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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
9972971 Hepatitis C virus infection: prevalence in psoriasis and psoriatic arthritis. 1999 Feb OBJECTIVE: To study the prevalence of hepatitis C virus (HCV) infection in 2 groups of patients, one group with psoriasis and the other with psoriatic arthritis (PsA). METHODS: We detected anti-HCV antibodies by ELISA and by a recombinant immunoblot assay (RIBA) in the sera of 50 patients with psoriasis and 50 with PsA. As controls we used a group of 76 patients with rheumatoid arthritis (RA), and referred to data on the prevalence of HCV in the general Italian population. RESULTS: By ELISA, anti-HCV antibodies were detected in 6/50 (12%) patients with PsA, in 5/50 (10%) patients with psoriasis, and in 4/76 (5.2%) patients with RA. All the reactive PsA and RA sera also tested positive on RIBA, while only 3 of the 5 positive results for sera of patients with psoriasis were confirmed by RIBA. The prevalence of HCV infection in patients with psoriasis was not significantly higher than in controls. In contrast, the rate of HCV infection observed in the 50 patients with PsA was higher than that in the other groups, the difference being statistically significant between patients with PsA and the general population. CONCLUSION: Our data do not support the hypothesis that HCV infection may play a role in the pathogenesis of psoriasis. On the other hand they show a statistically significant difference between the prevalence of HCV infection in patients with PsA and the general population.
11083285 Therapeutic efficacy of a novel membrane-targeted complement regulator in antigen-induced 2000 Nov OBJECTIVE: Complement system activation is strongly implicated as a factor in the pathogenesis of chronic synovitis in human rheumatoid arthritis. The objective of this study was to explore the therapeutic potential and local retention of a novel membrane-targeting complement regulatory protein, derived from human complement receptor 1, in the experimental setting of rat antigen-induced arthritis. METHODS: Sensitized animals were treated at the time of arthritis induction with a single intraarticular (IA) dose of the membrane-targeting regulator APT070, a non-membrane-targeting control regulator (APT898), or vehicle control, and disease was assessed clinically and histologically. In addition, immunocytochemical analysis was performed on sections from normal rat knee joints at various time points after IA injection with APT070. RESULTS: Animals treated with APT070 showed a dose-dependent therapeutic effect, with significantly milder clinical and histologic disease compared with both other treatment groups (P < 0.008 at the higher dose) and minimal evidence of erosive disease at study end in the active treatment group. Immunoperoxidase and immunofluorescence studies demonstrated local retention of APT070 on cell surface membranes within the normal joint up to 48 hours after IA injection. CONCLUSION: These results show that IA complement inhibition represents an effective therapeutic strategy in experimental arthritis, by demonstrating that the exogenous delivery of a membrane-targeting complement regulator can result in prolonged synovial cell surface binding and significant clinical benefit in vivo. Complement inhibitory strategies of this type should be considered as novel therapies in human inflammatory arthritis.
9273175 [Systemic autoimmune diseases with neurocutaneous alterations]. 1997 Sep Autoimmune diseases depend on the pathologic activation of cellular clones, potentially harmful, against soft tissues. They can be classified into systemic and organ-specific diseases. In the systemic subtype, in which the abnormal hyperactivity is not as specific, the most remarkable component of the clinical syndrome is frequently the presence of neurological and/or cutaneous manifestations. This article reviews the major pathogenic mechanisms involved in the principal systemic autoimmune conditions including connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosus, polimyositis, dermatomyositis, scleroderma, mixed connective tissue disease, Sjögren's syndrome, overlap syndromes) and vasculitic syndromes (nodous polyarteritis, giant cell arteritis. Wegener's granulomatosis. Behçet disease, microscopic polyarteritis, cryoglobulinemia) as well as their clinical manifestations, focused mainly on neurocutaneous characteristics.
11242280 Exuberant transverse ligament degeneration causing high cervical myelopathy. 2001 Feb Two patients with cervical myelopathy and C1-C2 retro-odontoid masses were examined. Preoperative magnetic resonance imaging studies suggested soft tissue pannus, as might be seen in rheumatoid arthritis; however, the results of serologic testing for rheumatoid factor were negative in both patients. Intraoperative findings and pathologic examination revealed degenerative fibrocartilage without inflammation or neoplasia. Similar lesions reported in the literature have been described as retro-odontoid disk hernia, damaged transverse ligaments, transverse ligament degeneration, synovial cysts, ganglion cysts, and degenerative articular cysts. These lesions may share a common pathophysiologic origin and represent a single disease process, namely exuberant degeneration of the transverse ligament.
9853331 Rhenium-188 microspheres: a new radiation synovectomy agent. 1998 May Radiation synovectomy is efficacious in controlling the symptoms of rheumatoid arthritis. However, the procedure is not widely used because of concerns about leakage of radiopharmaceuticals from the treated joints. Leakage can be minimized by selecting particles of an appropriate size. In this study, we labelled microspheres with 188Re and analysed its biodistribution after intra-articular injection in rabbits with antigen-induced arthritis. Gamma camera imaging was performed to quantify the mean retention of 188Re in the knees. The mean retention of 188Re was 98.7, 94.6 and 93.6% at 1, 24 and 48 h, respectively. The biodistribution data revealed very low radioactivity in all organs at different times, which suggests the leakage of radiotracer from the knee was negligible. Our preliminary results indicate that 188Re microspheres are a potentially effective radiopharmaceutical for radiation synovectomy.
9158875 Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors. 1997 Apr The synthesis and biological evaluation of orally active inhibitors of matrix metalloproteinase are reported. Modifications of the P2' position and the alpha-substituent of hydroxamic acid derivatives were carried out, and revealed that the P2' substituent influenced the MMP inhibitory activities in vitro and in plasma after oral administration. The hydroxamates with phenylglycine at the P2' position were absorbed well orally. Compound 15e, which exhibited the longest duration of inhibitory activity in plasma after oral administration among the phenylglycine derivatives (5a-5d, 15a, 15c, 15e), was evaluated in a rat adjuvant arthritis model. A reduction in hind foot pad swelling and improvements of some inflammatory parameters were demonstrated when the compound was administered orally. These results indicate the potential of MMP inhibitors for rheumatoid arthritis.
9163287 Prevalence of antineutrophil cytoplasmic antibodies in a large inception cohort of patient 1997 Jun 1 BACKGROUND: Two types of antineutrophil cytoplasmic antibodies (ANCA), antiproteinase 3 antibodies (anti-PR3) and antimyeloperoxidase antibodies (anti-MPO), are useful in the diagnosis of such types of vasculitis as Wegener granulomatosis and microscopic polyangiitis. Connective tissue diseases frequently appear in the differential diagnosis of this spectrum of vasculitis. OBJECTIVE: To determine the prevalence of ANCA in patients with connective tissue disease. DESIGN: Blinded, controlled study of a 5-year inception cohort. SETTING: Tertiary-care university teaching hospitals. PATIENTS: 70 patients with rheumatoid arthritis, 70 patients with systemic lupus erythematosus, 45 patients with scleroderma, 36 patients with inflammatory myositis, 44 patients with the sjögren syndrome, 33 patients with the antiphospholipid syndrome, and 165 patients with early undifferentiated connective tissue disease (EUCTD). Serum was taken from 200 blood donors and 52 patients who had known vasculitis and positive results on tests for anti-PR3 or anti-MPO; these patients served as controls. MEASUREMENTS: The presence of anti-PR3 and anti-MPO was determined by combining the results of indirect immunofluorescence tests for cytoplasmic (C-ANCA) and perinuclear (P-ANCA) patterns with the results of enzymelinked immunosorbent assays (ELISAs) directed to measure antigen. RESULTS: Cytoplasmic ANCA was not detected in any study or control patient. Perinuclear ANCA was commonly detected among patients with lupus (31%) but was uncommon among patients in other groups (0% to 5%). In all cases, P-ANCA was associated with the presence of antinuclear antibodies. Atypical ANCA immunofluorescence patterns were fairly common in all groups (11% to 39%). Antiproteinase 3 was detected by ELISA in study patients (1 patient with rheumatoid arthritis, 1 with lupus, 1 with polymyositis, and 6 with EUCTD). Antimyeloperoxidase was detected by ELISA in 2 study patients (1 with rheumatoid arthritis and 1 with lupus). None of the patients with positive ELISA results had evidence of renal vasculitis during follow-up. When an ANCA scoring system that combines immunofluorescence and ELISA was used, the test specificity for vasculitis was 99.5% among patients with connective tissue disease. CONCLUSIONS: Patients with connective tissue disease are known to develop multiple autoantibodies; positivity for anti-PR3 and anti-MPO ANCA in such patients is highly specific for anti-PR3. However, P-ANCA immunofluorescence, which may have positive results because of the presence of antinuclear antibodies, is not a specific marker of anti-MPO. A rigorous ANCA testing system that combines the results of immunofluorescence with those of ELISA is highly specific for Wegener granulomatosis and related vasculitides even in patients with connective tissue disease.
10084031 A trial of clodronate-liposomes as anti-macrophage treatment in a sheep model of arthritis 1999 Jan OBJECTIVE: Our previous research has concerned the role of macrophages in joint inflammation in rheumatoid arthritis. We have therefore been interested in liposomes containing clodronate as an antimacrophage treatment for arthritis. We have used the antigen-induced arthritis model in sheep to evaluate the effect of clodronate liposomes. METHODS: Arthritis was induced in the right hock joint (day 0). We were able to demonstrate uptake of liposomes into macrophages within the inflamed joint lining. On day 7, sheep were given a single intra-articular injection of clodronate liposomes (group 1, n = 10) or saline liposomes (group 2, n = 10). A further 6 sheep (group 3) had no arthritis and no treatment. RESULTS: No difference in joint diameter was observed between the sheep in group 1 (clodronate) and group 2 (saline treated). Both groups had joint swelling which persisted until the end of the trial (day 20). Histologic scoring was also similar in group 1 and group 2 animals, and both were worse than group 3. CONCLUSION: In vitro studies have shown that interaction of liposomes with neutrophils and monocytes stimulates a respiratory burst. Despite this possible pro-inflammatory effect we did not observe any increase in joint diameter following liposome injection. Thus we were unable to demonstrate a therapeutic effect of a single dose of clodronate liposomes in this large animal model of antigen-induced arthritis.
10028378 Age-depending effects of methotrexate treatment on systemic bone turnover in experimental 1999 Jan Adjuvant arthritis was induced in rats in the growth stage (aged 6 weeks) and those in the mature stage (aged 4 months), and changes in the systemic bone turnover and the effects of methotrexate (MTX, CAS 133073-73-1) were compared. After induction of adjuvant arthritis, the paw edema ratio and the urinary deoxypyridinoline (u-Dpy) level increased in both age groups. No marked changes were observed in the serum osteocalcin (s-OC) level in either group. In the 6-week-old rats, arthritis completely inhibited the bone mass, and strength of the femur and lumbar vertebral body. The 4-month-old rats showed more marked changes than the 6-week-old rats in the bone mass and strength of the lumbar, vertebral body. MTX administration (0.05, 0.1 and 0.2 mg/kg/day) resulted in significant dose-dependent inhibition of arthritis-induced changes, and the effects of MTX were similar between the two age groups. MTX was useful at each age. These results suggest that 4-month-old rats with arthritis are more appropriate as a model for evaluation of drugs for bone metabolic turnover in human chronic rheumatoid arthritis.
17984889 Rheumatological considerations in the qualification of rheumatoid patients for surgical tr 2000 Dec 30 The surgical treatment of rheumatoid arthritis patients can be safe because it is planned treatment, but it requires the close cooperation of the orthopedic surgeon, the rheumatologist, and the anesthesiologist. The proper evaluation of the risk factors for coexisting diseases decreases the possibility of general surgical and infectious complications. Thromboembolic preventive measures after surgery are an absolute requirement, for at least 15 days after the operation, using heparin of low molecular weight; preventive antibiotic therapy is also required, using second-generation cephalosporing for 3-5 days, depending on the risk factors. Methotrexate treatment should be suspended for 7 days during the peri-operative period. Prolonged steroid therapy creates a risk of adrenal failure in the event of illness or peri-operative stress, which increases with the steroid dosage and the prolongation of therapy. Steroid administration cannot be stopped prior to surgery. Treatment outcome depends on the activity level the disease and the skill of the surgeon, as well as pre- and post-operative care and rehabilitation.
11516754 A routine assay for the direct analysis of HLA-DR-related shared epitope and B27 alleles i 2001 Oct 1 Knowledge of the genetic background of patients with inflammatory arthritis may be useful for disease management. The main markers are the HLA-DR-associated Shared Epitope (SE) for Rheumatoid Arthritis (RA) and HLA-B27 for ankylosing spondylitis. We have developed a simple molecular biology-based test to provide this essential information. HLA targets are amplified by polymerase chain reaction (PCR), then simultaneously analyzed using 16 individual hybridization reactions in two 8-well ELISA strips with colorimetric detection. Concordance was evaluated using a cohort of RA patients with known genotype. Using this new assay, 100% concordance was observed with conventional genotyping in RA patients both for HLA-DR SE and B27 genotypes. Seventy-three percent of the patients with destructive RA had at least one susceptible allele within SE, compared to 38% of those patients with non-destructive disease. This new assay, which requires minute amount of blood, could be used to determine the genetic background of inflammatory arthritis, particularly in non-specialized settings and for large-scale clinical trials.
11249573 MFG-IRAP University of Pittsburgh. 2000 Oct The University of Pittsburgh is developing MFG-IRAP gene therapy for the potential treatment of arthritis. Phase II studies have commenced, including one trial in arthritis patients [225365]. A retrovirus (MFG-IRAP) is used in the ex vivo transfer of a cDNA encoding the human interleukin-1 receptor antagonist (IL-1Ra). The therapy is being tested in post-menopausal women, and involves the removal of some of their synovium, which is then transfected with the IRAP gene and reimplanted into the joint [188197]. A phase I rheumatoid arthritis trial of a therapy using the IL-1 antagonist gene therapy in synergy with soluble TNF alpha receptors was reported in March 1999 and was considered to be effective in producing an anti-arthritic effect [318398].
9566663 Nitric oxide and inflammatory joint diseases. 1998 Mar Nitric oxide (NO) is synthesized from L-arginine by the NO synthases. At present, mainly three NO synthase isoenzyme groups are differentiated: two constitutive NO synthases, responsible for homeostatic cardiovascular and neuronal functions of NO, and an inducible NO synthase. After induction by certain cytokines or endotoxin, this latter isoform produces large quantities of NO with cyto- and bacteriotoxic effects. High amounts of NO, synthesized systemically and intra-articularly, play an important role in inflammatory joint diseases, as shown in animal models of arthritis and in patients with rheumatoid arthritis or spondyloarthropathies. In experimental arthritis, administration of NO synthase inhibitors profoundly reduced disease activity. In humans, beneficial effects of NO synthesis inhibition are inferred from indirect evidence: glucocorticoids, inhibiting induction of the inducible NO synthase, reduce enhanced NO synthesis and disease activity. Thus, selective inhibition of the pathologically enhanced NO synthesis emerges as a new experimental therapeutic approach in the treatment of inflammatory joint diseases.
14517450 Angiogenesis in arthritis: role in disease pathogenesis and as a potential therapeutic tar 1998 Rheumatoid arthritis (RA) is a chronic destructive musculo-skeletal disorder, associated with thickening of the synovial membrane lining the joints, inflammation and hyperproliferation of synovial cells, as well as a pro-inflammatory cytokine cascade, leukocyte infiltration, and tissue damage and bone resorption. An early event in RA is an alteration in blood vessel density and prominent neovascularisation. The hyperplasia of the synovium necessitates a compensatory increase in the number of blood vessels to nourish and oxygenate the tissue. However, angiogenesis may not keep pace with synovial proliferation, leading to regions of hypoperfusion and hypoxia. VEGF, a potent endothelial cell mitogen, is expressed in RA synovium and elevated in the serum of RA patients. We have reported that dissociated RA synovial membrane cells spontaneously secrete VEGF, and that release of VEGF by these cells is upregulated by cytokines and hypoxia. In a murine model of RA, VEGF is released from synovial cells isolated from the knees of arthritic but not healthy mice, and the extent of VEGF production correlates with the severity of arthritis. VEGF thus appears to play a key role in mediating alterations in synovial vessel density in arthritis. As a consequence, RA may be a potential target for anti-angiogenic therapy, and targeting VEGF may prove to be especially beneficial.
11822787 Antibodies to PECAM-1 and glucocorticoids reduce leukocyte adhesion in adjuvant arthritis 2001 Dec OBJECTIVE AND DESIGN: To demonstrate the effect of monoclonal antibodies to the adhesion-molecule PECAM-1 (CD31) and of prednisolone on leukocyte adhesion in rat adjuvant arthritis. MATERIAL: Adjuvant arthritis was induced in male CD-rats (five groups of n = 6) 18 days prior to measurements. TREATMENT: Mouse-monoclonal antibody to rat CD-31 at 200 microg/kg or prednisolone at 24 mg/kg were administered i.v. 15 minutes prior to measurements. METHODS: Venules within the intact rat-knee synovium were focused by confocal laser scanning microscopy. Numbers of rolling and adherent leukocytes were assessed in vivo. RESULTS: Induction of arthritis significantly increased rolling and adherent leukocytes compared to healthy controls. Both monoclonal antibodies to PECAM-1 and prednisolone significantly reduced adherent, but not rolling leukocytes in arthritic animals. CONCLUSIONS: The method used is well suited for in vivo quantification of leukocyte adhesion under the influence of antiadhesive therapies. PECAM-1 might be an interesting target for novel therapies in rheumatoid arthritis.
9600974 Identification of rat susceptibility loci for adjuvant-oil-induced arthritis. 1998 May 26 One intradermal injection of incomplete Freund's adjuvant-oil induces a T cell-mediated inflammatory joint disease in DA rats. Susceptibility genes for oil-induced arthritis (OIA) are located both within and outside the major histocompatibility complex (MHC, Oia1). We have searched for disease-linked non-MHC loci in an F2 intercross between DA rats and MHC-identical but arthritis-resistant LEW.1AV1 rats. A genome-wide scan with microsatellite markers revealed two major chromosome regions that control disease incidence and severity: Oia2 on chromosome 4 (P = 4 x 10(-13)) and Oia3 on chromosome 10 (P = 1 x 10(-6)). All animals homozygous for DA alleles at both loci developed severe arthritis, whereas all those homozygous for LEW.1AV1 alleles were resistant. These results have general implications for situations where nonspecific activation of the immune system (e.g., incomplete Freund's adjuvant-oil) causes inflammation and disease, either alone or in conjunction with specific antigens. They may also provide clues to the etiology of inflammatory diseases in humans, including rheumatoid arthritis.
9649555 Exacerbation of antigen-induced arthritis in urokinase-deficient mice. 1998 Jul 1 In rheumatoid arthritis, synovial expression of urokinase (uPA) activity is greatly increased (Busso, N., V. Péclat, A. So, and A. -P. Sappino. 1997. Ann. Rheum. Dis. 56:550- 557). We report the same effect in murine antigen-induced arthritis. uPA-mediated plasminogen activation in arthritic joints may have deleterious effects via degradation of cartilage and bone matrix proteins as well as beneficial effects via fibrin degradation. We evaluated these contrasting effects in vivo by analyzing the phenotype of uPA-deficient (uPA-/-) and control mice during antigen-induced arthritis. Joint inflammation was comparable in both groups up to day 3 and subsequently declined in control mice, remaining significantly elevated in uPA-/- mice on days 10 and 30 after arthritis onset. Likewise, synovial thickness was markedly increased in uPA-deficient mice persisting for up to 2 mo, whereas it subsided in control animals. Bone erosion was exacerbated in uPA-/- mice on day 30. By contrast, no difference in articular cartilage proteoglycan content was found between both groups. Significantly increased accumulation of fibrin was observed by day 30 in arthritic joints of uPA-/- mice. We hypothesized that synovial fibrin deposition plays a role in joint inflammation. Accordingly, defibrinogenation of uPA-/- mice by ancrod significantly decreased the sustained joint inflammation. All the above observations were reproducible in plasminogen-deficient (Pln-/-) mice. In conclusion, synovial fibrin deposition plays a role as a nonimmunological mechanism which sustains chronic arthritis.
11181084 Neutralization of vascular endothelial growth factor prevents collagen-induced arthritis a 2001 Feb 23 Vascular endothelial growth factor (VEGF) is implicated in the pathogenesis of inflammatory joint diseases, including rheumatoid arthritis (RA). To determine the importance of this cytokine in vivo, the effect of administering VEGF-neutralizing antibodies to mice with collagen-induced arthritis (CIA), which has many immunological and pathological similarities to human RA, has been investigated. Either saline, normal rabbit immunoglobulin or anti-human VEGF121 rabbit polyclonal antibody was administered to mice subcutaneously either before the onset of arthritis or after the establishment of clinical disease. Anti-VEGF antibody administered prior to disease onset significantly delayed the development of arthritis and decreased clinical score and paw thickness as well as histological severity. On the other hand, the frequency of occurrence of disease compared to either the control group administered saline or normal rabbit immunoglobulin was not altered. Anti-VEGF antibody also significantly ameliorated clinical and histological parameters even when administered after disease onset. These results indicate a possible therapeutical potential for anti-VEGF treatment in human arthritis.
9101513 Synovial membrane cytokine profiles in reactive arthritis secondary to intravesical bacill 1997 Apr We describe the cellular infiltrate and cytokine profile in sequential synovial membrane biopsies from a patient with acute followed by chronic synovitis after intravesical bacillus Calmette-Guérin (BCG) therapy for an in situ transitional cell carcinoma of the bladder. Histological and immunohistochemical analysis of 3 synovial biopsies were done sequentially over a 9 month period. The patient was HLA-B27 positive, but HLA-DR4 negative, and did not have the "shared epitope." Unlike other cases, this patient's arthritis did not respond initially to nonsteroidal antiinflammatory drugs and was exacerbated by corticosteroid therapy. The synovitis took a neutrophilic form, with marked synovial membrane content of interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-alpha). It subsequently developed into chronic lymphoplasmacytoid synovitis, similar to rheumatoid arthritis (RA), with decreased IL-8 but continuing IL-1 and TNF-alpha production in the synovial membrane. The synovitis resolved to a fibrotic synovium with residual thickening of the synovial lining layer and continued production of TNF-alpha. Thus, during the evolution of this arthritis, the synovial layer and continued production of TNF-alpha. Thus, during the evolution of this arthritis, the synovial membrane yielded a cellular infiltrate and cytokine content that had marked similarities with that seen in RA; however, the arthritis eventually remitted spontaneously.
15995936 Use of nitric oxide synthase inhibitors for the treatment of inflammatory disease and pain 2001 Jul This article reviews the recent literature on selective inhibitors of nitric oxide synthase (NOS) between 1999 and the first quarter of 2001. The introduction highlights the major therapeutic objectives for NOS inhibitors, including rheumatoid arthritis (RA), osteoarthritis (OA) and pain. The review attempts to cover the structural diversity of small molecule NOS inhibitors currently being explored in the pharmaceutical and academic communities.