had had autoimmune thyroiditis. Three patients (7%) had verified diabetes mellitus. Erythrocyte sedimentation rate (ESR) was raised in 65% of the patients and 84% had a polyclonal increase of Ig. Rheumatoid factor (RF) was detected in 85%, antinuclear antibody (ANA) in 74%, anti-SS-A in 88% and anti-SS-B in 73% of the patients. CONCLUSION: Iron and vitamin deficiencies and thyroid diseases are common in patients with 1°SS. Since these disorders often are treatable and may affect the patients' distress as well as their immune and exocrine function, an active, recurrent search for deficiencies, endocrine diseases and other frequently recorded disorders is recommended. [source] Periodontal disease in primary Sjögren's syndromeORAL DISEASES, Issue 2 2001M Schiødt Occurrence of periodontal disease in Sjögrens's syndrome (SS) is still controversial. OBJECTIVE: To examine if the risk of gingival and periodontal conditions was increased in SS compared to the general population. MATERIALS AND METHODS: Fifty-seven patients (4 men, 53 women) with primary Sjögren's syndrome (Copenhagen criteria) and an age-matched representative sample of the general population of 80 controls (all women) were examined for gingival and periodontal disease. RESULTS: Gingival bleeding and supra-gingival calculus did not differ among SS patients and controls. Subgingival calculus occurred more often among the younger SS patients than controls, but did not differ among the older SS patients and controls. Periodontal pockets of 4,5 mm as well as pockets >5 mm occurred with similar prevalences among the two groups. Smoking habits did not influence the results. The health status of the gingival and periodontal tissues were thus similar in SS and controls. CONCLUSION: Primary SS is not associated with increased risk of periodontal disease. [source] Reactivity with dichotomous determinants of Ro 60 stratifies autoantibody responses in lupus and primary Sjögren's syndromeARTHRITIS & RHEUMATISM, Issue 5 2010Joanne H. Reed Objective Analysis of B cell determinants of Ro 60 exposed on the surface of apoptotic cells (apotopes) or intracellular epitopes provides insight into the structural forms of the autoantigen that break immune tolerance. This study was initiated to compare anti,Ro 60 responses in systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (SS) against membrane-bound and intracellular forms of Ro 60. Methods The reactivity of autoantibodies from patients with SLE and primary SS to Ro 60 apotopes and epitopes was assessed by multiparameter flow cytometry and solid-phase immunoassay. Anti,Ro 60 IgG was eluted from early apoptotic cells or recombinant Ro 60 immobilized on nitrocellulose, and binding to membrane-bound and intracellular forms of Ro 60 was quantitated by flow cytometry. Results An immunodominant apotope, which was recognized by IgG from a subset of SLE patients with anti-Ro, but not anti-La, autoantibodies, was mapped to a region forming a helix-loop-helix at the apical tip of the Ro 60 molecule. Immobilization of this region to the solid phase exposed an epitope that was recognized by IgG from primary SS and SLE patients whose sera had both anti-Ro and anti-La autoantibodies. Autoantibodies eluted from either the surface of apoptotic cells or the Ro 60 epitope on the solid phase were non,cross-reactive and specifically recognized membrane-bound or cytoplasmic forms of Ro 60. Conclusion This is the first example of a dichotomy of human autoantibody responses against mutually exclusive determinants linked to a single domain of a systemic autoantigen and supports a model in which tolerance is broken by different immunogenic forms of Ro 60. [source] Effectiveness of rituximab treatment in primary Sjögren's syndrome: A randomized, double-blind, placebo-controlled trial,ARTHRITIS & RHEUMATISM, Issue 4 2010J. M. Meijer Objective To study the efficacy and safety of B cell depletion with rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, in patients with primary Sjögren's syndrome (SS) in a double-blind, randomized, placebo-controlled trial. Methods Patients with active primary SS, as determined by the revised American,European Consensus Group criteria, and a rate of stimulated whole saliva secretion of ,0.15 ml/minute were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2:1 (rituximab:placebo). Followup was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables. Results Thirty patients with primary SS (29 female) were randomly allocated to a treatment group. The mean ± SD age of the patients receiving rituximab was 43 ± 11 years and the disease duration was 63 ± 50 months, while patients in the placebo group were age 43 ± 17 years and had a disease duration of 67 ± 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (P = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extraglandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (P = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness,like disease. Conclusion These results indicate that rituximab is an effective and safe treatment strategy for patients with primary SS. [source] Increased expression of interleukin-7 in labial salivary glands of patients with primary Sjögren's syndrome correlates with increased inflammationARTHRITIS & RHEUMATISM, Issue 4 2010A. Bikker Objective To study the expression levels and immunostimulatory capacities of interleukin-7 (IL-7) in primary Sjögren's syndrome. Methods Labial salivary gland (LSG) IL-7 expression was determined by immunohistochemistry, using a quantitative scoring system, in 30 patients with sicca syndrome: 15 patients with primary Sjögren's syndrome (SS) and 15 patients with non-SS sicca syndrome. The correlation of IL-7 expression in LSGs with parameters of local and peripheral disease was studied, and serum and salivary IL-7 levels were determined. Additionally, the effects of IL-7 on cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with primary SS were determined in vitro by Luminex multicytokine assay and compared with the effects in control subjects. Results The expression of IL-7 in LSGs was higher in patients with primary SS compared with that in patients with non-SS sicca syndrome. IL-7 was observed primarily in the vicinity of lymphocytic infiltrates. Salivary IL-7 levels in patients with primary SS were higher than those in control subjects. In all 30 patients with sicca syndrome, IL-7 expression in LSGs correlated with parameters of both local and peripheral disease. Furthermore, IL-7 stimulated T cell,attracting and T cell,differentiating cytokines (monokine induced by interferon-, [IFN,], IFN,-inducible 10-kd protein, IL-12, and IL-15), as well as Th1 (IFN,), Th2 (IL-4), Th17 (IL-17A), proinflammatory (tumor necrosis factor , and IL-1,), and regulatory (IL-10 and IL-13) cytokine production by PBMCs. All of these cytokines were previously shown to be associated with primary SS. The IL-7,induced increase in IL-10 production in patients with primary SS was reduced compared with that in control subjects. Conclusion The correlation between LSG IL-7 expression and (local) disease parameters in primary SS as well as the IL-7,mediated induction of inflammatory cytokines indicate that IL-7 might contribute to the immunopathology of primary SS. [source] Autoantibodies against aquaporin-4 in patients with neuropsychiatric systemic lupus erythematosus and primary Sjögren's syndromeARTHRITIS & RHEUMATISM, Issue 4 2010Klaus-Peter Wandinger MD No abstract is available for this article. [source] Confirmation of an association between rs6822844 at the Il2,Il21 region and multiple autoimmune diseases: Evidence of a general susceptibility locusARTHRITIS & RHEUMATISM, Issue 2 2010Amit K. Maiti Objective Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2,IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in non-European populations, and to perform disease-specific and overall meta-analyses using data from previously published studies. Methods We evaluated case,control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçet's disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies. Results We detected significant associations of rs6822844 with SLE (P = 0.008), type 1 DM (P = 0.014), RA (P = 0.019), and primary SS (P = 0.033) but not with BD (P = 0.34) or CD (P = 0.98). We identified little evidence of population differentiation (FST = 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (Pmeta = 3.61 × 10,6), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) (Pmeta = 3.48 × 10,12), type 1 DM (Pmeta = 5.33 × 10,5), and CD (Pmeta = 5.30 × 10,3). Overall meta-analysis across all autoimmune diseases reinforced association with rs6822844 (23 data sets; Pmeta = 2.61 × 10,25, odds ratio 0.73 [95% confidence interval 0.69,0.78]). Conclusion Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations. [source] Clinical and histologic evidence of salivary gland restoration supports the efficacy of rituximab treatment in Sjögren's syndrome,ARTHRITIS & RHEUMATISM, Issue 11 2009J. Pijpe Objective To assess the effect of rituximab (anti-CD20 antibody) therapy on the (immuno)histopathology of parotid tissue in patients with primary Sjögren's syndrome (SS) and the correlation of histologic findings with the flow rate and composition of parotid saliva. Methods In a phase II study, an incisional parotid biopsy specimen was obtained from 5 patients with primary SS before and 12 weeks after rituximab treatment (4 infusions of 375 mg/m2). The relative amount of parotid parenchyma, lymphocytic infiltrate, and fat, and the presence/quantity of germinal centers and lymphoepithelial duct lesions were evaluated. Immunohistochemical characterization was performed to analyze the B:T cell ratio of the lymphocytic infiltrate (CD20, CD79a, CD3) and cellular proliferation in the acinar parenchyma (by double immunohistologic labeling for cytokeratin 14 and Ki-67). Histologic data were assessed for correlations with the parotid flow rate and saliva composition. Results Four patients showed an increased salivary flow rate and normalization of the initially increased salivary sodium concentration. Following rituximab treatment, the lymphocytic infiltrate was reduced, with a decreased B:T cell ratio and (partial) disappearance of germinal centers. The amount and extent of lymphoepithelial lesions decreased in 3 patients and was completely absent in 2 patients. The initially increased proliferation of acinar parenchyma in response to inflammation was reduced in all patients. Conclusion Sequential parotid biopsy specimens obtained from patients with primary SS before and after rituximab treatment demonstrated histopathologic evidence of reduced glandular inflammation and redifferentiation of lymphoepithelial duct lesions to regular striated ducts as a putative morphologic correlate of increased parotid flow and normalization of the salivary sodium content. These histopathologic findings in a few patients underline the efficacy of B cell depletion and indicate the potential for glandular restoration in SS. [source] The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndromeARTHRITIS & RHEUMATISM, Issue 7 2009Corinne Miceli-Richard Objective Interferon regulatory factor 5 is a transcription factor involved in type I interferon (IFN) secretion. This study was undertaken to investigate whether a 5-bp (CGGGG insertion/deletion) promoter polymorphism is involved in genetic predisposition to primary Sjögren's syndrome (SS) and to assess the functional consequences of this polymorphism. Methods The exploratory cohort consisted of 185 patients with primary SS and 157 healthy controls, and the replication cohort consisted of 200 patients with primary SS and 282 healthy controls. Levels of IRF5 messenger RNA (mRNA) were assessed at baseline and after in vitro infection with reovirus in peripheral blood mononuclear cells (PBMCs) from 30 patients with primary SS and from salivary gland epithelial cells that had been cultured for 4 weeks from patients with primary SS or sicca symptoms. Results Carriage of the IRF5 4R CGGGG allele was associated with a greatly increased risk of primary SS in both cohorts (odds ratio 2.00 [95% confidence interval 1.5,2.7], P = 6.6 × 10,6). The CGGGG insertion/deletion polymorphism alone was sufficient to explain the association of primary SS with IRF5. The level of IRF5 mRNA in PBMCs depended significantly on genotype (P = 0.002) and was correlated with the levels of mRNA for the IFN-induced genes MX1 and IFITM1. Cultured salivary gland epithelial cells from patients carrying the 4R CGGGG IRF5 allele showed a high level of IRF5 mRNA (P = 0.04), which was amplified after reovirus infection (P = 0.026). Conclusion Our findings indicate an association of the CGGGG insertion/deletion polymorphism of the IRF5 promoter with primary SS. Patients carrying the 4R CGGGG IRF5 allele had a high level of mRNA for IRF5 in PBMCs and salivary gland epithelial cells, mainly after in vitro viral infection. Patients with high levels of mRNA for IRF5 also had high levels of mRNA for type I IFN,induced genes in PBMCs. [source] Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cellsARTHRITIS & RHEUMATISM, Issue 4 2006L. J. Dawson Objective Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. Methods Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+ -dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. Results IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by ,50%. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R,positive serum had no effect on Ca2+ -dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. Conclusion These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research. [source] Dissemination of a Sjögren's syndrome,associated extranodal marginal-zone B cell lymphoma: Circulating lymphoma cells and invariant mutation pattern of nodal Ig heavy- and light-chain variable-region gene rearrangementsARTHRITIS & RHEUMATISM, Issue 1 2006A. Hansen Objective Both the genesis and outgrowth of extranodal marginal-zone B cell lymphomas (MZLs) of the mucosa-associated lymphoid tissue (MALT) type are generally thought to represent antigen-driven processes. We undertook this study to analyze lymphoma progression and dissemination outside of the MALT-type lesions. Methods Histopathologic and Ig heavy- and light-chain variable-region gene (VH/L) analyses were performed in sequential tissue samples from a patient with primary Sjögren's syndrome (SS) with glandular (parotid) manifestations and subsequent nodal dissemination of a low-grade MZL. Results This MZL expressed a CD20+,CD27+,sIgM/,+,IgD,,CD5,,CD10,,Bcl-6,,CD23,,p53,,p21,,MDM2, phenotype and mutated VH1,69/D2,21/JH4,,V,A27/J,2 Ig rearrangements. Notably, circulating lymphoma cells from the parotid glands occurred transiently in the patient's blood, as detected by single-cell polymerase chain reaction. In addition, 2 minor B cell clones (clones 2 and 3, with VH3,07/D3,22/JH3b,V,3L/J,2/3 and VH3,64/D3,03/JH2,V,A19/J,2 rearrangements, respectively) were also detected in the parotid glands and blood, and 1 of these (clone 2) was also detected in the lymph nodes. Ig VH/L analyses revealed ongoing (antigen-driven) mutations of the glandular lymphoma rearrangements, but an invariant mutation pattern of their nodal counterparts. Conclusion These data indicate coexpansion and transient (re)circulation of the lymphoma clone and 2 additional glandular B cell clones in a primary SS,associated extranodal MZL. Combined histologic and molecular features of the nodal lymphoma subclone reflect a process of "follicular colonization" that eventually froze the mutation machinery after accumulation of additional (antigen-driven) Ig VH/L mutations. [source] Aquaporins in primary Sjögren's syndrome: Comment on the articles by Steinfeld et alARTHRITIS & RHEUMATISM, Issue 4 2003Sally A. Waterman PhD No abstract is available for this article. [source] Post-translational modifications of the major linear epitope 169,190aa of Ro60 kDa autoantigen alter the autoantibody bindingCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2006A. G. Terzoglou Summary Ro60 kDa is a member of the Ro/LaRNP ribonucleoprotein complex and its major linear B cell epitope, corresponding to the region 169,190aa, has been found to be the initial target of the autoimmune response in patients with systemic lupus erythematosus. This sequence contains one serine and two arginine amino acid residues, which can potentially be modified post-translationally by phosphorylation or citrullination, respectively. The aim of this study was to develop an immunoassay for anti-Ro60 kDa epitope antibody detection and to investigate the changes in the antigenicity of the Ro60 kDa epitope when it is post-translationally modified, by either citrullination or phosphorylation. Peptide analogues corresponding to the unmodified form of the epitope, its phosphorylated form, and a form with both arginine residues citrullinated were synthesized. The peptide coating conditions were investigated and it was found that the use of highly hydrophilic surfaces increase the efficiency of the coating, as well as the sensitivity of the method for anti-peptide antibody detection. All peptides were tested by the optimized enzyme-linked immunosorbent assay (ELISA) against 119 sera from patients with primary Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis with anti-Ro/SSA reactivity, 20 sera from patients with systemic diseases without anti-Ro/SSA immune reactivity, as well as against 65 sera from normal individuals. A large proportion of the tested sera reacted against all three peptide analogues, although with a preference for the unmodified form of the epitope. In conclusion, post-translational modifications of the major Ro60 kDa B cell epitope can alter the autoantibody binding. [source] | ||||||||||