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ID PMID Title PublicationDate abstract
12571844 Expression of the dendritic cell-associated C-type lectin DC-SIGN by inflammatory matrix m 2003 Feb OBJECTIVE: To determine whether matrix metalloproteinase (MMP)-producing inflammatory macrophages in the synovium of rheumatoid arthritis (RA) patients express the novel dendritic cell (DC)-specific C-type lectin DC-SIGN and whether this expression is associated with the presence of naive T cells expressing the DC-SIGN ligand, intercellular adhesion molecule 3 (ICAM-3). METHODS: Reverse transcription-polymerase chain reaction was performed to study the expression of DC-SIGN in synovium samples from RA, osteoarthritis (OA), and trauma patients. DC-SIGN expression on RA monocytes or on monocytes stimulated with granulocyte-macrophage colony-stimulating factor and interleukin-4 was further investigated by flow cytometry. To localize DC-SIGN in the synovium, the DC markers ICAM-3 and MMP-1 were analyzed by immunohistochemistry (single and double labeling) on serial cryostat sections. RESULTS: Seventy percent of the inflammatory cells in the synovium of RA patients showed high expression of DC-SIGN. DC-SIGN was expressed by 80% of CD68-positive macrophages, but not by CD83-positive, DC-LAMP-positive, or Fascin-positive cells. Normal numbers of DC-SIGN-positive cells were found in the peripheral blood of RA patients, suggesting that DC-SIGN is up-regulated locally in the joint. In RA synovium, ICAM-3-positive resting T cells were found in close proximity to DC-SIGN cells. Unexpectedly, a lower percentage of DC-SIGN-expressing cells was found in OA synovium compared with RA synovium. Furthermore, ICAM-3-expressing T cells, which are known to bind DC-SIGN, were almost absent within the synovium of OA and trauma patients. DC-SIGN-positive macrophages adjacent to these T cells were located in close proximity to the cartilage-degrading proteins extracellular MMP inducer (EMMPRIN) and MMP-1. CONCLUSION: The C-type lectin DC-SIGN is almost absent in the synovium of trauma patients but is highly expressed by most CD68-positive macrophages in the synovium of RA patients. The lack of correlation between DC-SIGN expression and the expression of CD83, DC-LAMP, or Fascin indicates that multiple DC/macrophage subsets are present in RA synovium. Expression of DC-SIGN and its ligand, ICAM-3, is found in substantial amounts only in RA synovium, suggesting that their interaction is implicated in the additional activation of synovial macrophages that leads to the production of EMMPRIN and MMP-1.
12695151 Arterial stiffness and central blood pressure, as determined by pulse wave analysis, in rh 2003 May BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular mortality for reasons which are insufficiently understood. Chronic inflammation may impair vascular function and lead to an increase of arterial stiffness, an important determinant of cardiovascular risk. OBJECTIVE: To investigate the augmentation index (AIx) as a measure of arterial stiffness in patients with RA, free of cardiovascular disease or risk factors, by means of a matched cohort pilot study. METHOD: Patients with a diagnosis of RA, aged 50 years or younger, were screened for the absence of clinical cardiovascular disease and risk factors, such as smoking, hypercholesterolaemia, hypertension, and excessive systemic steroid use. Suitable subjects were assessed by non-invasive radial pulse wave analysis to determine their AIx. These data were compared with those from healthy controls, matched closely for sex, age, mean peripheral blood pressure, heart rate, and height. RESULTS: 14 suitable patients (11 female; mean (SD) age 42 (6) years, mean RA duration 11 (6) years; mean C reactive protein 19 (15) mg/l, no clinical systemic rheumatoid vasculitis) and matched controls were identified. The RA group had a higher mean (SD) AIx and mean (SD) central blood pressure (BP) than the control group: AIx 26.2 (6.7) v 18.9 (10.8)%, p=0.028; mean central BP 91.3 (7.8) v 88.2 (8.9) mm Hg, p<0.0001, by two tailed, paired t test. CONCLUSIONS: This preliminary study suggests that RA is associated with increased arterial stiffness and central BP, independently of clinically manifest cardiovascular disease or risk factors. This may contribute to the increased cardiovascular mortality in RA.
12207127 Outcome of penetrating keratoplasty in rheumatoid arthritis. 2002 Jul BACKGROUND: Keratolysis in rheumatoid arthritis is a well-known disorder that may rapidly destroy the entire corneal stroma, resulting in descemetocele formation and eventually corneal perforation. The purpose of this study was to determine the anatomical and functional results of therapeutic penetrating keratoplasty (PK) in these patients. PATIENTS AND METHODS: We reviewed the charts of patients having undergone PK over a 5-year period and evaluated the outcome. In 16 eyes of 15 patients, PKs were performed (graft diameter 3.0-11.0 mm) because of corneal melting with perforation or descemetocele formation. In 9 eyes, we used topical cyclosporine A (2%) as an adjunct therapy after transplantation in addition to systemic immunosuppressive agents. RESULTS: Following a mean follow-up time of 17 months, anatomical success could be achieved in all eyes; none of the eyes underwent enucleation or evisceration. Postoperative complications following the first PK were epithelial keratopathy in 8 eyes (50%), corneal ulceration in 5 eyes (31%), fistulation in 4 eyes (25%), suture loosing in 4 eyes (25%) and graft rejection in 2 eyes (13%). Additionally 5 regrafts were required because of recurrence of corneal melting or persistent deep stromal defects. Comparison of complications of the patients receiving topical cyclosporine A to the control group showed a statistically significant lower incidence of epithelial keratopathy (p < 0.025) and ulcer recurrence in the cyclosporine A group during the first 3 months postoperatively (p < 0.05). The final best corrected visual acuity was 20/40 in 4 eyes but was limited to 20/200 or less in 7 eyes. CONCLUSION: Whereas PK can be successful to restore the anatomical integrity of severely altered eyes, the high prevalence of complications limits the indication for PK as a last stage procedure when other methods of management have failed. The use of topical cyclosporine A as adjunct therapy needs further evaluation.
12768477 Synergistic induction of apoptosis of rheumatoid arthritis synovial cells by H(2)O(2) and 2003 The effects of proteolysis inhibitors on hydrogen peroxide (H(2)O(2))-induced apoptosis were examined in cultured human synovial cells of rheumatoid arthritis (RA) patients. RA synovial cells were resistant to apoptosis induced by H(2)O(2). In the presence of 100 microM N-acetyl-leucyl-leucyl-norleucinal (ALLN, known as calpain inhibitor 1 and also a proteasome inhibitor), but not N-acetyl-leucyl-leucyl-methioninal (ALLM), apoptotic cell death was elicited by 400 microM H(2)O(2) at a concentration that alone never induced cell death. ALLN induced the expression of tumor suppressor p53 protein and p21(WAF-1) protein, probably through inhibition of proteasome. H(2)O(2) further potentiated ALLN-induced p53 expression. H(2)O(2) appeared to activate c-Jun N-terminal kinase (JNK) as well as extracellular signal-regulated kinase (ERK) and AKT. After administration of H(2)O(2) and p53 induction by ALLN, we found that either one alone is insufficient to induce apoptosis of RA synovial cells but their combination synergistically does so. These results suggest that induction of p53 by ALLN may be potentially important for triggering H(2)O(2)-induced apoptosis processes in RA synovial cells.
15325803 The polymorphisms of Th1 cell surface gene Tim-3 are associated in a Korean population wit 2004 Aug 15 The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of TIM family, TIM-3 is selectively expressed on the surface of differentiated Th1 cells. TIM-3 might have an important role in the induction of autoimmune diseases by regulating macrophage activation and interacts with TIM-3 ligand to regulate Th1 responses. In the present study, we analyzed the association of the genotype and allele frequencies between rheumatoid arthritis (RA) patients and the controls without RA using large samples size at the -1516G>T, -574T>G and 4259G>T polymorphic sites of human Tim-3 gene. We further investigated the relationships between the genotypes of each single nucleotide polymorphisms (SNPs) and C-reactive protein (CRP) or rheumatoid factor (RF) levels in RA patients. The genotype and allele frequencies of the -574T>G (P = 0.001 and 0.001, respectively) as well as the 4259G>T (P = 0.001 ands 0.003, respectively) between RA patients and non-RA controls were significantly different. These results strongly suggest that -574T>G and 4259G>T polymorphism of the Tim-3 might be associated with susceptibility to RA.
11868082 MRI of the arthritic finger joints: synovial membrane volume determination, a manual vs a 2002 Jan The aim of this study was to compare the stereology method for estimation of synovial volume on MR images with manually outlining method in inflammatory joint diseases. As manual outlining of the synovial volume is too time-consuming a method for clinical use, a less time-consuming methods are needed. Post-contrast 3D T1-weighted turbo gradient MR images of the finger (metacarpophalangeal and interphalangeal) joints (14 joints) were acquired from 11 patients with rheumatoid arthritis ( n=8) and reactive arthritis ( n=3). Manually outlined volume was taken as a gold standard and compared with stereologic volume estimation on transverse 1-mm-thick slices. The mathematical basis of the stereologic volume estimator is based on a two-step procedure: a 2D nucleator is used for estimation of the area of the synovial membrane on an MR slice and unbiased estimates of volumes are obtained by Cavalieri's principle. The 2D nucleator estimates the area of any object irrespective of its size, shape, and orientation by measuring the distance between a "central point" in the object and the intersections between the object boundary and radiating test lines. The total volume of 154 finger joints was estimated. A significant correlation between manual and stereologic estimations of synovial volumes was found (Spearman rho=0.71, P=0.002). Ninety-five percent limits of agreement were +/- 5-6 ml (14 finger joints per patient). The time used for volume determination in a patient varied from 1 to 2.5 h by manual outlining and from 0.5 to 1 h by stereologic determination. Stereologic volume estimation can provide measures of synovial volumes comparable to the manual outlining method and is less time-consuming. Stereologic volume estimation seems to be a clinically useful method, especially if it is integrated in the MR unit's workstation.
15458276 Effects of n-3 fatty acids on serum interleukin-6, tumour necrosis factor-alpha and solubl 2004 Sep We investigated the effects of a low n-6 fatty acid (FA) diet supplemented with fish oil on serum pro-inflammatory cytokine concentrations and clinical variables in patients with active rheumatoid arthritis (RA). Sixty patients were randomly assigned to receive a diet low in n-6 FAs and n-3 FAs supplement (fish oil group), a diet low in n-6 FAs and placebo (placebo group), or no special diet or intervention (control group). Serum cytokines and clinical and biochemical variables were evaluated at baseline and various timepoints. At week 18 the fish oil group had significant reductions in linoleic acid, C-reactive protein (CRP) and soluble tumour necrosis factor receptor p55 (sTNF-R p55), and significant elevations in eicosapentaenoic acid and docosahexaenoic acid compared with baseline. There were no significant differences in the clinical variables between the three groups. At week 24 there were significant reductions in interleukin-6 and TNF-alpha in the fish oil and placebo groups. Supplementation with n-3 FA and a low n-6 FA intake decreased serum sTNF-R p55 and CRP levels in patients with RA.
12885274 Cellular FLICE-inhibitory protein: an attractive therapeutic target? 2003 Aug Cellular FLIP (c-FLIP), also known as FLICE-inhibitory protein, has been identified as an inhibitor of apoptosis triggered by engagement of death receptors (DRs) such as Fas or TRAIL (TNF-related apoptosis-inducing ligand). cFLIP is recruited to DR signalling complexes, where it prevents caspase activation. Animal models have indicated that c-FLIP plays an important role in T cell proliferation and heart development. Abnormal c-FLIP expression has been identified in various diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), diabetes mellitus, rheumatoid arthritis (RA) and various cancers. This review focuses on recent insights into c-FLIP dysregulation associated with human diseases and addresses the possibilities of using c-FLIP as a therapeutic target.
11849114 Cytokine inhibitors in the treatment of rheumatoid arthritis. 2002 Feb Rheumatoid arthritis (RA) is an immune-mediated disease characterised by articular inflammation and subsequent tissue damage leading to severe disability and increased mortality. A variety of cytokines are produced locally in the rheumatoid joints. Numerous studies have demonstrated that IL-1 and TNF-alpha, two prototypic pro-inflammatory cytokines, play an important role in the mechanisms involved in synovial inflammation and in progressive joint destruction. Indeed, the administration of TNF-alpha and IL-1 inhibitors in patients with RA led to a dramatic improvement of clinical and biological signs of inflammation and a reduction of radiological signs of bone erosion and cartilage destruction. However, despite these encouraging results, a significant percentage of patients do not respond to these agents, suggesting that other mediators are also involved in the pathophysiology of arthritis. This review describes the results of clinical trials with TNF-alpha inhibitors and a specific IL-1 inhibitor (IL-1 receptor antagonist [IL-1Ra]). In addition, other therapeutic strategies are also discussed.
12734882 Corticotropin-releasing hormone promoter polymorphisms in patients with rheumatoid arthrit 2003 May OBJECTIVE: To investigate the possible implications of polymorphism in the CRH promoter in rheumatoid arthritis (RA) susceptibility, we examined a series of patients with RA from a defined area of Northwest Spain. METHODS: A total of 177 patients with RA and 147 ethnically matched controls from the Lugo region of Northwest Spain were studied. Patients and controls were genotyped for CRH polymorphisms in the 5' regulatory region of the gene at position 1273 (alleles A1 and A2) and at position 225 (alleles B1 and B2) by PCR-restriction fragment length polymorphism. Patients were stratified for age at onset of disease and rheumatoid factor status. RESULTS: When the whole group of patients was examined, no significant differences in CRH allele or genotype frequency were found compared with controls. However, the CRH allele A2 was significantly increased in patients with late onset seronegative RA compared with the seronegative group with younger age of disease onset (p = 0.03). In addition, 4 (36.4%) of the 11 patients with late onset seronegative RA carried the CRH-A2 allele versus only 2 (6.6%) of 31 patients with seronegative RA beginning before age 61 (OR 8.3, 95% CI 1.4-47.0; p = 0.015). CONCLUSION: In Northwest Spain, polymorphism in the CRH gene regulatory region may play a role as a disease susceptibility marker for late onset seronegative RA.
12672840 Acetabular revision with impacted morselized cancellous bone graft and a cemented cup in p 2003 Apr BACKGROUND: Acetabular revision in patients with rheumatoid arthritis is often difficult because of the poor quality and quantity of the acetabular bone stock. The purpose of this study was to evaluate the midterm clinical and radiographic outcomes of acetabular revision with use of an impaction bone-grafting technique and a cemented polyethylene cup. METHODS: Thirty-five consecutive acetabular revisions were performed with impaction bone-grafting and use of a cemented cup in twenty-eight patients with rheumatoid arthritis. The average age at the revision was fifty-seven years. The minimum duration of follow-up of all reconstructions that were still functioning or that were followed until the time of death was three years (mean, 7.5 years; range, three to fourteen years). No patient was lost to follow-up, but five patients (six hips) died before the time of the review. The acetabular bone defects were classified as cavitary in twelve hips and as combined segmental-cavitary in twenty-three. RESULTS: The five patients (six hips) who died had been doing well at the time of their latest follow-up. Of the remaining patients, six (six hips) had a repeat revision. The average Harris hip score of the living patients with a surviving implant at the time of follow-up was 82 points, and there was no or only mild pain in twenty-one of the twenty-three hips. Radiographic analysis of all twenty-nine hips that had not been revised showed loosening in one hip and a nonprogressive radiolucent line in one zone in two others. Kaplan-Meier analysis demonstrated a prosthetic survival rate, with aseptic loosening as the end point, of 90% at eight years. CONCLUSION: Acetabular revision with impaction bone-grafting and a cemented cup in patients with rheumatoid arthritis had acceptable results at an average of 7.5 years postoperatively.
15077289 Association of the major histocompatibility complex with response to infliximab therapy in 2004 Apr OBJECTIVE: To determine whether major histocompatibility complex (MHC) polymorphisms are associated with a good or poor response to infliximab therapy in patients with rheumatoid arthritis (RA). METHODS: Seventy-eight infliximab-treated patients with RA were genotyped for HLA-DRB1, HLA-DQA1, HLA-DQB1, MHC class I chain-related gene A (MICA) transmembrane polymorphism alleles, and tumor necrosis factor a (TNFa), TNFb, TNFc, TNFd, TNFe, D6S273, HLA-B-associated transcript 2 (BAT2), and D6S2223 microsatellites. Chi-square tests were performed to compare allele proportions between responder and nonresponder patients. A control sample of 342 healthy individuals was also included to detect linkage disequilibrium between pairs of markers. RESULTS: Among responders, the frequency of the TNFa11;b4 minihaplotype was increased (41% versus 16% in nonresponders; P = 0.01) and that of the D6S273_3 allele was decreased (32% versus 56% in nonresponders; P = 0.04). The D6S273_4/BAT2_2 pair was much more frequently observed among responders (46% versus 11% in nonresponders; P = 0.001). When compared with controls, this pair of alleles was found to be associated only with the group of responder patients (46% in responders versus 17% in controls; P = 0.00002). Most of the time, these markers are present in a DRB1*0404/D6S273_4/BAT2_2/TNFa11;b4 context. No statistically significant differences were observed for MICA and D6S2223 polymorphisms and for shared epitope status. CONCLUSION: The data suggest that genetic determinants of response to infliximab therapy exist in the HLA complex.
12453313 VLA-4-dependent and -independent pathways in cell contact-induced proinflammatory cytokine 2002 Nurse-like stromal cell lines from the synovial tissue of patients with rheumatoid arthritis (RA-SNC) produce, on coculture with lymphocytes, large amounts of proinflammatory cytokines. In the present paper, we analyze the molecular events necessary for the induction of cytokine release from RA-SNC cells, and particularly the roles played by cell adhesion and the transmigration (also known as pseudoemperipolesis) of lymphocytes. For this purpose, the effects of various mAbs on the binding and transmigration of a human B-cell line, MC/car, were examined using a cloned RA-SNC line, RA-SNC77. To analyze the role of lymphocyte binding and transmigration on upregulated cytokine production by the RA-SNC77 cells, we used C3 exoenzyme-treated MC/car cells, which could bind to RA-SNC77 cells but could not transmigrate. Treatment with anti-CD29 or anti-CD49d mAb significantly reduced binding and transmigration of the MC/car cells. In contrast, the neutralizing anti-CD106/vascular cell adhesion molecule 1 mAb did not show any inhibitory effect. Likewise, none of the neutralizing mAbs against CD11a, CD18, CD44, CD49e, or CD54 showed significant effects. Binding of C3-treated or untreated MC/car cells to RA-SNC77 cells induced comparable levels of IL-6 and IL-8 production. In addition, the enhanced cytokine production by RA-SNC77 cells required direct lymphocyte contact via a very late antigen-4 (VLA-4)-independent adhesion pathway. These results indicate that, although both the VLA-4-dependent/vascular cell adhesion molecule 1-independent and the VLA4-independent adhesion pathways are involved in MC/car binding and subsequent transmigration, only the VLA4-independent adhesion pathway is necessary and sufficient for the enhanced proinflammatory cytokine production by RA-SNC77 cells. The transmigration process, which is dependent on Rho-GTPase, is not a prerequisite for this phenomenon.
12748811 Unstable pelvic insufficiency fracture in a patient with rheumatoid arthritis. 2004 Jan The occurrence of pelvic insufficiency fractures in patients with rheumatoid arthritis has not previously been well emphasized. These fractures are difficult to detect clinically, and appropriate radiological investigation is necessary for diagnosis. A 72-year-old woman with rheumatoid arthritis presented with severe left groin pain. Pelvic radiographs showed parasymphyseal fractures, and marked instability of these fractures was observed at the follow-up 2 weeks later. Computed tomographic scan of the sacrum showed a widened linear fracture gap in the left sacral ala. Because the patient's pain was so severe that she could not change position, external fixation was performed to achieve rapid pain relief and early mobilization. Although most patients with these fractures respond well to simple conservative treatments, parasymphyseal fractures combined with sacral fractures may cause disruption of the pelvic ring and occasionally need operative management.
15287534 Respiratory symptoms in rheumatoid arthritis: relation between high resolution CT findings 2004 May PURPOSE: The objectives of this study were to analyze the high resolution computed tomography (HRCT) findings in rheumatoid arthritis (RA) patients with respiratory symptoms and to evaluate the relation between the extent of HRCT findings and functional impairment as assessed by spirometry. MATERIALS AND METHODS: HRCT examination of the thorax and pulmonary function tests (PFTs) were performed in 34 RA patients with respiratory symptoms. Patients with smoking history or with emphysema evident on HRCT were excluded from the study. CT findings were assessed for the presence and pattern of abnormalities. Extent was scored based on the number of pulmonary segments involved. PFTs included forced expiratory flows (FEFs) and forced vital capacity (FVC). RESULTS: Bronchial wall thickening was detected in 29 of 34 RA patients (85%), small nodules in 24 patients (71%), and bronchial dilatation in 21 patients (62%). The extent of bronchial wall thickening correlated with FEF25-75, FEF75, and FEF50 (p<0.0001, respectively) (Spearman's rank correlation). Extent of small nodules correlated with FEF25-75, FEF50, and FEF25 (p<0.01, respectively). Stepwise regression analysis showed independent correlations of bronchial wall thickening with decreases in FEF25-75 and FEF75 (p<0.0001, both). Bronchial dilatation was also independently associated with a decrease in FVC (p<0.05). CONCLUSION: The most common HRCT findings in RA patients with respiratory symptoms are bronchial wall thickening and small nodules, and the extent of these findings correlates significantly with functional impairment.
14997006 Patient- versus physician-reported outcomes in rheumatoid arthritis patients treated with 2004 Jun OBJECTIVES: To determine whether patient-reported outcomes may differentiate treatment response better than physician-reported outcomes for rheumatoid arthritis (RA) patients being treated with anakinra. METHODS: A meta-analysis was conducted using data obtained from three separate randomized controlled clinical trials (RCTs) (n = 1007). Outcomes from 6-month assessments were grouped into four categories: American College of Rheumatology (ACR) response criteria, patient-reported measures (patient-reported pain, patient global assessment, and assessment of physical function using the Health Assessment Questionnaire), physician-reported measures (tender and swollen joint counts and physician global assessment), and laboratory tests (C-reactive protein and erythrocyte sedimentation rate). Effect sizes were calculated using changes from baseline and pooled standard deviations for each of these types of outcome. RESULTS: Active treatment with anakinra was superior to placebo by ACR(20) responses in all three RCTs. Effect sizes for patient-reported outcomes were greater than for physician-reported outcomes, and also greater than ACR(20) in three of five anakinra cohorts. Across the RCTs, placebo responses were greater with physician-reported than with patient-reported outcomes. In the two studies evaluating patients with longer-standing disease, differences between pooled effect sizes for patient-reported and physician-reported outcomes were even more pronounced. CONCLUSIONS: In three pivotal RCTs, active treatment with anakinra resulted in greater improvements in patient-reported than physician-reported outcomes compared with placebo. These observations confirm those previously reported from RCTs evaluating conventional DMARDs, demonstrating better discrimination of treatment effect with patient-reported outcomes.
12754134 [Analysis of the relation between serum immunoglobulin and auto-antibody levels in patient 2003 May OBJECTIVE: To explore the relationship between serum immunoglobulin (Ig) levels and the positivity rate for auto- antibodies in patients with rheumatoid arthritis (RA). METHODS: The levels of immunoglobulins (IgG, IgM, IgA) and rheumatoid factor (RF) were measured using Olympus AU600 system, and indirect immunofluorescence and immunoblotting methods were employed respectively for detecting the autoantibodies in the serum from 40 RA patients and 30 normal adults. Statistical analysis of the relation between the Ig levels and autoantibodies was performed. RESULTS: Compared with normal control group, significantly higher serum IgA, IgG and IgM levels were detected in RA patients (P < 0.01), and at least one autoantibody was present in the serum sample from 26 out of the 40 RA patients, who had the highest RF positivity rate of 20% (8 cases). The serum IgA level in autoantibody-positive patients was significantly higher than that in autoantibody-negative ones (P < 0.01), and in the 18 patients with serum IgA level beyond the normal range, 15 (83.3%) were positive for autoantibody, while in the 22 patients with normal serum IgA level, the autoantibody positivity rate was only 50% (11/22), showing significant difference (P < 0.05). CONCLUSION: Serum immunoglobulins A (IgA) level is closely associated with the positivity rate for autoantibodies in RA patients, and RA patients with serum IgA level beyond the normal range was more likely to be positive for the autoantibodies.
15044921 Latent Epstein-Barr virus (EBV) infection and cytomegalovirus (CMV) infection in synovial 2004 Jul In rheumatoid arthritis (RA) viral triggers, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV), have been suggested. By PCR analysis DNA of several viruses among which EBV, CMV, and parvovirus B19 (B19) has been detected in RA synovial fluid and synovial tissue. In 63 synovial tissues of 29 rheumatoid arthritis (RA), 6 psoriatic arthritis (PsA), 26 reactive arthritis/synovitis (rA/S), and two normal synovial cases, we recently could demonstrate a high percentage of replicative B19 infection within the synovial tissue, being significantly more frequent in autoimmune arthritis. To further investigate the influence of synovial virus infections in rheumatoid arthritis, we now analyzed the same sample of synovial tissues for CMV and EBV infections by DNA-in situ hybridization (CMV), EBER1/2-RNA-in situ hybridization (EBV), and immunohistochemistry. A significant latent EBV infection of synovial lining cells, synovial fibroblasts, and/or infiltrating lymphocytes was identified in 5/29 (17.2 %) RA, 1/6 (16.7%) PsA, and to a much lower degree in 1/26 (3.8%) rA/S specimens. CMV-DNA was detected in 31% of RA, 3/6 (50%) of PsA, and 11.5% of rA/S. Immunohistochemical analysis of CMV early antigen revealed replicative CMV activity in 20.7% of RA and 2/6 (33.3%) of PsA specimens but not in reactive arthritis synovia. Comparative analysis of the EBV-, CMV-, and published B19-data demonstrated that relevant synovial virus infections in general and furthermore double or multiple infections are far more common in autoimmune arthritis than in rA/S. A triple virus infection was found solely in RA in 10.3% of cases. The evidence of increased synovial persistence of EBV, CMV, or B19 either alone or even more as coinciding infections may further reinforce the notion of a primary role of these viruses in autoimmune arthritis.
15066863 Treatment with tumour necrosis factor alpha antagonists in patients with rheumatoid arthri 2004 Sep OBJECTIVE: To determine the frequency and clinical impact of anticardiolipin antibodies (aCL) in patients with rheumatoid arthritis treated with infliximab and etanercept. METHODS: 121 patients from the Stockholm tumour necrosis factor alpha (TNFalpha) follow up registry (STURE) treated with infliximab or etanercept were studied. RESULTS: At baseline 9/65 (14%) infliximab and 10/56 (18%) etanercept treated patients had positive aCL. After 3 months the frequencies of aCL positivity were 29% (p<0.05 compared with baseline) and 27%, respectively, and after 6 months 28% and 25%. Increases were seen for both IgG and IgM aCL. Increasing age, a higher number of prior DMARDs, and higher DAS28 were predictors for the development of aCL. In the infliximab treated patients, 26/30 (87%) aCL(-) but only 7/14 (50%) aCL(+) patients met the ACR20 criteria (p<0.05), and the frequency of treatment limiting infusion reactions in the aCL(+) patients was higher than expected (17%). aCL positivity in the etanercept treated patients did not show such a clinical correlate. Four patients had thromboembolic events, of whom two were aCL(+) and two aCL(-). CONCLUSION: Frequencies of both IgM and IgG aCL positivity increase in patients treated with these TNFalpha antagonists for 3 months or longer. Increasing age, a greater number of prior DMARDs and a greater disease activity at baseline are predictors for the development of aCL. The development of aCL during treatment with infliximab, but not etanercept, is associated with worse clinical results and more frequent serious infusion reactions. aCL are an important class of autoantibodies associated with TNFalpha blocking therapy.
12672180 Interleukin 10 treatment of patients with rheumatoid arthritis enhances Fc gamma receptor 2003 Apr OBJECTIVE: Several clinical studies performed with human recombinant interleukin 10 (IL-10) in patients with rheumatoid arthritis (RA) have shown little efficacy. We investigated potentially proinflammatory in vivo effects of IL-10 in humans. We evaluated the upregulation of Fc gamma receptor (Fc gamma R) expression on monocytes/macrophages (and granulocytes) in patients with RA receiving different dosages of IL-10. METHODS: Together with changes in disease activity and several cell markers, the expression of Fc gamma RI, Fc gamma RIIa, and Fc gamma RIII was determined on granulocytes and monocytes/macrophages from the peripheral blood of 6 patients with active RA before and after treatment with recombinant human IL-10. In addition, the in vitro effect of IL-10 on Fc gamma R expression on monocytes/macrophages in combination with their susceptibility to immune complex induced production of tumor necrosis factor-alpha(TNF-alpha) was assessed. RESULTS: Clinical improvement was not observed in the IL-10 treated patients (based on ACR20 criteria). Significant decreases in thrombocyte numbers were observed in patients receiving IL-10. No changes in cell markers such as CD14 were found. On the other hand, expression of Fc gamma RI and Fc gamma RIIa on monocytes/macrophages was increased upon high dose IL-10 treatment. Interestingly, increases in expression of Fc gamma RI and Fc gamma RIIa correlated with a decrease in thrombocyte numbers. In vitro, IL-10 similarly upregulated Fc gamma RI and Fc gamma RIIa expression on monocytes/macrophages from RA patients. This was accompanied by increased TNF-a production after immune complex stimulation. CONCLUSION: These findings indicate that upregulation of Fc gamma R expression in RA with IL-10 treatment may counteract the otherwise antiinflammatory effects of IL-10 by potentiating immune complex mediated proinflammatory responses.