Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 8913935 | Cytokine expression and networks in rheumatoid arthritis: rationale for anti-TNF alpha ant | 1995 | The cloning of cytokine cDNAs has permitted the analysis of cytokine expression in diseased sites such as rheumatoid joints. A very wide range of cytokines were detected, mostly with proinflammatory activities. From the analysis of cytokine regulation in rheumatoid joint cell cultures using neutralizing anti-cytokine antibodies, it was found that blockade of TNF alpha reduced the production of other proinflammatory cytokines. Hence TNF alpha was a potential therapeutic target. This concept was tested successfully in collagen induced arthritis in mice and led to clinical trials of anti-TNF alpha antibody in rheumatoid arthritis (RA) in humans. The mechanism of action of anti-TNF alpha will be discussed. | |
| 7846674 | [Discospondylitis and immune-mediated polyarthritis in a Bernese mountain-dog]. | 1995 Feb 1 | In this case report we describe the clinical picture and treatment of a Bernese mountain dog with discospondylitis and a presumably reactive immune-mediated polyarthritis. The clinical signs consisted of apathy, fever, anorexia, and a stiff gait. The diagnosis was based on the typical radiographic signs of discospondylitis and the cytology of the synovial fluid. The dog was treated with a broad-spectrum antibiotic for 6 weeks and thereafter with a synthetic glucocorticoid for the polyarthritis. Five months after cessation of therapy, the dog was free from the initial signs. | |
| 7842529 | Linkage disequilibrium of HLA-DR3 and HLA-DR4 with HLA-B alleles in Mexican patients with | 1994 Sep | OBJECTIVE: We studied the gene frequencies of classes I, II and III antigens of the Major Histocompatibility Complex (MHC) in 32 Mexican mestizo patients with rheumatoid arthritis (RA) and compared them with those obtained from 110 of their first degree relatives and 100 Mexican mestizo controls. Furthermore, we analyzed the observed and expected frequencies of the haplotypes and calculated the delta values in the three groups. METHODS: The class I and class II MHC antigens were determined by the microlymphocytotoxicity test; class III MHC antigens were obtained by high voltage agarose gel electrophoresis and immunofixation. The significance of differences among the three groups was tested by chi-square analysis; linkage disequilibrium among the different alleles in each haplotype was estimated by computing the delta values (observed vs expected frequencies). RESULTS: Patients showed a significantly increased frequency of HLA-A1 (corrected p = 10(-5)), DR3 (corrected p = 0.04) and DQ2 (corrected p = 10(-4)) and a decreased frequency of A31 (corrected p = 0.003) as compared to the normal controls. First degree relatives compared to patients and controls showed a decreased frequency of HLA-DR4 (corrected p = 0.02 and 0.008 respectively); consequently, DQ3 was also diminished (corrected p = 10(-4)). Analysis of MHC haplotypes within families revealed in the patients seven MHC haplotypes with significant differences between the observed and expected frequencies (statistically significant delta values). These haplotypes were: [HLA-B8; DR3], [HLAB44; FC31], [HLA-B8; SC42], [HLA-DR4; SC31], [HLA-B35; SC32], [HLA-DR7; FC31] and [HLA-DR2; SC31]. On the other hand, the control haplotypes showed significant delta values in only one of these haplotypes ([HLA-DR4; SC31]), whereas first degree relatives showed none. Analysis of all the class I, II and III alleles, either alone or as part of specific haplotypes, showed two B-DR haplotypes with higher relative risks than their alleles alone. These haplotypes were: [B44; DR4] (RR = 6.0, p = 0.005), and [B8; DR3] (RR = 8.3, p = 0.010). CONCLUSION: The results suggest that a specific combination of antigens in the same haplotype (for instance between HLA-B and HLA-DR) could contribute to increasing the genetic susceptibility to develop RA. | |
| 8856612 | Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovia | 1996 Aug | OBJECTIVE: There is evidence that proliferation of synovial fibroblasts and invasive growth in rheumatoid arthritis (RA) is due to impaired regulation of the cell cycle, i.e., the balance between proliferation and physiological cell death (apoptosis) We examined synovial tissues from patients with RA and osteoarthritis (OA) to determine the ultrastructural changes during apoptosis and the expression of the apoptosis regulating molecules Fas and Bcl-2 in synovial fibroblasts. METHODS: We examined synovial tissues obtained from patients with RA and OA by electron microscopy and immunoelectron microscopy to evaluate the characteristics of apoptosis in RA synovial fibroblasts as well as Fas and Bcl-2 antigen expression. RESULTS: Ultrastructurally, the majority of the RA synovial fibroblasts appeared transformed, and 3% of these were in different stages of apoptosis. In OA, no apoptotic cells could be observed. Apoptosis of synovial fibroblasts in RA showed a characteristic multistage pattern. In each of the distinguishable 4 stages, specific ultrastructural changes could be detected. The apoptotic synovial fibroblasts were mainly located in the deeper sublining layers of the synovium. Immunoelectron microscopy revealed that Fas antigen expression was limited to the first stage of apoptosis. Conversely, the synovial fibroblasts located in the synovial lining layer neither underwent apoptosis nor expressed Fas antigen. Several synovial lining cells expressed the cell death suppressor (anti-apoptosis) gene product Bcl-2. CONCLUSION: Apoptosis of fibroblasts in the RA synovial sublining is characterized by a distinct multistep ultrastructural pattern with a detectable initial Fas antigen expression; conversely, reduced apoptosis in the synovial lining associated with the expression of Bcl-2 results in extended life of matrix degrading synovial fibroblasts at the site of synovial invasion into cartilage and bone. | |
| 7777830 | Correlations between PAF-acether and tumor necrosis factor in rheumatoid arthritis. Influe | 1995 | The aim of this study was to evaluate the presence of PAF-acether (PAF), its specific degrading enzyme acetylhydrolase, and tumor necrosis factor (TNF) concentrations in blood and synovial fluid (SF) from patients with active RA. The variations of the mediators were also evaluated after corticosteroid perfusions in 7 patients. Lipo-PAF (PAF complexed to lipoproteins) was the main form of PAF detected both in blood and in SF, whereas unbound PAF was uncommon. Acetylhydrolase activity was also present in SF, with a strong correlation between serum and SF levels. TNF was detected in most of the samples, and TNF and acetylhydrolase levels were strongly correlated both in blood and in SF. Despite dramatic clinical improvement, corticosteroid treatment was not accompanied by a significant reduction of the concentration of blood mediators, suggesting that these molecules should not be considered as markers of disease activity. | |
| 8311548 | Excretion of pyridinium crosslinks correlates with disease activity and appendicular bone | 1994 Jan | OBJECTIVE: To establish if urinary excretion rates of the collagen crosslinks pyridinoline and deoxypyridinoline, which are known to be elevated in established rheumatoid arthritis (RA), are useful markers of bone loss in this disease. METHODS: Eight hour urine collections on all patients and 52 controls were performed, and the rates of pyridinoline and deoxypyridinoline excretion were measured. Bone mineral density (BMD), by dual energy x-ray absorption, and full laboratory and clinical assessments were performed. RESULTS: The rates of excretion of pyridinoline and deoxypyridinoline were significantly increased in patients compared with controls (p < 0.001). Pyridinoline excretion was associated with increased disease activity (ESR/CRP) but not disability (HAQ score/Functional Grade), and correlated with BMD loss at the femoral neck (p < 0.01). CONCLUSION: The excretion of collagen crosslinks may be useful as markers of bone and cartilage turnover in patients with RA. | |
| 8452767 | Interplay of T lymphocytes and HLA-DR molecules in rheumatoid arthritis. | 1993 Mar | One of the genetic components of seropositive rheumatoid arthritis has been mapped to a short sequence stretch in the third hypervariable region of the HLA-DRB1 gene. A new concept has emerged, proposing that the shared-sequence motif is functional in determining the clinical patterns of rheumatoid arthritis and the severity of the disease in a codominant mode. Patients with a double dose of the shared sequence tend to have more serious disease manifestations, suggesting a model in which the genetic element is involved in perpetuating the disease. The pathogenetic model in which the shared epitope selectively binds and presents an arthritogenic peptide appears too simplistic to account for these findings. Our understanding of how the shared epitope may contribute to forming the molecular complex of the T-cell receptor, peptide, and HLA-DR molecule is advancing. Molecular analyses of the synovial T-cell infiltrate continue to define the various components involved in recruiting T cells to the site of synovial inflammation. Adhesion molecules, predominantly the endothelial cell ligands vascular adhesion molecule 1 and endothelial leukocyte adhesion molecule 1, attract phenotypically selected T cells with a wide spectrum of specificities. The rheumatoid factor-positive B cells may be important antigen-presenting cells in the joint and may activate T cells with many different specificities. Rheumatoid factor immunoglobulin genes show clear evidence of somatic mutation, indicating a T cell-dependent, antigen-driven process. Thus, multiple factors contribute to the composition of the inflammatory infiltrate and may well modulate the repertoire of T cells recruited to the tissue.(ABSTRACT TRUNCATED AT 250 WORDS) | |
| 8248582 | [The temporo-mandibular joint in pathologic conditions: rheumatoid arthritis and seronegat | 1993 Oct | Pain and dysfunction of the temporomandibular joint (TMJ) are major clinical problems, especially in arthritides and allied conditions. In the last 10 years, such new imaging methods as arthrography, CT and MRI have been developed, but many problems are still to be solved. This study was aimed at reporting the radiographic patterns of lesions in TMJ rheumatoid arthritis and seronegative spondyloarthropathies and at investigating the role of conventional radiology in the assessment of these disorders. Digital hypocycloidal tomography of the TMJ was performed on 44 patients affected with rheumatoid arthritis, on 2 with Sjögren's syndrome, 2 with ankylosing spondylitis, 4 with psoriatic arthritis and 1 with Reiter's syndrome. CT, with sagittal and coronal scans, was performed only on 9 patients (18 joints) whose clinical and radiographic findings were particularly severe. The radiographic features of the lesions--i.e., erosions, osteophytes, subchondral bone sclerosis and condylar-glenoid fossa remodelling--cannot be distinguished from one another and from the so-called allied conditions; nevertheless, in rheumatoid arthritis abnormalities are usually bilateral and symmetric, whereas in seronegative arthropathies joint involvement is usually unilateral. In the first stage of the disease, these lesions are better demonstrated by CT than by tomography, thanks to better contrast and spatial resolution of the former, especially on the lateral and medial aspects of the joint. The most common findings were: erosions (68.2%), osteophytes (31.8%), subchondral bone sclerosis (28.6%) and condylar-glenoid fossa remodelling (9.1%). In the clinical practice sagittal multidirectional tomography remains today the method of choice because it can demonstrate several areas on the condylar surface, with finer anatomical detailing, and it can solve most diagnostic problems in TMJ disorders. Thus, CT is recommended only in the patients whose diagnosis remains questionable with the above techniques. | |
| 8542621 | [Loculated pericardial effusion leading to functional tricuspid stenosis in a case of rheu | 1995 Sep | We describe a case of loculated pericardial effusion, occurring in a women affected by rheumatoid arthritis. Because of its peculiar location, close to the atrioventricular plane, the effusion caused a haemodynamic pattern resembling tricuspid valve stenosis. | |
| 8052926 | [Causes of death in 140 patients with rheumatoid arthritis]. | 1994 Jun | The causes of death in 140 patients (30 male and 110 female) with rheumatoid arthritis (RA) at Kawasaki Municipal Hospital are analyzed. Autopsies were performed in 58%. The causes of death were infection (25.7%), heart disease (20.0%), renal failure (10.7%), cerebrovascular disease (10.0%), and respiratory failure (8.5%). The causes of death in RA patients were compared with those of 243 non-rheumatoid patients. Infection, congestive heart failure, renal failure and respiratory failure were more common causes of death in RA than in the control group. It should be noted that neoplasms are infrequent causes of death in patients with RA. The survival time (onset to death) of RA patients appears to be increasing year by year. | |
| 8073710 | [The differential diagnostic significance of the binding capacity of serum immunoglobulins | 1994 Feb | The ability of immunoglobulins (Ig) G, A and M to bind to amino acids was studied in 27 patients with rheumatism (R), 28 with rheumatoid arthritis (RA) and 27 patients with systemic lupus erythematosus (SLE) with minimum degree of activity. The enhancement of the binding capacity of IgG with respect to arginine, glutamic acid, lysine and decrease of that of IgM towards serine was established to be of diagnostic value in R as was the enhancement of the above capacity of IgG and A with respect to proline and oxyproline in RA and enhancement of that of Ig of all three classes with respect to a broad range of amino acids in SLE. Information criteria were established of differential diagnosis of R, RA and SLE. | |
| 8162454 | Anti-Proteus antibodies and Proteus organisms in rheumatoid arthritis: a clinical study. | 1994 Jan | We have studied anti-Proteus antibodies (APA), isolation of Proteus, and their relation to various measures of RA disease activity. Seventy RA patients with a CRP > 10 mg/l had higher APA titres than 17 RA patients with CRP < or = 10 mg/l (P = 0.006), and 36 non-RA controls (P = 0.003). However, in a cross-sectional study of the RA group, there was no correlation between APA and a number of clinical and laboratory measures of disease activity, including the CRP and Stoke RA activity index. A longitudinal study showed no correlation between changes in these measures of disease activity and change in APA titre. We were unable to isolate Proteus in the urine or faeces of RA patients more frequently than controls, and the isolation of Proteus did not correlate with serum APA titres. Urinary APA was present in equal frequencies in RA and non-RA patients. NSAIDs, DMARDs and steroids did not appear to influence APA titres in the RA group. These results suggest that APA may act as an acute phase protein, distinct from CRP, but not correlating with RA disease activity in its broadest context. The fact that the antibody we are measuring binds to Proteus may be irrelevant, and the study does not support a role for Proteus in RA. | |
| 9355681 | Different modes of action of high-dose immunoglobulins in rheumatoid arthritis. | 1994 | Several clinical trials have demonstrated that in patients with rheumatoid arthritis, high doses intravenous immunoglobulins (i.v.i.g.) are frequently leading to an improvement of the morning stiffness and the extra articular symptoms, as well as to a steroid-sparing effect. This i.v.i.g. therapy seems furthermore to have immunomodulatory activities in rheumatoid arthritis, since the clinical benefit is concomitant with a reduction in the number of CD4+ T-lymphocytes, with a significant dtop in the level of circulating immune complexes (CIC), and with an inhibition of the early phases of the B-lymphocytes activation. Due to the heterogeneic aspects of the rheumatoid arthritis pathogeny, it is to be expected that i.v.i.g. may interfere in different ways with many of the sequential processes in operation in the development of this disease. 1. IgGs may facilitate the reticulo endothelial clearance of inflammatory CICs by increasing their size as a consequence of the addition of exogeneous antibodies (Ab) which offers more IgG-Fc fragments as ligands for the monocytes/macrophages Fc-gamma III receptors. 2. i.v.i.g are known to down regulate the activation of B-lymphocytes and their differentiation in specialized Abs-secreting plasma-cells, and this process could affect the clones of B-cells producing anti-collagen II auto-antibodies and Abs with rheumatoid factor activity. 3. Some experimental data allow to suspect the responsibility of a super-Ag in certain forms of rheumatoid arthritis. I.v.i.g. preparations contain specific Abs which bind some of these super Ags, and impair their adequate presentation to T helper-cells. 4. Cytokines and specially the interleukin I (IL-1) which stimulates the collagenase activity, are pivotal elements in the perpetuation of the inflammatory connective tissue damages in rheumatoid arthritis. I.v.i.g. preparations contain soluble cytokine-receptors, as well as anti-IL-1 and IL-6 specific Abs which both act as cytokines agonists and sustain the effective antiinflammatory action of high-dose polyclonal IgGs. Although more clinical data are still needed to sustain the routine use of i.v.i.g. in rheumatoid arthritis, the efficacy of this therapy is not disputable any more in other pathologies with similar immunological disorders. | |
| 8853225 | Ocular complications of adult rheumatoid arthritis. | 1996 | In a prospective study of 325 patients with adult rheumatoid arthritis, ocular complications were seen in 73 patients (22.4%). Keratoconjunctivitis sicca was the most common ocular lesion. Other lesions were episcleritis, scleritis, marginal thinning of the cornea with keratolysis, stromal corneal opacities with peripheral vascularisation, and iridocyclitis. The mean duration of the arthritis and the mean duration of seropositivity were found to be significantly higher in patients with ocular complications. Physicians should include ophthalmic examination as a routine in their protocol for patients with rheumatoid arthritis to facilitate early diagnosis and treatment of ocular complications. | |
| 8171982 | Scaphoid exostosis causing rupture of the flexor pollicis longus. | 1994 | A case of attrition rupture of the flexor pollicis longus (FPL) tendon caused by a scaphoid osteophyte in a patient with rheumatoid arthritis is reported. This lesion was found only after a thorough search of the floor of the carpal tunnel was performed. | |
| 1475634 | Cyclosporin A. Mode of action and effects on bone and joint tissues. | 1992 | Cyclosporin A is an established immunomodulatory agent with an increasing number of clinical applications. Although its precise mechanisms of action remain elusive, one of the most important known properties of CyA is its ability to inhibit the production of cytokines involved in the regulation of T-cell activation. In particular, CyA inhibits de novo synthesis of interleukin 2(IL-2), the major cytokine involved in T-cell proliferation, as well as other cytokines, probably at the level of gene transcription, as shown by the suppression of mRNA levels in activated T-cells. Although the major actions of CyA are on T-cells, there is some evidence for possible direct effects on other cell types e.g. B-cells, macrophages and, from our own work, on bone and cartilage cells. Cyclosporin A is thought to enter cells and to bind to cyclophilins, which are members of a family of high-affinity cyclosporin A-binding proteins, now known as immunophilins. The binding of cyclosporins to such proteins appears to be closely linked to the immunosuppressive action of cyclosporins. The immunophilins possess enzyme activity, ie. peptidyl-prolyl cis-trans isomerase, also known as rotamase, which can regulate protein folding, and may therefore alter the functional state of many cell proteins. Cyclosporin A blocks peptidyl-prolyl cis-trans isomerase activity but it is not clear whether this plays a part in its selective inhibition of cytokine-gene transcription. Moreover, the ubiquitous presence of cyclophilins and immunophilins raises the question of why cyclosporin A has its apparent major effects only on T-cells. Recent proposals regarding the intracellular mode of action of CyA suggest that it interacts with cyclophilin and other regulatory proteins including calmodulin and calcineurin, which is a serine/threonine phosphatase, and thereby affects the functional state of key regulators of gene transcription in its target cells. The effects of CyA on T-cells and directly or indirectly on connective tissue cells, including bone, cartilage and synovial cells, which all can produce a range of cytokines, are of interest in relation to the tissue changes that occur in inflammatory diseases, such as rheumatoid arthritis. Thus, for example, cyclosporin A inhibits in vitro the bone resorbing activity of interleukin 1, 1,25-dihydroxy-vitamin D3, parathyroid hormone and prostaglandin E2 by apparently non-T-cell effects, while in vivo protects against bone and cartilage loss in adjuvant arthritis. More needs to be known about the direct and indirect modulation of cytokine production by cyclosporin A in connective tissues, in order to understand its potential value in clinical disorders. | |
| 7552064 | The anatomy of the rheumatoid lesion. | 1995 Apr | Rheumatoid arthritis primarily involves the synovial membrane of the joints, together with that of the tendon sheaths and bursae. These structures are targeted in a selective and symmetrical manner. The inflammatory cell infiltrate is usually dominated by mononuclear phagocytes. These are recruited into the synovial lining as type A synoviocytes. A proportion of the mononuclear cell population has proven to be specialized antigen-presenting accessory cells. The T and B lymphocyte infiltrate is quite variable in intensity, but may become highly organized. Polymorphonuclear leukocytes pass rapidly into the joint space. The cellular characteristics of rheumatoid nodules have some similarities with those of the synovial membrane. In a minority of patients, immunoglobulin production and circulating immune complex formation reaches levels which precipitate the appearance of a complement mediated vasculitis. This may lead to tissue damage in remote organs. | |
| 8173854 | Evidence for a hypothetical non-HLA susceptibility gene in rheumatoid arthritis. | 1994 May | In this study investigating possible reasons for the increased female prevalence of RA, family histories were obtained from 719 patients with classical RA by direct interview. Thirty-one per cent positively identified at least one affected relative. Compared with the expected population sex distribution ratio of 3:1 and local prevalence data, mothers with RA were eight times more common than predicted and fathers with RA 15 times more frequent. Mean age of onset of clinical disease was 7 yr younger in probands with affected fathers, compared to those with no or only maternal family history (P < 0.001). On the basis of other diseases where there is a gender discrepancy in prevalence, the characteristics of a major susceptibility gene product is proposed to connect these inheritance patterns with the known female preponderance for developing RA. Although there are clearly methodological uncertainties in a study of this type, it is felt that by concentrating on parental data only that these have been kept to a minimum, and that the conclusion is not unexpected. | |
| 8619103 | The changing face of therapy for rheumatoid arthritis. | 1995 Aug | This article reviews past and present prescribing patterns for patients with rheumatoid arthritis and reveals some striking differences over time. For many practitioners, methotrexate has become the centerpiece around which other therapies are built; however, we are still learning a great deal about this drug. In this article, some recent advances are described. The prospects for further therapeutic development are discussed, with a focus on the present state-of-the-art combination chemotherapeutic regimens. Consideration is given to ways in which new approaches might facilitate clinical research in this severely underfunded area. | |
| 7558919 | T-cell receptor variable region of the beta-chain gene use in peripheral blood and multipl | 1995 Apr | In order to look for a site-specific T-cell response in RA SM, PCR analyses using oligonucleotide primers specific for 24 TCRBV (V beta) families were performed to compare the respective usage of each TCRBV gene by T cells present in PB and SM of 13 patients with RA. In four patients, SM cells from two or three sites of inflammation were subjected to analysis. In one patient, synovial tissue was studied at two different phases of the disease, resulting in a total number of 19 samples of SM cells, which were compared with paired samples of PB cells. The results showed that whereas all 24 TCRBV gene families could be detected in both PB and SM cells, there was some skewing of increased or decreased usage frequencies of particular TCR V beta genes among SM cells. Three TCRBV families were often overexpressed in SM: V beta 3, V beta 17, and V beta 22. Moreover, V beta 4 was often decreased in SM (7 out of 13). This decrease was statistically significant in the RA population studied. SM from different joints of a given patient showed similar variations of T-cell repertoire compared to PB, even 6 months later in the course of the disease. These results demonstrate a biased TCRBV gene utilization in RA SM. This bias appears to be similar in different joints and at different times in the course of the disease. No correlation was found between the bias of TCR repertoire in SM and the HLA typing of these patients. |