Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 17317608 | Autoimmune disease etiology--a perplexing paradox or a turning leaf? | 2007 Mar | Autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma have been considered to represent disorders associated with reaction of the patient's own immune system against self-antigens or body systems. In many such disorders, tissues involved show lesions or morphology indicating destructive inflammatory or reactive features clearly produced by or associated with cell-mediated or antibody-driven reactions of the patient against his own tissues. After an exhaustive search which has stretched back in time for at least the last five decades, we seem to understand how the immune system works better than previously. However, despite the fact that we now understand molecular mechanisms of antibody selection and structure, how the cell-mediated and humoral antibody system is activated in terms of signal peptides and in the context of HLA molecules, we have not yet exactly identified inciting antigens which clearly cause these diseases. The focus recently has shifted towards being able to down-modulate potentially harmful parts of a self-directed inflammatory process by abrogating harmful messenger molecules participating in tissue injury. Following such a path, we may actually alleviate or cure these diseases before eventually identifying their original cause. | |
| 16949684 | Signaling mechanisms of vasoactive intestinal peptide in inflammatory conditions. | 2006 Nov 15 | The vasoactive intestinal peptide (VIP) is a neuropeptide belonging to the secretin/glucagon family of peptides, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has emerged as a potent anti-inflammatory factor, which exerts its function by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been proposed as a promising candidate, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis and Crohn's disease. The present work reviews the involvement of the specific receptors and or different transduction pathways and transcription factors in the anti-inflammatory action of VIP, and their implication on its therapeutic effect on inflammatory/autoimmune disorders. | |
| 16763678 | Development of a linear type of low molecular weight CXCR4 antagonists based on T140 analo | 2006 Jun 21 | A linear type of several low molecular weight CXCR4 antagonists were developed based on T140 analogs, which were previously found to be strong CXCR4 antagonists that block X4-HIV-1 entry and have inhibitory activities against cancer metastasis/progression and rheumatoid arthritis. | |
| 16550253 | Leptin: a metabolic hormone that functions like a proinflammatory adipokine. | 2006 Jan | Initially described as a satiety factor with neuroendocrine properties, leptin has been shown to regulate immune and inflammatory processes. Mainly produced by white adipose tissue, this hormone was first known to regulate energy homeostasis by inhibiting food intake and by upregulating energy consumption. Leptin is a dual molecule: apart from its actions as a hormone involved in energy homeostasis, increasing evidence suggests that leptin is a novel proinflammatory adipocyte-derived factor that operates in the cytokine network by linking immune and inflammatory processes to the neuroendocrine system. In fact, recent findings have shown that leptin regulates and participates both in immune homeostasis and inflammatory processes not only by acting as a modulator of T-cell activity, but also by playing a key role in a host of autoimmune inflammatory conditions such as autoimmune encephalomyelitis, type 1 diabetes, bowel inflammation and articular degenerative diseases such as osteoarthritis and rheumatoid arthritis. This review will more closely address leptin's cytokine properties rather than its role as a metabolic hormone by focusing on its biological actions in inflammatory processes, specifically those related to degenerative inflammatory diseases of the joints. | |
| 16434333 | Serum sickness-like reactions in patients receiving intravenous infliximab. | 2006 Jan | Infliximab, a monoclonal antibody against tumor necrosis factor (TNF) has been used successfully for the treatment of certain forms of Crohn's disease and rheumatoid arthritis. Both acute and delayed hypersensitivity reactions have been associated with the intravenous use of this drug. The delayed forms may present as a serum sickness-like illness and recognition of the clinical manifestations becomes crucial for early diagnosis and treatment. With the dramatic increase in the use of infliximab, there will likely be increased numbers of patients with this type of reaction. These patients may have received this drug days or even weeks before the clinical presentation. These types of reactions also have been reported with the use of other monoclonal antibodies. | |
| 16403633 | Amyloid in neurosurgical and neurological practice. | 2006 Feb | The amyloidoses are a diverse group of diseases characterized by the deposition of specific proteins with distinct affinity to the dye Congo red, collectively called amyloid. The amyloidogenic proteins have acquired an abnormal, highly ordered, beta-pleated sheet configuration with a propensity to self-aggregate. The amyloid may be distributed in different organs with a remarkable diversity. Two broad categories of amyloidoses are recognised: The systemic (consisting of the primary or light chain form, the secondary or reactive form and the familial or hereditary form) and the localised that target specific organs. A tropism of amyloid proteins to the neural tissue produces certain patterns of central nervous system diseases: cerebral amyloid angiopathy, a substrate of spontaneous intracerebral haemorrhage; mature neuritic plaques found in Alzheimer disease and a subset of prion diseases; a topographically restricted accumulation of extracellular proteins giving rise to tumour-mimicking masses, the amyloidomas; and finally, spinal extradural amyloid collections that occasionally are found in the context of rheumatoid arthritis. In this review article we present original illustrative cases of amyloid diseases of the central nervous system that may be encountered in neurosurgical and neurological practice. Molecular aspects and clinical management problems are discussed. | |
| 16329644 | Inhibition of IFN-gamma as a method of treatment of various autoimmune diseases, including | 2006 | We pioneered anticytokine therapy (ACT) for autoimmune diseases (ADs). In 1974, we proposed that hyperproduced interferon (IFN) can bring AD and anti-IFN can be therapeutic. In 1989, we proposed removing tumor necrosis factor (TNF)-alpha together with certain types of IFN to treat various ADs. We found IFN in patients with different ADs and conducted the first clinical trial of ACT in 1975. Anti-IFN-gamma and anti-TNF-alpha work in similar ways, but the latter brings serious complications in some patients. We obtained good, sometimes striking, therapeutic effects treating many different Th-1-mediated ADs with anti-IFN-gamma, including rheumatoid arthritis, multiple sclerosis (MS), corneal transplant rejection, and various autoimmune skin diseases such as psoriasis, alopecia areata, vitiligo, acne vulgaris, and others. Anti-IFN-gamma was in some ways superior to anti-TNF-alpha, which was ineffective in MS. Anti-IFN-gamma therapy holds great promise for treating many Th-1 ADs, especially skin diseases. | |
| 20089001 | Laboratory findings in CD4(+) large granular lymphocytoses. | 2010 Feb | Large granular lymphocytic (LGL) leukemia is an uncommon disorder of mature T or natural killer (NK) cells. Most T-LGL proliferations are CD3(+)/CD8(+), although rare CD4(+) clonal T-LGL expansions have been reported. We report the clinicopathologic features of eight patients with aberrant CD4(+), cytotoxic T-cell lymphocytoses. Median follow-up was 29 months (range 8-100), during which all were alive without requirement for therapy. Four of eight patients had an additional malignancy; none had a history of rheumatoid arthritis, lymphadenopathy or hepatosplenomegaly. Morphologic expansions of granulated lymphocytes were evident in 6/8. All had immunophenotypically aberrant populations of CD4(+) T cells with uniform, moderate or bright CD56. Seven of eight expressed CD57, and four were CD8(partial dim +). Abnormal levels of expression of two or more T-cell antigens were seen in all cases. All tested cases were Tgamma PCR positive. Our results support that CD4(+) T-LGL lymphocytosis is a clonal disorder with clinicopathologic characteristics distinct from the more common CD8(+) variant. | |
| 21794552 | [New therapeutic targets]. | 2008 Mar | The success obtained with biologic therapies in rheumatoid arthritis and other inflammatory arthropathies has led to its use in other rheumatic diseases such as systemic lupus erythematosus (SLE) and, to a lesser degree, in Sjögren's syndrome (SS) and progressive systemic sclerosis (PSS). This review summarizes the biologic therapies that are still in a development phase, albeit a relatively advanced one, with the aim of applying them clinically in the near future. In this sense, SLE is the disease for which most trials are being carried out, including treatment with agents such as sodic abetimus (LJP 394) a synthetic analog of DNA, edratide (TV4710) a peptide from the antigen-binding site of anti-double stranded DNA, or monoclonal antibodies with different effects: B cell depletion (rituximab [anti-CD20+] and epratuzumab [anti-CD22]), lymphocyte proliferation inhibitors (belimumab [anti-BAFF]) or inhibition of costimulation (BG9588 [anti-CD40L] and abatacept [CTLA-4Ig]). In SS the agent that shows the most promise is rituximab though there are some studies with efalizumab, a monoclonal antibody directed against the LFA-1 (CD-11) molecule. Finally, in PSS there is development of monoclonal antibodies against TGFβ a cytokine implicated in the fibrotic reaction that is the result of this disease, as well as one trial that is employing abatacept. However, in this disease the most important advances are being seen with the use of agents such as endothelin inhibitors or tyrosin-kinases, which are not considered biologic therapies. | |
| 21901066 | Cardiovascular pharmacology of sinomenine: the mechanical and electropharmacological actio | 2007 | Sinomenine is one of the alkaloids extracted from Chinese medical plant, Sinomenium acutum Rehder et Wilson. Sinomenine has been used for Rheumatoid arthritis as an anti-inflammatory and immunomodulative drugs. We have so far been investigated the cardiovascular pharmacological actions of sinomenine. Sinomenine dilated NE (5 μM)-, KCl (60 mM)- and PDB (300 nM)-induced vasoconstrictions. The pretreatment with nicardipine (0.1 μM), staurosporine (30 nM), L-NMMA (100 μM), indomethacin (10 μM) or propranolol significantly attenuated the sinomenine-induced vasorelaxation. Therefore, these results indicate that sinomenine causes the vasorelaxation by the involvement with the inhibitions of Ca(2+) current (I(Ca)) and PK-C, β-adrenoceptor stimulation, and the activation of NO and PGI(2) syntheses in endothelium. On the other hand, in the ventricular cardiomyocytes of guinea pig, sinomenine inhibits I(Ca) and simultaneously decreases the delayed rectifier K(+) current (I(K)), resulting in the prolongation of action potential duration. Sinomenine also suppresses the dysrhysmias induced by triggered activities under the Ca(2+) overload condition. Therefore, sinomenine may be expected as one of effective therapeutic drugs for heart failure and dysrhythmias, and may maintain the cardiovascular functions due to modulation of cardiac ionic channels and blood vessels. | |
| 17332143 | Effect of DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopy | 2007 Jun | DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] is a potent human tumor necrosis factor alpha-converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [14C]MTX (0.5 mg/kg) did not alter the plasma concentration-time profile of MTX; however, the total amount of radioactivity excreted in urine increased from 58.7% to 92.2% of the dose, and the renal clearance increased from 1.8 ml/min/kg to 2.9 ml/min/kg, suggesting a decrease in MTX disposition via biliary excretion. The biliary excretion of MTX was investigated in isolated perfused livers prepared from wild-type and TR(-) [multidrug resistance-associated protein 2 (Mrp2)-deficient] Wistar rats in the absence and presence of DPC 333. Mrp2-mediated biliary excretion of MTX was confirmed with 95.8% and 5.1% of MTX recovered in the bile of wild-type and TR(-) Wistar rats, respectively. DPC 333 at an initial perfusate concentration of 50 microM completely blocked the biliary excretion of MTX, but not the clearance from perfusate, in both wild-type and TR(-) rats. These results suggest that the enhanced renal elimination of MTX may be due to the potent inhibition of biliary excretion and active renal reabsorption by DPC 333 and/or its metabolites. | |
| 17960951 | The cost effectiveness of bisphosphonates for the prevention and treatment of osteoporosis | 2007 | Osteoporotic fragility fractures constitute a significant public health concern. The lifetime risk of any osteoporotic fracture is very high (40-50% in women and 13-22% in men). Fractures are associated with significant mortality and morbidity and represent a substantial economic burden to society. Bisphosphonates (alendronate, etidronate, risedronate and ibandronate) are indicated for the treatment and prevention of osteoporosis but are costly compared with other treatments, such as vitamin D and calcium. Our search identified 23 studies evaluating the cost effectiveness of bisphosphonate therapy for the treatment and prevention of fragility fractures; these studies were from five geographical areas and employed a variety of comparators and assumptions. We identified 11 studies investigating bisphosphonates in women with low bone mineral density (BMD) [T-score >2.5 standard deviations {SDs} below normal {mean} peak values for young adults] and previous fractures, five studies investigating bisphosphonates in women with low BMD and no previous fracture, one study of bisphosphonates in women with osteopenia, five studies involving screening and two studies of bisphosphonates in special populations (women initiating corticosteroid treatment and men). In women with low BMD and previous fractures, bisphosphonate therapy was most cost effective in populations aged > or =70 years and was unlikely to be cost effective in populations aged < or =50 years. There was uncertainty concerning the cost effectiveness of bisphosphonates in such populations aged 60-69 years. In women with low BMD without previous fractures, treatment with alendronate or risedronate appeared to be cost effective across countries (UK, US, Denmark), but there was some uncertainty about the cost effectiveness of etidronate in patients in the highest age groups. Identifying risk factors for fractures through means such as spine radiographs to detect vertebral deformities improves the cost effectiveness of treatment. In women with osteopenia, alendronate therapy may be cost effective in women with a T-score of -2.4SD in the US. Screening for low BMD and treatment with alendronate or etidronate appears to be cost effective in postmenopausal women in general and in women with rheumatoid arthritis initiating corticosteroid therapy. Alendronate therapy without screening was also shown to be potentially cost effective in certain at-risk male populations, as well as in women initiating corticosteroid therapy after the age of 40 years. Decision makers in the US, UK and Sweden should consider funding the use of bisphosphonates for the prevention and treatment of osteoporosis in women aged >70 years, particularly if they have other risk factors for fracture. Further studies are required to make more definitive conclusions in other countries and patient populations. Screening strategies for low BMD followed by bisphosphonate treatment should also be considered in the general female population aged >65 years in the UK and US and in patients with rheumatoid arthritis initiating corticosteroid therapy. | |
| 17590116 | [Use and cost of biological disease-modifying anti-rheumatic drugs in Spain (PRAXIS study) | 2007 Mar | OBJECTIVE: To analyse the use of health care resources and the associated costs in patients with rheumatoid arthritis (RA) treated with three biological disease-modifying anti-rheumatic drugs (bDMARDs): etanercept, infliximab and adalimumab. DESIGN: observational, retrospective, multicentre study. Length of study: 6 months. TARGET POPULATION: patients with RA, who have been undergoing treatment for at least one year. SCOPE: Spanish National Health System hospitals. Use of resources: review of the patient records of all patients included in the study by the Hospital Pharmacy Departments. Health care costs: the unit costs were obtained from Spanish databases; disease costs per patient were estimated from the use of resources results (euro in July 2006). Sensitivity analysis: univariate of base case. Budget impact analysis: replacement of infliximab and adalimumab by etanercept for three hospital populations. RESULTS: 1,111 patient records from 41 Spanish hospitals were reviewed, 432 patients were treated with etanercept, 396 were treated with infliximab and 283 with adalimumab. Mean doses: etanercept: 48.90 mg per week; infliximab: 4.14 mg/kg every 8 weeks; adalimumab: 41.58 mg every two weeks (97.8, 138 and 104% respectively, of recommended doses). Treatment with etanercept led to fewer costs. Compared to infliximab, six-monthly costs per patient were reduced with etanercept as follows: bDMARD treatment (232.23 euro), treatment failure (163.42 euro), consultations (54.88 euro), tests (22.52 euro) and costs associated to bDMARD administration (euro 474.42). The saving per patient treated with etanercept compared to infliximab for six months was 577.94 euro. With respect to adalimumab, the savings with etanercept were mainly related to bDMARDs (1,111.74 euro) and test costs (10.16 euro), obtaining a six-monthly saving of euro 906.68 per patient treated with etanercept. Sensitivity analysis confirmed the robustness of the base case in the majority of cases, with six-monthly savings of 395.79-644.32 euro per patient compared to infliximab and of 672.09-1.159.46 euro compared to adalimumab. Infliximab treatment was less expensive than etanercept and adalimumab treatment when taking into consideration the minimum possible number of doses of infliximab (3 doses for six months). Hospital budget savings could be obtained as a consequence of a reduction in costs due to use of etanercept, ranging from 14,500-231,100 euro when replacing infliximab with etanercept and from 22,600-362,600 euro when replacing adalimumab with etanercept, according to the hospital population included (50 to 200 patients). CONCLUSIONS: Our results showed that in most cases, the treatment of rheumatoid arthritis with etanercept compared to infliximab and adalimumab reduced hospital costs. | |
| 17237833 | Is long-term glucocorticoid therapy associated with a high prevalence of asymptomatic vert | 2007 Feb | BACKGROUND: Chronic administration of glucocorticoids is associated with bone loss and increased fracture risk, particularly in the trabecular bone of the vertebrae. OBJECTIVE: To assess the prevalence of asymptomatic vertebral fractures in postmenopausal women undergoing long-term glucocorticoid therapy. DESIGN AND INTERVENTION: This was a multicenter, cross-sectional outpatient study of postmenopausal women. Inclusion criteria included age >45 years, glucocorticoid therapy for ≥6 months with a cumulative dose ≥1.35 g of a prednisone equivalent, and diagnosis of rheumatoid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, other vasculitides or connective tissue diseases, asthma, or chronic obstructive pulmonary disease. Patients with back pain, previous vertebral fracture, Paget’s disease, or using antiosteoporotic medication were excluded; however, calcium and vitamin D supplements were permitted. Participants underwent a medical interview that assessed socio-demographic factors, details of glucocorticoid therapy, and risk factors for osteoporosis. Health-related quality of life was evaluated with the European Foundation for Osteoporosis questionnaire. A back-function questionnaire rated the participants’ ability to perform activities of daily living. Vertebral fractures were identified from lateral and antero-posterior thoracolumbar radiographs. Hip and lumbar spine BMD were assessed by dual energy X-ray absorptiometry and quantitative ultrasound. OUTCOME MEASURE: The primary outcome measure was the prevalence of asymptomatic vertebral fractures. RESULTS: The study enrolled a total of 551 women (median age 65.2 years). Rheumatoid arthritis was the most common reason for glucocorticoid therapy (53.2%). One or more asymptomatic vertebral fractures were present in 37.02% of participants, whereas 14.42% had two or more fractures. A bimodal distribution of these fractures was observed, with peaks at the T7 and T11 thoracic vertebrae. The prevalence of asymptomatic vertebral fractures increased with age; 47.98% of participants ≥70 years of age presented with at least one fracture (P = 0.006). There was a strong association between polymyalgia rheumatica and fracture prevalence; 51.09% of affected patients had one or more fracture (P=0.012). When the data were adjusted for age, cumulative glucocorticoid dose, therapy duration, and fracture history, however, this association became weaker (43.20%), and was similar to the fracture prevalence of 43.36% observed in patients with other vasculitides or connective-tissue diseases. There was no correlation between fracture prevalence and cumulative glucocorticoid dose or therapy duration. Additionally, lumbar spine and hip BMD, calcaneal bone stiffness, and health-related quality of life were not associated with the number or severity of vertebral fractures. Time since menopause and history of nonvertebral fractures both showed a significant association with asymptomatic vertebral fracture (P<0.001 and P = 0.002, respectively). Back function score showed a modest association with the number of asymptomatic vertebral fractures. CONCLUSION: A high prevalence of asymptomatic vertebral fractures was observed in postmenopausal women undergoing long-term glucocorticoid therapy, which suggests a need for careful evaluation of this patient subgroup. | |
| 19095294 | Wnt pathway and IL-17: novel regulators of joint remodeling in rheumatic diseases. Looking | 2010 Apr | OBJECTIVES: During the last decade research has focused on the RANK-RANKL-OPG (Receptor Activator of Nuclear factor KappaB-Receptor Activator of Nuclear factor KappaB Ligand-Osteoprotegerin) pathway that is currently considered the final common route to bone and joint remodeling. The potential role of novel additional mediators has been highlighted by several reports. This review focuses on the recent information about the pathophysiology of the Wingless (Wnt) pathway and interleukin-17 (IL-17) in relation of their role in bone and joint remodeling. METHODS: An extensive internet search was performed (PubMed) from 1998 and onward using the following keywords: Wnt, bone remodeling, bone, rheumatic diseases, rheumatoid arthritis, IL-17, Th17, osteoblastogenesis, and osteoclastogenesis. RESULTS: Several members of the Wnt pathway play an important role in bone remodeling. Recent experimental data indicate a key role for Dickkopf-1, a soluble inhibitor of the Wnt pathway, in bone remodeling. Increased Dickkopf-1 levels are linked to bone resorption and decreased levels to new bone formation. Low-density lipoprotein receptor-related protein-5, the main receptor that mediates Wnt signaling, plays a critical role in bone mass regulation. Gain-of-function mutations of lipoprotein receptor-related protein-5 cause high bone mass phenotypes, whereas loss-of-function mutations are linked to severe osteoporosis. IL-17 is a proinflammatory cytokine that is produced by a recently described T-cell subset, known as Th17 cells. Evidence suggests that IL-17 is a critical mediator of joint destruction in animal models of arthritis. IL-17 blockade has beneficial effects on murine arthritis, a fact that points to the direction of this cytokine as a potential therapeutic target in human inflammatory arthritides as well. CONCLUSIONS: The available data suggest that mediators in these 2 biologic systems are critical in joint remodeling and may be appropriate targets in the treatment of bone and joint abnormalities that characterize a variety of inflammatory arthritides and bone diseases. | |
| 17094335 | [Recommendations for the diagnosis and treatment of latent and active tuberculosis in pati | 2006 Jul | The Portuguese Society of Rheumatology (SPR) and the Portuguese Society of Pulmonology (SPP) have developed guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (AT) in patients with inflammatory joint diseases (IJD), namely rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with tumour necrosis factor alpha (TNF-alpha) antagonists. Due to the high risk of tuberculosis (TB) in patients with IJD, LTBI and AT screening should be performed as soon as possible, ideally at the moment of IJD diagnosis. Even if TB screening was performed at the beginning of the disease, the evaluation should be repeated before starting anti-TNF-alpha therapy. When TB (LTBI orAT) treatment is indicated, it should be performed before the beginning of anti-TNF-alpha therapy. If the IJD activity requires urgent anti-TNF-alpha therapy, these drugs can be started after two months of antituberculosis therapy in AT cases, or after one month in LTBI cases. Chest X-ray is mandatory for all patients. If abnormal, e.g. Gohn complex, the patient should be treated as LTBI; residual lesions require the exclusion of AT and patients with history of untreated or incomplete TB treatment should be treated as LTBI. In cases of suspected active lesions, AT diagnosis should be confirmed and adequate therapy initiated. Tuberculin skin test (TST), with two units of RT23, should be performed in all patients. If induration is less than 5 mm, the test should be repeated after 1 to 2 weeks, on the opposite forearm, and should be considered negative if the result is again inferior to 5 mm. Positive TST implicates LTBI treatment. IfTST is performed in immunosupressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFalpha therapy, even in the presence of a negative test. | |
| 16960943 | Chondrocyte death induced by pathological concentration of chemokine stromal cell-derived | 2006 Sep | OBJECTIVE: It had been found that the concentration of chemokine stromal cell-derived factor-1 (SDF-1) was significantly higher in synovial fluid (SF) of patients with osteoarthritis (OA; > or = 200 ng/ml) and rheumatoid arthritis (RA; > or = 700 ng/ml) compared to controls (< or = 100 ng/ml). Our aim was to determine whether the pathological concentration of SDF-1 induces chondrocyte death and to investigate mechanisms underlying such death. METHODS: Human OA chondrocytes were treated with different doses of SDF-1, or in combination with SF from patients with arthritis. Apoptotic and necrotic cells were labeled by annexin V and propidium iodide, respectively, and quantified by FACS analysis. Caspase-3 activity was quantified by a plate absorbance assay, and matrix metalloproteinase 13 mRNA levels were determined by RT-PCR. The release of high mobility group box chromatin protein 1, a specific marker of cell necrosis, and the activities of chondrocyte mitogen-activated protein kinases (MAPK) including ERK, JNK, and p38 in response to SDF-1 treatment were quantified by Western blot analysis. RESULTS: Pathological concentrations of SDF-1 (> or = 200 ng/ml) in SF or in recombinant form induced death of human chondrocytes in a necrosis-dependent manner. Chondrocyte death was inhibited by the treatment of cells with anti-CXCR4, an antibody blocking the interaction between SDF-1 and its receptor CXCR4. However, the rate of chondrocyte apoptosis and the level of caspase-3, a key apoptotic enzyme, were not affected by the treatment with anti-CXCR4. SDF-1 stimulated p38 MAPK activity in a dose- and time-dependent manner. The presence of the p38 MAPK inhibitor SB203580 during SDF-1 treatment abolished the induction of chondrocyte death by SDF-1. CONCLUSION: Our findings suggest a novel pathological mechanism by which high concentrations of SDF-1 in SF induce chondrocyte death during OA and RA. | |
| 18240214 | Serum type I interferon activity is dependent on maternal diagnosis in anti-SSA/Ro-positiv | 2008 Feb | OBJECTIVE: The type I interferon (IFN) pathway is activated in many patients with systemic lupus erythematosus (SLE), and high serum levels of IFN are associated with anti-SSA/Ro autoantibodies. To investigate the clinical features associated with type I IFN production in vivo, we compared serum IFN activity in individuals with anti-SSA/Ro antibodies who were asymptomatic with that in individuals with clinical manifestations of SLE or Sjögren's syndrome (SS). METHODS: Antibody-positive sera from 84 mothers of children with manifestations of neonatal lupus were studied for type I IFN activity, using a functional reporter cell assay. Maternal health status was characterized as asymptomatic, SS, SLE, pauci-SLE, or pauci-SS, based on a screening questionnaire, telephone interview, and review of medical records. The prefix "pauci-" indicates symptoms insufficient for a formal classification of the disease. RESULTS: Only 4% of asymptomatic mothers had high serum type I IFN activity, compared with 73% with pauci-SLE (P = 5.7 x 10(-5)), 35% with SLE (P = 0.011), and 32% of patients with SS (P = 0.032). One of the 4 patients with pauci-SS had high levels of IFN. The majority of patients for whom longitudinal data were available had stable type I IFN activity over time, and changes in IFN activity were not clearly accompanied by changes in the clinical diagnosis. CONCLUSION: Patients with SLE, patients with pauci-SLE, and patients with SS are more likely to have high serum IFN activity than asymptomatic individuals with SSA/Ro autoantibodies, suggesting that these autoantibodies are insufficient for activation of the type I IFN pathway, and that disease-specific factors are important for type I IFN generation in vivo. | |
| 17899308 | The efficacy of cevimeline hydrochloride in the treatment of xerostomia in Sjögren's synd | 2008 Apr | Cevimeline hydrochloride, a specific agonist of the M3 muscarinic receptor, is beneficial in the treatment of symptoms of xerostomia and xerophthalmia associated with Sjögren's syndrome (SS). Cevimeline has not been evaluated in southern Chinese patients. Furthermore, the effects of cevimeline on health-related quality of life and oral health status are not known. In this randomised, double-blind, placebo-controlled crossover study, patients received cevimeline 30 mg or matched placebo three times per day over 10 weeks followed by a 4-week washout period before treatment crossover. Participants self-completed the following questionnaires: Xerostomia Inventory (XI), the General Oral Health Assessment Index (GOHAI), the Ocular Surface Disease Index (OSDI) and the Medical Outcomes Short Form (SF-36). Clinical assessments included sialometry, examination of the oral cavity for the degree of xerostomia and dental complications of xerostomia. Fifty patients (22 primary SS and 28 secondary SS) were enrolled in the trial. Forty-four patients completed the study. There was a significant improvement in the XI and GOHAI scores as well as the objective rating of xerostomic signs of the oral cavity after treatment with cevimeline. However, there was no improvement in salivary flow rates and dry eye symptoms. SS patients had lower SF-36 scores, but these did not improve after treatment with cevimeline. | |
| 17325149 | Role of heat shock protein 47, a collagen-binding chaperone, in lacrimal gland pathology i | 2007 Mar | PURPOSE: Uncontrolled fibrosis due to excessive accumulation of extracellular matrix proteins in the lacrimal glands of patients with chronic graft-versus-host disease (cGVHD) is well documented. Heat-shock protein 47 (HSP47) is involved in the molecular maturation of collagen and has been shown to have a fibrogenic role in various fibrotic diseases. In this study, the role of HSP47 in the pathogenesis of lacrimal gland of patients with cGVHD was investigated. METHODS: The expression of HSP47, Ki67 (a proliferation marker), types I and III collagen, and alpha-smooth muscle actin (alpha-SMA) was examined in tissue sections and in primary cultures of fibroblasts obtained from the lacrimal glands of patients with cGVHD (n = 8) and Sjögren's syndrome (SS; n = 7). RESULTS: Tissue sections of the lacrimal glands of patients with cGVHD showed markedly increased expression of HSP47 in fibroblasts around the medium-sized ducts than did those from patients with SS. The elevated expression of HSP47 in patients with cGVHD was mostly detected in Ki67-positive fibroblasts and was associated with increased accumulation of types I and III collagen in and around the fibrotic areas. Primary fibroblast cultures generated from cGVHD lacrimal gland showed higher HSP47 mRNA expression than did fibroblasts isolated from SS biopsy tissue, as determined by RT-PCR (P < 0.05). In contrast, alpha-SMA was higher in the SS than cGVHD fibroblasts at both mRNA and protein levels, and more lacrimal gland fibroblasts in the SS were positive for alpha-SMA than cGVHD (P < 0.01). CONCLUSIONS: In cGVHD, increased expression of HSP47 may promote excessive collagen assembly in and around the periductal areas where fibroblasts are mostly in an active state. The less alpha-SMA in the cGVHD lacrimal gland fibroblasts suggests a relative lack of myofibroblastic transformation. It is likely that fibroblasts incapable of myofibroblastic transformation are the main source of HSP47 and collagen production, and the resultant effect is the periductal fibrotic changes seen in lacrimal glands of patients with cGVHD. |