Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 8187448 | A clinical and biochemical assessment of methotrexate in rheumatoid arthritis. | 1994 Mar | Low-dose methotrexate has gained widespread acceptance as a second-line agent in rheumatoid arthritis (RA). The Leeds Human Model Screening System (LHMSS) is a validated screening mechanism allowing the rapid evaluation of compounds for their potential as anti-rheumatic agents, the results of which have been confirmed in longer term studies. We have evaluated methotrexate in patients with RA using the LHMSS at a maintenance dose of 10mg/week. Significant change occurred in four out of eleven variables over a 24-week period (p < 0.01). This degree of change is greater than that seen with nonsteroidal anti-inflammatory agents but less than with other recognised second-line agents such as D-penicillamine, suggesting that methotrexate may have less potential as a second-line agent than D-penicillamine. | |
| 7644787 | [Methotrexate treatment of amyloidosis secondary to rheumatoid arthritis]. | 1995 Jun | Amyloidosis secondary to rheumatoid arthritis is a complication with a poor prognosis and as yet an undefined medical therapy. In the last decades the use of different cytostatics has been advocated to avoid renal function deterioration. The clinical characteristics and course in eight patients with amyloidosis secondary to rheumatoid arthritis are here reported after therapy with low dosage methotrexate. In twelve patients who followed a 12-month therapy a clinical improvement was observed, with a marked decrease in proteinuria; in one of them proteinuria disappeared. These results suggest that methotrexate at low doses might be an alternative in the early treatment of amyloidosis secondary to rheumatoid arthritis in patients with preserved renal function. | |
| 8609945 | Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloro | 1996 May 16 | BACKGROUND: Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality. The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug, such as methotrexate, are often suboptimal. Despite limited data, many patients are treated with combinations of these drugs. METHODS: We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year, double-blind, randomized study of treatment with methotrexate alone (7.5 to 17.5 mg per week), the combination of sulfasalazine (500 mg twice daily) and hydroxychloroquine (200 mg twice daily), or all three drugs. The dose of methotrexate was adjusted in an attempt to achieve remission in all patients. The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity. RESULTS: Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity. Among them were 24 of 31 patients treated with all three drugs (77 percent), 12 of 36 patients treated with methotrexate alone (33 percent, P < 0.001 for the comparison with the three-drug group), and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine (40 percent), P = 0.003 for the comparison with the three-drug group). Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity. CONCLUSIONS: In patients with rheumatoid arthritis, combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine, and hydroxychloroquine. | |
| 7914383 | [Study on combined of auranofin, salazosulfapyridine and methotrexate in rheumatoid arthri | 1994 Jun | Patients with rheumatoid arthritis who did not respond sufficiently to auranofin therapy were divided into three groups to be continued on auranofin monotherapy (1), to be on combination therapy of auranofin and salazosulfapyridine (2) and to be given methotrexate concomitantly with auranofin (3), and clinical responses were compared in a prospective manner. Patients on combination therapy either with salazosulfapyridine or with methotrexate demonstrated higher improvement than those on continued auranofin monotherapy. No unknown side effects associated with monotherapy of any of the three compounds were seen in any of the three groups. The study suggests usefulness of combination therapy either with methotrexate or with salazosulfapyridine for patients who failed to respond sufficiently to auranofin. | |
| 8668961 | Effects of methotrexate, sulphasalazine and aurothiomalate on polymorphonuclear leucocytes | 1996 | The aim of the study was to evaluate the effects of treatment with methotrexate, sulphasalazine and aurothiomalate on polymorphonuclear leucocytes (PMN) in rheumatoid arthritis (RA). Circulating PMNs from 58 RA patients treated with either methotrexate (n = 27), sulphasalazine (n = 16) or aurothiomalate (n = 15) were assayed for their chemotactic capacity and generation of superoxide anions. The expression of CD18/CD11b was measured for 17 RA patients treated with methotrexate. Chemotaxis and generation of superoxide anions were not affected by any of the three drugs. We found no difference in the expression of CD18/CD11b in RA patients treated with methotrexate compared to healthy subjects. Further methotrexate and aurothiomalate did not in vitro alter chemotaxis, generation of superoxide anion or expression of CD18/CD11b on normal PMNs. In conclusion we found no evidence that the effect of methotrexate, aurothiomalate or sulphasalazine in RA can be explained by modulation of chemotactic ability or superoxide anion generation of peripheral circulating PMNs. | |
| 7697687 | Methotrexate: the emerging drug of choice for serious rheumatoid arthritis. | 1994 Nov | The recently recognized high morbidity and unexpected mortality associated with rheumatoid arthritis (RA) has spurred new interest in more aggressive, early treatment of this disease. Methotrexate (MTX) has rapidly become the rheumatologist's drug of choice for serious RA because of its favorable efficacy to toxicity ratio and rapid onset of action compared with other second-line agents. The initial concerns about hepatic fibrosis and cirrhosis in psoriatic patients has subsided somewhat as long-term liver toxicity data are accumulating in patients with RA. Routine liver biopsy with incremental doses of MTX is no longer recommended. Potential for severe lung, hematologic, and infectious complications exists, mandating careful monitoring of RA patients taking MTX. | |
| 8280401 | Methotrexate in juvenile rheumatoid arthritis. Do the benefits outweigh the risks? | 1993 Nov | Juvenile rheumatoid arthritis (JRA) is a heterogeneous group of autoimmune diseases resulting in chronic idiopathic peripheral arthritis. The aetiology of JRA is unclear, and current pharmacotherapy is ameliorative rather than curative. Nonsteroidal anti-inflammatory drugs are given initially, but only one-third to one-fourth of patients are managed adequately with these agents. Advanced therapeutic drugs, frequently referred to as disease-modifying antirheumatic drugs or second-line agents, are given to the child with aggressive or resistant disease. Among these, the antimetabolite methotrexate has proven to be the most effective in alleviating articular disease manifestations and reducing laboratory parameters of inflammation. When given orally in low dosages (10 to 15 mg/m2/week), methotrexate is well tolerated, without evidence of substantial bone marrow suppression or severe hepatotoxicity. Extensive long term tolerability data are not yet available for children, but longitudinal studies in adult patients with rheumatoid arthritis suggest that the drug may be given safely for extended periods in many patients. Paediatric rheumatologists are beginning to give higher dosages of methotrexate (up to 1 mg/kg/week) parenterally with some success. The long term consequences of higher dose methotrexate in children are unknown. Methotrexate has now become, and will probably remain for some time, the drug of first choice for children with recalcitrant JRA. | |
| 8026822 | Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of | 1994 Jul | We recently reported two cases of reversible Epstein-Barr virus (EBV)-associated lymphomas in patients undergoing methotrexate therapy for rheumatic disease. The current study was undertaken to investigate how frequently lymphoid neoplasms in patients with rheumatic disease show features of lymphoproliferations occurring in immunocompromised patients. Eighteen patients (including the two previously reported patients) with rheumatoid arthritis or dermatomyositis who developed lymphoproliferative lesions and on whom detailed clinical information was available were studied. As a group these patients developed a spectrum of lymphoproliferative lesions; however, a subset of patients developed neoplasms with features associated with immunosuppression. The neoplasms occurred in extranodal sites in 10 (56%) patients, showed a diffuse large-cell histology in nine (50%) patients, and contained EBV (EBER1) transcripts and EBV latent membrane protein in six (33%) patients. In three (17%) patients the neoplasms showed the entire constellation of features typical of immunosuppression-associated lymphoproliferations, including extranodal location, large-cell or polymorphous histology, geographic areas of necrosis, and the presence of EBV. These three patients were receiving both steroids and methotrexate at the time they developed their neoplasms. The findings of this study support the hypothesis that a subset of lymphoid neoplasms in rheumatic patients occurs in an immunocompromised setting and suggest that therapeutic immunosuppression may contribute, at least in part, to the development of these lymphoid neoplasms. | |
| 1733350 | Lipogranulomas and gold in the liver in rheumatoid arthritis. | 1992 Feb | Liver biopsies have been performed routinely as part of a protocol to evaluate methotrexate therapy in severe rheumatoid arthritis. All patients in the study had failed standard medical therapy, including gold treatment. Twenty-three of 41 patients (56%) had well-formed lipogranulomas (LGs) in the lobules, compared with an incidence of approximately 5% in our general biopsy population. Twenty-seven of 41 patients (66%) had a unique pigment in their livers. In 20 of these, the pigment was in LGs; in the seven patients with pigment not associated with lobular LG, it was found in lipid droplets in portal triads. The pigment varied from irregular pale brown granules slightly larger than those of hemosiderin, to smaller black round granules. Lipogranuloma-associated pigment of this type is an unusual finding, reminiscent of argyria. There was a variable appearance upon polarization, the black granules at times being strikingly refractile. There was a positive correlation between the prominence of LG and the quantity of pigment. The pigment resembled that described with gold deposition in other tissues. Radiographic microanalysis of both brown and black granules was performed in three cases. Characteristic spectra (energy-dispersive spectroscopy) demonstrated the presence of gold in each case. Silver was not identified. The high incidence of LG may reflect the frequent administration of gold in an oily vehicle. Gold may remain trapped in the liver for a prolonged time. Thus far, we have not detected any adverse effect from the presence of LG-associated gold. | |
| 7553043 | [A young woman with rheumatoid arthritis who rapidly developed secondary amyloidosis]. | 1995 Feb | A 22-year-old woman, who had been diagnosed as having rheumatoid arthritis (RA) 2 years before, was admitted to our hospital complaining of watery diarrhea (several times/day). She had been treated with low dose prednisolone (PSL) and auranofin in out-patient clinic. On admission, laboratory data showed moderate proteinuria (0.3 g/day) and positive CRP (2.7 mg/dl). Although the activity of RA was controlled by the administration of low dose methotrexate (7.5 mg/week) in addition to PSL, watery diarrhea and proteinuria did not improve. The biopsy of the stomach, rectum and kidney revealed the deposition of AA type amyloid protein, resulting in the diagnosis of secondary amyloidosis. Secondary amyloidosis has been reported as one of the common complications in RA patients, especially in old patients with a long history of RA. To our knowledge, however, there have been few reported cases who developed secondary amyloidosis so early during the course of RA as our case. We should be careful for the development of secondary amyloidosis even in young RA patients with short history of RA, when the disease is active. | |
| 8834013 | Effects of antirheumatic agents on cytokines. | 1996 Feb | A review of the literature concerning the effects of traditional antirheumatic drugs on cytokines and the cytokine and anticytokine approaches already used in the therapy of rheumatoid arthritis (RA) is presented. Many antirheumatic drugs are capable of cytokine modulation in vitro. Corticosteroids inhibit the transcription of a broad spectrum of genes including those encoding monocyte, T cell-derived cytokines and several hemopoietic growth factors, whereas drugs such as cyclosporin A and D-penicillamine interfere with T cell activation more specifically by suppressing interleukin 2 (IL-2) production. The in vivo effects of drug therapy on cytokines in RA patients are less well established. Gold compounds reduce circulating IL-6 levels and the expression of monocyte-derived cytokines, such as IL-1, tumor necrosis factor (TNF), and IL-6, in the rheumatoid synovium. Decreases in circulating IL-6, soluble IL-2 (sIL-2R), and TNF receptors and in synovial fluid IL-1 levels have been reported with methotrexate. Reductions in circulating IL-6 and sIL-2R concentrations have also been observed with cyclosporin and corticosteroids, whereas azathioprine reduces IL-6 but not sIL-2R. Studies on sulfasalazine are conflicting and the in vivo effects of D-penicillamine and antimalarials have not been studied yet. Interferon gamma therapy is not effective in RA but may prove a useful antifibrotic for systemic sclerosis. Colony stimulating factors improve the granulocytopenia associated with Felty's syndrome or drug toxicities but can induce arthritis flares and should be reserved to treat infectious complications. Promising results are being obtained with selective antagonism of TNF and IL-1 in RA, and combinations of anticytokine strategies with traditional antirheumatic drugs have been already envisaged. These should preferably be based in a broader knowledge of the effects of antirheumatic agents on the cytokine network. | |
| 8832982 | Oral administration of an easily prepared solution of injectable methotrexate diluted in w | 1996 Mar | OBJECTIVE: To investigate whether the injectable formulation of methotrexate (MTX) given as an easily prepared oral solution of MTX diluted in water results in serum concentrations similar to those obtained with MTX tablets; to describe an easy and safe method of dispensing the drug. METHODS: Six patients (5 women, 1 man) with rheumatoid arthritis were given 10 mg of liquid MTX orally. The liquid was prepared by diluting 0.4 ml of the injectable formulation of MTX (50 mg/2 ml) in 8 ounces of water. One to 2 weeks later these patients were given 10 mg of MTX in the tablet form. MTX serum concentrations were determined using a fluorescence polarization immunoassay. The area under the concentration vs time curve (AUC), maximum concentration (Cmax) and the time to reach maximum concentration (tmax) were determined from the resulting concentration vs time curves. RESULTS: There was no statistical difference in the variables measured (AUC, Cmax, tmax), demonstrating comparable concentrations with these 2 methods of MTX administration. Patients found the medication easy to administer, potential hazards with the use of needles were avoided, and the cost of the drug was greatly decreased. CONCLUSION: The administrator of this easily prepared MTX solution is an alternative to the conventional administration of MTX tables, and may be of particular benefit in patients with financial limitations. | |
| 7914751 | Interference of circulating azathioprine but not methotrexate or sulfasalazine with measur | 1994 Apr | Bioassays are currently used to measure the presence of functionally active cytokines in biological fluids. These assays may be influenced by the presence of other substances, either cytokine specific or not, in such fluids. In the present study, we analyzed whether some currently used disease-modifying antirheumatic drugs (DMARDs) could interfere with the measurements of circulating interleukin-6 (IL-6) bioactivity in the B9 hybridoma assay. When sera from healthy controls and patients treated with various DMARDs, such as azathioprine (AZA), methotrexate (MTX), intramuscular gold, and sulfasalazine (SASP), were tested in the IL-6 bioassay, an inhibitory effect was observed only with sera from patients treated with AZA. Addition of exogenous AZA, 6-mercaptopurine (6-MP), and MTX to the IL-6 bioassay resulted in a dose-dependent inhibition of the B9 cell proliferation induced by IL-6, AZA being most potent on a molar basis. Concentrations of AZA and 6-MP compatible with serum concentrations achieved in RA patients were able to inhibit the bioassay, but this was not the case for MTX. Exogenous SASP and its metabolites did not modify the IL-6-induced B9 cell proliferation. This study shows that circulating AZA (or its metabolites) exert an inhibitory effect in the IL-6 bioassay. This method is therefore not suitable to measure IL-6 concentrations in patients treated with AZA. Interference of drugs must be ruled out when bioassays are used to evaluate cytokine levels in biological fluids. | |
| 7588084 | Sulfasalazine. A review of its pharmacological properties and therapeutic efficacy in the | 1995 Jul | Sulfasalazine was first used for rheumatic polyarthritis in the 1940s and in the past 2 decades has become firmly established as a disease-modifying antirheumatic drug (DMARD). The drug is split by the action of bacterial azoreductases in the large intestine into sulfapyridine and mesalazine (mesalamine, 5-aminosalicylic acid), although whether the parent molecule or the sulfapyridine moiety, or both, is the active principle remains uncertain. Sulfasalazine is an effective treatment for rheumatoid arthritis (RA), producing improvements in disease parameters similar to those seen with penicillamine, hydroxychloroquine or oral or parenteral gold in comparative clinical trials. However, there are no direct comparisons of the drug with methotrexate. Most adverse events associated with sulfasalazine are minor and tend to occur within 3 months of starting therapy. A meta-analysis of studies investigating DMARD therapy, which included almost 5000 evaluable patients, concluded that sulfasalazine was close to methotrexate in terms of efficacy but was slightly less well tolerated. However, unlike sulfasalazine, many DMARDs may be unsuitable for women who are, or may become, pregnant because of their potential to cause teratogenic effects. Sulfasalazine may also offer a more rapid onset of action than other DMARDs and may slow down the radiological progression of RA. Combination therapy with other DMARDs, particularly methotrexate, appears more effective than single DMARD therapy. If the safety of these regimens is shown in large numbers of patients they are likely to become more widely used in the future. Sulfasalazine is a therapy of first choice in patients with RA and may be the DMARD of choice in women who are, or may become, pregnant. | |
| 8833056 | Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 we | 1996 Mar | To assess the relative efficacy of methotrexate (MTX), azathioprine (AZA), and their combination in the treatment of rheumatoid arthritis (RA), a double blind, prospective, multicenter, controlled trial was carried out. Two hundred nine patients with active RA were treated with escalating doses of MTX (5-15 mg/week), AZA (50-150 mg/day), or combination (5/50-7.5/100) with opportunity to increase dosage at 6 week intervals. Patients were evaluated for clinical and laboratory improvement and assessed for radiologic progression at 48 weeks. One hundred ten patients remained on the initial, randomly assigned therapy. Response was defined as 30% or greater improvement in at least 3 of 4 variables, and occurred in the following: 38% on the combination arm, 26% on AZA, and 45% on MTX (p = 0.06). A trend for decreased radiologic progression was seen in the MTX group. Adverse experiences and treatment termination occurred more frequently in the combination and AZA arms relative to the MTX group. The most frequent causes for treatment discontinuations were lack of effectiveness, gastrointestinal adverse effects and liver enzyme elevation. This study establishes that the combination of MTX and AZA in the dosages employed is not associated with more toxicity than treatment with single agents, but enhanced efficacy is not seen. A trend toward decreased radiographic progression was noted in the MTX treated patients. | |
| 8808186 | Do changes in clinical improvement in rheumatoid arthritis patients treated with immunosup | 1995 | We sought to investigate whether clinical improvement after immunosuppressive treatment reflects changes in acute phase response (APR) in rheumatoid arthritis (RA). Fifty-eight patients (pts) were treated with methotrexate (MTX), nineteen with intravenous cyclophosphamide (CTX), and fifteen with cyclosporin A (CSA). C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), alpha-1 antichymotrypsin (ACT), and alpha-1 antitrypsin (AT) serum levels were measured by nephelometry or rocket immunoelectrophoresis. Clinical improvement was observed in 67% MTX pts, 53% CTX pts, and 47% CSA pts. Baseline serum levels of CRP, AGP, ACT, and AT were significantly higher as compared to healthy controls. After MTX and CTX therapy CRP level significantly decreased. The decrease in serum level of ACT and AT in CTX treated patients was also observed. All analyzed acute phase proteins remained substantially elevated after CSA therapy despite a clear reduction in disease activity. We established a correlation between changes in disease activity and all acute phase proteins (APP) in MTX and CTX pts. From our study we can conclude that clinical improvement after immunosuppressive treatment correlated with quantitative changes in all APR markers in MTX and CTX treated pts, and none in CSA pts. Although measurement of APP remains the best marker for monitoring RA pts, not always they properly reflect changes in disease activity. | |
| 7775811 | Zyn-Linker delivery of antirheumatic agents. | 1994 | Despite our increasing ability to manage rheumatoid arthritis through systemic medication, refractory joints require local administration of more aggressive therapy in a substantial number of patients. These studies tested whether a new class of molecules designated Zyn-Linkers could deliver and retain therapeutics in a joint. Zyn-Linkers are synthetic lipid-like molecules designed to insert into cell membranes and enhance drug delivery to cells. After intra-articular injection into the knee of NZW rabbits, Zyn-Linkers bound rapidly and homogenously to synovial lining cells. Chelating Zyn-Linkers which contained Re-186 or Y-90 were synthesized to evaluate localization and retention after intra-articular injection. Initial studies using Re-186 Zyn-Linker gave excellent localization as evaluated by whole-body imaging: counts in the knee region represented > 90% of counts present in the whole body for at least 4-6 days postinjection. Similar results were obtained using a Y-90 Zyn-Linker and this agent was used for biodistribution studies due to its greater stability and ease of preparation. Efficacy and safety of Y-90 Zyn-Linker as a potential radiation synovectomy agent were estimated by extrapolation of biodistribution data to humans. A therapeutically effective dose of 8,000 cGy to synovium was calculated to require intra-articular injection of 3.4 mCi Y-90 Zyn-Linker, a value less than or equal to doses of particulate Y-90 agents used clinically in Europe. The predicted safety profile for Y-90 Zyn-Linker was excellent, with estimated doses to nontarget organs and tissues falling well within FDA-recommended safety levels for research-only radiopharmaceuticals. In addition to exhibiting desirable localization and retention properties, Zyn-Linkers may also be synthesized to release antirheumatic drugs such as methotrexate at controlled rates. This suggests substantial potential for these drug delivery molecules as chemical synovectomy agents which may be used concurrently with systemic chemotherapy to improve management of refractory joints. | |
| 7903012 | [Basic therapy of rheumatoid arthritis. Comparison of methotrexate and sulfasalazine]. | 1993 Oct | In a retrospective analysis a total of 167 patients with rheumatoid arthritis (RA) who had been treated with the basic therapy formulas of methotrexate (MTX) or sulfasalazine (SUL) were evaluated with respect to therapeutical result and side effects after a period of 12 months. There was no randomization as to either MTX (n = 87) or SUL therapy (n = 80), but deliberate use of therapy according to prior treatment and activity of the illness. Apart from a significantly higher number of inflammatory joint conditions in the MTX group there was no difference in the two patient groups at the beginning of the study. MTX treatment led clearly to a more conspicuous activity decrease of the illness (ESR, joint index) and a more favourable effect on the locomotor function. Furthermore, the sphygmomanometer readings (for grip strength determination), the dose reduction of the concomitant prednisolone medication as well as the doctor's opinion were in favour of MTX. The portion of patients who had to discontinue the therapy because of side effects (= 11%) and lack of effect (= 9%) was exactly identical in both groups of patients. Both substances have shown to be effective basic therapy formulas for rheumatoid arthritis, while methotrexate has a few advantages. | |
| 7791185 | Listeria monocytogenes infection in a patient treated with methotrexate for rheumatoid art | 1995 Apr | We describe a patient with rheumatoid arthritis who developed bacteremia from Listeria monocytogenes after treatment with low dose oral pulse methotrexate. We discuss possible immunologic mechanisms for susceptibility to Listeria infections. As the elderly population increases with more frequent use of immunosuppressive medications, clinical suspicion must be maintained to correctly diagnose and treat infections such as Listeria. | |
| 8016424 | Methotrexate: adverse reactions and major toxicities. | 1994 May | The long-term efficacy of methotrexate has been proved in prospective trials. With the chronic administration of methotrexate, however, concern has been raised about its safety. While side effects are common, they are seldom life threatening and rarely necessitate withdrawal of the drug. Serious side effects of methotrexate include hepatic, hematologic, and pulmonary toxicity. These toxicities are much less common, but usually result in the withdrawal of the drug. With careful monitoring of patients symptoms and laboratory test, however, these toxicities can be minimized or even prevented. |