Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 11351775 | Tumour necrosis factor as a therapeutic target in rheumatoid arthritis and other chronic i | 2001 Apr | Therapeutic strategies that aim to neutralise the important pro-inflammatory cytokine tumour necrosis factor alpha (TNF alpha) have gained considerable prominence in the therapy of chronic inflammatory diseases, notably rheumatoid arthritis and Crohn's disease. This drug focus review will concentrate on the antitumour necrosis factor antibody infliximab (Remicade), which has been approved for the treatment of rheumatoid arthritis and Crohn's disease in both the US and Europe. In addition, infliximab is under investigation for several other indications, mainly inflammatory rheumatic diseases. Clinical trials have been persuasive that infliximab is both safe and effective, and it has been proven to be far superior to the conventional drug therapy in both rheumatoid arthritis and Crohn's disease. Remarkably, infliximab in combination with methotrexate controls both the inflammatory joint symptoms and the progression of joint damage, which renders it a very attractive therapeutic option in moderate to severe, therapy-resistant rheumatoid arthritis. | |
| 11735673 | A cost-cost study comparing etanercept with infliximab in rheumatoid arthritis. | 2001 | OBJECTIVE: The objective of this study was to compare the total costs associated with the administration of two different tumour necrosis factor (TNF) strategies used in the treatment of rheumatoid arthritis (RA): etanercept, a soluble TNF receptor that can be administered at home by subcutaneous injection, versus infliximab, an antibody that requires an intravenous infusion in a hospital outpatient setting. DESIGN AND SETTING: The main analytical framework of the study was a cost-cost analysis comparing the total annual costs associated with the administration of etanercept and infliximab in adult RA patients. The perspective of the study was that of the Dutch society. An economic model was constructed to determine the costs of both treatments. The cost evaluation included direct medical costs, direct nonmedical costs and indirect costs. The base-case analysis compared monotherapy with etanercept versus a combination therapy with infliximab and methotrexate. Data for the economic model came from published literature, expert opinion and official price and tariff lists. All costs were in 1999 values. PATIENTS AND PARTICIPANTS: The analysis was performed for the adult RA population eligible for treatment with etanercept or infliximab in The Netherlands. MAIN OUTCOME MEASURES AND RESULTS: The analysis showed that the total annual drug costs per patient do not differ substantially between infliximab and etanercept, with costs of Netherland guilders (NLG)31,526 (12,610 US dollars) and NLG31,334 (12,534 US dollars), respectively. However, the other medical costs (i.e. excluding the costs of the two drugs themselves) are substantially higher for infliximab due to the additional costs associated with administration in an outpatient clinic and the use of methotrexate [NLG 12,621 (5048 US dollars) versus NLG269 (107 US dollars) for etanercept]. The impact of direct nonmedical costs (transportation) and indirect costs were negligible. Overall treatment with infliximab is more expensive than treatment with etanercept with total costs of NLG45 115 (18,046 US dollars) and NLG3I,621 (12,648 US dollars), respectively (42.7% increase). CONCLUSIONS: Based on the assumptions used in the model, we may conclude that the use of etanercept compares favourably with infliximab from a budgetary and health economic perspective: the total costs are substantially lower when the efficacy of etanercept is assumed to be at least equivalent to the efficacy of infliximab. | |
| 9549387 | [Combined drug therapy in recent-onset rheumatoid arthritis. Evaluation after 1 year of tr | 1998 Jan | The aim of our study is to evaluate the efficacy and safety of a combination therapy with hydroxycloroquine, gold sodium thiomalate and methotrexate in patients affected by recent onset active rheumatoid arthritis. Twenty-five patients (6 men e 19 women, average age 46.2 +/- 12.2) were enrolled in this study and 18 of them have been treated for 1 year with the three above-mentioned drugs at optimal doses. Drug toxicity was carefully monitored. Clinical and hematochemical parameters of efficacy were evaluated every three months. Radiographic joint study was performed at the beginning and at the end of the study. Seven patients dropped out, six of them for side effects, due to hydroxycloroquine in 1 case and to gold sodium thiomalate in 5 cases; 1 patient withdrew his consent. No life-threatening or irreversible adverse reactions were observed. The eighteen patients who completed the one year trial presented a remarkable improvement of clinical and hematochemical parameters. In only 1 case one erosion appeared at the end of the study. In conclusion, the combination therapy with hydroxycloroquine, gold sodium thiomalate and methotrexate seems to be effective and burdened by an acceptable level of toxicity. | |
| 9770962 | [Pulse therapy with prospidin and methotrexate: comparative efficacy in rheumatoid arthrit | 1998 | Efficiency of pulse-therapy with prospidin (500 mg for 5 days in hospital, 500-1000 mg for a month as maintenance) and methotrexate (30 mg a week i.v. in hospital, 7-10 mg a week as maintenance) was investigated in 93 patients with severe RA. The response to prospidin and methotrexate arose quickly (within 10-14 and 4-5 weeks, respectively) and occurred in 73 and 70% of patients, respectively. Withdrawal of the drug was caused by side effects of methotrexate (19.3%) and resistance to prospidin (23.2%). | |
| 10468411 | Methotrexate and leflunomide: biochemical basis for combination therapy in the treatment o | 1999 Aug | OBJECTIVES: Methotrexate is currently one of the most widely prescribed disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA). Combination therapy of methotrexate with other DMARDs increases the clinical success of low-dose methotrexate treatment. Leflunomide is a new DMARD that may have a high potential for success in combination therapy with methotrexate. This review compares the mode of action of methotrexate and leflunomide and speculates on how this contributes to therapeutic efficacy in RA when these agents are used singly or in combination. METHODS: A literature review of the biochemical mechanisms considered to be the basis for the therapeutic efficacy of methotrexate and leflunomide in treating RA is presented. RESULTS: Low-dose methotrexate inhibits cytokine production, purine biosynthesis, and, in an animal model, causes the release of adenosine, a potent antiinflammatory agent. Leflunomide, through inhibition of de novo pyrimidine biosynthesis, can regulate lymphocyte proliferation. CONCLUSIONS: The biochemical mechanisms underlying the therapeutic efficacy of low-dose methotrexate and leflunomide in the treatment of RA are quite different. The potentially complementary mechanisms of action of these two effective DMARDs should provide a rationale for their use in combination therapy for patients whose condition no longer responds to methotrexate alone. | |
| 10953409 | [Secondary hemophagocytic syndrome in a systemic disease]. | 2000 Jun 21 | 20 year old man 2 years treated for the seropositive rheumatoid arthritis was admitted for fever accompanied with jaundice, anemia and leukopenia. The underlying disease has been compensated already for long period of time, before his admission only Prednisone (in the dose of 5 mg daily) and Methotrexate (15 mg once a week) was given. His physical examination of admission was without any significant abnormalities, out of the routine laboratory examination the value of leukocytes count was 2.1 x 10(9)/L, erythrocytes 3.7 x 10(12)/L, hemoglobin 95 g/l, hematocrit 0.29, platelets 156 x 10(9)/L. Since admission to hospital the hepatic enzymes ALT, AST, GMT, ALP were about ten times elevated comparing to normal values, the coagulation examination has shown the decrease of Quick test to 55%. With respect to the permanent leukopenia the bone marrow aspiration was taken with the finding of the increase number the RES elements (18.4%) with the signs of hemophagocytosis. The phagocytic reticulum absorbs blood elements erythrocytes, normoblasts, granulocytes, platelets. According to the literature experience we started the combination of the immunosuppressive treatment consisting of corticosteroids and Cyclosporine. Already the day following the application of the high dose of corticosteroids the fever subsided, icterus went away gradually with the normalization of the liver tests. After 20 days of hospitalisation the patient was discharged in good shape. Now, after 4 months the is stabilized on the follow-up treatment of Prednisone a Cyclosporine. | |
| 9231504 | [Treatment with low dose methotrexate in rheumatoid arthritis: risk factors for severe com | 1997 Mar | Treatment with low dose methotrexate in rheumatoid arthritis is associated with serious side effects in about 5 per cent of cases (respiratory, haematological or infectious). The goal of a null risk seems unrealistic because of the idiosyncrasy of some of the risks and our poor understanding of others (enzymatic polymorphisms might be operational, and infectious agents could act as co-factors). However, risk can be greatly reduced by a careful selection of patients. Some contraindications are strict: poor compliance and the possibility of mistake in the timing of the administration; pregnancy or desire for pregnancy; treatment with trimetoprim; haemodialysis; renal insufficiency (clearance < or = 50 ml/min) (and therefore old age), alcoholism. Others remain relative although well established; hypoalbuminaemia, diabetes mellitus, obesity, past infection with hepatitis virus. Others are dubious: starvation, macrocytosis, surgical stress, NSAIDs. An extensive large study of side effects is warranted. | |
| 10600330 | Mechanism of action for leflunomide in rheumatoid arthritis. | 1999 Dec | Leflunomide (Arava) has recently been approved by the Food and Drug Administration for the treatment of rheumatoid arthritis (RA). This approval was based on data from a double-blind, multicenter trials in the United States (leflunomide versus methotrexate versus placebo) in which leflunomide was superior to placebo and similar to methotrexate (Strand et al., Arch. Intern. Med., in press, 1999). In a multicenter European trial, leflunomide was similar to sulfasalazine in efficacy and side effects (Smolen et al., Lancet 353, 259-266, 1999). Both methotrexate and leflunomide retarded the rate of radiolographic progression, entitling them to qualify as disease-modifying agents (Strand et al., Arch. Intern. Med., in press, 1999). Leflunomide is an immunomodulatory drug that may exert its effects by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which plays a key role in the de novo synthesis of the pyrimidine ribonucleotide uridine monophosphate (rUMP). The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of RA. We propose that leflunomide prevents the expansion of activated and autoimmune lymphocytes by interfering with the cell cycle progression due to inadequate production of rUMP and utilizing mechanisms involving p53. The relative lack of toxicity of A77 1726 on nonlymphoid cells may be due to the ability of these cells to fulfill their ribonucleotide requirements by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis. | |
| 9870877 | Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti-tumor | 1998 Dec | OBJECTIVE: Peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA) have increased expression of nitric oxide synthase type 2 (NOS2) protein and enhanced formation of nitric oxide (NO) that correlate with disease activity. NO may play a role in the inflammation of RA. Treatment of RA patients with a chimeric monoclonal antibody against tumor necrosis factor alpha (TNFalpha; cA2) results in clinical improvement in the majority of patients. The present study was designed to determine if cA2 therapy decreases PBMC NOS2 protein expression and NOS enzyme activity in RA patients. METHODS: RA patients receiving background oral methotrexate participated in a double-blind, placebo-controlled clinical trial in which they were randomly assigned to receive a single infusion of either placebo or cA2 at 5, 10, or 20 mg/kg. NOS2 protein and NOS enzyme activity were measured in PBMC at baseline and 4 weeks following cA2 therapy. These results were compared with the degree of clinical change in disease activity. RESULTS: At baseline, elevated levels of NOS2 protein and NOS enzyme activity were more frequently detected in PBMC from RA patients than in those from healthy controls. Treatment of the RA patients with cA2 significantly reduced NOS2 protein expression and NOS enzyme activity. Changes in NOS activity following treatment correlated significantly with changes in the number of tender joints. CONCLUSION: These results indicate that TNFalpha likely plays an important role in enhancing NOS2 expression in RA, and that the antiinflammatory effects of cA2 treatment may be mediated by a reduction of NO overproduction. | |
| 11124283 | Renal toxicity associated with disease-modifying antirheumatic drugs used for the treatmen | 2000 Dec | OBJECTIVE: To provide a review of the renal toxicity of disease-modifying antirheumatic drugs (DMARDs) currently used for the treatment of rheumatoid arthritis. METHODS: Papers in American and European medical journals related to renal toxicity of DMARDs used for the treatment of rheumatoid arthritis were reviewed. Specific DMARDs reviewed were cyclosporine, gold, D-penicillamine, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, infliximab, and DMARD combination therapy. RESULTS: The renal toxicity of DMARDs varies widely. Cyclosporine, gold, and D-penicillamine all have a serious potential for renal side effects, particularly in the elderly or in patients with compromised renal function. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the potential for renal damage. In contrast, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, and infliximab have relatively little renal toxicity. CONCLUSIONS: The potential for renal toxicity should always be considered when determining which DMARD to use for RA therapy. DMARDs that combine efficacy with negligible renal adverse effects should be used for the treatment of patients susceptible to DMARD-associated renal damage. | |
| 11324791 | Were the patterns of treatment for rheumatoid arthritis during 1977-1992 consistent with m | 2001 | OBJECTIVE: Quality assessment of the long-term treatment of patients with rheumatoid arthritis (RA). METHODS: Treatment patterns in a cohort of 70 local and 77 distant RA patients during 1977-1992 were reviewed retrospectively and compared to modern clinical guidelines. RESULTS: In 1977 disease-modifying anti-rheumatic drugs (DMARDs) were given to 62% of the new, hospitalised patients, systemic corticosteroids to 7%, and corticosteroid joint injections to 24%. Patients with short disease duration and/or serious disease were selected for DMARD-treatment. Rheumasurgery was performed on 21%. During follow-up of local patients 54% were recorded with DMARDs for a mean duration of 29 months; approximately 1/5 of the follow-up period. Methotrexate was used infrequently. Local and systemic corticosteroids were recorded in approximately 20%. Rheumasurgery, predominantly non-prosthetic, was performed on 27%. CONCLUSIONS: Patients with early and serious disease were selected for DMARD-therapy, but the treatment duration was too short for modern requirements. Pharmaceutical and surgical treatment patterns were otherwise mainly consistent with present guidelines. | |
| 11437678 | The prospect of treating rheumatoid arthritis with recombinant human interleukin-1 recepto | 2001 | The prospect of introducing a potent novel therapy that specifically targets a pivotal mediator of disease offers new hope to patients with rheumatoid arthritis (RA). There is convincing evidence that interleukin-1 (IL-1) plays a critical role in the pathogenesis of RA. In RA, the inadequate production of IL-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1, results in increased IL-1-mediated pathophysiological activity. Unregulated IL-1-mediated effects produce enhanced tissue inflammation and progressive degradation of cartilage and bone matrix. Recombinant IL-1Ra treatment in experimental models of arthritis results in profound suppression of synovial inflammation and joint damage. Recombinant human IL-1Ra (rhu-IL-1Ra) has been evaluated in RA in several randomised clinical trials and was shown to significantly reduce both the clinical manifestations of arthritis and the rate of progressive joint damage. Firstly, in a 6-month placebo-controlled study, 43% of the patients who received the highest dose of rhu-IL-1Ra (150 mg/day) demonstrated a 20% improvement (American College of Rheumatology clinical criteria) compared to 27% of the patients who received placebo. In addition, the patients who received rhu-IL-1Ra demonstrated 46% less joint damage (Larsen scores). Secondly, in a 6-month extension of the placebo-controlled study, the treated patients maintained their clinical improvement and there was further significant reduction in the rate of progressive joint damage. The patients who had originally received placebo demonstrated both clinical and radiological responses that were similar to those observed in the treated patients during the initial phase of the study. Finally, in a combination study with methotrexate (MTX), 42% of patients who received MTX and the optimal dose of rhu-IL-1Ra (1.0 mg/kg/day) demonstrated an ACR 20% clinical response, compared to 23% of those receiving MTX and placebo. rhu-IL-1Ra was well tolerated in all studies and adverse events were uncommon. The most frequently reported adverse event causing withdrawal of treatment was an injection site reaction, occurring in approximately 5% of patients. In conclusion, targeted IL-1 inhibition significantly reduced both the clinical manifestations and the rate of progressive joint damage in patients with RA. These observations suggest that rhu-IL-1Ra has a potential role as a novel therapeutic modality in the future management of RA. | |
| 11826745 | [Combined basic therapeutic drugs. From individual hope to targeted use]. | 2001 Dec | Accumulating evidence suggests that treatment of rheumatoid arthritis (RA) with two or more disease-modifying antirheumatic drugs (DMARDs) is more efficient than single agent therapy. Randomized clinical trials demonstrated the efficacy of various combinations such as methotrexate plus sulfasalazine plus hydroxychloroquine, methotrexate plus ciclosporine or methotrexate plus infliximab, respectively. In contrast to these data, however, most German rheumatologists use combination therapy in a small percentage of patients with active RA. Thus, consensus criteria should be defined when and how to use combination therapy in the treatment of active disease. We suggest that combination therapy should be started if active disease is still present after three months of treatment with a single standard DMARD, mostly methotrexate, plus low dose prednisolone and that combination DMARD therapy should be used before TNF blocking agents. | |
| 10589362 | Combination therapy of the chimeric monoclonal anti-tumor necrosis factor alpha antibody ( | 1999 Nov | Infliximab, a chimeric anti-TNF alpha antibody, showed in two double-blind placebo-controlled trials efficacy in combination with methotrexate (MTX) in patients with severe rheumatoid arthritis (RA). Whereas in the first trial low-dose MTX or placebo was compared to infliximab alone and in combination, the second trial compared infliximab to placebo in patients with active RA despite maximal tolerated MTX treatment. Infliximab showed synergistic effects in combination with MTX. The immunogenicity of infliximab was reduced by the combination. Infliximab in combination with high-dose MTX is effective and safe in long-term treatment up to 54 weeks. | |
| 10332987 | US consensus guidelines for the use of cyclosporin A in rheumatoid arthritis. | 1999 May | Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that often leads to irreversible joint damage and loss of function. Although there are numerous treatment options, it is difficult to manage the disease in most patients. Use of cyclosporin A (CsA) for RA was first reported in 1979, and since that time many trials have investigated CsA use for this disease. Based on clinical evidence, CsA is an efficacious second-line agent for patients with active RA who have not responded adequately to methotrexate (MTX). In addition, CsA has been shown to provide clinical benefit when used in combination with MTX in patients responding inadequately to MTX monotherapy. Side effects associated with CsA treatment are manageable if dosing, monitoring, and intervention guidelines are followed. The purpose of this review is to provide recommendations for the use of CsA in severe RA to physicians experienced in the management of systemic immunosuppressive therapy for RA. Where possible and appropriate, recommendations are based on evidence available in the literature. | |
| 9663484 | Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha | 1998 Jul | OBJECTIVE: To investigate the regulation of expression of the angiogenic cytokine vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA), in order to determine whether new blood vessel formation could be a potential therapeutic target in RA. METHODS: Dissociated RA synovial membrane cells were cultured in the presence of cytokine inhibitors, or under hypoxic conditions. Serum VEGF levels were serially measured in RA patients enrolled in clinical trials of anti-tumor necrosis factor alpha (anti-TNFalpha) monoclonal antibody treatment. RESULTS: Combined neutralization of TNFalpha and interleukin-1 (IL-1) in RA synovial membrane cultures reduced VEGF release by 45% (P < 0.05 versus control), although blockade of either TNFalpha or IL-1 activities alone resulted in only small inhibitory effects. In addition, release of VEGF from RA synovial membrane cells was selectively up-regulated by hypoxia. Serum VEGF levels were significantly elevated in RA patients relative to control subjects, and correlated with disease activity. Treatment of RA patients with anti-TNFalpha significantly decreased serum VEGF, and this effect was enhanced by cotreatment with methotrexate. CONCLUSION: Inhibition of TNFalpha and IL-1 activity in vivo could reduce the drive to new blood vessel formation, and hence pannus mass, adding to other therapeutic effects of anti-TNFalpha therapy in RA. | |
| 9196524 | Bronchoalveolar lavage cell profile in methotrexate induced pneumonitis. | 1997 Apr | BACKGROUND: Pneumonitis is a rare but potentially life threatening side effect of methotrexate treatment for rheumatoid arthritis which needs to be distinguished from interstitial lung disease due to rheumatoid arthritis. METHODS: To examine the value of bronchoalveolar lavage (BAL) in diagnosing methotrexate pneumonitis, the BAL cell profile of four patients with methotrexate pneumonitis was compared with findings in 16 patients with rheumatoid arthritis treated with methotrexate without clinical or radiological evidence of lung disease and eight patients with interstitial lung disease secondary to rheumatoid arthritis treated with methotrexate. RESULTS: Methotrexate pneumonitis was associated with an increase in the lymphocytes in the BAL fluid to 33-68% of total BAL cells. BAL lymphocytosis was also found in five patients in each of the two control groups. The four patients with methotrexate pneumonitis had a disproportionate increase in CD4+ cells to 72-84% of total lymphocytes and in the CD4/CD8 ratio to 17.0, 6.6, 8.7, and 4.0, respectively, figures which exceeded those of the two control groups. CONCLUSIONS: Methotrexate pneumonitis was associated with lymphocytic alveolitis with a preferential increase in CD4+ cells. This pattern differs from that in interstitial lung disease due to rheumatoid arthritis and may therefore assist in making an early diagnosis of methotrexate pneumonitis. | |
| 9328983 | Photodynamic therapy for rheumatoid arthritis? | 1997 | BACKGROUND AND OBJECTIVE: The only early surgical therapy of rheumatoid arthritis is synovectomy. But even an arthroscopic synovectomy is restricted to more or less big joints. It has been shown recently that for smaller joints a laser synovectomy is possible but more time-consuming than with mechanical instruments. An alternative method may be photodynamic therapy. STUDY DESIGN/MATERIALS AND METHODS: In this study, possible photodynamic effects of Chloroquine, Methotrexate, Piroxicam, and Sodium Morrhuate were examined using a cell culture model of human synovial fibroblasts from patients having rheumatoid arthritis. RESULTS: Incubation with Chloroquine or Methotrexate and subsequent laser irradiation at a wavelength of 351 nm resulted in an at least twenty-fold enhanced cytotoxicity. CONCLUSION: Both substances therefore may serve for a photodynamic therapy of rheumatoid arthritis. | |
| 9300938 | Interleukin-6, soluble interleukin-2-receptor and soluble interleukin-6-receptor in sera o | 1997 Sep 29 | Cytokines and their receptors play a fundamental role in the development and maintenance of the inflammatory process in rheumatoid arthritis (RA). The purpose of this study was to evaluate sIL-2R, sIL-6R and IL-6 levels in the sera of 48 RA patients and to correlate them with disease activity, indicators of inflammatory process as ESR and CRP, and drug treatment modalities. IL-6 and sIL-2R levels were positively correlated with disease activity, ESR and CRP. No correlation between sIL-6R levels and these markers were observed. Our results suggest that different drug therapies have a decisive influence on the levels of selected cytokines. All investigated disease-modifying antirheumatic drugs (DMARDs) were able to reduce the IL-6 level significantly. Non-immunosuppressive DMARDs decreased the amount of circulating sIL-2R more than immunosuppressive drugs. Treatment with methotrexate resulted in a significant reduction of circulating levels of sIL-6R compared to azathioprine therapy. Under low dose glucocorticoid therapy, significantly lower levels of sIL-6R were found than in patients without glucocorticoids. In conclusion, the results provide some arguments in favour of combined drug therapies, which might possibly enhance the effectiveness of RA therapy. | |
| 11771529 | Eosinophilia as a side-effect of methotrexate in patients with chronic arthritis. | 2001 | This report describes isolated reversible eosinophilia without additional subjective symptoms or signs in three patients on methotrexate therapy, two of them with juvenile idiopathic arthritis and one with rheumatoid arthritis. |