Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 8601050 | Disease-modifying antirheumatic drugs. Potential effects in older patients. | 1995 Dec | Disease-modifying antirheumatic drugs (DMARDs) are frequently used in rheumatoid arthritis. A number of physiological changes occur in the elderly which may modify the use of these medications. The most commonly used DMARDs are antimalarial drugs (particularly hydroxychloroquine), sulfasalazine and methotrexate. The principal mechanism of action of the antimalarials relates to the fact that they change intracellular pH, which downregulates numerous immune functions. Hydroxychloroquine is metabolised to 3 metabolites and has a very low clearance. It is moderately effective in dosages up to 6.4 mg/kg/day. While it is not the most effective of the DMARDs, it is the least toxic. Sulfasalazine is a prodrug which is enzymatically split in the bowel to form sulfapyridine (the principal active metabolite) and 5-aminosalicylic acid. The metabolism of sulfasalazine is complex and, to some extent, genetically determined. The mechanism of action of the drug is not well understood, but involves decreased production of cytokines and decreased proliferative response of lymphocytes. It may slow the rate of bony damage associated with rheumatoid arthritis. Nearly 50% of the patients who are prescribed sulfasalazine continue to receive the drug for up to 4 years. Sulfasalazine is not as well tolerated as hydroxychloroquine. Gastrointestinal toxicity, in particular, seems to be a problem in elderly patients taking this medication. Methotrexate is presently the most popular of the DMARDs for the treatment of rheumatoid arthritis. Methotrexate inhibits dihydrofolate reductase and adenosine release and has a secondary effect on cytokines and polymorphonuclear chemotaxis. It is highly metabolised within cells and remains there for prolonged periods. Up to 70% of patients who are prescribed methotrexate continue treatment for 5 years. Methotrexate treatment is associated with gastrointestinal, hepatic, cutaneous and, possibly, pulmonary adverse effects. The use of azathioprine, penicillamine and gold compounds is briefly reviewed in this article. Elderly patients have an increased incidence of rashes when using penicillamine, relative to young patients. There are no age-related differences in the efficacy and tolerability of azathioprine or gold therapy. The poor absorption and renal toxicity associated with cyclosporin, the new 'salvage' therapy in rheumatoid arthritis, make it generally unsuitable for use in the elderly, except under specialists' supervision. | |
| 8290397 | Postoperative results of rheumatoid arthritis patients on methotrexate at the time of reco | 1993 Nov | We conducted a retrospective chart review examining the frequency of local postoperative infection and poor wound healing of 15 methotrexate-treated rheumatoid arthritis patients undergoing 155 procedures during 39 surgeries. The patients were compared to a group of rheumatoid patients not on methotrexate who underwent similar reconstructive surgery of the hand. The patients taking methotrexate were followed postoperatively for a minimum of 10 weeks, with a mean follow-up time of 1 year, 42 weeks. There were no postoperative complications that would lead to the belief that the administration of methotrexate results in poor wound healing or leaves the patient more susceptible to postoperative infection. Our findings and a review of the literature support a continuation of methotrexate therapy in rheumatoid arthritis patients scheduled for reconstructive surgery of the hand and wrist. | |
| 8952180 | Plasma reactive nitrogen intermediate levels in patients with clinically active rheumatoid | 1996 Oct | We studied reactive nitrogen intermediate levels in 31 patients with active rheumatoid arthritis (RA) taking indomethacin and 20 healthy controls using nitrite and citrulline levels, measured by spectrophotometry, as markers. Twenty patients with RA were followed up after 4 and 8 wk of treatment with additional therapy in the form of methotrexate. Mean nitrite levels in 31 patients were 0.94 +/- 0.41 mumol/ml and 20 controls it was 1.18 +/- 0.99. After treatment with methotrexate for 4 and 8 wk the levels were 0.9 +/- 0.45 and 1.25 +/- 1.15 mumol/ml, respectively. Mean citrulline levels in all patients was 1.68 +/- 0.11 and controls was 1.39 +/- 0.6 mumol/ml. Following therapy with methotrexate for 4 and 8 wk the levels were 1.40 +/- 0.49 and 1.40 +/- 0.51 mumol/ml, respectively. It is possible that serum levels of these products may not reflect alterations in the synovial fluid levels. Alternatively, whatever lowering may have been achieved by the anti-inflammatory effect of the therapy may have been countered by drug derived free radicals. | |
| 1455371 | [A comparative evaluation of combined immunocorrective therapy in rheumatoid arthritis wit | 1992 | Thirty-two patients with rheumatoid arthritis were included in the trial. Each of them was assigned to one of the 4 groups comparable by the main features. Each group entered 8 patients. Group 1 patients underwent hemosorption weekly for 3 weeks. After the second procedure cyclophosphamide was added at a single IV dose 1000 mg. After the third procedure the treatment was continued with methotrexate (7.5 mg, weekly). Group 2 began the treatment with methotrexate (7.5 mg, weekly). Group 3 received cyclophosphamide 200 mg IV twice a week 6 times and then 200 mg weekly orally till a total dose of 2 g. Group 4 received azathioprine in a daily dose 100 mg. The treatment with nonsteroidal antirheumatic drugs and corticosteroids was continued unchanged. After 6 months we did not see significant differences between the 4 groups. | |
| 7968721 | Plasma thiols, copper and rheumatoid arthritis. | 1994 Jul | A means by which methotrexate diminishes the overproduction of leukotriene B4 by neutrophils from rheumatoid arthritic patients is described. It is postulated that neutrophil intracellular reduced glutathione is decreased by increased cellular copper, which results in leukotriene B4 overproduction. In the arthritic patient it is proposed that there is an inappropriate amount of a copper donor form of ceruloplasmin which contains a reduced copper that was formed during ceruloplasmin's oxidation of plasma cysteine. Oxidation of increased amounts of plasma homocysteine, present during methotrexate administration, restores ceruloplasmin's redox state leading to decreased copper transport into cells. | |
| 8275586 | The effect of D-penicillamine on lung function parameters (diffusion capacity) in rheumato | 1993 Sep | Sequential lung function tests were performed on 28 rheumatoid arthritis (RA) patients who were treated with D-penicillamine (total of 101 treatment years) and on 42 control RA patients who were not treated or who were treated with NSAIDs, chloroquine, gold salts, corticosteroids, salazopyrine or methotrexate. A decline in lung function parameters was found in both groups, although it was only significant for the carbon monoxide diffusing capacity corrected for lung volume (DLCO/VL). This decrease in DLCO/VL was less pronounced in the D-penicillamine group (mean -6.9%) than in the control group (mean -11.3%). This difference could not be attributed to smoking, which was more frequent in the control group. When reviewing only the patients with an initial DLCO/VL < 80% of the predicted value and having, with some exceptions, chest X-ray abnormalities, we even observed an amelioration in the mean DLCO/VL in the D-penicillamine group, in contrast with a deterioration in the control group (+5.1% versus -5.6%). | |
| 8882023 | Serum phospholipase A2 activity in patients with rheumatoid arthritis before and after tre | 1996 Feb | OBJECTIVE: (1) To confirm a previous observation that serum phospholipase A2 (PLA2) activity correlates with disease activity in rheumatoid arthritis (RA); and (2) to determine whether serum PLA2 activity changes after treatment with methotrexate (MTX), auranofin (AF), or a combination of the 2 (COMBO). METHODS: Sera obtained at baseline and after treatment from 100 patients with RA (40 MTX, 32 AF, and 28 COMBO) who participated in a multicenter, double blind trial were tested for PLA2 activity using an assay that measures the release of radiolabeled 14C oleic acid from the cell membrane of Escherichia coli. Detailed statistical analysis was performed using previously collected clinical data to determine whether correlations exist between RA disease activity and serum PLA2 activity; whether baseline serum PLA2 activity predicted a therapeutic response in any treatment group; and whether there was a significant change in serum PLA2 activity after treatment in patients who responded to the various drugs. RESULTS: Baseline serum PLA2 activity was significantly increased in patients with RA compared to healthy controls. No correlation between serum PLA2 activity and RA disease activity was noted at baseline. Mean serum PLA2 activity did not change significantly after treatment with MTX, AF, or COMBO in either treatment responders or nonresponders. CONCLUSION: Serum PLA2 activity is increased in patients with RA compared to healthy controls, but does not correlate with disease activity in patients, nor does it predict a response to treatment with MTX, AF, or COMBO. Serum PLA2 activity also did not change significantly after treatment with any of the above agents. | |
| 1734902 | Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arth | 1992 Feb | OBJECTIVE: To determine and describe the clinical, radiographic, and toxicity profile in a cohort of rheumatoid arthritis patients receiving weekly oral methotrexate (MTX) over a mean period of 90 months, and to compare and contrast these data with our previous data on this cohort, reported after 53 months. METHODS: Prospective, open observational study over a mean treatment period of 90 months (range 79-107 months). Standard clinical and laboratory measures of disease activity were assessed by the same investigator at baseline, 1 month, 3 months, and every 3 months thereafter. RESULTS: A significant improvement from baseline was maintained in all clinical parameters but the number of tender joints. Toxic reactions were as common in months 54-90 as during the first 53 months. The mean dosage of MTX decreased from 14.6 mg/week at the time of the last report to 11.7 mg/week, while the mean prednisone dosage increased from 1.9 mg/day to 2.1 mg/day. Radiographic scores for erosive disease became statistically significantly different from baseline at year 8, and scores for joint space narrowing differed significantly from baseline at years 5 and 8. Since study entry, 2 patients (6.9%) have experienced MTX pneumonitis. CONCLUSION: We conclude that a majority of rheumatoid arthritis patients are able to continue MTX treatment with generally sustained efficacy, for intervals that meaningfully exceed those reported previously. | |
| 1622410 | Precision of the Larsen and the Sharp methods of assessing radiologic change in patients w | 1992 Jul | OBJECTIVE: To compare the sensitivity of Sharp's and Larsen's radiographic scoring methods for detecting change in rheumatoid arthritis (RA) over time. METHODS: Radiographs of the hands and wrists were taken at the beginning and at the end of a 2-year followup period, in 42 patients with active RA. Films were scored blindly using both scoring methods. Patients were under treatment with methotrexate (intramuscular injections). RESULTS: Radiographic evidence of progression or amelioration was detected in 25 patients by Larsen's method and in 35 patients by Sharp's method. The relative sensitivity to change over time was greater for Sharp's method (0.01 less than P less than 0.025). CONCLUSION: Sharp's radiographic scoring method seems to be more sensitive to change over time than is Larsen's method. The clinical importance of the change needs to be definitively established. | |
| 8097536 | Validity of single variables and indices to measure disease activity in rheumatoid arthrit | 1993 Mar | We compared the sensitivity of several variables in 2 trials between second-line agents in our clinic. In a trial comparing sulfasalazine with hydroxychloroquine significant differences were found in favor of sulfasalazine by the Ritchie score, number of swollen joints, disease activity score (DAS), physical disability and radiographic damage. This could not be determined by number of tender joints, patient's global assessment, pain, morning stiffness, or erythrocyte sedimentation rate (ESR). In a trial comparing methotrexate with azathioprine significant differences could be found in favor of methotrexate by the variables of pain, DAS, ESR, C-reactive protein, hemoglobin and thrombocytes; not by Ritchie score, number of tender joints and number of swollen joints. Combining the results of the various validation procedures leads to relative quality of the variables. | |
| 8346572 | [Methotrexate therapy of rheumatoid arthritis. An open observation study of 110 patients w | 1993 Jul 26 | Effects and side-effects of treating patients with rheumatoid arthritis with methotrexate given as weekly pulse-treatment are examined in an open observation study. One hundred and ten consecutive patients with active rheumatoid arthritis entered the study. Six criteria of remission were registered as effect variables. Median length of treatment at the time of investigation was 17.8 months. At this point, 34 patients were in complete remission, with a median effect score of five point five out of six possible points. Twenty-nine were in partial remission and 47 (42.7%) had not improved. The median effect score for all patients was three point 6 (95% confidence limits (2-4). Methotrexate treatment was stopped in 24 patients, in 15 of these because of a combination of side-effects and lack of therapeutic response. Prednisone treatment could be discontinued in 20 out of 57 patients during the course of methotrexate treatment. Side-effects were registered in 67 cases (62.7%), and led to treatment being discontinued in 21 cases. Nearly half the side-effects consisted of dyspepsia and rises in amino-transferase levels (48 of 67 patients). Consistently raised amino-transferase levels were found in five cases, all returned to normal after methotrexate was stopped. Serious side-effect were registered in four cases, consisting of two cases of short-term pancytopenia following overdosage and two cases of severe hypoxia following methotrexate-induced alveolitis. | |
| 8535649 | Efficacy of methotrexate in rheumatoid arthritis. | 1995 Nov | Methotrexate (MTX), an antifolate agent, has been used in the treatment of rheumatoid arthritis (RA) for over two decades. Open clinical studies and short-term, randomized, placebo-controlled studies demonstrate the efficacy of MTX in active RA. Long-term prospective studies, including two of over 7 yr duration, report a sustained response and a corticosteroid-sparing effect. Comparative studies demonstrate superior efficacy to auranofin, azathioprine and cyclosporin A. A highly favourable retention rate with the drug has been noted in large studies from academic and community-based practices. Radiographic studies suggest a slowing of radiographic progression with the compound. MTX has become an accepted and widely used treatment for active RA. | |
| 8619101 | Antibiotic therapy for rheumatoid arthritis. Scientific and anecdotal appraisals. | 1995 Aug | Minocycline is arguably the most interesting new drug for rheumatoid arthritis since the development of methotrexate. Tetracycline compounds have long been used by rheumatologists who were considered mavericks by their peers, and recent controlled studies have demonstrated their antirheumatic activity. The reason that minocycline works is unclear, and their niche in the treatment of rheumatoid arthritis remains to be established. Nonetheless, it is clear that some patients with rheumatoid arthritis respond favorably to this form of treatment. | |
| 7670776 | Methotrexate action in rheumatoid arthritis: stimulation of cytokine inhibitor and inhibit | 1995 Jul | This open label study examines whether methotrexate (MTX) treatment modulates ex vivo synthesis of interleukin-1 receptor antagonist (IL-1ra), soluble tumour necrosis factor receptors (sTNFR p55 and p75), interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by peripheral blood mononuclear cells (PBMC) and whether changes reflect clinical response. Significant stimulation of IL-1ra and sTNFR p75 as well as inhibition of IL-8 production of PBMC were associated with clinical improvement observed in patients treated with MTX. When defining the characteristics of patients at study entry retrospectively in responders and non-responders, a significantly lower ratio of IL-1ra:IL-1 beta production before and its increase upon treatment was associated with clinical response in 13 patients compared to five patients not responding to MTX. In addition, clinical improvement was associated with decreased synthesis of IL-1 beta, TNF-alpha and IL-8 induced by bacterial lipopolysaccharide, IL-1 alpha and IL-1 beta in PBMC in vitro. These findings suggest that MTX therapy reverses the inflammatory type of rheumatoid arthritis (RA) blood mononuclear cells by stimulating cytokine inhibitor production while inhibiting inflammatory cytokine release at the same time. This may explain the powerful anti-inflammatory properties of low-dose MTX as observed in most RA patients. Pretreatment determination of the IL-1ra:IL-1 beta ratio in PBMC may be predictive with regard to a favourable therapeutic response and therefore may be useful for the selection of RA patients to be treated with MTX. | |
| 7981583 | Cell-type specific response of peripheral blood lymphocytes to methotrexate in the treatme | 1994 Jul | The mode of action of methotrexate in the treatment of rheumatoid arthritis is still questionable. Although in vitro results suggest an immunosuppressive effect of methotrexate, several clinical studies have failed to confirm these effects in patients treated with oral low-dose methotrexate. With respect to the highly variable bioavailability of methotrexate, we investigated the effects of an intravenous administration of 15 mg methotrexate per week on peripheral blood lymphocyte subsets in eight patients with rheumatoid arthritis. Methotrexate after 12 weeks significantly (P < 0.01) reduced total peripheral blood lymphocytes and led to a pronounced redistribution of lymphocyte subsets with a preferred reductive effect on B-lymphocytes (P < 0.005) and T-lymphocytes (P < 0.05). Natural killer cells and killer cell-like T cells, on the other hand, were unaffected by the treatment. Our results suggest a cell-type specific effect of intravenously administered low-dose methotrexate on peripheral blood lymphocytes. This effect, in our opinion, may contribute to the mode of action of methotrexate as an immunosuppressive drug in the treatment of rheumatoid arthritis. | |
| 8935189 | Acute phase response in rheumatoid arthritis patients treated with immunosuppressive drugs | 1995 Apr | We sought to investigate an influence of immunosuppressive drugs on acute phase response (APR) in rheumatoid arthritis (RA). Ninety-six patients (pts) were treated with methotrexate (MTX), or with cyclophosphamide (CTX) (9-intravenously, 19-orally), or with cyclosporin A (CSA). C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), and alpha-1 antichymotrypsin (ACT) serum levels were measured by rocket immunoelectrophoresis. AGP and ACT microheterogenities evaluated using immunoelectrophoresis were expressed as reactivity coefficient (RC). Clinical improvement was observed in 71.4% MTX pts, 77.8% CTX intravenously pts, 36.8% CTX orally pts, 60.0% CSA pts. The number of side effects was the highest in CTX oral group (57.9% left the study). CRP, AGP, and ACT serum levels were increased in all groups of RA pts as compared to healthy controls. CRP level decreased only after MTX and CTX intravenous treatment. Moreover, a decrease in ACT was observed in CTX intravenously treated pts. AGP-RC was lower in the initial population of RA pts as compared to healthy control. After 6 months of treatment RC became significantly higher in MTX pts only. In opposite ACT-RC in RA pts was found to be elevated as compared to controls. After the treatment it fell down. The decrease was found to be significant only in pts treated with MTX. From our study we can conclude that MTX is the safest and the most effective agent among immunosuppressive drugs applied in RA. CTX given orally causes a number of adverse reactions, which frequently make continuous and effective treatment impossible. CTX intravenously and CSA are attractive in the treatment of the patients with severe and refractory RA. A lack of clinical benefit is reflected in the absence of acute markers changes. | |
| 1488677 | Treatment strategies in rheumatoid arthritis. | 1992 Dec | Intervention therapies in rheumatoid arthritis (RA) are directed at the immune dysregulation and chronic inflammatory events in the joint. An ideal therapeutic program would rapidly control inflammation, prevent joint damage and preserve function. The various strategies of treatment involve the use of disease-modifying anti-rheumatic agents (DMARDs) either singly or in combination. Gold salts, penicillamine, sulphasalazine, methotrexate and hydroxychloroquine are used when NSAIDs fail to control inflammation. RA not only decreases the functional disability but the life-span of patients. The traditional pyramid strategy which uses single DMARDs consecutively has been found to be inadequate and slow in suppressing joint inflammation. Hence the race to find treatment regimes and strategies that will favourably alter the outcome of RA patients. Both the "step-down bridge" approach and saw-tooth strategy have been advocated in the attempt to break the progression of joint disease. None of the known regimes can be said to be most beneficial and least toxic. | |
| 8817749 | Validation of the French version of the arthritis impact measurement scales 2 and comparis | 1996 Jun | Appropriate attention can be directed to quality of life indices in the evaluation of therapeutic interventions only if reliable, valid measurement tools with good sensitivity to change are available. The goal of this study was to validate the French version of the Arthritis Impact Measurement Scales 2 (AIMS2), called EMIR (Echelle de Mesure de l'Impact de la polyarthrite Rhumatoïde) and to compare it with the validated French version of the Nottingham Health Profile, called ISPN (Indicateur de Santé Perceptuelle de Nottingham). The French version of the AIMS2 (37 items, 12 dimensions) was obtained via several independent translations and back-translations, followed by selection of the most relevant items by a panel of experts and a preliminary evaluation in rheumatoid arthritis patients. The measurement properties of EMIR (reliability, validity and sensitivity to change) were investigated in a cohort of rheumatoid arthritis patients who were put under methotrexate therapy and followed up for six months. Reliability was evaluated by test-retest at a ten-day interval (intraclass coefficients of correlation). Principal component factorial analysis was used to study construct validity and Cronbach's alpha coefficients to study internal consistency. Convergent validity was evaluated based on correlations between the quality of life scores obtained in selected dimensions of the EMIR and a number of other parameters (number of painful/swollen joints, pain severity score on a visual analog scale, erythrocyte sedimentation rate). Sensitivity to change after three and six months was determined by calculating mean standardized response means. The EMIR and ISPN were compared based on scores and sensitivity to change for the dimensions that investigated the same concepts. One hundred twenty-seven rheumatoid arthritis patients scheduled for methotrexate therapy were entered into the study. Principal component analysis established that all dimensions of the EMIR were independent from one another, except the "walking and bending" dimension. Internal consistency was satisfactory for each of the 12 dimensions, with Cronbach's alpha coefficients ranging from 0.70 to 0.90. Most correlations between quality of life scores and clinical or laboratory parameters were significant, indicating satisfactory convergent validity. The reliability study also yielded satisfactory results, with intraclass coefficients ranging from 0.65 to 0.90. Sensitivity to change after three and six months was significant for 11 of the 12 dimensions (mean standardized responses, 0.30 to 0.77). Sensitivity to change was slightly better for the EMIR than for the ISPN. Analysis of scores demonstrated that these two instruments did not measure quality of life in exactly the same way but complemented each other. | |
| 8923380 | Exacerbation of rheumatoid arthritis after termination of chemotherapy for breast carcinom | 1996 Nov | Three women with breast carcinoma were treated with combination chemotherapy, including cyclophosphamide, 5-fluorouracil, and methotrexate, after mastectomy. Within two months of termination of chemotherapy, all 3 patients developed florid synovitis. Two patients had prior clinical manifestations consistent with rheumatoid arthritis; one patient had no antecedent history of arthritis. We suggest that this presentation may represent exacerbation of mild or subclinical rheumatoid arthritis as a consequence of withdrawal of methotrexate therapy. | |
| 8358980 | Better effect of methotrexate on C-reactive protein during daily compared to weekly treatm | 1993 Jun | Treatment with methotrexate (MTX) is well established in rheumatoid arthritis (RA), but dosing remains arbitrary as studies on the effect of different dosing schedules are lacking. In a randomised crossover design of 20 patients with RA, the effect of low (2.5mg) oral daily doses of MTX (15 mg weekly) was compared to intermittent weekly dosing (15 mg). C-reactive protein (CRP) values were lower and more stable on daily dosing compared to the significant (p < 0.05) changes in CRP observed during treatment with the same weekly dose. It may be postulated that nonresponders or patients with dose-dependent side effects may have clinical advantage from daily MTX dosing if hepatotoxicity and other side effects are not increased. |