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ID PMID Title PublicationDate abstract
16249227 Anchorage on fibronectin via VLA-5 (alpha5beta1 integrin) protects rheumatoid synovial cel 2006 Jun BACKGROUND: Rheumatoid synovial cells are resistant to apoptosis induction in vivo, whereas, fibroblast-like synovial cells in rheumatoid arthritis (RA-FLS) are vulnerable to Fas-induced apoptosis in vitro. OBJECTIVE: To clarify this discrepancy by studying the contribution of the interaction between cellular integrin and matrix fibronectin (Fn), which is significantly increased in the rheumatoid joints, to the induction of apoptosis in RA-FLS. METHODS: Integrin and Fas mRNAs were measured by reverse transcription-polymerase chain reaction in RA-FLS. Integrins expressed in rheumatoid synovial tissues were analysed by immunohistochemistry. RA-FLS plated either on Fn or on control poly-L-lysine were incubated with agonistic anti-Fas monoclonal antibodies (mAbs). Apoptosis induction was evaluated using terminal deoxynucleotidyl transferase mediated UTP nick end labelling (TUNEL) and immunoblotting for caspase-3 and poly (ADP-ribose) polymerase in the presence or absence of anti-VLA-5 mAb. RESULTS: VLA-5 (alpha5beta1 integrin), a major integrin expressed on RA-FLS, was required for the adhesion of RA-FLS on Fn. RA-FLS plated on Fn were more resistant to Fas-induced apoptosis than those plated on control poly-L-lysine. This protection by Fn was reversed by anti-VLA-5 mAb. CONCLUSION: Anchorage of RA-FLS on matrix Fn via VLA-5 protects RA-FLS from Fas-induced apoptosis, and Fn abundantly present in rheumatoid synovium appears to afford RA-FLS resistance against apoptosis induction in vivo.
15498798 Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovi 2005 May BACKGROUND: Rheumatoid arthritis (RA) synovium is characterised by enhanced NF-kappaB activity and proinflammatory cytokines. Cryopyrin (CIAS-1, NALP-3, PYPAF-1) has been shown to regulate NF-kappaB and caspase-1 activation. OBJECTIVE: To study the expression of cryopyrin, its effector molecule ASC, and its putative antagonist pyrin in RA and osteoarthritis (OA) synovium, and the main two cellular constituents of synovial lining, cultured fibroblast-like synoviocytes (FLS) and macrophages. METHODS: FLS and macrophages were cultured in the presence of inflammatory mediators. Real time polymerase chain reaction was used to quantify message levels in synovial biopsy specimens and cells. In situ hybridisation was employed to localise expression of cryopyrin mRNA. RESULTS: Cryopyrin mRNA was raised in RA synovium and detected in both lining and sublining regions. FLS from RA and OA tissue expressed low baseline levels of cryopyrin transcripts that were induced by tumour necrosis factor alpha (TNFalpha). In contrast, macrophages differentiated in vitro expressed relatively high cryopyrin levels, which were further induced by TNFalpha, but not by interleukin 1beta. ASC mRNA levels were comparable in RA and OA tissue, FLS, and macrophages, and were depressed by TNFalpha in macrophages. Pyrin expression was higher in RA synovium than in OA tissue, and virtually undetectable in FLS but high in macrophages where it was unchanged by TNFalpha treatment. CONCLUSION: These results suggest that enhanced cryopyrin levels in RA synovium are due to a greater numbers of tissue macrophages, and demonstrate transcriptional regulation of cryopyrin in a chronic inflammatory disease.
16935544 Retention of the patella in total knee arthroplasty for rheumatoid arthritis. 2006 Oct AIM: To determine whether retention of the native patella during total knee arthroplasty is appropriate in patients with rheumatoid arthritis. METHODS: All patients undergoing total knee arthroplasty with a diagnosis of rheumatoid arthritis were identified between January 1997 and December 2000. Subsequently, each individual underwent both radiological and clinical assessments at a designated follow-up clinic. RESULTS: A total of 30 total knee arthroplasties were studied in 28 patients. Twenty-six patients (93%) were female with a mean age of 74.7 years (range 60-83 years). The average post-operative interval was 59.4 months (range 46-82 months). All individuals were noted to have satisfactory patellar tracking and bone stock at the time of surgery. No patient subsequently underwent revision surgery during follow-up and no episodes of implant sepsis were identified. The mean Patellar Score at final follow-up was 26.2 (range 22-30) with an average anterior knee pain score of 14.2 (range 10-15). The mean Oxford Knee Score was 18.7 (range 16-23) with a mean pain score component of 5.9. Patients were finally assessed with respect to the Knee Society Score. The mean Knee Score was 83.8 (range 71-96) with a mean Function Score of 79.7 (range 40-90). CONCLUSION: By retaining the native patella we were still able to obtain highly satisfactory medium-term results in terms of pain relief and function. In addition, the potential complications associated with prosthetic replacement of the patella were avoided.
16126996 Autoimmunity and anti-TNF-alpha agents. 2005 Jun Treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor-alpha (anti-TNF-alpha) biologic agents has been associated with a reduction in the levels of specific autoantibodies, such as rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP), and the induction of non- organ-specific autoantibodies (antinuclear antibodies [ANAs], anti-dsDNA, and antiphospholipid antibodies [aPLs]). The mechanisms by which the blockade of anti-TNF-alpha decreases the generation of specific autoantibodies, such as anti-CCP and RF, are not yet known. However, it has been shown that these agents can downregulate the production of several inflammatory cytokines and mediators and that these anti-inflammatory effects may account for reduced autoantibody generation, particularly in the synovial compartment. Infliximab treatment leads to the induction of ANAs in 63.8% of RA patients and 49.1% of Crohn's disease (CD) patients, and anti-dsDNA antibodies in 13% of RA patients and 21.5% of CD patients, respectively. The development of ANAs and anti-dsDNA antibodies has also been described after etanercept therapy in 11% and 15% of RA patients, respectively. In the controlled trials, increases in ANA and anti-dsDNA titers were observed in 5.3% and in 12.9% of adalimumab-treated RA patients. Only limited data on the induction of aPL antibodies during TNF-alpha blocking treatment are available.
16508940 Sphingosine kinase 1-mediated inhibition of Fas death signaling in rheumatoid arthritis B 2006 Mar OBJECTIVE: It is becoming increasingly apparent that B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). Due to the scarcity of B cells in RA, it has been technically difficult to functionally characterize B cell apoptosis in this disease. As a necessary first step to identify candidate aberrations, we investigated Fas-mediated signaling events in immortalized peripheral blood B lymphoblastoid cell lines (LCLs) from patients with RA and controls. METHODS: Cell death was determined by the MTS assay, and apoptosis was detected by the TUNEL assay and DNA laddering. Proteolytic activation of caspase 3 was determined by immunoblotting, and its enzymatic activity was determined by a fluorometric technique. Messenger RNA (mRNA) expression was quantified by real-time polymerase chain reaction (PCR) analysis. The functional role of sphingosine kinase (SPHK) was determined by measuring its enzymatic activity, by quantifying the levels of its product, sphingosine 1-phosphate (S1P), and by investigating the ability of the SPHK inhibitor N,N-dimethylsphingosine and isozyme-specific small interfering RNA (siRNA) oligonucleotides to reverse signaling aberrations. RESULTS: LCLs from patients with RA displayed disease-specific Fas-mediated signal transduction impairment with consequent resistance to cell death. RA LCLs displayed high constitutive SPHK activity and increased levels of S1P. Real-time PCR analysis showed higher SPHK-1 mRNA expression levels in RA patients compared with paired controls. Increased SPHK-1 (but not SPHK-2) mRNA levels were observed in synovial tissue from RA patients. Competitive inhibitors of SPHK reversed the resistance of RA LCLs to Fas-induced apoptosis. Additionally, resistance to Fas-mediated signaling was reversed by siRNA oligonucleotides specific for SPHK-1 but not by oligonucleotides specific for SPHK-2. CONCLUSION: These findings demonstrate disease-specific resistance to Fas-mediated death signaling in patients with RA and implicate increased SPHK-1 activity as the cause of this aberration.
15681256 DRESS syndrome in a patient on sulfasalazine for rheumatoid arthritis. 2005 Jan DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) is a drug-induced hypersensitivity syndrome that can mimic malignant lymphoma. We report a case in a 63-year-old woman who had been on sulfasalazine for 2 months to treat rheumatoid arthritis. She was admitted a few days after onset of a flu-like syndrome with a pruriginous maculopapular erythema initially involving the face, trunk, and proximal limbs; a fever of 41 degrees C; and enlargement of the liver, spleen, and several peripheral lymph nodes. Blood tests showed marked eosinophilia (9300/mm3), lymphocytosis, hyperbasophilic cells, and severe inflammation. DRESS syndrome was diagnosed. An indirect immunofluorescence assay for human herpesvirus 6 (HHV6) was positive, supporting recent HHV6 infection. Primary HHV6 infection and HHV6 reactivation have been incriminated in the genesis of DRESS syndrome. DRESS syndrome continues to carry a high mortality rate of about 10%. Drugs previously reported to cause DRESS syndrome include sulfasalazine, hydantoin, d-penicillamine, allopurinol, hydrochlorothiazide, and cyclosporine. A high index of suspicion for DRESS syndrome should be maintained in patients receiving these drugs. Serological tests for HHV6 should be performed routinely in patients with suspected DRESS syndrome, although uncertainty persists about the link between HHV6 infection and DRESS syndrome.
16052584 The comparative effectiveness of tumor necrosis factor-blocking agents in patients with rh 2005 Aug OBJECTIVE: To compare the effectiveness of tumor necrosis factor (TNF)-blocking agents (etanercept and infliximab) in patients with rheumatoid arthritis (RA) and patients with ankylosing spondylitis (AS). METHODS: Data from an ongoing longitudinal, observational study in Norway were used to assess changes in health-related quality of life (HRQOL) in patients with RA (n = 291) and AS (n = 62). Patients received anti-TNF therapy, and changes in scores on the Short Form 36 (SF-36), SF-6D, modified Health Assessment Questionnaire, and visual analog scales for patients' assessments of pain, fatigue, and global status from baseline to followup examinations at 3 and 6 months were compared. Data were adjusted for age, sex, and baseline values and are presented as crude estimates as well as standardized response means. RESULTS: Both groups had improvements in all measures at 3 and 6 months. At 3 months, the changes were significantly better in the AS group compared with the RA group for all measures except the SF-36 social functioning scores. At 6 months, all changes were numerically greater in the AS group. Differences were significant for the SF-36 role emotional scores and were borderline significant for the SF-36 physical functioning, role physical, and vitality scores and for the SF-6D scores. CONCLUSION: In this real-life setting, patients with AS experienced improvement in HRQOL that was comparable to, and sometimes greater than, that observed in RA patients. These results support the idea that patients with AS should have the same access to TNF-blocking agents as patients with RA.
15986342 Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic assoc 2005 Jul OBJECTIVE: Rheumatoid arthritis (RA) is characterized by inflammation and destruction of synovial joints. Fibroblast-like synoviocytes (FLS) harvested from synovial tissue of patients with RA can invade normal human cartilage in severe combined immunodeficient (SCID) mice and Matrigel basement membrane matrix in vitro. This study was undertaken to investigate the association of these in vitro characteristics with disease characteristics in patients with RA. METHODS: Synovial tissue samples from 72 RA and 49 osteoarthritis (OA) patients were obtained. Samples of different joints were collected from 7 patients with RA. The FLS invasiveness in Matrigel was studied, and the intraindividual and interindividual differences were compared. From the patients with FLS who exhibited the most extreme differences in in vitro ingrowth (most and least invasive FLS), radiographs of the hands and feet were collected and scored according to the Sharp/van der Heijde method to determine the relationship between in vitro invasion data and estimated yearly joint damage progression. RESULTS: FLS from patients with RA were more invasive than FLS from patients with OA (P < 0.001). The mean intraindividual variation in FLS invasion was much less than the mean interindividual variation (mean +/- SD 1,067 +/- 926 and 3,845 +/- 2,367 for intraindividual and interindividual variation, respectively; P = 0.035), which shows that the level of FLS invasion is a patient characteristic. The mean +/- SEM Sharp score on radiographs of the hands or feet divided by the disease duration was 4.4 +/- 1.1 units per year of disease duration in patients with the least invasive FLS (n = 9), which was much lower compared with the 21.8 +/- 3.1 units per year of disease duration in patients with the most invasive FLS (n = 9) (P < 0.001). CONCLUSION: The ex vivo invasive behavior of FLS from RA patients is associated with the rate of joint destruction and is a patient characteristic, given the much smaller intraindividual than interindividual FLS variation.
17105853 Evaluation of a modified ACR20 scoring system in patients with rheumatoid arthritis receiv 2006 Dec OBJECTIVE: To evaluate a modified American College of Rheumatology 20 (mACR20) scoring system for patients with rheumatoid arthritis. METHODS: The data were evaluated from one study on patients with methotrexate (MTX)-naive early rheumatoid arthritis (ERA) and another study on patients with DMARD-refractory late rheumatoid arthritis (LRA). For mACR20 scoring, acute-phase reactant measurements were excluded, and 20% improvement from baseline was determined by 2 or 3 of the 4 remaining ACR components. RESULTS: For full joint counts with data from patients with ERA, marked differences favoured 25 mg etanercept (ETN) over 10 mg ETN by using the unmodified ACR20 (69% v 55%), the mACR20(3 of 4) (63% v 49%) and the mACR20(2 of 4) (72% v 58%). An assessment of 28 joints showed similar findings. In the trial on patients with LRA, considerably more patients in both ETN groups achieved a clinical response compared with placebo by using the ACR20, the mACR20(3 of 4) and the mACR20(2 of 4), whether using full or 28 joint counts. The mACR20(3 of 4) and full joint counts with data on patients with ERA showed a marked difference between the MTX and 10 mg ETN groups (63% v 49%), which was not observed with the ACR20. CONCLUSION: Patterns of improvement indicated by mACR20 scores were consistent with standard ACR20 scores.
16538908 Comparison of phalangeal bone mineral content and density between the dominant and non-dom 2005 Dec Compared to the non-dominant side, higher bone mineral content (BMC) and density (BMD) have been demonstrated in the forearm bones in the dominant side. Clinicians are compelled to scan the dominant side when deformities or artifacts are found in the non-dominant side. This study was done to evaluate the differences in phalangeal BMC and BMD, measured using accuDXA, between the dominant and non-dominant hands. Design and participants A group of 333 subjects, comprising 267 healthy volunteers (185 women and 82 men) and 66 women with rheumatoid arthritis. Phalangeal BMD and BMC, were measured using accuDEXA, both in the non-dominant and dominant hands. Main results BMC and BMD showed strong correlations between the two sides (r = 0.95, p < 0.001 for both). Compared to the non-dominant side, dominant side BMC was 5% higher (mean values =1.54 and 1.47, mean difference = 0.064, 95% CI for the mean difference = 0.048-0.081 g, p < 0.001) and BMD was 4% higher (mean values = 0.480 and 0.463, mean difference = 0.018, 95% CI for the mean difference = 0.014-0.021 g/cm2, p < 0.001). In the subgroup analysis, percentage differences of BMD between the two sides were found to be similar among men (n=82), women (n=251), people below 50 years (n=24), people above 50 years (n=122) and also among patients with rheumatoid arthritis (n=66). Conclusions When the non-dominant hand is not suitable for scanning, the clinician should consider scanning the dominant hand instead. However, the differences in BMD between the two hands should be taken into consideration when interpreting results.
15833144 Modulating co-stimulation: a rational strategy in the treatment of rheumatoid arthritis? 2005 Rheumatoid arthritis (RA) is a common destructive inflammatory disease that affects 0.5-1% of the population in many countries. Even though several new treatments have been introduced for patients with RA, a considerable proportion of patients do not benefit from these, and the need for alternative treatment strategies is clear. This review explores the potential for a therapy targeting the adaptive immune system by modulating co-stimulation of T cells with a CTLA4-Ig fusion protein (abatacept).
16164220 [Disease modifying antirheumatic drugs with inhibitory effect on osteoclastogenesis]. 2005 Sep Suppression of bone destruction is a requirement for effective therapeutic strategies for autoimmune arthritis. Although numerous antirheumatic drugs are in clinical use, little is known about whether they ameliorate bone destruction by acting on activated T cells or other cell types, such as bone-resorbing osteoclasts. Leflunomide has a direct inhibitory effect on RANKL-mediated osteoclast differentiation by inhibiting the induction of NFATc1, the master switch regulator for osteoclast differentiation. We show that the direct inhibitory action of leflunomide on osteoclast differentiation constitutes an important aspect to ameliorate bone destruction, and that RANKL dependent NFATc1 induction pathway is an auspicious target for pharmacological intervention into arthritic bone destruction.
17079248 High IgA rheumatoid factor levels are associated with poor clinical response to tumour nec 2007 Mar OBJECTIVE: To investigate whether rheumatoid factor isotypes and anti-cyclic citrullinated peptide (anti-CCP) antibodies are related to clinical response in patients with rheumatoid arthritis treated with tumour necrosis factor alpha (TNFalpha) inhibitors. METHODS: The study was carried out on 132 patients with advanced rheumatoid arthritis refractory to disease-modifying antirheumatic drugs. Patients were treated with infliximab (n = 63), etanercept (n = 35) or adalimumab (n = 34). All patients completed 1 year of follow-up, and 126 were evaluable for clinical response according to the disease activity score (DAS) criteria. IgM, IgA and IgG rheumatoid factors and anti-CCP antibodies were assessed by ELISA both before anti-TNFalpha treatment and 1 year later. RESULTS: The DAS response was reached in 66% of evaluable patients (61% infliximab, 65% etanercept and 76% adalimumab; p = 0.354). A significant reduction in the rheumatoid factor level was reported by all treatment groups after 1 year. The frequency of positive tests for the different antibodies did not differ between responders and non-responders at baseline; however, significantly higher IgA rheumatoid factor levels were reported by the non-responder group (130.4 U/ml (interquartile range 13.8-276.7) v 24.8 U/ml (10.2-90.8); p = 0.003). A significant decrease (p<0.001) in the levels of all rheumatoid factor isotypes in the responder group was reported after 1 year of treatment, whereas anti-CCP antibody levels were not significantly affected. CONCLUSIONS: According to the clinical response, anti-TNFalpha agents seem to reduce IgM, IgG and IgA rheumatoid factor levels. More interestingly, high pretreatment levels of IgA rheumatoid factor are associated with a poor clinical response to TNFalpha inhibitors.
17142787 Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rh 2006 Dec 15 T cell activation and function are critically regulated by positive and negative costimulatory molecules. Aberrant expression and function of costimulatory molecules have been associated with persistent activation of self-reactive T cells in autoimmune diseases such as rheumatoid arthritis (RA). In this study, initial analysis of costimulatory molecules led to the unexpected observation that, in addition to CD80, several negative regulators (e.g., CTLA-4, programmed death-1 (PD-1), and PD ligand-1) were overexpressed in synovial T cells and macrophages derived from RA patients as opposed to controls. The expression of CD80 and PD ligand-1 on monocytes could be induced in vitro by IFN-gamma and TNF-alpha that were produced abundantly in RA-derived synovial fluid (SF). Furthermore, the soluble form of negative costimulatory molecules occurred at high concentrations in sera and SF of RA patients and correlated with titers of rheumatoid factor in RA patients. In particular, the levels of soluble PD-1 were found to correlate significantly with those of TNF-alpha in SF derived from RA patients. Detailed characterization of soluble PD-1 revealed that it corresponded to an alternative splice variant (PD-1Deltaex3) and could functionally block the regulatory effect of membrane-bound PD-1 on T cell activation. Our data indicate a novel pathogenic pathway in which overexpression of negative costimulatory molecules to restrict synovial inflammation in RA is overruled by the excessive production of soluble costimulatory molecules.
16739207 Trust in physicians and elements of the medical interaction in patients with rheumatoid ar 2006 Jun 15 OBJECTIVE: To identify components of the patient-doctor relationship associated with trust in physicians. METHODS: We assessed 102 patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) seen at publicly funded hospitals in Houston, Texas. Patients completed a self-response survey examining patient perceptions of the medical encounter and trust in their physicians. Evaluated components of physicians' behaviors included: informativeness, sensitivity to concerns, reassurance and support, patient-centeredness, and participatory decision-making style. Scales were scored 0 to 10, with higher numbers indicating more positive perceptions of communication. RESULTS: Seventy patients had RA and 32 SLE; 25% were white, 43% Latino, 31% African American, and 75% were female. Mean scores for the medical interaction and trust scales ranged from 6.2-7.1, indicating moderate degrees of positive perceptions. All components were highly and positively correlated with each other, and with trust, suggesting that these traits are all elements of a positive style of doctor-patient communication. In multivariate analysis, ethnicity, physicians' informativeness, physicians' sensitivity to concerns, patient-centeredness, disease activity, and patient trust in the US health care system were independent predictors of trust in physicians. A separate model examined the predictors of patient disclosure of information. Patient perceptions of physicians' patient-centeredness and severity of disease activity were independently predictive of patient disclosure of information. CONCLUSION: In patients with SLE and RA, trust in physicians is significantly associated with patients' ethnicity and their perceptions about specific components of physicians' communication style. Trust in physicians can be improved by using a patient-centered approach, being sensitive to patient concerns, and providing adequate clinical information. Furthermore, patients appear to be more willing to disclose concerns when physicians use a patient-centered communication style.
16831828 A survey of inclusion of the time element when reporting adverse effects in randomised con 2007 Jan BACKGROUND: The adequacy of reporting the time element in adverse effects in articles on randomised clinical trials of cyclo-oxygenase-2 and tumour necrosis factor (TNF)alpha antagonists was surveyed. METHODS: Prominent rheumatology and general/internal medicine journals were searched for all randomised controlled trials published about cyclo-oxygenase-2 and TNFalpha inhibitor use in rheumatological diseases up to November 2005. Reporting of time to the occurrence of the adverse effects, the use of patient years as the time frame of the reported adverse effects and the use of annual standard incidence ratios based on the surveillance, epidemiology and end-results (SEER) programme when reporting neoplasms as potential adverse effects of TNFalpha antagonists were specifically tabulated. RESULTS: Only 23 of 70 (33%) of all articles gave the specific time of onset of an adverse effect. Nine studies used patient years to report the adverse effects and six studies used annual standard incidence ratios, using SEER, as the comparator. CONCLUSION: In reporting of adverse effects in randomised clinical trials, a particularly neglected issue is the reporting of the time dimension of adverse effects.
15681243 Role for innate immunity in rheumatoid arthritis. 2005 Jan Innate immunity is the first line of defense against pathogenic microorganisms (bacteria, viruses, fungi, and parasites). After a long period of neglect, innate immunity is again recognized as a key mechanism not only in preventing invasion of the body by microorganisms, but also in contributing to the pathogenesis of autoimmune and inflammatory diseases by deviating the immune response or promoting the emergence of a regulatory response. The many factors involved in innate immunity often act in parallel or in alternation to generate adaptive immune responses. Innate immune responses are specific for groups of molecules or macromolecules found in components of microorganisms, usually the cell wall. The cellular and protein effectors of innate immunity are found in the rheumatoid synovium, and an increasing body of evidence indicates that they are directly involved in joint inflammation and in destruction of the joint cartilage and bone. In addition, they may have regulatory effects on inflammation and immunity. Whether innate immune mechanisms are causes or consequences of inflammation, and whether they regulate or amplify adaptive immune responses, they constitute a target of choice for new antiinflammatory and immunoregulating treatment strategies.
16960244 Use of biologics in rheumatoid arthritis: where are we going? 2006 Sep 15 PURPOSE: The pharmacology, efficacy, safety, and costs of biologic agents that are approved by the Food and Drug Administration or are under review for the management of rheumatoid arthritis (RA) are discussed. Biologic therapies that are currently under investigation in early- and late-phase clinical trials are summarized at the end of this report. SUMMARY: The use of biologic agents for the treatment of RA has significantly improved the management of this disease. Experimental and clinical studies have shown that these agents ameliorate the signs and symptoms of RA, slow radiographic progression of disease, and improve physical function and quality of life. Data also support that early initiation of therapy with these agents improves long-term outcomes. However, biologic agents are associated with adverse effects that health care providers need to recognize and manage. CONCLUSION: Biologic agents have revolutionized the treatment of RA by reducing the signs and symptoms of RA, slowing radiographic progression of joint destruction, and improving physical function and quality of life in affected patients.
16681944 [Inhibition of HLA-DRB1*0405 gene expression by siRNA]. 2006 Mar 21 OBJECTIVE: To investigate the effects of small interfering RNA (siRNA) of HLA DRB1(*)0405 HLA-DRB1(*)0405 gene expression with plasmid-based siRNAs. METHOD: Plasmid expressing HLA-DRB1(*)0405-renilla fusion protein-siCHECK-2/HLA-DRB1(*)0405, 6 different short hairpin RNAs (shRNAs) targeting 6 19 bp nucleotide sequences of HLA-DRB1(*)0405 (siRNA1 approximately 6), and one shRNA targeting the control non-specific sequence (siRNAC) were designed and constructed. Human embryonic kidney cells of the line 293 were cultured and co-transfected by lipids some with the plasmid siCHECK-2/HLA-DRB1(*)0405 and one specific shRNA expressing vector transiently, and cells without shRNA-transfection were used as negative controls. The impact of RNAi on HLA-DRB1(*)0405 expression was analyzed by real time fluorescence quantification RT-PCR and luciferase test. RESULTS: The expression of HLA-DRB1(*)0405 gene RNA of the 293 cells transfected with siRNA1, siRNA2, siRNA3, siRNA, and siRNA6 were down-regulated to 10.75%, 83.22%, 30.63%, 48.54%, and 89.92% that of the control group with the inhibition rates of 89.25%, 16.78%, 69.37%, 51.46%, and 10.08% respectively. However, no significant downregulation was showed in the cells transfected with siRNA4 and siRNAC. The 293 cells transfected with siRNA1 and siRNA 3 showed a significant downregulation of the protein expression of HLA-DRB1(*)0405 gene with the inhibitory rates of 6.70% and 36.85% respectively; however, the cells transfected with siRNA2, siRNA4, siRNA5, and siRNA6 did not show a significant downregulation. CONCLUSION: The significant inhibition of HLA-DRB1(*)0405 gene expression by siRNA suggests a therapeutic approach in rheumatoid arthritis: to use RNA interference (RNAi) to inhibit the abnormal immune reaction mediated by HLA-DRB1 in rheumatoid arthritis.
16820934 Expression of TNF-alpha, tristetraprolin, T-cell intracellular antigen-1 and Hu antigen R 2006 Aug Post-transcriptional regulation through the AU-rich element (ARE) by ARE binding proteins (ARBPs) has an important role in controlling the production of cytokines, including tumor necrosis factor (TNF)-alpha. Therefore, expression of ARBPs may influence, or may be influenced, by the severity of rheumatoid arthritis (RA). We measured the gene expression of ARBPs, including tristetraprolin, T-cell intracellular antigen (TIA)-1 and Hu antigen R (HuR), in synovial tissues from RA and osteoarthritis patients. cDNA was constructed from synovial tissues obtained from 21 patients with RA, and those from 12 patients with osteoarthritis. Gene expression was measured using the TaqMan PCR real-time quantification method. No significant differences were observed in the expression of tristetraprolin, TIA-1 or HuR genes between RA and osteo-arthritis synovium samples. No significant relationships between expression of tristetraprolin, TIA-1 or HuR genes and TNF-alpha gene expression serum CRP levels in samples from RA patients were observed. A significant positive relationship was observed between gene expression levels of TIA-1 and HuR. While HuR stabilizes TNF-alpha mRNA and enhances TNF-alpha production, TIA-1 acts as a post-transcriptional silencer, and suppresses the production of the TNF-alpha protein. The clear positive relationship between the expression of these two ARBPs may imply that the expression of either gene affects the expression of the other, or the mechanisms that control the expression of these genes have some factors in common.