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ID PMID Title PublicationDate abstract
19405951 RANKL increases the level of Mcl-1 in osteoclasts and reduces bisphosphonate-induced osteo 2009 INTRODUCTION: Bisphosphonates are the most widely used class of drug for inhibiting osteoclast-mediated bone loss, but their effectiveness at preventing joint destruction in rheumatoid arthritis has generally been disappointing. We examined whether the ability of bisphosphonates to induce osteoclast apoptosis and inhibit bone resorption in vitro is influenced by the cytokine receptor activator of nuclear factor-kappa B ligand (RANKL), an important mediator of inflammation-induced bone loss. METHODS: Rabbit osteoclasts were treated with the bisphosphonates clodronate or alendronate for up to 48 hours in the absence or presence of RANKL. Changes in cell morphology and induction of apoptosis were examined by scanning electron microscopy, whilst resorptive activity was determined by measuring the area of resorption cavities. Changes in the level of anti-apoptotic proteins, including Mcl-1, Bcl-2, and Bcl-x>L, were determined in rabbit osteoclasts and in cytokine-starved mouse osteoclasts by Western blotting. RESULTS: RANKL significantly attenuated the ability of both clodronate and alendronate to induce osteoclast apoptosis and inhibit bone resorption. Treatment of rabbit osteoclasts with RANKL was associated with an increase in the anti-apoptotic protein Mcl-1 but not Bcl-2. A role for Mcl-1 in osteoclast survival was suggested using osteoclasts generated from mouse bone marrow macrophages in the presence of RANKL + macrophage colony-stimulating factor (M-CSF) since cytokine deprivation of mouse osteoclasts caused a rapid loss of Mcl-1 (but not Bcl-2 or Bcl-xL), which preceded the biochemical and morphological changes associated with apoptosis. Loss of Mcl-1 from mouse osteoclasts could be prevented by factors known to promote osteoclast survival (RANKL, M-CSF, tumour necrosis factor-alpha [TNF-alpha], or lipopolysaccharide [LPS]). CONCLUSIONS: RANKL protects osteoclasts from the apoptosis-inducing and anti-resorptive effects of bisphosphonates in vitro. The ability of RANKL (and other pro-inflammatory factors such as TNF-alpha and LPS) to increase the level of Mcl-1 in osteoclasts may explain the lack of effectiveness of some bisphosphonates in preventing inflammation-induced bone loss.
19226472 In vitro model for the analysis of synovial fibroblast-mediated degradation of intact cart 2009 INTRODUCTION: Activated synovial fibroblasts are thought to play a major role in the destruction of cartilage in chronic, inflammatory rheumatoid arthritis (RA). However, profound insight into the pathogenic mechanisms and the impact of synovial fibroblasts in the initial early stages of cartilage destruction is limited. Hence, the present study sought to establish a standardised in vitro model for early cartilage destruction with native, intact cartilage in order to analyse the matrix-degrading capacity of synovial fibroblasts and their influence on cartilage metabolism. METHODS: A standardised model was established by co-culturing bovine cartilage discs with early-passage human synovial fibroblasts for 14 days under continuous stimulation with TNF-alpha, IL-1beta or a combination of TNF-alpha/IL-1beta. To assess cartilage destruction, the co-cultures were analysed by histology, immunohistochemistry, electron microscopy and laser scanning microscopy. In addition, content and/or neosynthesis of the matrix molecules cartilage oligomeric matrix protein (COMP) and collagen II was quantified. Finally, gene and protein expression of matrix-degrading enzymes and pro-inflammatory cytokines were profiled in both synovial fibroblasts and cartilage. RESULTS: Histological and immunohistological analyses revealed that non-stimulated synovial fibroblasts are capable of demasking/degrading cartilage matrix components (proteoglycans, COMP, collagen) and stimulated synovial fibroblasts clearly augment chondrocyte-mediated, cytokine-induced cartilage destruction. Cytokine stimulation led to an upregulation of tissue-degrading enzymes (aggrecanases I/II, matrix-metalloproteinase (MMP) 1, MMP-3) and pro-inflammatory cytokines (IL-6 and IL-8) in both cartilage and synovial fibroblasts. In general, the activity of tissue-degrading enzymes was consistently higher in co-cultures with synovial fibroblasts than in cartilage monocultures. In addition, stimulated synovial fibroblasts suppressed the synthesis of collagen type II mRNA in cartilage. CONCLUSIONS: The results demonstrate for the first time the capacity of synovial fibroblasts to degrade intact cartilage matrix by disturbing the homeostasis of cartilage via the production of catabolic enzymes/pro-inflammatory cytokines and suppression of anabolic matrix synthesis (i.e., collagen type II). This new in vitro model may closely reflect the complex process of early stage in vivo destruction in RA and help to elucidate the role of synovial fibroblasts and other synovial cells in this process, and the molecular mechanisms involved in cartilage degradation.
21068096 Efficacy of a single ultrasound-guided injection for the treatment of hip osteoarthritis. 2011 Jan BACKGROUND: Intra-articular injection is effective for osteoarthritis, but the best single injection strategy is not known, nor are there established predictors of response. The objectives of this study were to assess and predict response to a single ultrasound-guided injection in moderate to severe hip osteoarthritis. METHODS: 77 hip osteoarthritis patients entered a prospective, randomised controlled trial, randomised to one of four groups: standard care (no injection); normal saline; non-animal stabilised hyaluronic acid (durolane) or methylprednisolone acetate (depomedrone). MAIN OUTCOME MEASURES: Numerical rating scale (NRS 0-10) 'worst pain', Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain/function. Potential predictors of response (including radiographic severity, ultrasound synovitis and baseline symptom severity) were examined using univariate logistic regression analysis and Fisher's exact test. RESULTS: NRS pain, WOMAC pain and function improved significantly for the steroid arm alone. Effect sizes at week 1 were striking: NRS pain 1.5, WOMAC pain 1.9 and WOMAC function 1.3. Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society responder criteria identified 22 responders (intention-to-treat): steroid 14 (74%; number needed to treat, two); saline, four (21%); durolane, two (11%); and no injection, two (10%; χ(2) test between groups, p<0.001). Corticosteroid arm response was maintained over 8 weeks (summary measures analysis of variance, p<0.002 for NRS pain). Synovitis was a significant predictor of response at weeks 4 and 8 (p<0.05, Fisher's exact test; week 4 OR 16.7, 95% CI 1.4 to 204). CONCLUSIONS: Ultrasound-guided corticosteroid injections are highly efficacious; furthermore synovitis on ultrasound is a biomarker of response to injection.
20435236 Strategies to optimize treatment with NSAIDs in patients at risk for gastrointestinal and 2010 Apr BACKGROUND: NSAIDs, including cyclooxygenase (COX)-2 inhibitors, are among the most widely prescribed medications worldwide. However, NSAIDs have been associated with gastrointestinal (GI) toxicity. The cardiovascular (CV) toxicity associated with COX-2 inhibitors and some other NSAIDs further complicates the choice of therapy. OBJECTIVE: The aim of this commentary was to appraise current NSAID treatment strategies and provide clinicians with guidance on the GI and CV risks of these strategies and choosing an appropriate treatment in individual patients. METHODS: A literature search of PubMed was conducted (1989-August 2009) to gather relevant studies, meta-analyses, reviews, and treatment guidelines using the following terms, either alone or in combination: NSAID, gastrointestinal, cardiovascular, toxicity, gastroprotection, proton pump inhibitor, COX-2 inhibitor, aspirin, fixed-dose combination, and adherence. RESULTS: Based on the data from the literature search, gastroprotective strategies (eg, proton pump inhibitors [PPIs]) are underused in patients at risk for NSAIDrelated GI complications, including in those patients most at risk. Risk factors for GI toxicity with NSAID use include high NSAID dose, a history of NSAID-associated GI adverse events or the presence of upper GI symptoms, advanced age, corticosteroid use, concurrent aspirin use, and certain comorbidities (eg, rheumatoid arthritis). Risk factors for CV toxicity with NSAID use include established CV disease or an estimated 10-year CV risk >20%. Findings from randomized controlled trials have suggested that, in patients with an increased risk for GI complications, the use of a nonselective NSAID with a PPI may be at least as effective as the use of a COX-2 selective inhibitor in preventing the recurrence of ulcer complications. In patients with a high GI risk and a moderate CV risk, the use of a COX-2 inhibitor with a PPI may be appropriate. CONCLUSIONS: The choice of NSAID should be tailored to the GI and CV risks in the patient. The risk profile can be affected by numerous factors, including NSAID dosing and concurrent aspirin use. Thus, individualized risk stratification should be the clinician's primary consideration when selecting treatment.
21187010 Surprising negative association between IgG1 allotype disparity and anti-adalimumab format 2010 INTRODUCTION: The human monoclonal antibody adalimumab is known to induce an anti-globulin response in some adalimumab-treated patients. Antibodies against adalimumab (AAA) are associated with non-response to treatment. Immunoglobulins, such as adalimumab, carry allotypes which represent slight differences in the amino acid sequences of the constant chains of an IgG molecule. Immunoglobulins with particular IgG (Gm) allotypes are racially distributed and could be immunogenic for individuals who do not express these allotypes. Therefore, we investigated whether a mismatch in IgG allotypes between adalimumab and IgG in adalimumab-treated patients is associated with the development of AAA. METHODS: This cohort study consisted of 250 adalimumab-treated rheumatoid arthritis (RA) patients. IgG allotypes were determined for adalimumab and for all patients. Anti-idiotype antibodies against adalimumab were measured with a regular radio immunoassay (RIA), and a newly developed bridging enzyme linked immunosorbent assay (ELISA) was used to measure anti-allotype antibodies against adalimumab. The association between AAA and the G1m3 and the G1m17 allotypes was determined. For differences between groups we used the independent or paired samples t-test, Mann-Whitney test or Chi square/Fisher's exact test as appropriate. To investigate the influence of confounders on the presence or absence of AAA a multiple logistic regression-analysis was used. RESULTS: Adalimumab carries the G1m17 allotype. No anti-allotype antibodies against adalimumab were detected. Thirty-nine out of 249 patients had anti-idiotype antibodies against adalimumab (16%). IgG allotypes of RA patients were associated with the frequency of AAA: patients homozygous for G1m17 had the highest frequency of AAA (41%), patients homozygous for G1m3 the lowest frequency (10%), and heterozygous patients' AAA frequency was 14% (P = 0.0001). CONCLUSIONS: An allotype mismatch between adalimumab and IgG in adalimumab-treated patients did not lead to a higher frequency of AAA. On the contrary, patients who carried the same IgG allotype as present on the adalimumab IgG molecule, had the highest frequency of anti-adalimumab antibodies compared to patients whose IgG allotype differed from adalimumab. This suggests that the allotype of adalimumab may not be highly immunogenic. Furthermore, patients carrying the G1m17-allotype might be more prone to antibody responses.
20131244 Mediation of nonerosive arthritis in a mouse model of lupus by interferon-alpha-stimulated 2010 Apr OBJECTIVE: In contrast to rheumatoid arthritis (RA), the joint inflammation referred to as Jaccoud's arthritis that occurs in systemic lupus erythematosus (SLE) is nonerosive. Although the mechanism responsible is unknown, the antiosteoclastogenic cytokine interferon-alpha (IFNalpha), whose transcriptome is present in SLE monocytes, may be responsible. This study was undertaken to examine the effects of IFNalpha and lupus on osteoclasts and erosion in the (NZB x NZW)F(1) mouse model of SLE with K/BxN serum-induced arthritis. METHODS: Systemic IFNalpha levels in (NZB x NZW)F(1) mice were elevated by administration of AdIFNalpha. SLE disease was marked by anti-double-stranded DNA (anti-dsDNA) antibody titer and proteinuria, and Ifi202 and Mx1 expression represented the IFNalpha transcriptome. Microfocal computed tomography was used to evaluate bone erosions. Flow cytometry for CD11b and CD11c was used to evaluate the frequency of circulating osteoclast precursors (OCPs) and myeloid dendritic cells (DCs) in blood. RESULTS: Administration of AdIFNalpha to (NZB x NZW)F(1) mice induced osteopetrosis. (NZB x NZW)F(1) mice without autoimmune disease were fully susceptible to focal erosions in the setting of serum-induced arthritis. However, (NZB x NZW)F(1) mice with high anti-dsDNA antibody titers and the IFNalpha transcriptome were protected against bone erosions. AdIFNalpha pretreatment of NZW mice before K/BxN serum administration also resulted in protection against bone erosion (r(2) = 0.4720, P < 0.01), which was associated with a decrease in the frequency of circulating CD11b+CD11c- OCPs and a concomitant increase in the percentage of CD11b+CD11c+ cells (r(2) = 0.6330, P < 0.05), which are phenotypic of myeloid DCs. CONCLUSION: These findings suggest that IFNalpha in SLE shifts monocyte development toward myeloid DCs at the expense of osteoclastogenesis, thereby resulting in decreased bone erosion.
20623943 Methodological studies of orofacial aesthetics, orofacial function and oral health-related 2010 Among researchers and in the general population, awareness of the impact of health and health care on the quality of human life is increasing. An important medical and dental research area that addresses this issue is health measurement scales and psychometrics. Such instruments have numerous uses, such as to screen psychosocial aspects in individual patient care, assess perceived health or disease in population surveys, measure outcome in clinical trials, and gather data for cost-utility analyses. Assessing and improving oral health-related quality of life (OHRQoL), orofacial function, and orofacial aesthetics are three major goals in dental care. The overall aim of this thesis was to describe how three assessment tools were developed-using current scientific methodology-to measure these concepts in the Swedish culture. This thesis comprises five studies. In article I, recommended guidelines were used to translate the Oral Health Impact Profile (OHIP), an OHRQoL instrument, into Swedish. A group of 145 consecutive patients comprising five diagnostic groups participated in reliability and validity evaluations of OHIP-S, the Swedish OHIP version. Data supported excellent reliability and acceptable validity. In article II, the Jaw Functional Limitation Scale (JFLS) was developed, and reliability and validity were assessed in 132 consecutive patients from five diagnostic groups. An expert panel identified 52 functional limitation items. Rasch methodology reduced the number of items to 20 and assessed model fit. Three constructs were identified-mastication, vertical jaw mobility, and emotional and verbal expression-and good reliability and validity were found. The JFLS-20 is an organ-specific instrument for assessing functional status of the masticatory system while the shorter JFLS-8 assesses global functional limitation. Article III describes development of the Orofacial Aesthetic Scale (OAS), in particular its conceptual framework, measurement model, and method of questionnaire item generation. Interview and questionnaire data from 17 prosthodontic patients created an initial 28-item pool. After focus group reduction and pilot testing, a final 8-item instrument was generated. Exploratory factor analysis investigated OAS dimensionality, and item analysis was performed in 119 subjects. Forward and backward translations and reconciliation produced an English version of the instrument. Exploratory factor analysis supported OAS unidimensionality. In article IV, psychometric properties of the OAS were evaluated in 119 patients from four groups: aesthetically compromised, functional disability, and two age- and gender-matched control groups. Various methods of testing reliability and validity supported good score reliability and validity. In article V, the OAS was part of a mail survey to a national sample of 3000 persons and normative values were derived. Survey respondents totaled 1406, and missing data were analyzed. There was a significant difference in OAS for age, gender, self-reported oral health, and self-reported general health status groups. Subjects who reported extreme satisfaction (item score of 10) varied between 17% for "color of the teeth" and 30% for "appearance of face" and "profile". The OHIP, JFLS, and OAS are considered well suited for use in research and as clinical outcome measures in patients with functional and aesthetic concerns, such as prosthodontic patients.
20556729 Treatment of postsurgical pyoderma gangrenosum with a high-potency topical steroid. 2010 Jun Pyoderma gangrenosum is a rare disease characterized by chronic, nonhealing, noninfectious ulcers that can become exacerbated by trauma or manipulation, including surgical treatment. We describe the case of a 30-year-old woman who presented with a large ulcer at the site of an excisional cervical lymph node biopsy; she also had a smaller ulcer at the site of an earlier biopsy that had been previously well healed. The ulcers persisted despite local care, and the larger ulcer was exacerbated by surgical debridement. Histopathology revealed the presence of intense neutrophilic infiltrates with sterile microabscesses-a finding consistent with pyoderma gangrenosum. With 9 weeks of treatment with a high-potency topical steroid, both ulcers gradually healed.
19928688 [A 25-year-old woman with primary Sjögren syndrome who developed optic neuritis and encep 2009 Sep We report a 25-year-old woman who developed optic neuritis and encephalomyelitis following primary Sjögren's syndrome (SjS). SjS began with Sicca syndrome when she was 8 years old, and neurological involvement subsequently developed at the age of 10 with right hemiparesis. Based on clinical symptoms, serum positive for SS-A and SS-B antibodies and pathological findings of the salivary gland, we confirmed a diagnosis of primary SjS. Magnetic resonance imaging (MRI) revealed multiple lesions in the brain and the spinal cord. These led diagnosis of SjS with central nervous system involvement (CNS-SjS) and initiated steroid therapy. At the age of 25, the patient developed left visual loss due to retrobulbar optic neuritis, left lower quadrantic hemianopia, numbness of the right upper limb, and weakness of both legs. Laboratory examinations showed that her serum was positive for SS-A and SS-B antibodies, and her cerebrospinal fluid had elevated levels of total protein and myelin basic protein without pleocytosis. Her brain MRI revealed multiple T2-high-intensity lesions bilaterally in the frontal subcortical white matter and in the right temporo-parietal subcortical white matter. The lesions included a tumefactive lesion and an active lesion. Additionally, the spinal MRI revealed a severely atrophied spinal cord with T2-high-intensity lesions extending longitudinally and centromedullary in the spinal cord. These findings led us to examine the patient's serum for anti-aquaporin (AQP) 4 antibodies and the test confirmed that her serum was positive for the antibodies. After administering intravenous high-dose methylprednisolone (1,000 mg/day for 3 days), her symptoms markedly improved with normalization of myelin basic protein. However, her serum remained positive for AQP 4 antibodies. We think that the patient's diagnosis belongs to the neuromyelitis optica (NMO) spectrum disorders associated with autoimmune disorders. This is a rare case in that the initial presentation was SjS and occurred at a very young age.
19430860 MALT lymphoma of the thymus with Sjögren's syndrome: biphasic changes in serological abno 2009 Jun Thymic mucosa-associated lymphoid tissue (MALT) lymphoma shows distinct immunological characteristics, such as the expression of the IgA isotype, the frequent presence of immunoglobulin abnormalities, and a strong association with autoimmune disease, especially Sjögren's syndrome (SjS). We report a case of thymic MALT lymphoma, who exhibited biphasic changes in her clinical characteristics during the 4-year observation period after thymectomy. A 71-year-old woman was admitted because of suspected SjS. A diagnosis of primary thymic MALT lymphoma was made, and SjS was confirmed. Serological abnormalities such as polyclonal hypergammaglobulinemia, IgA M protein, and elevated levels of rheumatoid factor were noted. These abnormalities improved rapidly after the thymectomy, but did not completely disappear. Interestingly, the remaining abnormalities, which can be ascribed to the proliferation of B cells throughout the body under the influence of SjS, have been improving slowly but steadily during the 4-year observation period. It is suspected that the removal of the tumor by thymectomy has more or less normalized the immunological environment and alleviated the SjS disease activity.
19429907 A role for nitric oxide-mediated glandular hypofunction in a non-apoptotic model for Sjogr 2009 Jul OBJECTIVE: To investigate a role for the inflammatory mediator, nitric oxide (NO) in SS, an autoimmune condition characterized by salivary and lacrimal gland hypofunction resulting from failure of acinar cells to secrete. METHODS: FURA-2 microfluorimetry was used to measure agonist-evoked changes of [Ca(2+)](i) in isolated mouse and human salivary acinar cells following exposure to NO donors. RESULTS: NO had a biphasic effect on salivary acinar function. Acute exposure to NO (2 min) caused a cyclic guanosine monophosphate (GMP)-dependent, 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-sensitive increase in the Ca(2+) signal elicited in response to acetylcholine (ACh) stimulation, consistent with stimulation of ryanodine receptors by cyclic adenosine diphosphate ribose. Prolonged exposure to NO (>40 min) significantly reduced the ACh-evoked Ca(2+) signal by a mechanism independent of cyclic GMP. We found no differences between the responses of human and mouse acinar cells. CONCLUSION: Our data show that chronic exposure to NO, which is known to be elevated in SS, could have a role in salivary gland hypofunction. We note a similarity in the response to stimulation of salivary acinar exposed to NO and that which we have previously reported in salivary acinar cells isolated from patients with SS. We speculate that NO-mediated nitrosylation of one or more elements of the signal transduction pathway could underlie down-regulation of salivary function in SS.
19200376 Impaired vascular responses to parasympathetic nerve stimulation and muscarinic receptor a 2009 INTRODUCTION: Decreased vascular responses to salivary gland stimulation are observed in Sjögren's syndrome patients. We investigate whether impaired vascular responses to parasympathetic stimulation and muscarinic receptor activation in salivary glands parallels hyposalivation in an experimental model for Sjögren's syndrome. METHODS: Blood flow responses in the salivary glands were measured by laser Doppler flowmeter. Muscarinic receptor activation was followed by saliva secretion measurements. Nitric oxide synthesis-mediated blood flow responses were studied after administration of a nitric oxide synthase inhibitor. Glandular autonomic nerves and muscarinic 3 receptor distributions were also investigated. RESULTS: Maximal blood flow responses to parasympathetic stimulation and muscarinic receptor activation were significantly lower in nonobese diabetic (NOD) mice compared with BALB/c mice, coinciding with impaired saliva secretion in nonobese diabetic mice (P < 0.005). Nitric oxide synthase inhibitor had less effect on blood flow responses after parasympathetic nerve stimulation in nonobese diabetic mice compared with BALB/c mice (P < 0.02). In nonobese diabetic mice, salivary gland parasympathetic nerve fibres were absent in areas of focal infiltrates. Muscarinic 3 receptor might be localized in the blood vessel walls of salivary glands. CONCLUSIONS: Impaired vasodilatation in response to parasympathetic nerve stimulation and muscarinic receptor activation may contribute to hyposalivation observed in nonobese diabetic mice. Reduced nitric oxide signalling after parasympathetic nerve stimulation may contribute in part to the impaired blood flow responses. The possibility of muscarinic 3 receptor in the vasculature supports the notion that muscarinic 3 receptor autoantibodies present in nonobese diabetic mice might impair the fluid transport required for salivation. Parasympathetic nerves were absent in areas of focal infiltrates, whereas a normal distribution was found within glandular epithelium. TRIAL REGISTRATION: The trial registration number for the present study is 79-04/BBB, given by the Norwegian State Commission for Laboratory Animals.
20462524 Functional role of M3 muscarinic acetylcholine receptor (M3R) reactive T cells and anti-M3 2010 Jul Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into the lachrymal and salivary glands, leading to dry eyes and mouth. Infiltration is also found in the kidneys, lungs, thyroid, and liver. Immunohistochemical studies have shown that most infiltrating lymphocytes are CD4(+) T cell receptor (TCR) alphabeta T cells. The antigen specificity of T cells is decided by TCR expressed on T cells. The usage of TCRalpha and TCRbeta genes have been examined by immunological and molecular biological methods. Autoantigens recognized by T cells infiltrating into salivary glands have been analyzed and several candidates for autoantigens have been clarified. In the present study, we focused on M3 muscarinic acetylcholine receptor (M3R) as a salivary gland-specific autoantigen and clarified T cell epitopes and B cell epitopes on M3R. The functions of anti-M3R antibodies and M3R reactive T cells were also carried out. To clarify whether M3R reactive T cells play a crucial role in the generation of autoimmune sialoadenitis, splenic CD3+T cells form M3R(-/-) mice immunized by M3R peptides were transferred into Rag-1(-/-) mice and sialoadenitis analyzed. The functional role of M3R reactive T cells in the generation of SS was also discussed.
19101478 Association between IFN-alpha and primary Sjogren's syndrome. 2009 Jan OBJECTIVE: To determine the level of IFN-alpha in labial salivary glands, plasma, and peripheral blood cells from patients with primary Sjogren's syndrome (pSS). METHODS: Labial salivary gland biopsy specimens, plasma, and peripheral blood cells from patients with pSS were investigated. The IFN-alpha-positive cells, measurable IFN-alpha level, and IFN-alpha gene mRNA level were determined by using immunohistochemistry, ELISA, and real-time PCR, respectively. Statistical analysis was performed by Student t test or Fisher's exact test. RESULTS: About 60% of patients (22/37) with pSS had significantly higher scores of IFN-alpha-positive cells in labial gland biopsy and most IFN-alpha-positive cells were localized predominantly in the lymphocytes and ductal epithelial cells. But in 3 of the control samples (3/24), the IFN-alpha-positive cells existed only in the ductal epithelial cells with lower scores. Forty-three percents of the patients with pSS were found with detectable IFN-alpha concentration in plasma (> or = 12.5 pg/mL), and their concentration was higher than that of control group. Furthermore, the IFN-alpha mRNA levels in peripheral blood cells were up-regulated in the patients with pSS. CONCLUSION: No matter in labial salivary glands or hematoplasma, or peripheral blood cells, IFN-alpha expression levels are up-regulated in patients with primary Sjogren's syndrome.
18939961 Different proteomic protein patterns in saliva of Sjögren's syndrome patients. 2009 Jan OBJECTIVE: To investigate the salivary protein profile in patients with Sjögren's syndrome (SS), and healthy control subjects. MATERIALS AND METHODS: Unstimulated whole saliva samples were collected from 16 age-matched females; eight healthy subjects and eight patients diagnosed with SS (six primary SS, one incomplete SS and one primary SS associated with B cell lymphoma). Proteins were extracted and separated individually by 2D sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Selected protein spots of interest were analysed by electrospray ionization--tandem mass spectrometry. Obtained data were searched against the Swiss-Prot and NCBI non-redundant protein databases using Mascot software. RESULTS: Two groups of patterns of protein expression were observed in the eight SS patients: a major group (six patients) with significant expression differences from the healthy subjects and the second group (two patients) with a pattern similar to the eight healthy subjects. CONCLUSION: In this preliminary study, protein expression differences were found between SS patients and healthy subjects. Individual analysis of SS patients exhibited two patterns of protein expression with no direct relation to the clinical, serological or histological severity of disease. This study emphasizes the difficulty of the present proteomic knowledge to diagnose and monitor the sequel of SS development.
19512904 Acidic mammalian chitinase in dry eye conditions. 2009 Jul PURPOSE: An acidic mammalian chitinase (AMCase) seems to be implicated in allergic asthma and allergic ocular pathologies. The aim of this work was to investigate the role of AMCase during Sjögren's Syndrome (SS) and Meibomian Gland Dysfunction (MGD) dry eye diseases. METHODS: Six patients with MGD dry eye (20-58 years, median 40) and six patients with dry eye associated to SS (32-60 years, median 47) were enrolled in this study. AMCase activity was measured in tears and AMCase mRNA expression was evaluated by real-time polymerase chain reaction from RNA extracted from epithelial cells of the conjunctiva. Six healthy adult subjects of the same age (34-44 years, median 39) were also studied as the control group. RESULTS: AMCase activity was significantly increased in patients affected by MGD dry eye (18.54 +/- 1.5 nmol/ml/h) and SS dry eye (8.94 +/- 1.0 nmol/ml/h) respectively, compared to healthy controls (1.6 +/- 0.2 nmol/ml/h). AMCase activity was higher in the tears of subjects with MGD dry eye (P < 0.001). AMCase mRNA was detected in conjunctival epithelial cells and the expression was significantly higher in MGD dry eye than SS dry eye. A significant correlation between AMCase activity in the tears and mRNA in conjunctival epithelial cells was found. CONCLUSION: AMCase may be an important marker in the pathogenesis of dry eye, suggesting the potential role of AMCase as a therapeutic target in these frequent pathologies.
20506370 Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onse 2010 Aug OBJECTIVE: To evaluate the efficacy of antiinflammatory agents, steroids, immunosuppressants, and biologic agents in patients with adult-onset Still's disease (AOSD) who have either chronic articular disease or nonchronic disease. METHODS: Forty-five patients with AOSD were seen and followed up for at least 2 years at our institution, from 1991 to 2008. The majority of patients were treated with several therapeutic regimens; a total of 152 efficacy trials were administered. Data regarding the type of medication, the dosage used, and the outcome of these trials were collected and analyzed. RESULTS: Our data showed that the efficacy of monotherapy with a nonsteroidal antiinflammatory drug was very low (16%) and confirmed good efficacy of steroid therapy (63%), particularly in patients without chronic articular disease (78%). Patients whose disease did not respond to steroid therapy at the time of disease onset were at risk of the subsequent development of chronic arthritis. Disease-modifying antirheumatic drug (DMARD) monotherapy was successful in controlling steroid-resistant or steroid-dependent disease in 60% of patients. Methotrexate and cyclosporine showed the best response rates. The combination of high-dose steroids and cyclosporine was administered to successfully control some acute life-threatening complications. Only 6 patients had disease that was both steroid resistant and DMARD resistant. Treatment with biologic agents eventually led to satisfactory control of disease manifestations in 5 (83%) of these 6 patients. CONCLUSION: Steroids were less effective in patients with chronic articular disease than in those with nonchronic disease. The administration of DMARDs early after disease onset could be beneficial in patients with steroid-resistant disease who are at risk of the development of chronic articular disease. Biologic agents proved to be highly effective in both steroid-resistant and DMARD-resistant AOSD.
21159832 Cortisol during the day in patients with systemic lupus erythematosus or primary Sjogren's 2011 Feb OBJECTIVE: To compare the level and change of cortisol during the day of patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) with low and high erythrocyte sedimentation rate (ESR). METHODS: Saliva was collected in the real-life environment of 21 women with SLE, 16 women with pSS, and 30 age-matched healthy women at 9 fixed timepoints during 2 consecutive days. Repeated measures ANOVA was performed to examine whether cortisol levels during the day were different for the patients with low ESR (≤ 20 mm/h) versus those with high ESR (> 20 mm/h). RESULTS: The groups with low and high ESR showed the characteristic change of cortisol during the day (time-of-day effect, F = 124.9, p < 0.001). The cortisol awakening level was lower for patients with high ESR than for patients with low ESR (group*time effect, F = 3.1, p = 0.02). CONCLUSION: The cortisol awakening level differs for patients with low and high ESR, which indicates the usefulness of further studies of hypothalamic-pituitary-adrenal axis dynamics in patients with SLE and pSS.
20685081 Salivary epithelial cells from Sjogren's syndrome patients are highly sensitive to anoikis 2010 Nov In certain types of cells, Toll-like receptor-3 (TLR-3) ligation by viral dsRNA induces apoptotic death, likely engaged into the elimination of virus-infected cells. We have previously shown that TLR-3 ligation on cultured non-neoplastic salivary gland epithelial cells (SGEC) with polyI:C (a synthetic analogue of viral dsRNA) results in the induction of surface immunoactive molecules, however, the pro-apoptotic effect of such signaling has not been addressed. In this study, polyI:C-treated SGEC were found to suffer severe detachment from substratum and subsequent apoptosis, a phenomenon suggestive of anoikis or anoikia (detachment-induced apoptosis). PolyI:C-induced anoikis in SGEC was associated with the upregulation of the pro-apoptotic Bmf, BimEL and Bax and the down-regulation of the pro-survival Bcl-2 (real-time PCR analyses). Finally, the comparative analysis of SGEC lines derived from primary Sjogren's syndrome (SS) patients (SS-SGEC) and non-SS controls had revealed that SS-SGEC are particularly susceptible to TLR-3-induced anoikis, as it was triggered by suboptimally low concentrations of polyI:C. This finding correlated with significantly higher constitutive surface TLR-3 expression by SS-SGEC, a feature indicative of their intrinsic activation status. In conclusion, TLR-3 signaling pathway in the salivary epithelium appears to extend beyond the induction of innate immune responses and to involve the activation of programmed-cell death via anoikis. In the same context, the increased vulnerability of SS-SGEC to the injurious effect of TLR-3 ligation is likely associated with the intrinsic activation processes that apparently operate in the epithelia of SS patients, and a feature of key pathogenetic importance for the disorder.
20015272 Decrease of blood dendritic cells and increase of tissue-infiltrating dendritic cells are 2010 Mar We have demonstrated previously that, in primary Sjögren's syndrome (SS), immature myeloid dendritic cells (DCs) are decreased in blood and mature myeloid DCs are accumulated in salivary glands, suggesting recruitment of the myeloid DCs from blood to salivary glands. To verify whether this finding is universal in patients of not only primary SS but also secondary SS, in this study we analysed the blood DCs of secondary SS patients. We examined 24 secondary SS and 29 primary SS patients. A direct correlation between the decreased number of myeloid DCs and the duration of Sicca syndrome in primary and secondary SS was observed; namely, the reduction of myeloid DCs in blood was restored spontaneously with duration time of Sicca syndrome. We also examined the immunohistochemical staining of salivary glands of SS patients with monoclonal antibodies against fascin, CD11c and human leucocyte antigen DR (HLA-DR). Fascin(+) or CD11c(+)/HLA-DR(+) mononuclear cells were present in the salivary glands of secondary SS patients, as in primary SS. However, fascin(+) mononuclear cells were barely detected in the salivary glands of a chronic phase of SS patients. We also found a negative correlation between the frequency of blood myeloid DCs and salivary gland-infiltrating DCs in secondary SS patients, as well as primary SS. Our results suggest that the reduction of blood myeloid DCs and preferential trafficking of myeloid DCs into salivary glands is a common event in the early stage of SS. Myeloid DCs may play essential roles in the pathogenesis of Sicca syndrome of SS by initiating T helper cell immune responses.