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ID PMID Title PublicationDate abstract
12674768 Relationship between glucocorticoid-induced osteoporosis and vitamin D receptor genotypes. 2002 By means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, the association between vitamin D receptor (VDR) genotypes and bone mineral density (BMD) in the patients receiving long-term glucocorticoid therapy was studied. The clinical data and blood of 71 patients with rheumatosis who received long-term glucocorticoid therapy were collected. BMD was measured by dual-energy X-ray absorptimometry. VDR gene fragment (about 185 bp) was amplified by PCR from the extracted genomic DNA, then digested with restriction endonuclease Bsm I. The genotypes were evaluated based on the fragment length following endonuclease digestion and the association between genotypes and BMD or Z-score values was analyzed. Among the 71 cases, the detected genotypes were Bb and bb with the distribution frequency being 11.3% and 88.7% respectively. The distribution frequency of the alleles was in agreement with the Hardy-Weinberg equilibrium. There was no significant difference between the two genotypes in age, gender, body mass index (BMI), disease duration, disease types, time of glucocorticoid administration and cumulative dosage (P > 0.05). Osteoporosis rate of the patients with Bb or bb genotype was 37.5% and 33.3% respectively, with the difference being not significant (chi 2 = 0.05, P = 0.8). The BMD and Z-score values at lumbar spine and femur in two genotypes were not similar, but the difference had no significant (P > 0.05). The distribution frequency of bb type of VDR genotypes in Han populations of China was more prevalent, followed by Bb and bb types in turn. In the patients receiving long-term glucocorticoid therapy, there was no significant difference in BMD between Bb and bb genotypes. The data suggest that the VDR genotypes may not be means of identifying patients at greater risk of glucocorticoid-induced osteoporosis, which await to be further confirmed by a large sample size.
12923598 Spinal epidural lipomatosis with thoracic osteoporotic compression fracture causing parapl 2003 Jun Spinal epidural lipomatosis (SEL) frequently occurs as a result of long-term steroid administration for various disorders, and patients often present with osteoporosis. Acute paraplegia in patients with extensive thoracic SEL is rare. We report a case of acute paraplegia caused by osteoporotic compression fracture with extensive thoracic SEL in a 44-year-old man with rheumatoid arthritis who had received steroid therapy for 4 years. He presented initially with abdominal distension and weakness of lower limbs, and a sudden onset of paraplegia with complete motor and sensory loss below the T6 level ensued. Plain radiographs showed an osteoporotic compression fracture of the T6 vertebra. Magnetic resonance imaging showed osteoporotic compression fractures of the T5 and T6 vertebrae and SEL from T2 to T10 vertebrae. Decompressive laminectomy with epidural fat debulking was performed, and the pathology was confirmed as epidural lipomatosis. His neurological condition showed no improvement below the T6 level 3 months after surgery. Osteoporotic compression fracture is a risk factor for acute paraplegia in patients with thoracic SEL and decompressive surgery should be performed without delay.
12937131 Detection of oncofetal h19 RNA in rheumatoid arthritis synovial tissue. 2003 Sep The expression of oncofetal H19 RNA and its localization/cellular source was analyzed in synovial tissue (ST) and isolated synovial macrophages (Mphi) or synovial fibroblasts (SFBs) by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. RT-PCR showed significantly higher H19 expression in ST from patients with rheumatoid arthritis (RA) (P = 0.000) and osteoarthritis (OA) (P = 0.009) than in normal/joint trauma controls (N/JT), but comparable levels in reactive arthritis. In situ hybridization demonstrated strong signals in all RA-ST samples (n = 8), with > or =85% positive cells in the lining layer, diffuse infiltrates, and stroma regions. In lymphoid aggregates and endothelial cells only 20% were positive. RA-ST contained a significantly higher percentage of strongly positive lining cells than OA-ST and N/JT-ST. H19 RNA was expressed in both Mphi and SFBs, as confirmed by RT-PCR in isolated RA Mphi and SFBs (n = 3). In RA-SFBs, low constitutive H19 RNA expression in culture (10% fetal calf serum) was strongly increased on starvation (3.5-fold, 1% fetal calf serum), with or without the addition of interleukin-1beta (10 to 100 U/ml), tumor necrosis factor-alpha (1 to 25 ng/ml), or platelet-derived growth factor-BB (2.5 to 10 U/ml). In OA-SFBs, this starvation-induced increase was lower (twofold), reaching significant differences compared with RA-SFBs after stimulation with interleukin-1beta and platelet-derived growth factor-BB. In both RA- and OA-SFBs, the MAP-kinase ERK-1/2 pathway and the phosphatidylinositol-3 kinase pathway influenced H19 RNA expression, as shown by inhibitor studies. Significant overexpression of H19 RNA and its increased sensitivity to starvation/cytokine regulation in RA suggests a pathogenetic role of this oncofetal gene, possibly reflecting embryonal dedifferentiation of the adult ST and/or ongoing inflammatory/oxidative stress.
12954238 Detection of collagen type II and proteoglycans in the synovial fluids of patients diagnos 2003 Sep OBJECTIVE: We have sought to determine if markers of proteoglycans and collagen type II (CII) degradation can be detected at an early stage following acute knee injury in the synovial fluid (SF) from a group of patients diagnosed with non-infectious knee joint synovitis (KJS). CII, proteoglycans and elastase activity in the SF from patients with KJS were compared to SF from patients with two chronic arthritis conditions: osteoarthritis (OA) and rheumatoid arthritis (RA) as well as normal SF controls. METHODS: CII peptides were measured by sandwich ELISA using two monoclonal antibodies: 8:6:D8, a CII-specific antibody, and 14:7:D8 which binds to an amino acid sequence on CII as well as collagens type I, III and V. Epitope 9A4, a neo-epitope resulting from collagenase digestion of CI, CII, and CIII was measured by inhibition ELISA. Proteoglycans measurement included total sulfated glycosaminoglycans (sGAG) by dye-binding assay and 5-D-4 epitope, a keratan sulfate epitope, by inhibition ELISA. Elastase activity was measured colorimetircally using N-succinyl trialanine p-nitroanilide (SANA) substrate. RESULTS: The quantified CII peptide concentrations by sandwich and inhibition ELISA were significantly higher in SF from patients with KJS (P<0.05) compared to SF from patients with OA, RA and normal aspirates. 5-D-4 and sGAG concentrations were significantly lower (P<0.05) in SF from patients with KJS compared to SF from patients with OA and RA. Elastase activity in SF from patients with KJS and RA were significantly higher (P<0.05) than SF from patients with OA. A significant correlation exists between elastase activity and 9A4 epitope concentration in SF from patients with KJS. CONCLUSION: The elevated CII peptides concentrations in KJS SF compared to normal and OA aspirates indicate early signs of cartilage network damage. The low proteoglycans concentrations in SF from patients with KJS may indicate that injury is limited to the superficial zone of cartilage in the patient population studied. The high elastase activity in SF from patients with KJS and RA are linked to the high CII peptides concentration. The elastase activity in the SF from patients with KJS is due to the action of neutrophil elastase (NE) and collagenases, where both contribute to the destruction of the articular cartilage.
12180437 Induction of anti-RA33 hnRNP autoantibodies and transient spread to U1-A snRNP complex of 2002 Jul OBJECTIVE: Anti-RA33 antibodies occur in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD) and target the A2/B1 protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex 4 which forms part of the spliceosome. The aim of the present study was to evaluate the immune response and pathological features induced in mice immunized with anti-RA33 antibodies or patient-derived recombinant single-chain variable fragments (scFv) of anti-RA33 antibodies. METHODS: In the first set of the experiment, two strains of mice (C57BL/6J and BALB/c) were immunized with IgG preparations obtained from two patients with RA and one normal donor. One of the patients had high titer anti-RA33 antibodies; the other one showed weak borderline reactivity. In the second set of the experiment three groups of C57BL/6J mice were immunized, respectively, with affinity-purified (AP) anti-RA33 antibodies, scFv of anti-RA33 antibodies and normal human IgG. The immunological response induced in immunized mice was studied by immunoblotting and line immunoassay (LIA). The presence of arthritis, serositis or myositis was assessed six-months following initial immunization. RESULTS: While anti-RA33 antibodies developed in only two of the mice immunized with different human IgG fractions, anti-RA33 antibodies were clearly detected in 7 sera of 13 mice immunized with AP anti-RA33 antibodies three months after the boost immunization and, moreover, also in 2 sera of 13 mice immunized with scFv of anti-RA33 antibodies. In contrast, mice immunized with normal human IgG did not develop anti-RA33 antibodies. Interestingly, transient autoantibody production against another nuclear autoantigen, U1 snRNP, was observed in 3 C57BL/6J mice immunized with scFv and in 1 mouse immunized with AP autoantibodies. However, these immunological responses were not associated with pathological findings. CONCLUSIONS: Active immunization of naive mice with AP anti-RA33 antibodies and scFv of anti-RA33 antibodies resulted on the one hand in the production of murine anti-RA33 antibodies and led, on the other hand, to transient "autoantibody spread" to snRNP component of the spliceosome and other nuclear autoantigens. This "autoantibody spread" probably reflected disregulation of the idiotypic anti-idiotypic cascade.
12904888 Immunopathogenesis of collagen arthritis. 2003 Aug Collagen-induced arthritis (CIA) is an animal model of autoimmunity that has been studied extensively because of its similarities to rheumatoid arthritis (RA). CIA is induced in genetically susceptible strains of mice by immunization with type II collagen (CII), and both T cell and B cell immunity to CII are required for disease manifestation. Like RA, CIA is primarily an autoimmune disease of articular joints and susceptibility to CIA is linked to specific class II molecules of the major histocompatibility complex (H-2(r) and H-2(q)). Recently, it was demonstrated that transgenic expression of HLA-DR1 (*0101) or DR4 (*0401) molecules associated with susceptibility to RA also conferred susceptibility to CIA in the mouse model. The T cell response to CII has been extensively characterized in both the DR transgenic and naturally susceptible mouse strains, including the antigenic determinants recognized, the role of post transcriptional modifications of these determinants in the pathogenic T cell response, and the cytokines produced. Like most class II-mediated autoimmune diseases, the cytokine production of CII-specific T cells reflects a Th1 phenotype of the autoimmune response. While the direct role of T cells in the pathogenesis of CIA is unclear, the B cell response in terms of anti-CII immunoglobulin is critical to the development of the disease. This response, predominated by the IgG2 isotype, requires the activation of the complement cascade for the development of CIA. In recent years, the pathogenesis of this model has been studied extensively and the CIA model is proving to be a valuable asset for the design of new immunotherapeutics for the potential treatment of RA and other autoimmune diseases.
15312407 [The expression and significance of costimulatory molecule in peripheral blood B lymphocyt 2004 Jul OBJECTIVE: To research the mechanisms of immune function disorder in the patients with rheumatoid arthritis (RA). METHODS: Monoclonal antibodies against CD(80), CD(86), CD(40) were used for flow cytometry and expression of costimulatory molecule CD(80), CD(86), CD(40) on peripheral blood B lymphocytes was studied in patients with RA, and healthy human were used as control groups. We also used enzyme linked immunosorbent assay to detect the cytokines level of Th1 cell including interleukin (IL)-2, interferon-gamma and those of Th2 cell including IL-6, IL-10. These samples are serum and synovial fluid of patients with RA, respectively. RESULTS: Compared with control group, the expression of CD(86) on peripheral blood B lymphocytes in patients with RA was obviously decreased (P < 0.01), the expression of CD(40) was also significantly increased (P < 0.05). No statistically significant differences in CD(80) positive peripheral blood B lymphocytes between RA group and control group were observed. Comparing with control group, the level of IL-2 and interferon-gamma in serum and synovial fluid of patients with RA are obviously increase (P < 0.01 or P < 0.05). While, the level of IL-6 and IL-10 are decrease (P < 0.01 or P < 0.05). CONCLUSIONS: The disorder expression of costimulatory molecule CD(86), CD(40) on peripheral blood B lymphocytes may be associated closely with the imbalance of Th1/Th2 cytokines level in patients with RA. These will give us a new idea on the therapeutic strategy of RA.
12571629 Lentivirus-mediated expression of angiostatin efficiently inhibits neovascularization in a 2003 Feb Ischemic retinal diseases, such as diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration, are a major cause of blindness worldwide. Angiostatin is an internal peptide fragment of plasminogen that inhibits endothelial proliferation in vitro and tumor growth in vivo. We now demonstrate that HIV vector encoding angiostatin (HIV-angiostatin) can inhibit retinal neovascularization in a mouse model of proliferative retinopathy. Intravitreal injections of HIV-angiostatin led to stable expression of the angiostatin gene in retinal tissue. Retinal neovascularization was histologically quantitated by a masked protocol. Retinal neovascularization in the eye injected with HIV-angiostatin was reduced in 90% (9/10; P=0.025) of animals, compared with the eye injected with phosphate-buffered saline. Reduction of histologically evident neovascular nuclei per 6-microm section averaged 68%, with maximal inhibitory effects of 87%. Neovascularization was not reduced in the eyes injected with HIV vector encoding enhanced green fluorescent protein. This is the first report that HIV-angiostatin can reduce neovascular cell nuclei in a murine proliferative retinopathy model. These data suggest that the anti-angiogenic activity of angiostatin has therapeutic potential for the treatment of retinal neovascularization.
12695149 Suprascapular nerve block (using bupivacaine and methylprednisolone acetate) in chronic sh 2003 May BACKGROUND: Shoulder pain from inflammatory arthritis and/or degenerative disease is a common cause of morbidity in the community. It is difficult to treat and there are limited data on the efficacy of most interventions. Suprascapular nerve block has shown promise in limited trials in reducing shoulder pain. There have been no large randomised placebo controlled trials examining the efficacy of suprascapular nerve block for shoulder pain in arthritis and/or degenerative disease using pain and disability end points. OBJECTIVE: To perform a randomised, double blind, placebo controlled trial of the efficacy of suprascapular nerve block for shoulder pain in rheumatoid arthritis (RA) and/or degenerative disease of the shoulder. METHODS: 83 people with chronic shoulder pain from degenerative disease or RA took part in the trial. If a person had two painful shoulders, these were randomised separately. A total of 108 shoulders were randomised. Patients in the group receiving active treatment had a single suprascapular nerve block following the protocol described by Dangoisse et al, while those in the other group received a placebo injection of normal saline administered subcutaneously. The patients were followed up for 12 weeks by an observer who was unaware of the randomisation and reviewed at weeks 1, 4, and 12 after the injection. Pain, disability, and range of movement data were gathered. RESULTS: Clinically and statistically significant improvements in all pain scores, all disability scores, and some range of movement scores in the shoulders receiving suprascapular nerve block compared with those receiving placebo were seen at weeks 1, 4, and 12. There were no significant adverse effects in either group. CONCLUSION: Suprascapular nerve block is a safe and efficacious treatment for the treatment of shoulder pain in degenerative disease and/or arthritis. It improves pain, disability, and range of movement at the shoulder compared with placebo. It is a useful adjunct treatment for the practising clinician to assist in the management of a difficult and common clinical problem.
15212963 Anti-angiogenic effects of Shiraiachrome A, a compound isolated from a Chinese folk medici 2004 Jun 28 The Chinese folk medicine Shiraia bambusicola has long been utilized in the treatment of rheumatoid arthritis, a disease in which angiogenesis plays an important role. We report here the isolation of the compound Shiraiachrome A from S. bambusicola and the demonstration of its anti-angiogenic properties. We found that Shiraiachrome A significantly inhibited the proliferation, migration, and tube formation of human microvascular endothelial cells (HMEC) in a dose-dependent manner, with average IC(50) values of 2.1+/-0.36, 1.97+/-0.44, and 1.65+/-0.59 microM, respectively. In addition, Shiraiachrome A inhibited the formation of new microvessels in a rat aorta culture model as well as in the chick embryo chorioallantoic membrane (CAM) assay. Investigation of the mechanism of action of Shiraiachrome A demonstrated that this compound suppressed the autophosphorylation of four receptor tyrosine kinases (RTKs), with IC(50) values ranging from 2.2 to 4.3 microM. These results suggest that Shiraiachrome A inhibits angiogenesis by blocking growth factor-stimulated autophosphorylation of RTKs. These findings also indicate that Shiraiachrome A may be a potent therapeutic agent for angiogenesis-related diseases such as cancer, rheumatoid arthritis, and diabetic retinopathy.
12084003 Rheumatoid arthritis: developing pharmacological therapies. 2002 Jul Rheumatoid arthritis (RA) is a chronic inflammatory disease that, despite recent advances in therapy, still results in significant morbidity, mortality and disability. The aetiology remains unknown and past therapies, although helpful for the majority of patients, have been suboptimal. The recent introduction of newer agents has changed the treatment paradigm of RA. COX-2 inhibitors, anti-TNF agents and interleukin-1 antagonists have allowed us to treat RA more effectively with relatively low risk of side effects. Investigations of other possible treatment pathways, such as inhibition of angiogenesis, may produce still better treatment and rapid unraveling of the immune system and how it relates to RA greatly enhances the opportunities for improved therapeutics in RA.
12867385 The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine 2003 Jul PURPOSE: To define the risk of hydroxychloroquine (HCQ)-related retinal toxicity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who are receiving recommended dosages of the drug (< or =6.5 mg/kg/day). DESIGN: Prospective cohort study, from 1985 to 2000. PARTICIPANTS: Greek patients with RA (n = 335) and SLE (n = 191) treated with HCQ, 400 of whom had completed at least 6 years of treatment. METHODS: Ophthalmologic evaluation was performed every 6 months from 1985 to 1995, and yearly thereafter. This consisted of best-corrected visual acuity, color vision testing, static central visual field testing, fundoscopy, electroretinography, and fluorescein angiography, when indicated. MAIN OUTCOME MEASURES: Fundus lesions attributed to HCQ. RESULTS: No HCQ retinal toxicity was noted in any of the 526 patients during the first 6 years of treatment. Two (3.4%) of the first 58 long-term (>6 years) treated patients developed HCQ-related maculopathy at 8 and 6.5 years of treatment, despite regular ophthalmologic evaluation. On follow-up 7 and 9 years after cessation of HCQ treatment, both patients had stable eye disease. No HCQ retinal toxicity was observed in the subsequent 342 patients who were treated for >6 years. Overall, the incidence of HCQ-related retinopathy in 400 patients who were treated with recommended dosages of the drug for a mean of 8.7 years was reduced to 0.5%. CONCLUSIONS: After a baseline ophthalmic examination to confirm the absence of preexisting fundus pathology, patients with normal renal function may receive HCQ at a maximal daily dosage of 6.5 mg/kg and continue safely for 6 years. However, annual screening is recommended in patients who have taken the drug, even in recommended doses, for >6 years.
12913924 Recombinant human monoclonal autoantibodies specific for citrulline-containing peptides fr 2003 Aug OBJECTIVE: To isolate and characterize monoclonal autoantibodies (Mab) directed to citrullinated antigens from patients with rheumatoid arthritis (RA). METHODS: Using lymphocytes from bone marrow or peripheral blood from RA patients, we constructed antibody fragment libraries representing the antibody repertoire of these individuals. Antibody fragments recognizing a citrulline-containing peptide were selected from these patient libraries. Individual antibody clones were analyzed for germline gene usage and reactivity toward citrullinated (auto)-antigens. RESULTS: Sequence analysis of the cDNA encoding the 21 distinct antibody fragments that were obtained revealed a restricted germline gene usage. Individual antibody clones were positive in both antiperinuclear factor (APF) and antikeratin antibody (AKA) tests, stained citrullinated filaggrin and fibrinogen on Western blots, and reacted with subsets of citrulline-containing peptides in ELISA, but not with noncitrullinated peptides. CONCLUSION: Our report describes the first recombinant human Mab fragments reactive with citrulline-containing peptides. The restricted germline gene usage of these antibodies, and the fact that the VH alleles used are not present in all individuals, may indicate the existence of a genetic predisposition for the development of anticitrulline antibodies in individuals with these germline alleles. The selected antibody clones may facilitate studies on the role of these autoantibodies and their target antigens in the development of RA.
14655010 [Intra-articular injection. Substances and techniques]. 2003 Dec Intra-articular injections are widely used in the treatment of joint pain and/or inflammation. Low costs, effectiveness, and safety are offered as possible reasons. The method remains controversial, as the evidence supporting the efficacy of these procedures has been poor. To evaluate intra-articular therapy, a meta-analysis of the efficacy of various agents injected intra-articularly was performed. Furthermore, indications and medications are discussed.
11908554 Dose response and safety study of meloxicam up to 22.5 mg daily in rheumatoid arthritis: a 2002 Mar OBJECTIVE: This Phase III, placebo and active controlled, multicenter trial evaluated the efficacy and safety of meloxicam 7.5, 15, and 22.5 mg daily for the treatment of rheumatoid arthritis (RA). METHODS: A 12 week, randomized, double blind, double dummy, parallel group trial compared daily oral meloxicam 7.5, 15, and 22.5 mg to placebo (negative control) and diclofenac 75 mg BID (positive control). A total of 894 patients (18 years of age with confirmed RA who flared following an NSAID-free period) were randomized to be treated. Baseline scores for all endpoints were similar among the treatment groups. Patient assessments were at 0, 2, 4, 8, and 12 weeks or early termination. RESULTS: All treatment groups demonstrated significant improvement from baseline (p < 0.001). Meloxicam 7.5 and 22.5 mg was significantly superior to placebo in all 5 primary efficacy endpoints (swollen joint count, tender joint count, patient pain, patient and physician global; all p < 0.05). Diclofenac 150 mg was superior to placebo for 4 of 5 primary efficacy measures (all but swollen joint count; p < 0.05) and meloxicam 15 mg was superior for 3 of 5 primary endpoints (patient pain and patient and physician global). AUC of patient global, patient pain, and modified Health Assessment Questionnaire demonstrated dose-response (p < 0.04), while AUC ACR20 showed a qualitative trend in the same direction. The rate of gastrointestinal (GI) events during the 12 week trial for all doses of meloxicam and diclofenac did not differ significantly from placebo (23.2-32.0%). GI withdrawals were comparable and not significantly different across all treatment groups (4.3-5.7%). CONCLUSION: This trial demonstrated a dose response relationship for meloxicam 7.5, 15, and 22.5 mg using AUC measurement of response for the treatment of RA. All 3 doses of meloxicam. and positive control, were effective in the treatment of RA. The overall incidence rate of GI events did not differ significantly from placebo in either the meloxicam treatment groups or the positive control.
12784384 Expression and function of the co-stimulator H4/ICOS on activated T cells of patients with 2003 Jun OBJECTIVE: To investigate the expression and function of the inducible co-stimulator H4/ICOS in rheumatoid arthritis (RA) patients. H4/ICOS is the newest member of the CD28/CTLA-4 family to have been found to be expressed on activated T cells, and it participates in a variety of important immunoregulatory functions. METHODS: The levels of H4/ICOS expression on T cells among peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) from 28 patients with RA were analyzed by flow cytometry. To explore the role of H4/ICOS function in the inflammation of rheumatoid joints, lymphokine production by SF CD4+ T cells co-stimulated by H4/ICOS was assayed. Expression of H4/ICOS ligand (B7RP-1) mRNA in synovial tissues from patients with RA was examined by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: H4/ICOS-positive cells were increased significantly in whole, CD4+, and CD8+ T-cell fractions of SFMC compared with control PBMC. Comparison between control PB and PB from patients with active RA showed that H4/ICOS-positive whole and CD8+ T-cell fractions were increased significantly in the PB of RA patients. H4/ICOS costimulation clearly increased interferon-g, interleukin 4 (IL-4), and IL-10 production by SF CD4+ T cells. By RT-PCR, RA synovial tissue was shown to express mRNA of B7RP-1. CONCLUSION: Our results suggest that local immune responses may be modulated by H4/ICOS expressed on T cells in the joints of patients with RA, and thus H4/ICOS may be involved in the pathogenetic mechanism of RA.
11838839 Constitutive expression of angiopoietin-1 and -2 and modulation of their expression by inf 2002 Feb OBJECTIVE: Angiopoietin- I (Ang-1) and Ang-2 are ligands for the receptor tyrosine kinase, Tie-2. Ang-1, a Tie-2 agonist, may have a vascular stabilizing role in angiogenesis, while Ang-2, an endogenous antagonist of Tie-2, may have an early role in angiogenesis, destabilizing existing vasculature. We show that these ligands are expressed by rheumatoid synovial fibroblasts (RSF) and investigate whether their expression was modulated by proinflammatory cytokines present in the joint in rheumatoid arthritis (RA). METHODS: Using quantitative PCR we determined the level of expression of these 2 ligands in RSF and chronic inflamed synovial tissue. The level of expression of these ligands after treatment with proinflammatory cytokines and hypoxia was also determined. RESULTS: We observed constitutive expression of Ang-1 and Ang-2 in RSF and chronic inflamed synovial tissue. Ang-1 was the most highly expressed ligand in late stage RA synovial fibroblasts; however, in chronic inflamed synovial tissue, Ang-2 was predominant and was expressed at strikingly high levels (70 to 120-fold increase). We observed that tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), but not interleukin 1beta or hypoxia, stimulated Ang-1 gene expression in RSE This was confirmed at the protein level as media from TNF-alpha treated RSF resulted in increased autophosphorylation of Tie-2. In contrast, TNF-alpha and TGF-beta had no effect on Ang-2 expression in RSF, but augmented expression of Ang-2 in normal synovial fibroblasts. CONCLUSION: The angiopoietins are important angiogenic factors constitutively present in RA, and their expression is modulated by certain cytokines. Ang-2 may have an important role in rheumatoid tissue where vigorous angiogenesis is occurring.
14577718 Treatment compliance and dosage administration among rheumatoid arthritis patients receivi 2003 Oct OBJECTIVE: To examine treatment compliance and dosage administration associated with infliximab, etanercept, and methotrexate therapy for rheumatoid arthritis (RA). STUDY DESIGN: Retrospective analysis using administrative and claims data from a large US health plan. PATIENTS AND METHODS: Patients were Medicare or commercial enrollees in a health plan with a pharmacy benefit and had a diagnosis of RA. The first (index) claim for infliximab, etanercept, or methotrexate occurred between July 1, 1998, and December 31, 2000. Continuous enrollment in the plan was required from 182 days before to 365 days after the index claim. Treatment groups were compared according to compliance (defined as the actual number of therapy administrations or filled prescriptions divided by the expected number) and changes in dosage administration over time. The costs of infliximab therapy also were explored. RESULTS: A total of 2662 patients (infliximab = 141; etanercept = 853; and methotrexate = 1668) were included in the analyses. Infliximab patients were older and more likely to have a Medicare benefit. In addition, infliximab patients had more comorbidities and had greater medical costs preceding the index claim. Compliance with at least 80% of the expected dosages was significantly lower for etanercept (odds ratio [OR] 0.462; 95% confidence interval [CI] 0.290-0.736) and methotrexate (OR 0.385; 95% CI 0.245-0.604) patients than infliximab patients. Methotrexate patients had the largest dosage increases (61.6%), followed by infliximab (37.4%) and etanercept (7.4%) patients. Assuming 6.5 dosages per year, the annual cost of infliximab was dollars 10446 to dollars 12363, or dollars 1887 to dollars 1902 per administration, depending on site of service. CONCLUSIONS: Compliance is higher with infliximab compared with etanercept or methotrexate; whereas, fewer etanercept patients change dosages. The cost of infliximab was lower than expected based on previous predictions, even with a 37% increase in dosage.
12010788 Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective 2002 Jun 1 A national prospective study was designed to collect all cases of lymphoma appearing in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) throughout France over a period of 3 years. A total of 25 cases of lymphoma were recorded, 18 cases of non-Hodgkin lymphoma (NHL), 3 of which were associated with the presence of Epstein-Barr virus (EBV) in lymphoma cells, and 7 cases of Hodgkin disease (HD), 5 of them associated with EBV. Among the 8 patients who were treated by MTX withdrawal alone, 3 underwent remission, but 2 of them had a relapse, the third patient with clonal EBV-associated large granular lymphocytes T-cell NHL remaining alive in complete remission. The estimated annual incidence rate of NHL in RA patients treated with MTX was 33.3.10(-5) (0-80.5) among men and 16.7.10(-5) (0-33.3) among women. There was no significant excess with the French population as a comparison: the standardized mortality ratio (SMR) adjusted for age and sex was 1.07 (0.6-1.7). The estimated annual incidence rate of HD among men and women was, respectively, 27.8.10(-5) (0-70.1) and 2.8.10(-5) (0- 9.6). The incidence of HD was significantly increased compared with the French incidence, with an SMR adjusted for age and sex of 7.4 (3.0-15.3; P <.001). Thus, this 3-year prospective study indicated that, whereas the risk of NHL was not significantly increased in RA patients treated with MTX, the incidence of HD appeared to be higher in these patients compared to the French population.
12639750 Anti-inflammatory and analgesic activity in the polyherbal formulation Maharasnadhi Quatha 2003 Apr Maharasnadhi Quathar (MRQ) is a polyherbal preparation recommended by Ayurvedic medical practitioners for treatment of arthritic conditions. An investigation has been carried out with rats and human rheumatoid arthritis (RA) patients, to determine the anti-inflammatory and analgesic potential of MRQ. Results obtained demonstrate that MRQ can significantly and dose-dependently inhibit carrageenan-induced rat paw oedema (the inhibition at 3h was greater than at 1h after induction of oedema). MRQ could also increase the reaction time of rats in the hot-plate test (by 57% after the first hour of treatment), although it had no effect on the reaction time in the tail-flick test, indicating that MRQ possesses analgesic activity that is probably mediated via a supra-spinal effect.MRQ also exerted a dose-dependent (a) protective effect on heat-induced erythrocyte lysis, and (b) inhibition of 5-lipoxygenase activity. In RA patients, after 3 months of MRQ treatment, there was a marked improvement in the pain and inflammation experienced by the patients as well as in the mobility of the affected joints. From the overall results obtained, it may be concluded that MRQ possesses significant anti-inflammatory and analgesic activities. Alteration in synthesis of prostaglandins and leukotrienes, membrane stabilization and anti-oxidant activity are some of the possible mechanisms through which MRQ mediates its anti-arthritic effects.