Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 7674228 | The relationship of preexisting lung disease to the development of methotrexate pneumoniti | 1995 Jun | OBJECTIVE: To test the hypothesis that preexisting lung disease is a risk factor for the development of methotrexate (MTX) pneumonitis in patients with rheumatoid arthritis (RA) treated with low dose MTX. METHODS: We measured the proportion of patients with and without preexisting lung disease who developed MTX pneumonitis in a historical cohort from a university affiliated rheumatology private practice in Chicago. Patients comprised 93 women and 32 men with RA treated with MTX for any period of time between January, 1980 and July, 1989. RESULTS: MTX pneumonitis occurred in 4 of 77 patients without preexisting lung disease (5.2%) and 5 of 29 (17.2%) patients with preexisting lung disease (p = 0.0610, Fisher's exact test). Five of 24 (20.1%) patients with preexisting lung disease characterized by the report of an abnormal chest radiograph developed MTX pneumonitis (p = 0.2328, Fisher's exact test) and 4 of 16 (25%) patients with interstitial infiltrates reported on their chest radiograph developed MTX pneumonitis (p = 0.0276, Fisher's exact test). CONCLUSION: The presence of preexisting lung disease characterized by radiographic interstitial infiltrates predisposes patients with RA to develop MTX pneumonitis. | |
| 8835551 | Death attributed to antirheumatic medication in a nationwide series of 1666 patients with | 1995 Dec | OBJECTIVE: Most drugs used in rheumatoid arthritis (RA) can have fatal side effects, but there are no good data on the frequency of such complications. Our study was designed to obtain information on deaths attributable to different antirheumatic drugs. METHODS: The role of antirheumatic medication as a cause of death was studied in 1666 subjects who died in Finland in 1989 and had been entitled under the nationwide sickness insurance scheme to receive specially reimbursed medication for RA. RESULTS: Forty-seven deaths were attributed to antirheumatic medication. Thirty deaths were attributed to the use of nonsteroidal antiinflammatory drugs (NSAID) (17 from peptic ulcer, 11 perforation or hemorrhage of the lower intestinal tract, one renal failure, and one bone marrow depression) and 11 deaths to the use of glucocorticoids (2 from perforations of the lower intestinal tract, 5 osteoporotic fractures, 3 septicemias after intraarticular injections and one adrenal insufficiency after abrupt discontinuation of treatment). There were 2 cases of fatal bone marrow depression attributed to methotrexate and 2 to sulfasalazine, one case of lymphoma induced by azathioprine and one hydroxychloroquine intoxication. In spite of widespread use of injectable gold in Finland, there were no deaths attributed to side effects of gold. CONCLUSION: The data emphasize the frequent occurrence of fatal side effects from NSAID and from glucocorticoids and the relative safety of treatment with gold. | |
| 8129774 | Mechanisms of methotrexate action in rheumatoid arthritis. Selective decrease in synovial | 1994 Feb | OBJECTIVE: To measure the effect of methotrexate (MTX) treatment in rheumatoid arthritis (RA) on the expression of synovial collagenase, stromelysin, and tissue inhibitor of metalloproteinase 1 (TIMP-1) gene expression in a prospective study. METHODS: Serial percutaneous synovial biopsies (pretreatment and after 3-4 months) were performed on the knees of 8 patients (7 with RA, 1 with seronegative arthritis) who were beginning oral MTX therapy. Synovial gene expression was determined by quantitative in situ hybridization using computer-assisted image analysis. RESULTS: After therapy, patients had decreased joint counts, morning stiffness, and erythrocyte sedimentation rates. Synovial inflammation in the biopsy tissues was slightly decreased after therapy. In situ hybridization on pretreatment and posttreatment frozen sections was performed to quantify synovial messenger RNA (mRNA) levels. Collagenase gene expression significantly decreased after MTX therapy (P = 0.006) even though cell density in the region was unchanged. TIMP-1 and stromelysin mRNA levels were not changed by MTX therapy. To study the mechanism of MTX action in vitro, MTX-treated and control fibroblast-like synoviocytes were stimulated with interleukin-1 beta (IL-1 beta). MTX did not alter collagenase or TIMP-1 mRNA levels after IL-1 exposure. CONCLUSION: MTX therapy decreases collagenase gene expression but not TIMP-1 or stromelysin gene expression in the synovium. This action is probably an indirect effect due to an alteration in the synovial cytokine milieu, rather than a direct effect on gene expression. | |
| 8324932 | Antifolates in rheumatoid arthritis: a hypothetical mechanism of action. | 1993 Mar | The antifolates, methotrexate, aminopterin, 10-deazaaminopterin and sulfasalazine are clinically useful in the treatment of rheumatoid arthritis. Toxicity, rather than efficacy, appears to the the major factor limiting the usefulness of the classical antifolates (i.e., methotrexate and 10-deazaaminopterin). The fact that folate supplementation of methotrexate-treated rheumatoid arthritis patients reduces toxicity without altering efficacy also suggests that inhibition of the drug's target enzyme, dihydrofolate reductase, is not complete and not essential for efficacy. Since polyglutamates of methotrexate are direct inhibitors of thymidylate synthase and folate dependent enzymes of purine biosynthesis, the efficacy of this agent may involve blockade of these pathways. We hypothesize that blockage of aminoimidazole carboxamide ribotide transformylase, the folate dependent enzyme responsible for the insertion of carbon 2 into the purine ring, produces an immunosuppression mediated by secondary inhibition of adenosine deaminase, and S-adenosyl homocystein hydrolase by aminoimidazolecarboxamide metabolites. This mechanism of immunosuppression may explain the clinical effect of methotrexate, 10-deazaaminopterin, and possibly sulfasalazine. Since purine biosynthesis is a fundamental process, blockading this pathway may also decrease leukotriene production and interleukin-1 expression, which also could contribute to the efficacy of methotrexate. | |
| 8838508 | Validity, reliability, and sensitivity to change of a French version of the arthritis impa | 1996 Jan | OBJECTIVE: To develop and validate a cross cultural version of the Arthritis Impact Measurement Scales 2 (AIMS2) to be used by French speaking populations. METHODS: A French version of the AIMS2 was obtained using back translation, committee review, and pretesting. The French AIMS2 was studied in 127 patients with rheumatoid arthritis (RA) about to receive therapy with methotrexate (MTX). Construct validity of the questionnaire was assessed by factor analysis. Convergent validity was evaluated by correlation coefficients with joint counts, pain assessment, and sedimentation rate. Reliability was assessed by test-retest procedure at a 10-day interval, Cronbach's coefficients of internal consistency, and within scale factor analyses. Sensitivity to change after 12 and 24 weeks of therapy with MTX was assessed with computation of standardized response means (SRM) and paired t test comparisons. RESULTS: Factor analyses of the French version clearly identified the same scales of the AIMS2, except for the walking and bending scale which loaded on several factors. Convergent validity of the physical and symptom components of the instrument was demonstrated by significant correlations with clinical and laboratory features. All the scales were reliable (intraclass correlation coefficients: 0.65 to 0.90; percentage of explained variance larger than 50% in all but one scale; Cronbach's alpha: 0.70 to 0.90). Sensitivity to change was demonstrated in 11 of the 12 scales (SRM: 0.30 to 0.77). Most of the improvement was noted by Week 12. CONCLUSIONS: This cross cultural adaptation of AIMS2 in French is valid, reliable, and responsive in patients with RA in whom MTX therapy is instituted. It would permit international comparison studies. This study provides evidence for construct validity and responsiveness of the original version of the AIMS2, not demonstrated previously. | |
| 7779126 | Use of magnetic resonance imaging and positron emission tomography in the assessment of sy | 1995 Jun | OBJECTIVE: To measure the anatomic and physiologic changes in the synovium of patients with active rheumatoid arthritis (RA) before and after the initiation of treatment with low-dose systemic glucocorticoids and methotrexate (MTX). METHODS: Two patients with RA with active synovitis involving the carpus were evaluated by imaging parameters at baseline and again after 14 weeks (of treatment with low-dose prednisone and MTX). Standard clinical parameters, laboratory measurements, and contrast-enhanced magnetic resonance imaging (MRI) (synovial volume estimate) and positron emission tomography (PET) with 18F-fluoro-2-deoxyglucose (18-FDG) (synovial metabolism estimate) were performed. RESULTS: Compared with baseline, standard clinical parameters (i.e., joint count, joint index, morning stiffness, global assessments of arthritis activity, and erythrocyte sedimentation rate) improved dramatically in both patients after treatment with low-dose prednisone and MTX. In concert with this trend, the synovial volume of the affected wrist was reduced by 60%, and 76% and the metabolism of 18-FDG was reduced by 66% and 69% in the 2 patients. CONCLUSION: These preliminary observations indicate that a volumetric estimate of inflamed synovium (using contrast-enhanced MRI) and quantification of synovial deoxyglucose metabolism (using PET) are technically feasible and, in the 2 reported cases, correlate well with standard outcome measures. These imaging modalities may provide new objective parameters to determine RA disease activity and effectiveness of antirheumatic medications; however, the potential clinical utility of these measures remains to be defined. | |
| 8777850 | Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dos | 1996 Mar | We reviewed the records of 315 patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX) and evaluated the conditions contributing to thrombocytopenia. Thirteen out of 315 patients with RA presented with low platelet counts (< or = 100.000/mm3). The age of these patients (51 +/- 12.6 years) did not correlate with thrombocytopenia (r = 0.211, p > 0.05). Thrombocytopenia resulted from coadministration of MTX and NSAID or multiple drug interactions. We observed a significant (r = 0.48, p < 0.05) increase of discontinuation of NSAID's but not of MTX therapy (r = 0.42, p > 0.05) with a mounting weekly dosage of MTX (12.5 +/- 5 mg orally). There was a significant correlation between this weekly dosage of MTX coadministered on the same day with NSAID and thrombocytopenia (r = 0.6, p < 0.05). In most cases (9/13) MTX was not or just temporarily withdrawn. Three of the remaining patients had multiple drug interactions. Reintroduction of low dose MTX treatment in patients having had thrombocytopenia could be performed safely, if thrombocytopenia occurred as a result of concomitant application of MTX and NSAID and no other multiple drug interactions. Preferably, MTX and NSAID should be given to these risk patients on separate days or intervals considering half time clearance of NSAIDs. This procedure has avoided the reoccurrence of thrombocytopenia and controlled further drug interactions of NSAIDs and MTX in our patients. | |
| 8833057 | Combination sulfasalazine and methotrexate in the management of rheumatoid arthritis. | 1996 Mar | I wished to review the pharmacology and current clinical experience with the combination of methotrexate and sulfasalazine as a management for rheumatoid arthritis. To date, no double blind randomized placebo controlled studies have been reported, though such studies are under way. Published experience is in excess of 100 patients and for as long as 8 years of followup. To date, the combination would appear to be well tolerated, with comparable toxicities to the individual agents taken as monotherapy. Withdrawal flare reports support a positive clinical effect of this combination. The results of ongoing controlled trials are awaited with interest. | |
| 7738942 | Interleukin 6 (IL-6) and soluble IL-2 receptor levels in patients with rheumatoid arthriti | 1995 Feb | OBJECTIVE: To investigate the effect of oral methotrexate (MTX) on circulating levels of interleukin 6 (IL-6) and soluble IL-2 receptor (sIL-2R) in patients with rheumatoid arthritis (RA). METHODS: We measured serum concentrations of IL-6 (n = 20) and sIL-2R (n = 16) before MTX therapy and again after 12 weeks. RESULTS: MTX significantly reduced IL-6 and sIL-2R after 12 weeks of therapy, and although the levels remained low at 24 weeks of therapy, the reduction was not significant. Reduction in cytokine levels was paralleled by an improvement in clinical indices. Placebo treatment did not significantly alter IL-6 or sIL-2R. CONCLUSION: MTX appears capable of cytokine modulation, although the mechanism is not clear. | |
| 7945475 | Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study. | 1994 Oct | OBJECTIVE: To evaluate the efficacy and tolerability of oral methotrexate (MTX) in rheumatoid arthritis (RA) in a long-term prospective trial. METHODS: One hundred twenty-three patients with RA who completed a 9-month multicenter randomized trial comparing MTX and auranofin enrolled in this 5-year prospective study of MTX. RESULTS: Significant (P = 0.0001) improvement compared with baseline was noted in all clinical disease variables, functional status, and the Westergren erythrocyte sedimentation rate (ESR). "Marked improvement" occurred in 87 (71%) and 85 (69%) of the patients, respectively, in the joint pain/tenderness index and the joint swelling index at the last evaluable visit. Forty-four patients (36%) withdrew during the study. Eight (7%) withdrew due to lack of efficacy, and 8 (7%) due to adverse experiences, including 1 patient with cirrhosis. At 5 years, 64% of patients were still taking MTX and completed the study. CONCLUSION: This large prospective study of long-term MTX treatment demonstrates sustained clinical response and improvement in the Westergren ESR and functional assessment scores, with an acceptable toxicity profile. | |
| 8867548 | Postoperative joint infections in rheumatoid arthritis patients on methotrexate therapy. | 1996 Mar | The effect of low dose methotrexate (MTX) on postoperative complications in rheumatoid arthritis patients undergoing elective total joint arthroplasty was observed prospectively in 32 patients. Patients were assigned to discontinue MTX the week prior to and during the week of surgery (Group 1, n = 19) or to continue MTX throughout the perioperative period (Group 2, n = 13). Nineteen patients in Group 1 had 26 procedures, with no postoperative infections. Thirteen patients in Group 2 had 16 procedures, with 4 postoperative infections: 2 infected prostheses, 1 infected joint fusion, and 1 deep wound infection (P = .03). No patient had a postoperative flare of rheumatoid arthritis. Temporary discontinuation of MTX prior to joint arthroplasty appears to decrease the risk of postoperative infection. | |
| 8308783 | Association of methotrexate treatment with a decrease of double negative (CD4-CD8-) and ga | 1993 Nov | OBJECTIVE: It has been suggested that double negative (CD4-CD8-) (DN) and gamma/delta T cells may be involved in some autoimmune diseases. We investigated peripheral blood DN and gamma/delta T cell levels in patients with active juvenile rheumatoid arthritis (JRA). METHODS: DN and gamma/delta T cell levels were measured in 42 patients with active JRA and in 10 healthy controls comparable for age by an immunofluorescence double staining procedure. RESULTS: All 3 JRA onset types had DN and gamma/delta T cell levels not significantly different from those of controls, although a wide scattering of data was present. No correlation was found between DN or gamma/delta T cell levels and erythrocyte sedimentation rate values or the number of active joints. When patients were divided according to treatment, we found that DN and gamma/delta T cell levels were significantly lower (p = 0.001, p = 0.02, respectively) in patients receiving methotrexate (MTX) than in patients not receiving MTX. The association of MTX treatment with a decrease in DN and gamma/delta T cell levels was also confirmed in a followup study of individual patients. Among patients not receiving MTX, patients with systemic JRA presented DN T cell levels significantly higher than those of controls. In 5 patients with pauciarticular JRA DN and gamma/delta T cell levels were higher in synovial fluid than in the peripheral blood. CONCLUSIONS: We found an increase in peripheral blood DN T cell levels in systemic JRA; treatment with MTX appears to be associated with a decrease in DN and gamma/delta T cell levels. | |
| 8877921 | Increase of bone mineral density and anabolic variables in patients with rheumatoid arthri | 1996 Sep | OBJECTIVE: To determine the bone mineral density (BMD) and anabolic variables in a cohort of patients with severe, early rheumatoid arthritis (RA) resistant to weekly doses of methotrexate (MTX), after addition of cyclosporin A (CyA) therapy. METHODS: We studied 10 rheumatoid factor positive patients of 58 with early erosive, aggressive RA with poor response to a 6 month course of MTX (< 20% improvement in the American College of Rheumatology core set of criteria). BMD was assessed at entry, after 6 months of MTX, and after a further 6 months of combination therapy of MTX plus CyA. Bone Gla protein (BGP) dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor-1 (IGF-1, somatomedin C) levels were determined along with clinical variables and acute phase reactants (C-reactive protein, erythrocyte sedimentation rate). RESULTS: An average BMD decline of 4.05 +/- 0.8% (mean, SD) occurred in the first 6 months of MTX treatment, along with a statistically significant decline of IGF-1 (-24.8%), DHEAS (-21.6%), and BGP (-19.7%) levels. After adding CyA 3 mg/kg daily for 6 months, BMD had increased by 3.9 +/- 0.97%, IGF-1 by 42.4%, DHEAS by 34.2%, BGP by +34.3%. These changes mirrored the clinical variables (Health Assessment Questionnaire, morning stiffness, joint count) and acute phase reactants, which improved in a statistically significant manner. CONCLUSION: Patients with active RA, even in the early phases, lose bone very rapidly. Effective control of systemic inflammation allowed a rapid rescue of BMD, at least in the short term. This happened with a simultaneous increase in some anabolic variables such as IGF-1, BGP, and DHEAS. | |
| 8242109 | [A short-term randomized controlled study with methotrexate in rheumatoid arthritis]. | 1993 Apr | Randomized, controlled and double-blind study of 36 patients aimed at the evaluation of the efficacy and toxicity of MTX in the treatment of rheumatoid arthritis. Twenty-eight patients completed the study period: 14 in the MTX group and 14 in the placebo group. The patients treated with MTX presented a statistically significant improvement (p < 0.05) in pain, grip strength and functional ability when compared to placebo treated patients. Mild adverse effects were observed in 4 patients treated with MTX and in 2 patients treated with placebo. These findings support other studies and give to methotrexate a relevant position in the treatment of rheumatoid arthritis, owing to its convenient posology, beneficial effectivity and favourable toxicity. | |
| 8721274 | Total and free methotrexate pharmacokinetics in rheumatoid arthritis patients. | 1996 Apr | The pharmacokinetics of total and free methotrexate (MTX) were investigated in 50 patients with rheumatoid arthritis. Each patient received 10 mg MTX intramuscularly. The free and total plasma concentrations of MTX were measured over a 36-h period after drug administration by using the Abbott TDx fluorescence polarization immunoassay. Plasma concentrations of MTX were described by a biexponential function. The mean terminal elimination half-lives of total and free MTX were 9.4 and 8.4 h, respectively, and the corresponding mean residence times, 8.5 and 9.2 h. No difference in these parameters was found by comparing total and free MTX. Total plasma clearance of the free fraction averaged 215 ml/min. The statistical comparison of the variations with time of the ratio of free to total MTX during the 36 h after the dose showed that the free fraction was significantly increased for 8 h after drug administration (p < 0.001). To describe these variations, the changes of the free MTX concentrations (unbound) were related to the changes of the total MTX concentrations by using the Hill equation. Mean plasma protein binding ranged from 20 to 57% for these patients. | |
| 7788170 | Total and free methotrexate pharmacokinetics, with and without piroxicam, in rheumatoid ar | 1995 May | The pharmacokinetic profile of total and free methotrexate (MTX) and the effect of piroxicam on MTX pharmacokinetics was studied in 20 rheumatoid arthritis patients receiving a stable dosage of MTX (10 mg/week). Plasma protein binding ranged from 25 to 55%. To describe the variations with time of the unbound fractions a mathematical characterization relationship between the total and free MTX was used. Total and free MTX were correlated with the sigmoid maximum effect model. The slope factor (gamma) was proportional to the number of binding sites. The free fraction for a given patient can be evaluated from this relationship. Total clearance of MTX was not statistically different with piroxicam (8.0 l/h for total MTX, 13.7 l/h for free MTX) vs without piroxicam. Likewise, there were no significant difference in tmax, area under the plasma concentration vs time curve, distribution and elimination half-lives, mean resonance time, and volumes of distribution. Although the highest observed total MTX concentration was significantly lower with piroxicam, there were no significant pharmacokinetic interactions between low-dose MTX and piroxicam. | |
| 7895399 | Phospholipase A2 activity in peripheral blood cells of rheumatoid arthritis patients treat | 1994 Nov | OBJECTIVE: To measure the activity of phospholipase A2 (PLA2) in peripheral blood mononuclear cells (PBMC), polymorphonuclear leukocytes (PMN) and platelets in patients with rheumatoid arthritis (RA) before and during treatment with methotrexate (MTX). METHODS: Nine patients with RA treated with MTX were studied for six months. PBMC, PMN, and platelets were isolated at baseline and at monthly intervals thereafter. PLA2 activity was measured in lysates of the various cell fractions by the hydrolysis of radiolabeled lysocholine from phosphatidylcholine, L-Dipalmitoyl using thin layer chromatography. Data were calculated as pmol of 14C choline released per hour per milligram of cellular protein. RESULTS: At baseline, compared to normal controls, PLA2 activity was significantly increased in platelets (p = 0.02) but not in PBMC (p = 0.32) nor in PMN (p = 0.23). Seven of the nine patients responded clinically to treatment with MTX. In these 7 patients over the six-month treatment course, there was a significant decrease in PLA2 activity in the platelets which correlated with improvement in disease activity (R = 0.82, p = 0.03). PLA2 activity also decreased in PBMC and PMN, but the correlation with disease improvement was not statistically significant (R = 0.71, p = 0.07 for PBMC; and R = 0.43, p = 0.33 for PMN). CONCLUSION: PLA2 activity in platelets but not in PBMC or PMN is significantly increased in patients with RA compared to normal controls. Although PLA2 activity decreased in all the cells during treatment with MTX, only PLA2 activity in platelets correlated significantly with improvement in disease activity. | |
| 7671613 | Destructive corneal and scleral disease associated with rheumatoid arthritis. Medical and | 1995 Jul | The onset of necrotizing scleritis (NS) and peripheral ulcerative keratitis (PUK) in the clinical course of rheumatoid arthritis (RA) may reflect the presence of systemic, potentially lethal vasculitis. In an effort to better characterize this subset of patients with severe RA-associated corneal and/or scleral inflammation and to analyze the efficacy of therapy, we reviewed our experience in the medical and surgical management of 16 tertiary referral cases (25 eyes) unresponsive to aggressive conventional therapy with topical and systemic steroids as well as with systemic nonsteroidal drugs. Cytotoxic immunosuppressive therapy was instituted in all patients with NS and/or PUK. Cyclophosphamide and methotrexate were the most successful agents used. Cytotoxic immunosuppressive drugs in conjunction with early aggressive surgical treatment halted the relentlessly progressive inflammation and preserved the integrity of the globe in 92% of eyes. Visual acuity could be stabilized or improved in 83% of patients with NS and in 68% of patients with PUK. | |
| 1364169 | Does C-reactive protein modulate T-lymphocyte function in methotrexate-treated rheumatoid | 1992 Nov | Thirty-four patients with rheumatoid arthritis were treated with oral methotrexate for 6 months. Methotrexate was given as a single weekly dose of 7.5-10 mg. A correlation between serum concentration of CRP and proportion of CD8+ lymphocytes in peripheral blood was found in this group of patients. This correlation can be described by a linear regression equation. According to the results obtained, CRP suppresses lymphocyte function in patients with RA. This is the consequence of the stimulating effect on suppressor mechanisms. | |
| 8036601 | [A comparative evaluation of the treatment results with cyclosporin A, methotrexate and az | 1993 | In a randomized trial 43 patients with RA systemic manifestations received for 6 months immunodepressants: azathioprine, methotrexate and cyclosporin A (12.15 and 16 patients, respectively). Ten more patients resistant to immunodepressants were given cyclosporin A. The drugs were found to produce a positive effect on clinical symptoms and laboratory indices of the disease. Cyclosporin A is thought a basic immunodepressant without serious hematological or infectious complications. Occasionally it can be useful in failure of other immunodepressants administered to RA patients. |