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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
10493160 Effects of ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor, on indices of e 1999 Aug OBJECTIVE AND DESIGN: To investigate effects of ER-34122, a novel dual 5-lipoxygenase (LOX)/cyclooxygenase (COX) inhibitor, and indomethacin on progression of articular lesions in MRL/MpJ-lpr/lpr (MRL/1) mice. MATERIAL: 100 male MRL/l mice. TREATMENT: ER-34122 (1-100 mg/kg) and indomethacin (1 mg/kg) were orally administered once a day to MRL/l mice from 6 to 10 or 16 weeks old. METHODS: Articular lesions were analyzed histopathologically in the early (10 weeks old) or late (16 weeks old) stages of MRL/l mice arthritis. Serum levels of rheumatoid factor were measured by using enzyme-linked immunosorbent assay. RESULTS: Articular lesions in the late stage of MRL/l mice arthritis were characterized by cartilage degeneration and pannus formation which were severer than those in the early stage. Polymorphonuclear leukocyte (PMN) infiltration and subsynovial soft tissue edema were observed as characteristic lesions in the early stage. ER-34122 suppressed progression of PMN infiltration, subsynovial soft tissue edema and multiplication of synovial lining cells in the early stage of the arthritis, even though it had no significant effect on other indices of articular lesion, enlargement of lymph nodes and serum levels of rheumatoid factors. On indices of late articular lesion, ER-34122 had no significant beneficial effects. Neither in the early nor late stage, indomethacin, a COX inhibitor, had significant effect on the arthritis at the examined dose. CONCLUSIONS: These results disclosed that ER-34122, a dual LOX/COX inhibitor, has anti-inflammatory activity in the early stage of the spontaneous arthritis.
11557646 Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double 2001 Oct OBJECTIVE: Recent studies have demonstrated the short term efficacy of leflunomide. This study evaluates the efficacy and safety of leflunomide and sulfasalazine in rheumatoid arthritis over a two year follow up period. METHODS: 358 patients with rheumatoid arthritis in a double blind trial were randomly allocated to receive either leflunomide 20 mg/day, placebo, or sulfasalazine 2 g/day. Those completing six months of treatment (n=230) were given the option to continue in 12 (n=168) and 24 (n=146) month double blinded extensions; the placebo group switched to sulfasalazine. This report compares efficacy and safety of leflunomide with sulfasalazine in the 6, 12, and 24 month patient cohorts. RESULTS: The efficacy seen at six months was maintained at 12 and 24 months. Twenty four month cohorts on leflunomide showed significant improvement compared with sulfasalazine in doctor (-1.46 v -1.11, p=0.03) and patient (-1.61 v -1.04, p<0.001) global assessments, ACR20% response (82% v 60%, p<0.01), and functional ability (Deltamean HAQ -0.65 v -0.36, p=0.0149; DeltaHAQ disability index -0.89 v -0.60, p=0.059). Improvement in other variables was comparable for the two drugs, including slowing of disease progression. Improved HAQ scores in 6, 12, and 24 month leflunomide cohorts were seen in both non-responders (24%, 29%, 35%, respectively v sulfasalazine 8%, 10%, 27%) and ACR20% responders (leflunomide 63%, 62%, 66% v sulfasalazine 50%, 64%, 44%). Leflunomide is well tolerated at doses of 20 mg. No unexpected adverse events or late toxicity were noted during the two year period. Diarrhoea, nausea, and alopecia were less frequent with continued treatment. CONCLUSION: These long term data confirm that leflunomide is an efficacious and safe disease modifying antirheumatic drug.
9811053 Monoclonal expansion of synoviocytes in rheumatoid arthritis. 1998 Nov OBJECTIVE: To examine whether synoviocytes from patients with rheumatoid arthritis (RA) have a stronger growth ability than those from patients with osteoarthritis (OA), and to determine whether these synoviocytes clonally expand in situ. METHODS: Synovial tissues from 13 RA patients and 4 OA patients were cultured, and their ability to form colonies in soft agarose was examined. RA and OA synoviocytes were also examined in varying concentrations of fetal calf serum (FCS)-containing medium to test the effects of FCS on colony formation. DNA was extracted from clones with colony-forming ability in nonpannus lesions and from synoviocytes in pannus lesions. Restriction fragment length polymorphism (RFLP) analysis was used to examine phosphoglycerate kinase 1 (PGK-1) gene patterns. Production of cytokines by these cells was also assessed. RESULTS: All 13 RA synoviocytes exhibited colony formation, whereas none of the 4 OA synoviocytes did. This tendency was also seen with all of the concentrations of FCS examined, although growth varied in a dose-dependent manner. In contrast to OA synovial clones, cloned RA synoviocytes obtained from colonies exhibited a partial RFLP PGK-1 gene pattern, suggesting that the clones originated from monoclonal cells. Of note, 3 of 7 noncloned synoviocytes from pannus lesions exhibited a monoclonal pattern. Pannus cells produced high levels of transforming growth factor beta and platelet-derived growth factor. CONCLUSION: These findings suggest that synoviocytes with a strong growth ability are present in the rheumatoid synovium, and that these cells expand monoclonally, particularly in pannus lesions.
12476736 [Effect of rheumatoid arthritis on physical performance of patients]. 2001 To determine the changes occurRing in physical performance of patients with RA, 188 patients have been observed over a ten-year period. The observation included two groups: the test group comprising 93 patients with RA who have never been treated by any disease-modifying antirheumatic drugs (DMARDs) and the control group comprising 95 patients with RA who have regularly taken DMARDs under the rheumatologist's supervision. The average age of the test group was considerably higher, there were more retired persons with a prolonged course of illness, their physical performance being more intensely affected than that of the control group. Further analysis during the observation period showed significant decrease of physical performance in both groups regardless of their being treated or not by the DMARDs which, in our opinion, only modify the illness. To conclude, irrespective of the application of the DMARDs, RA is undoubtedly an illness with considerable socio-economic significance since it leads to great physical disability (invalidity) of all RA patients.
10424242 Prolactin and prolactin-like polypeptides in rheumatoid arthritis. 1999 Jun A bidirectional communication network exists between the neuroendocrine and immune systems, and a dysfunctional communication may contribute to the development of autoimmune diseases in various species, including humans. Experimental, epidemiological, and clinical data suggest that breast feeding and hyperprolactinemia constitute a risk factor for the development of diseases with autoimmune components, including rheumatoid arthritis (RA). We hypothesized that the anterior pituitary hormone prolactin (Prl) and locally produced Prl-like polypeptides may act as endocrine, autocrine, and paracrine regulators of synovial cell functions. They may participate not only in enhancing T-lymphocyte immune reactivity, but also in the exacerbation of RA lesions through their influence on synovial fibroblasts. In RA synovial tissue, Prl-like polypeptides could participate in a bidirectional communication between immunocytes and fibroblasts. Both Prl and Prl-like polypeptides might act via proto-oncogenes and transcriptional factors, leading to cell proliferation, i.e., synovial tissue hyperplasia, neo-angiogenesis, and the production of catabolic enzymes such as matrix metalloproteinases and cathepsins. In such cases, they could represent important regulators of the T-cell independent mechanism of joint destruction.
9457329 Long-term results of Yoshino total knee arthroplasties in rheumatoid arthritis. 1998 A review was made of 267 Yoshino total knee arthroplasties performed on 184 patients with rheumatoid arthritis between June 1978 and December 1983. The average duration of follow-up was 14.3 years. Of these patients 46.7% died during the follow-up period. The main causes of death were cardiac disease, respiratory disease and renal disease. According to the Japanese Orthopaedic Association (JOA) knee rating system, JOA scores decreased significantly with time after surgery, but remained significantly higher than the preoperative scores. The flexion angle after surgery had decreased compared with the preoperative flexion angle and decreased further 3 years after surgery and later. The cumulative survival rate was 88.6%. This rate was mainly affected by postoperative infection and aseptic loosening of the tibial components.
9411047 [A long experience in basic therapy of rheumatoid arthritis]. 1997 183 patients with rheumatoid arthritis (RA) received basic drugs for 3 to 15 years. The patients were followed up for 13.5 years, on the average, with intervals 6-48 months. Clinical, laboratory, instrumental and morphological methods of investigation were used. The findings are reviewed on the mortality and causes of death, lethal tumors, overall complications and those observed in 55 patients on glucocorticoids.
9610077 Methotrexate in rheumatoid arthritis: a 2 year experience at a university hospital in Paki 1998 Jan In this study we report our two years experience of methotrexate (MTX) in the management of rheumatoid arthritis (RA) at the Aga Khan University Hospital, Karachi. We studied the clinical course of 124 RA patients. The mean age was 44 +/- 11 years (range 19-72) and mean duration of RA was 5 +/- 4 years (range 0.3-25). Female to male ratio was 10:2.4 (100F:24M). All of them were diagnosed according to the criteria set by American Rheumatism Association. The mean value of ESR was 60 +/- 30 (Range 3-128). Fifty one percent had severe disease (> 10 joints involved and evidence of erosions and deformities). Twenty-one patients had extra-articular manifestations. None of them had received MTX previously. Their kidney and liver functions were assessed to be normal. Patients were divided into two groups. One group (n = 92) received MTX (7.5-10 mg/week) as initial treatment, while the other group (n = 32) was given other disease modifying anti-rheumatic drugs (penicillamine, salazopyrin, gold, or chloroquine) followed by MTX. Assessment of the treatment outcome and development of any adverse reactions was carried out at 3-month interval over an average period of 1 year. Assessment of the treatment outcome in the group which received MTX as initial drug revealed the response to be excellent in 13%, good in 70%, fair in 11% and variable in 4%. In the group which received MTX as second-line of therapy, 59% of the patients had the response from good to excellent, while 25% of the patients exhibited poor to fair response. Regarding side-effects of MTX treatment, 57% exhibited none, while 35% had nausea and vomiting. Alopecia was the next common toxicity in these patients. Two individuals had abnormal liver function tests (value twice more than normal), while one developed lung fibrosis. MTX despite its adverse effects in some of the patients is still an effective, well tolerated and inexpensive disease modifying drug in RA.
11094418 A revival of the B cell paradigm for rheumatoid arthritis pathogenesis? 2000 Dominant paradigms for the understanding of rheumatoid arthritis (RA) pathogenesis have changed over the years. A predominant role of B lymphocytes, and perhaps of the rheumatoid factor they produced, was initially invoked. In more recent years, recognition of antigens in the joint by T cells sparking an inflammatory cascade has been a more favored interpretation. Here, we re-examine some of the arguments that underpin this proposed role of joint T cells, in light of recent results from transgenic mice in which a self-reactive T-cell receptor provokes disease, but from outside the joint and indirectly via B lymphocytes and immunoglobulins.
10643711 Lack of evidence for an involvement of Epstein-Barr virus infection of synovial membranes 2000 Jan OBJECTIVE: To test the hypothesis that Epstein-Barr virus (EBV) infection of cells within the synovial membrane contributes to the pathogenesis of rheumatoid arthritis (RA). METHODS: Biopsy samples of synovial membrane from 37 patients with RA and from 51 patients with other joint diseases were studied for evidence of EBV infection using in situ hybridization specific for the EBV-encoded RNAs (EBERs). Latent membrane protein 1 (LMP1) and the lytic-cycle BZLF1 protein were detected by immunohistochemistry. RESULTS: Rare EBER-positive B lymphocytes were detected in 7 RA biopsy samples. EBV was not detectable in any other cells. Expression of the LMP1 and BZLF1 proteins of EBV was not observed in any of the samples. No EBV infection was detected in synovial membranes from patients with other joint diseases. CONCLUSION: Our data indicate that EBV infection is not directly involved in the pathogenesis of RA. Any contribution of EBV to the pathogenic process leading to RA is likely to be indirect.
11550961 Lack of effect of doxycycline on disease activity and joint damage in patients with rheuma 2001 Sep OBJECTIVE: To investigate the effects of doxycycline on disease activity and joint destruction in patients with rheumatoid arthritis (RA). METHODS: A 36 week double blind, placebo controlled crossover trial was conducted. Patients (n = 66) received 50 mg doxycycline or placebo twice a day during 12, 24, or 36 weeks. Patient assessments were performed before the treatment was administered, at 6, 12, 24 and 36 weeks of treatment, and finally at 4 weeks after cessation of treatment. Patient assessments, swollen and tender joint counts, duration of morning stiffness, erythrocyte sedimentation rate, and Modified Disease Activity Score were used as measures of disease activity. Effects on joint destruction were assessed by urinary excretion of the pyridinolines hydroxylysylpyridinoline and lysylpyridinoline and by scoring radiographic damage of hands and feet before and after treatment. RESULTS: The changes of clinical or laboratory disease activity measures, pyridinoline excretion, or progression of radiographic joint damage during doxycycline or placebo treatment did not differ significantly. CONCLUSION: The results indicate that 50 mg doxycycline twice a day provided no therapeutic benefit for patients with RA.
9174133 Dominant clones in immortalized T-cell lines from rheumatoid arthritis synovial membranes. 1997 May Transformation of human T cells by herpesvirus saimiri allows the production of an unlimited number of T cells which express a functional T-cell receptor. In this study we transformed four T-cell lines derived from rheumatoid arthritis synovial membranes. The transformed T cells were mainly CD4+ and expressed the phenotype of activated T cells. They were grown for more than 1 year in the absence of mitogen or feeder cells, and three of them could be maintained without exogenous IL-2. The presence of viral DNA in the transformed cells was shown by in situ hybridization with a probe from the H-DNA region of the virus. No infectious virus could be recovered from the transformed cells. The relative proportion of the 24 different Vbeta families between the four transformed lines showed variations that increased with time. In the two T-cell lines transformed at an early stage of culture, the Vbeta2 family was maintained at about 10%. The dominant Vbeta2 clones that previously have been characterized in the patient were found in all transformed T-cell lines. We have thus shown the feasibility of obtaining transformed T cells from synovial membranes. They contain the dominant clones that are considered of potential importance for the disease, permitting further functional studies.
9621780 [Rheumatoid arthritis and risk of cancer]. 1998 May 18 In the current study we linked data from the Danish Hospital Discharge Register and the Danish Cancer Registry to estimate cancer occurrence among more than 20,000 patients hospitalized at least once with rheumatoid arthritis during 1977-1987. During a follow-up interval of up to 15 years, we found increased risks of non-Hodgkin's lymphoma, Hodgkin's disease and lung cancer, while the risk of colorectal cancer was decreased. These findings were all in agreement with the results of previous studies from two other Nordic countries, which were based on a similar type of data. We also found an excess of non-melanoma skin cancer and a deficit of female breast cancer, of which only the breast cancer observation had been seen in an earlier study.
10846401 [Rheumatoid arthritis-associated bronchiolitis successfully treated with erythromycin]. 2000 Mar A 52-year-old man with a 4-year history of rheumatoid arthritis, and who had an episode of suspected BOOP in early 1994, was admitted to our hospital because of cough and fever. A chest X-ray film on admission showed small patchy infiltrates, and a computed tomographic (CT) scan showed centrilobular nodules and patchy infiltrates with thickened broncho-vascular bundles in both lungs. Transbronchial and thoracoscopic lung biopsies disclosed the coexistence of interstitial pneumonia with BOOP pattern, follicular bronchiolitis, and diffuse panbronchiolitis-like purulent and obliterative bronchiolitis. Due to findings of chronic sinusitis, the patient was treated with erythromycin for 8 weeks, and the abnormal CT shadows regressed. This was an interesting case of various pulmonary lesions associated with rheumatoid arthritis, and successfully treated with erythromycin.
10606983 Expression and production of the long pentraxin PTX3 in rheumatoid arthritis (RA). 2000 Jan PTX3 is a secreted molecule which consists of a C-terminal domain similar to classical pentraxins (e.g. C-reactive protein (CRP)) and of an unrelated N-terminal domain. Unlike the classical pentraxins, the long pentraxin PTX3 is expressed in response to IL-1beta and tumour necrosis factor-alpha (TNF-alpha), but not to IL-6, in various cell types. The present study was designed to investigate the expression of PTX3 in RA. Dissociated RA and osteoarthritis (OA) type B synoviocytes were cultured in the presence and in the absence of inflammatory cytokines. PTX3 mRNA expression in synoviocytes was evaluated by Northern analysis. PTX3 protein levels in synovial cell cultures and synovial fluid were estimated by ELISA, and PTX3 distribution in synovial tissues by immunohistochemical techniques. OA synoviocytes were induced to express high levels of PTX3 mRNA by TNF-alpha, but not by other cytokines including IL-1beta and IL-6. RA synoviocytes, unlike OA synoviocytes, constitutively expressed high levels of PTX3 in the absence of deliberate stimulation. The constitutive expression of PTX3 in RA synoviocytes was not modified by anti-TNF-alpha antibodies, IL-1 receptor antagonist or a combination of the two agents. In contrast, interferon-gamma and transforming growth factor-beta inhibited PTX3 constitutive expression in RA synoviocytes. The joint fluid from RA patients contained higher levels of immunoreactive PTX3 than controls and the synovial tissue contained endothelial cells and synoviocytes positive for PTX3 by immunohistochemistry. In conclusion, PTX3 may play a role in inflammatory circuits of RA, and its relevance as a marker of disease activity deserves further study.
9331953 Tumor necrosis factor locus polymorphisms in rheumatoid arthritis. 1997 Sep We examined six polymorphic elements in the tumor necrosis factor (TNF) locus and determined their allelic distribution in 98 Caucasian rheumatoid arthritis patients in comparison with 91 ethnically-matched controls. Polymorphic elements at four biallelic sites were distributed similarly between patients and controls, irrespective of the presence or absence of DR4. Differences were observed between the two groups at the TNFa and TNFe loci, but these were consistent with extended MHC haplotypes known to be present in rheumatoid arthritis patients. Therefore, this study suggests that there is little, if any, independent contribution of the TNF locus to the genetic background for rheumatoid arthritis susceptibility.
10991810 Endoscopic carpal tunnel release in selected rheumatoid patients. 2000 Oct Twenty endoscopic carpal tunnel releases were performed in 15 patients with quiescent seropositive rheumatoid arthritis using the Agee technique. Patients were not considered for endoscopic carpal tunnel release if there was florid synovitis with crepitus or loss of active finger flexion, if there was evidence of flexor tendon rupture or if they had previously undergone surgery in the region. Access to the tunnel was significantly easier than normal and visualization of the flexor retinaculum was satisfactory in all cases. There were no complications. We conclude that endoscopic carpal tunnel release can be safely performed in selected patients with rheumatoid arthritis. The absence of a palmar scar can be a great advantage to these disabled patients.
10914841 The possible role of c-fos expression in rheumatoid cartilage destruction. 2000 Jul OBJECTIVE: To determine the effect of c-fos on human chondrocytes and to examine the role of c-fos in cartilage destruction in rheumatoid arthritis (RA). METHODS: We examined changes in collagen synthesis by transfecting human c-fos into cultured human chondrocytes and evaluated expression of c-fos mRNA and localization of Type II collagen, matrix metalloproteinases-1 (MMP-1), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in articular cartilage samples from patients with RA or osteoarthritis (OA) by in situ hybridization and immunohistochemistry. RESULTS: Introduction of c-fos in the chondrocytes decreased endogenous transcription of Type II collagen and TIMP-1, and increased that of MMP-1. The effect of the activating protein-1 protein on the MMP-1 and TIMP-1 promoters in human articular chondrocytes was analyzed by chloramphenicol acetyltransferase activity assay. MMP-1 promoter was clearly activated by Jun related proteins as well as Fos/Jun related protein heterocomplex. On the other hand, c-fos combined with any of the Jun related proteins failed to stimulate the TIMP-1 promoter, although it was activated by Fra-1 or Fra-2/Jun related protein heterocomplexes. Expression of c-fos mRNA was detected in chondrocytes in the mid and deep layers of cartilage in 11/15 patients (73%) with RA, but only in the superficial layer of cartilage from 2/10 patients (20%) with OA. Although TIMP-1 staining exceeded that of MMP-1 in OA cartilage, it appeared to be less intense than MMP-1 staining in RA cartilage. CONCLUSION: These results suggest that activation of c-fos may be involved in cartilage metabolism and hence play a crucial role in the pathogenesis of arthritic destruction in RA.
10834863 Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids f 2000 Jun OBJECTIVE: Matrix metalloproteinases (MMPs) are expressed in joint tissues of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The objective of this study was to define the steady state levels of seven different MMPs and two tissue inhibitors of metalloproteinases (TIMPs) as well as the potential metalloproteinase activity in the synovial fluid (SF) to provide more insight into the role of MMPs in cartilage destruction in RA and OA. METHODS: Levels of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, TIMP-1, and TIMP-2 in SF aspirated from knee joints of 97 patients with RA and 103 patients with OA were measured by the corresponding one step sandwich enzyme immunoassays. Proteolytic activity of MMPs in these SFs was examined in an assay using [(3)H]carboxymethylated transferrin substrate in the presence of inhibitors of serine and cysteine proteinases after activation with p-aminophenylmercuric acetate (APMA). Destruction of RA knee joints was radiographically evaluated. RESULTS: Levels of MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 were significantly higher in RA SF than in OA SF. MMP-7 and MMP-13 were detectable in more than 45% of RA SFs and in less than 20% of OA SFs, respectively. Among the MMPs examined, MMP-3 levels were extremely high compared with those of other MMPs. Direct correlations were seen between the levels of MMP-1 and MMP-3 and between those of MMP-8 and MMP-9 in RA SF. Although the levels of MMP-1 and MMP-3 increased even in the early stage of RA, those of MMP-8 and MMP-9 were low in the early stage and increased with the progression of RA. Molar ratios of the total amounts of the MMPs to those of the TIMPs were 5.2-fold higher in patients with RA than in OA, which was significant. APMA-activated metalloproteinase activity in SF showed a similar result, and a direct correlation was seen between the molar ratios and the activity in RA SF. CONCLUSIONS: Our results show that high levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, and TIMP-1 are present in RA SF and suggest that once these MMPs are fully activated, they have an imbalance against TIMPs, which may contribute to the cartilage destruction in RA.
9431585 Splenic involvement in rheumatic diseases. 1997 Dec OBJECTIVES: To assess the major reports of splenic involvement in the rheumatic diseases and to highlight several conditions in which potentially life-threatening splenic complications may occur. METHODS: A search of the Medline database ('SilverPlatter': 1966 to 1997) was conducted for all English-language entries related to the spleen and the major rheumatic diseases. Original articles were reviewed from the bibliographies of these Medline-sourced articles. The major rheumatological textbooks were also reviewed for original references. RESULTS: Patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and polyarteritis nodosa (PAN) are at risk of experiencing spontaneous splenic rupture. Splenomegaly is common in both uncomplicated RA and as a feature of Felty's syndrome, in which the patient may be at risk of splenic abscess formation, again a possible complication of SLE and also PAN. Massive splenomegaly appears to be specific to SLE and may be confused with a malignant process. Abnormal splenic function has been documented in RA, SLE, and Wegener's granulomatosis. The spleen may show areas of infarction in several conditions, notably SLE and Wegener's granulomatosis. Splenic atrophy is not uncommon in SLE and may be associated with functional asplenia and a co-incident risk of potentially fatal infection with capsulated organisms. CONCLUSIONS: Serious and occasionally fatal complications within the spleen occur in many rheumatic diseases. Prompt recognition of these complications is important.