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ID PMID Title PublicationDate abstract
16460970 Falls risk is associated with pain and dysfunction but not radiographic osteoarthritis in 2006 Jun OBJECTIVE: To describe the association between knee and hip radiographic osteoarthritis (ROA), a measure of knee pain, stiffness and functional ability and objectively measured physiological falls risk predictors. METHODS: Cross-sectional, population-based study of 850 randomly selected men and women aged 50-80 years (mean 62.5, SD 7.4). Falls risk (Z score) was determined objectively with the short form Physiological Profile Assessment (PPA). Two observers assessed knee and hip ROA using the Altman atlas. Pain, stiffness and functional ability were assessed using the Western Ontario McMasters Osteoarthritis index (WOMAC). RESULTS: Overall, the study population was at a mild risk of falling. In multivariable analysis, the WOMAC function and pain score were significantly associated with reaction time, balance, proprioception, knee extension strength, and edge contrast sensitivity. Stiffness was associated with knee extension strength and edge contrast sensitivity. Males had a dose response association between the global WOMAC score and falls risk (r=0.17, P<0.001). Those who reported a global WOMAC score of 50 and above had a higher risk of falling compared to those with a score below 50 (Z score: 0.53 vs 0.14, P<0.001). Hip joint space narrowing (JSN) was significantly associated with knee extension strength (r=-0.10, P=0.003), however, no other significant associations were observed between ROA and falls risk predictors. CONCLUSION: Self-reported functional ability and pain, and to a lesser extent, stiffness (but not knee and hip ROA), have a modest but independent association with physiological predictors of falls risk.
16342095 Pattern of infliximab utilization in rheumatoid arthritis patients at an academic medical 2005 Dec 15 OBJECTIVE: To investigate the pattern of use of infliximab with an emphasis on treatment escalation and the durability of infliximab use in the management of rheumatoid arthritis (RA) in an academic setting. METHODS: We conducted a retrospective review of pharmacy and medical records of 183 patients with RA who received at least 1 infliximab infusion at the infusion centers of the Brigham and Women's Hospital. Treatment escalation was defined as an increase in the dosage of infliximab to >3 mg/kg and/or a decrease in the dosing interval to <7 weeks between infusions. RESULTS: A total of 183 patients with RA received infliximab infusions for a mean +/- SD duration of 58.2 +/- 56.6 weeks. Infliximab was discontinued in 48% of the patients during the first year of therapy and in 67% of the patients overall. A total of 126 patients had a treatment escalation, including 25 patients with a dose increase, 35 patients with a decrease in the interval, and 66 patients with both. Infliximab treatment was associated with a decrease in corticosteroid and methotrexate doses. Patients who had a treatment escalation were more likely to continue infliximab infusions compared with patients without a treatment escalation (odds ratio 2.0, 95% confidence interval 1.0-4.1). CONCLUSION: The use of infliximab may be an effective treatment for RA; however, a substantial number of patients will discontinue its use. Treatment escalation is commonly used in the management of RA with infliximab and is associated with longer duration of infliximab use.
16173242 Hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis. 2005 Sep OBJECTIVE: To study the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatoid arthritis (RA). METHODS: Fifty patients with RA participated in 3 groups: recent onset active RA (n = 20), longstanding active RA (n = 20) and long-standing RA in remission (n = 10), and were compared with 20 healthy controls. The activity of the HPA-axis was assessed under basal conditions and in response to stress (insulin tolerance test, ITT). In addition, patients with recent onset RA underwent a corticotropin releasing hormone (CRH) test and a dexamethasone suppression test. Plasma levels of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha) and IL-6 were also measured. RESULTS: Basal plasma, salivary and urinary cortisol levels and plasma adrenocorticotropic hormone (ACTH) levels were not different between patients with RA and healthy controls. During the ITT, cortisol levels were consistently lower in RA patients than in healthy controls. ACTH levels during the ITT were not different between patients with RA and healthy controls. ACTH and cortisol responses to CRH were assessed only in patients with recent onset RA and were found to be within normal limits. Basal circulating plasma IL-6 levels were significantly higher in patients with active RA than in the other groups. CONCLUSION: Under the standardized conditions of the ITT, patients with RA have decreased plasma cortisol levels compared to healthy controls, despite elevated levels of IL-6. The defect is probably located at the adrenal level and may be of pathogenetic significance for the development of chronic arthritis.
16265687 Safety and efficacy of rituximab in patients with rheumatoid arthritis refractory to disea 2005 Nov OBJECTIVE: To determine the safety and efficacy of rituximab treatment in patients with active seropositive rheumatoid arthritis (RA) who had experienced an inadequate response to treatment with anti-tumor necrosis factor-alpha agents and/or traditional disease modifying antirheumatic drugs. METHODS: Rituximab was administered to 17 patients as weekly infusions for 4 consecutive weeks. Patients continued their baseline therapy and were followed for 28 weeks. RESULTS: All patients were evaluable for safety, and 13 for efficacy. Profound B cell depletion occurred by 12 weeks and was sustained at 24 weeks, whereas T cell, complement, and immunoglobulin levels remained within normal ranges. Rituximab was well tolerated, with no infusion related reactions and only mild/moderate adverse events. American College of Rheumatology 20% response (ACR20) was achieved in 55% of patients by Week 5, 75% by Week 8, 50% at Week 16, and 67% at Week 28. Corresponding ACR50 and ACR70 responses were achieved in 36% and 18%, 25% and 17%, 42% and 25%, and 33% and 17% of patients at Weeks 5, 8, 16, and 28, respectively. There were significant improvements over baseline in tender and swollen joint counts (p < 0.0001), physician's global assessment of disease activity (p = 0.0001), and patient assessed pain (p = 0.0005) and disability (p = 0.0386). Erythrocyte sedimentation rate (p = 0.0361) and rheumatoid factor titers (p < 0.0001) also decreased significantly. CONCLUSION: These results support the hypothesis that B cells play an important role in RA pathophysiology, and suggest that rituximab is effective and well tolerated, with a rapid onset of clinical benefit, in patients with refractory, seropositive active RA.
17009241 The -786C/T single-nucleotide polymorphism in the promoter of the gene for endothelial nit 2006 Oct OBJECTIVE: Shear stress is the main physiologic stimulus for the expression of NOS3, the gene for human endothelial nitric oxide synthase. Interestingly, a promoter variant of the NOS3 gene, the -786C variant, is insensitive to shear stress, and individuals homozygous for this single-nucleotide polymorphism (SNP) have an increased risk of developing coronary artery disease. The cytokine interleukin-10 (IL-10) is also capable of up-regulating endothelial NOS3 expression through binding of the transcription factor STAT-3 to a nearby promoter sequence. The aim of this study was to explore the possibility that the -786C variant of the NOS3 gene is also insensitive to IL-10 and that individuals with the -786C/C genotype are more prone to developing rheumatoid arthritis (RA). METHODS: Endothelial cells were isolated from human umbilical cord veins, clonally expanded, and analyzed for NOS3 and IL-12 expression by real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Umbilical cord arteries and blood samples from RA patients were genotyped for the -786C/T SNP of the NOS3gene. RESULTS: In contrast to cells of other genotypes, endothelial cells of the -786C/C genotype did not reveal an increase in NOS3 expression upon exposure to IL-10, and the cytokine failed to suppress IL-12 expression upon stimulation of CD40. Preincubation of these cells with a 16-mer C-type decoy oligonucleotide fully reconstituted the defective IL-10-induced suppression of IL-12 synthesis. The frequency of the -786C/C genotype was significantly higher in the 596 RA patients than in the general population (19.1% versus 12.1%; P < 0.0001). CONCLUSION: Individuals with the -786C/C genotype have an increased risk of developing RA. This may be explained by the IL-10 insensitivity of the C-type NOS3 gene promoter and the resulting failure to subdue CD40-mediated proinflammatory gene expression.
17109072 Taurine chloramine inhibits proliferation of rheumatoid arthritis synoviocytes by triggeri 2006 Oct OBJECTIVE AND DESIGN: Taurine chloramine (Tau-Cl), originating from activated neutrophils, possesses antiinflammatory activities. Fibroblast-like synoviocytes (FLS) participate in the chronic synovitis and synovial membrane hyperplasia that are characteristic pathological features of rheumatoid arthritis (RA). The present study was conducted to investigate the mechanism of the Tau-Cl effect on the proliferation of these cells in culture. MATERIALS AND METHODS: FLS were stimulated in vitro with platelet derived growth factor (PDGF) alone or together with Tau-Cl. Cell proliferation was evaluated by counting the total and dividing cell numbers and by measurement of (3)H-thymidine incorporation. Expression of the key cell-cycle regulators was evaluated at the protein (Western blotting) and/or mRNA (RT-PCR) levels. RESULTS: Treatment of RA FLS with Tau-Cl (200-500 microM) resulted in an early nuclear accumulation of p53 tumor suppressor protein. Moreover, Tau-Cl inhibited PDGF-triggered cell proliferation (IC(50) value approximately 250-300 microM), accompanied by characteristic modulation of p53 transcriptional targets: down-regulation of proliferating cell nuclear antigen (PCNA) and survivin, and concomitant up-regulation of p21 mitotic inhibitor. CONCLUSION: We propose that Tau-Cl inhibits proliferation of RA FLS by triggering a p53-dependent cell-cycle arrest and conclude that this compound suppresses pathways in FLS that are known to contribute to the pathology of RA.
15990313 Rate of blood loss over 48 hours following total knee replacement. 2005 Aug The purpose of this study was to determine the rate of blood loss after total knee arthroplasty and assess the efficacy of drains using autologous blood transfusion. A prospective study was undertaken of 100 consecutive patients undergoing routine total knee arthroplasty. The diagnosis was osteoarthritis in 85% of patients and rheumatoid arthritis in 12% of cases. The rate of blood loss was recorded hourly for the first 12 h, 4 hourly for the subsequent 12 h and 6 hourly for the following 24 h. Autologous blood was reinfused within 12 h of surgery according to the protocol. Eighty-four percent of the total blood drained, was collected in the first 12 h and 94% in the first 24 h. 69% of the total blood which was drained was reinfused. The mean preoperative haemoglobin was 13.18 gm/dl and 10.23 gm/dl on the 5th day. A mean volume of 70-80 ml of homologous blood was reinfused in addition to the autologous transfusion in 11 of the 100 cases. There were no cases of deep or superficial sepsis, nor any identifiable complications related to the autologous blood transfusion. This study suggests it is safe to remove the postoperative joint drain after the 12-h period.
16736517 CD40 ligation of rheumatoid synovial fibroblasts regulates RANKL-mediated osteoclastogenes 2006 Jun OBJECTIVE: To determine whether CD40 ligation of rheumatoid arthritis synovial fibroblasts (RASFs) is able to induce RANKL expression and osteoclastogenesis in RASFs, and to identify its mechanism of action in patients with RA. METHODS: CD40 of RASFs was ligated with CD40 ligand (CD40L)-transfected L cells or activated T cells. The formation of osteoclasts in cocultures of CD40-ligated RASFs and T lymphocyte-depleted peripheral blood mononuclear cells was evaluated by tartrate-resistant acid phosphatase staining, detection of calcitonin receptor, and resorption pit formation assay. The expression of NF-kappaB, IkappaB alpha, ERK-1/2, phospho-ERK-1/2, p38, phospho-p38, and RANKL was examined by immunoblotting and/or semiquantitative reverse transcription-polymerase chain reaction. RESULTS: CD40 ligation of RASFs by CD40L-transfected L cells or activated T cells induced RANKL expression and enhanced osteoclastogenesis. CD40 ligation of RASFs also induced activation of ERK-1/2, p38 MAPK, and NF-kappaB and up-regulation of CD40 ligation-induced RANKL expression, whereas osteoclastogenesis was reduced in RASFs transfected with a dominant-negative mutant of IkappaB alpha or by an NF-kappaB inhibitor. However, specific inhibitors of MAPK/ERK-1/2 and p38 MAPK partially blocked the induction of RANKL expression and osteoclastogenesis. Monoclonal antibodies against interleukin-1 and tumor necrosis factor alpha partially inhibited CD40 ligation-mediated osteoclastogenesis. CONCLUSION: These results indicate that CD40 ligation of RASFs induces RANKL expression mainly via NF-kappaB activation and also results in enhanced osteoclast formation, both of which might play important roles in bone and cartilage destruction in RA. Inhibition of the CD40-CD40L interaction is a potential strategy for the prevention of bone damage in RA.
16848914 Are bone erosions detected by magnetic resonance imaging and ultrasonography true erosions 2006 The objective of the study was, with multidetector computed tomography (CT) as the reference method, to determine whether bone erosions in rheumatoid arthritis (RA) metacarpophalangeal (MCP) joints detected with magnetic resonance imaging (MRI) and ultrasonography (US), but not with radiography, represent true erosive changes. We included 17 RA patients with at least one, previously detected, radiographically invisible MCP joint MRI erosion, and four healthy control individuals. They all underwent CT, MRI, US and radiography of the 2nd to 5th MCP joints of one hand on the same day. Each imaging modality was evaluated for the presence of bone erosions in each MCP joint quadrant. In total, 336 quadrants were examined. The sensitivity, specificity and accuracy, respectively, for detecting bone erosions (with CT as the reference method) were 19%, 100% and 81% for radiography; 68%, 96% and 89% for MRI; and 42%, 91% and 80% for US. When the 16 quadrants with radiographic erosions were excluded from the analysis, similar values for MRI (65%, 96% and 90%) and US (30%, 92% and 80%) were obtained. CT and MRI detected at least one erosion in all patients but none in control individuals. US detected at least one erosion in 15 patients, however, erosion-like changes were seen on US in all control individuals. Nine patients had no erosions on radiography. In conclusion, with CT as the reference method, MRI and US exhibited high specificities (96% and 91%, respectively) in detecting bone erosions in RA MCP joints, even in the radiographically non-erosive joints (96% and 92%). The moderate sensitivities indicate that even more erosions than are seen on MRI and, particularly, US are present. Radiography exhibited high specificity (100%) but low sensitivity (19%). The present study strongly indicates that bone erosions, detected with MRI and US in RA patients, represent a loss of calcified tissue with cortical destruction, and therefore can be considered true bone erosions.
15989000 [Experience in long-term therapy of active rheumatoid arthritis with leflunomide]. 2005 AIM: To study therapeutic potential of a novel basic drug leflunomide in suppression of activity and progression of rheumatoid arthritis (RA). MATERIAL AND METHODS: Leflunomide efficacy was investigated in a 36 month trial including 50 patients with moderate and high activity RA. Monthly registrations were made of the articular syndrome quantitative parameters (Richi's index, number of painful and swollen joints, severity of pain and general condition of the patient), morning stiffness duration, ESR, CRP, RF. Leflunomide efficacy was assessed by EULAR and ACR criteria. Dynamics of the extrajoint manifestations observed in 70% patients before therapy were examined clinically and by device tests. Speed of progression of erosive arthritis was quantified by a modified Sharp's method in hand and foot joints, carpal bones each 6 months. Arava tolerance was controlled clinically and by laboratory tests. RESULTS: Leflunomide was found effective in 94% RA patients. A rapid (within the first month) and significant improvement in parameters of articular syndrome and CRP level was observed. To month 4 of therapy 1/5 patients achieved remission by EULAR criteria, to month 12--1/3 patients. By ACR criteria, 6-month leflunomide treatment produced good and exellent results in 71% patients which persisted up to the 36th month of therapy. The effect was better in shorter history of RA, moderate RA, in the absence of osteolyses and ankyloses. Leflunomide significantly reduced RF concentration in the serum, suppressed extrajoint RA manifestations (except Sjogren's syndrome). The mean number of new joint erosions for 6 consecutive months was 2.93 +/- 3.2, 1.41 +/- 1.8, 0.78 +/- 2.0 (median 0), while progression coefficient corresponded to slow progression to the treatment month 18. No new erosions occurred after 12 months of arava treatment in 41% patients and after 18 months--in 62%. CONCLUSION: Leflunomide is well tolerated. The drug was discontinued because of cutaneous pruritus and diarrhea in 5 and 1 patients, respectively.
17086604 Echocardiographically guided pericardiocentesis for treatment of clinically significant pe 2006 Nov OBJECTIVE: To assess the safety and efficacy of echocardiographically guided pericardiocentesis for patients with rheumatoid arthritis (RA) and hemodynamically significant pericardial effusion. METHODS: We identified 16 patients with RA who underwent 18 echocardiographically guided pericardiocentesis procedures at our institution over a 20-year period. Clinical and laboratory characteristics of the patients, response to treatment, complications, and need for future pericardial surgery were abstracted from the echocardiography database. RESULTS: Ten patients were men and 6 were women (mean age, 62 yrs; range, 36-75 yrs). On average, patients were diagnosed with RA 11 years before pericardial disease developed. Twelve of 15 patients were seropositive for rheumatoid factor, 10 patients had radiographic evidence of erosions, and 7 patients had rheumatoid nodules. Cardiac tamponade was present in 11 of the 18 cases. Mean volume drained on the first pericardiocentesis was 504 +/- 264 ml (range 120-1000 ml). The fluid was an exudate with a mean protein concentration of 5 g/dl (range 3.3-51.1 g/dl). All cultures and cytologic findings were negative for bacteria and neoplastic cells. No serious complications resulted from echocardiographically guided pericardiocentesis. For 11 patients, a catheter was placed for intermittent drainage over an average of 3 days. Seven patients ultimately required a more definitive surgical procedure. CONCLUSION: Echocardiographically guided pericardiocentesis is a safe and effective treatment for this uncommon but serious complication of RA.
15934085 Regulation of arthritis by p53: critical role of adaptive immunity. 2005 Jun OBJECTIVE: The p53 tumor-suppressor protein is expressed in rheumatoid arthritis synovium, and loss of p53 function through somatic mutation can occur in longstanding disease. Previous studies demonstrated that p53 is protective in murine collagen-induced arthritis (CIA). To determine if adaptive immune responses or synovial effector functions are responsible for this effect, passive models of arthritis were studied in p53 wild-type and knockout mice. METHODS: Models of passive CIA, passive K/BxN serum transfer arthritis, and active CIA were induced in DBA/1 p53(-/-) or p53(+) mice. Hind paws were evaluated for histologic evidence of inflammation and joint destruction. Synovial interleukin-6 and matrix metalloproteinases 3 and 13 gene expression was analyzed by real-time quantitative polymerase chain reaction. To evaluate T cell function in p53(-/-) mice, draining lymph node (LN) cells from mice immunized with type II collagen (CII) were evaluated in vitro. RESULTS: Increased disease severity in p53(-/-) mice was confirmed in the standard CIA model. However, clinical arthritis, joint destruction, and synovial gene expression in the passive CIA and K/BxN serum transfer arthritis models were similar in p53(-/-) and p53(+) mice. To determine if the p53 effect was related to T cell function, LN cells from CII-immunized mice were isolated and stimulated with antigen in vitro. CII-stimulated T cell proliferation and interferon-gamma production were significantly higher in p53(-/-) mice. An independent assessment of Th1 function using the cutaneous delayed-type hypersensitivity model confirmed that p53(-/-) mice have enhanced T cell responses in vivo. CONCLUSION: Adaptive immune responses, rather than antibody-mediated responses, in p53(-/-) mice account for increased disease severity in the active CIA model.
16492735 IL-32, a proinflammatory cytokine in rheumatoid arthritis. 2006 Feb 28 IL-32 is a recently discovered cytokine that induces TNFalpha, IL-1beta, IL-6, and chemokines. We investigated whether IL-32 is expressed in the synovia of patients with rheumatoid arthritis (RA) and studied associations with disease severity and the presence of other cytokines. Immunohistochemistry revealed that IL-32 is highly expressed in RA synovial tissue biopsies, whereas IL-32 was not observed in synovial tissues from patients with osteoarthritis. Moreover, in synovial biopsies from 29 RA patients with active disease, the level of IL-32 staining correlated with erythrocyte sedimentation rate, a marker of systemic inflammation (R = 0.63 and P < 0.0003). Synovial staining of IL-32 also correlated with indices of synovial inflammation (R = 0.80 and P < 0.0001) as well as synovial presence of TNFalpha (R = 0.68 and P < 0.004), IL-1beta (R = 0.79 and P < 0.0001), and IL-18 (R = 0.82 and P < 0.001). IL-32 was a potent inducer of prostaglandin E(2) release in mouse macrophages and human blood monocytes, an important property for inflammation. After the injection of human IL-32gamma into the knee joints of naïve mice, joint swelling, with pronounced influx of inflammatory cells and cartilage damage, was observed. In TNFalpha-deficient mice, IL-32-driven joint swelling was absent and cell influx was markedly reduced, but loss of proteoglycan was unaffected, suggesting that IL-32 activity is, in part, TNFalpha-dependent. IL-32, strongly associated with TNFalpha, IL-1beta, and IL-18, appears to play a role in human RA and may be a novel target in autoimmune diseases.
15986373 Tumor necrosis factor alpha blockade treatment down-modulates the increased systemic and l 2005 Jul OBJECTIVE: Abnormal host defense against pathogens has been implicated in the pathogenesis of spondylarthropathy (SpA), a disease characterized by abundant synovial infiltration with innate immune cells. Given the role of Toll-like receptors (TLRs) in activation of innate inflammation and the occurrence of TLR-dependent infections after tumor necrosis factor alpha (TNFalpha) blockade treatment, the present study was undertaken to analyze TLRs and their modulation by TNFalpha blockade in SpA. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from SpA and rheumatoid arthritis (RA) patients during infliximab therapy, and from healthy controls. TLR-2 and TLR-4 expression and TNFalpha production upon lipopolysaccharide (LPS) stimulation were analyzed by flow cytometry on different monocyte subsets. Synovial biopsy specimens from 23 SpA patients before and after infliximab or etanercept treatment, from 15 RA patients, and from 18 osteoarthritis (OA) patients were analyzed by immunohistochemistry. RESULTS: Expression of TLR-4, but not TLR-2, was increased on PBMCs from patients with SpA, whereas both TLRs were increased in RA patients. TLR expression was particularly increased on the CD163+ macrophage subset. Infliximab reduced TLR-2 and TLR-4 expression on monocytes of SpA and RA patients, leading to lower levels than in controls and to impaired TNFalpha production upon LPS stimulation. In inflamed synovium, the expression of both TLRs and of CD163 was significantly higher in patients with SpA than in those with RA or OA. Paralleling the systemic effect, TLRs in synovium were down-regulated following treatment with infliximab as well as etanercept, indicating a class effect of TNFalpha blockers. CONCLUSION: Inflammation in SpA is characterized by increased TLR-2 and TLR-4 expression, which is sharply reduced by TNFalpha blockade. These findings suggest a potential role of innate immunity-mediated inflammation in SpA and provide an additional clue regarding the mechanism of action as well as the potential side effects of TNFalpha blockade.
15717466 [Difficult airway management during emergency tracheostomy in a patient with severe rheuma 2005 Jan We experienced difficult airway management in a 65-year-old woman with acute dyspnea due to bilateral recurrent nerve palsy suffering from severe rheumatoid arthritis for fifty years. Her cervical spine was ankylosed and could not be extended at all. Tracheostomy was planned under local anesthesia because of difficulty of endotracheal intubation, possibility of airway obstruction and laryngeal edema. In this condition, the surgical area was narrow and difficult to approach. The surgical bleeding and blood-aspiration into the tracheostomy site occurred followed by airway obstruction. A rigid tracheal tube could not be inserted through the tracheal incision and SpO2 decreased to 81%. We inserted a percutaneous cricothyroidotomy cannula through the tracheal incision and superimposed HFJV on her spontaneous ventilation. Assisting the ventilation in this way finally, a spiral endtracheal tube was inserted and her oxygenation became stable.
15692975 Regulation of myeloid cell function and major histocompatibility complex class II expressi 2005 Feb OBJECTIVE: Tumor necrosis factor (TNF)-neutralizing agents are the most successful means of ameliorating systemic autoimmune inflammation. Neutralization of TNF, however, is often associated with the development of autoantibodies, particularly to nuclear antigens, and the mechanisms of this are unknown. We undertook this study to analyze the effect of TNF and its neutralization on the expression of major histocompatibility complex class II molecules and on the function of antigen-presenting myeloid cells in rheumatoid arthritis (RA). METHODS: Monocytes were isolated from the peripheral blood of RA patients before and after anti-TNF monoclonal antibody (mAb) treatment and from the peripheral blood of controls by negative selection, differentiated in vitro to macrophages, and analyzed by flow cytometry for HLA-DR expression. T cell responses to activation by myeloid cells were assessed in proliferation assays, and messenger RNA (mRNA) levels of the class II transactivator (CIITA) were determined by semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: HLA-DR expression was significantly reduced on myeloid cells from RA patients with active disease, but was increased to normal levels after anti-TNF mAb treatment. Concordantly, in vitro application of TNF to monocytes from healthy individuals reduced their ability to up-regulate HLA-DR during differentiation to macrophages and, importantly, inhibited their ability to stimulate T cells in mixed lymphocyte reactions. Molecular analysis revealed that the effect of TNF on HLA-DR expression was mediated via suppression of the transcription factor CIITA. CONCLUSION: The data indicate that TNF decreases HLA-DR expression by reducing CIITA mRNA levels in myeloid cells, functionally resulting in a decreased capacity of myeloid cells to stimulate T cells. Concordantly, ameliorating disease activity in chronic inflammatory diseases by neutralizing TNF restores expression of HLA-DR on myeloid cells as well as the ability of myeloid cells to stimulate T cells. Thus, anti-TNF treatment might lead to augmented T cell activation by myeloid cells, thereby promoting immune responses to (auto)antigens and the development of antinuclear antibodies that are frequently associated with anti-TNF therapy.
15389525 Downregulation of rheumatoid arthritis-related antigen RA-A47 (HSP47/colligin-2) in chondr 2005 Jan Previously, we showed that gene expression of the rheumatoid arthritis-related antigen RA-A47, which is identical to human heat shock protein (HSP)47, was downregulated in chondrocytes by inflammatory cytokines such as TNFalpha. Associated with this phenomenon, RA-A47 appeared on the cell surface concomitant with upregulation of metabolic factors related to cartilage destruction. The upregulation of the metabolic factors could be achieved by downregulation of RA-A47 expression with ra-a47-specific anti-sense oligonucleotide. Here, we show that the enhanced surface expression of RA-A47 on a chondrocytic cell line, HCS-2/8 was also a direct result of RA-A47 downregulation by ra-a47 anti-sense oligonucleotide, independent of the cytokine effects. Moreover, cell-surface expression of CD9, a beta1 integrin-associated transmembrane protein that is involved in cell adhesion and cell motility events, was enhanced in the ra-a47 anti-sense oligonucleotide-treated cells. The CD9 was colocalized with RA-A47 on the cell surface, where it may have affected integrin signaling. Furthermore, Annexin-V binding to the cell surface and the level of a number of apoptosis-related genes including caspase-9 were increased after ra-a47 anti-sense oligonucleotide treatment, suggesting that enhanced surface expression of RA-A47 and CD9 may be initiating apoptosis. Differential screening using a cDNA gene array showed induction of metallothionein-III and chemokine receptor CXCR4 and of factors of the Notch signaling pathway by the anti-sense treatment, but not by TNFalpha. Thus, here we show for the first time an alternative mechanism of inducing apoptosis by downregulating molecular chaperones, independent of the action of TNFalpha. The surface-exposed RA-A47 may induce autoantibodies and inflammatory reactions in autoimmune disease situations such as rheumatoid arthritis.
16060691 Is the Fab-fragment from monoclonal rheumatoid IgM flexible? A spin label dynamics study. 2005 Oct A comparative study of the Fab- and Fab-RF-fragments in the molecules of monoclonal IgM and IgM-RF, respectively, was performed by the spin label method. The spin label, 2,2,6,6-tetramethyl-4-dichloro-triazinylaminopiperidine-1-oxyl, was introduced into the peptide part of the protein. On the basis of the data on the temperature-viscosity dependences of the EPR spectral parameters of the resultant spin-labeled proteins, the rotational correlation time tau of the spin carrier was determined. It turned out that the reduced to normal conditions tau values for the molecules of the Fab- and Fab-RF-fragments were 21+/-2 and 11+/-1 ns, respectively. Analysis of the resultant data provides sufficient grounds for assuming that such a sharp decrease in the tau value for the molecule of the Fab-RF fragment is due to local flexibility of its globular structure, which, in turn, can determine the specific features of the IgM-RF functioning as an autoantibody.
15777996 Association between systemic lupus erythematosus, rheumatoid arthritis, hyperprolactinemia 2005 Jan BACKGROUND: Hyperprolactinemia (hyperPRL) has been associated with autoimmune rheumatic disorders and the presence of thyroid autoantibodies (tAb). The interrelation between these variables was the focus of this prospective study. METHODS: The study assessed six groups of individuals: 26 with systemic lupus erythematosus (SLE), 20 with rheumatoid arthritis (RA), 28 with tAb (tAb+), 14 with untreated hyperprolactinemia (hyperPRL), 10 with treated hyperPRL, and a control group (n = 28). Prolactin (PRL), free thyroxin, TSH, antibodies against thyroglobulin (TgAb), thyroid microsomal antigen (MsAb) and/or thyroid peroxidase (TPOAb) were determined in all patients. Those with hyperPRL had macroprolactin investigated by the polyethylene glycol (PEG) precipitation method. RESULTS: PRL (ng/mL) levels in the SLE, RA, and tAb+ groups were, respectively, 21.3 +/- 12.6, 11.5 +/- 7.4, and 12.5 +/- 8.6, and were significantly greater in the SLE group (p = 0.006) than in the controls (12.5 +/- 6.5) and in the other groups. Five patients had hyperPRL: three with SLE, one with RA, and one with tAb+. Macroprolactinemia was detected in three of the untreated hyperprolactinemic patients and in the hyperprolactinemic patient of the tAb+ group. Positivity for any of the tAb was 15% in the SLE, 15% in the RA, 57.1% in the untreated hyperPRL, 10% in the hyperPRL on treatment, and 3.6% in the control group. The presence of antibodies was significantly more frequent in the untreated hyperPRL group than in the control group (p = 0.001). CONCLUSIONS: The results indicate that the PRL level is higher in SLE patients and that in the presence of hyperPRL there is increased prevalence of antithyroid antibodies, evidencing the association of PRL and autoimmunity and pointing to the appropriateness of assessing and monitoring the progress of these markers in patients affected by these disorders.
15004722 The production of CXCR3-agonistic chemokines by synovial fibroblasts from patients with rh 2005 Jun The inflamed synovial tissue of rheumatoid arthritis (RA) is characterized by an infiltration with Th1 cells that predominantly express the chemokine receptors CXCR3 and CCR5. In this study, we investigated the production of the CXCR3-agonistic chemokines CXCL9, CXCL10, and CXCL11 by synovial tissue cells and synovial fibroblast-cell lines (fourth or fifth passage) from RA patients. Concentrations of all CXCR3 ligands in synovial fluids were markedly higher in RA patients than in osteoarthritis (OA) patients. Synovial tissue cells from RA patients more strongly expressed mRNAs for CXCR3 ligands and spontaneously secreted larger amounts of these chemokine proteins than the cells from OA patients. The mRNA expression of all CXCR3 ligands was induced in synovial fibroblasts from RA patients after stimulation with interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), or interleukin-1 beta (IL-1beta). However, synovial fibroblasts significantly secreted CXCL9 and CXCL10 proteins, but not CXCL11 protein, after IFN-gamma stimulation and secreted only CXCL10 protein after TNF-alpha or IL-1beta stimulation. When stimulated with a combination of IFN-gamma and TNF-alpha, these cells were able to secrete large amounts of all three chemokines. These results indicate that synovial fibroblasts may be involved in perpetuating the Th1 immune response by producing the Th1-associated CXCR3 ligands, and the synergistic effect of IFN-gamma and TNF-alpha may be important for their chemokine production in RA joints.