Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 2189302 | Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheuma | 1990 Jun | PURPOSE: Methotrexate (MTX), when used to treat malignancy or psoriasis, has been implicated in anecdotal reports as a teratogen or abortifacient in the first trimester of pregnancy. We are unaware of any previous reports that describe the course of gestation and the effect on subsequent offspring in patients treated with low-dose oral MTX for rheumatoid arthritis, and therefore present our experience. PATIENTS AND METHODS: We report on eight women experiencing 10 pregnancies. Mean number of weeks of gestation while taking MTX was 7.5 (range 2 to 20 weeks). Outcome of pregnancies included five full-term babies (FTB), three spontaneous abortions (SAB), and two elective abortions. RESULTS: There were no significant differences in either the FTB or SAB group when considering risk factors including smoking, alcohol, concomitant medications, and age. One of three in the SAB group had recurrent abortions prior to MTX therapy. All five of the FTB group had uncomplicated pregnancies and deliveries. All offspring were of normal height and weight at birth with no physical abnormalities. All children reached growth, development, and intellectual stages normally, and their present mean age is 11.5 years. No observed learning disabilities or medical abnormalities have occurred in any of these children. CONCLUSION: In this uncontrolled study we failed to demonstrate tertogenicity of MTX. However, the possibility of abortion due to MTX use remains. | |
| 3704718 | Hepatotoxicity after long-term methotrexate therapy. | 1986 May | To reassess the need for repeat liver biopsies in patients receiving long-term methotrexate therapy, we reviewed the results of 15 biopsies in 14 such patients seen from 1979 to 1984 at the Medical University of South Carolina. Significant changes in liver histology were found in seven patients. These findings did not correlate with biochemical abnormalities, presence of anemia or obesity, or age when methotrexate therapy was initiated. Four of the 15 biopsies (27%) showed grade III or IV histologic changes (fibrosis or cirrhosis), which led to discontinuance of treatment. The single most significant factor predisposing to toxicity appeared to be the duration of therapy, though the cumulative doses, no patient with grade III or IV histology had been treated for less than five years. Thus, surveillance liver biopsies at suitable intervals are advisable once the patient has been treated for five years or more. Conversely, liver biopsies within the first five years of treatment with methotrexate appear not to be necessary, though these results should be confirmed in a larger patient group. | |
| 3779322 | Comparison of methotrexate with azathioprine or 6-mercaptopurine in refractory rheumatoid | 1986 Nov | Methotrexate (MTX) appears to be useful in patients with rheumatoid arthritis (RA) refractory to other drugs but its long-term toxicity and efficacy are uncertain. A retrospective study of MTX in such patients in comparison with the purine analogues, azathioprine and 6-mercaptopurine was made using life-table analysis. Eighty-four patients took MTX in a median dose of 7.5 mg/week whilst 55 received purine analogues, 100 mg/day (median). By 12 months, 19.3% of patients had ceased MTX due to toxicity, compared with 29.3% for purine analogues. Toxicity severe enough to warrant stopping therapy was uncommon after 8 months with either drug. At 12 months 61.5% of the MTX patients had achieved defined criteria of improvement compared with 25.6% for the purine analogues (p less than 0.05). The number of patients improving on purine analogues did not increase substantially after 6 months, whereas the number improving with MTX continued to 12 months. MTX in a low-dose regimen is useful in refractory RA and superior to low-dose purine analogues. | |
| 2259842 | Methotrexate therapy in rheumatoid arthritis patients diminishes lectin-induced mononuclea | 1990 | Methotrexate (MTX) is an anti-folate drug used in cancer chemotherapy because of its anti-proliferative effects. However, it is unclear whether the anti-proliferative effects of MTX contribute to the efficacy of low-dose MTX in the treatment of rheumatoid arthritis (RA). To date, either no change or a paradoxical increase in lectin-induced proliferation has been observed in cultures of peripheral blood mononuclear cells (PBMC) from MTX-treated RA patients (RA + MTX). In these earlier studies, high folate-containing media and tritiated thymidine (3H-TdR) were used. Our studies were designed to test the hypothesis that the use of a culture medium with a low folate content along with tritiated deoxyuridine (3H-UdR) permits detection of diminished phytohemagglutinin (PHA)-induced proliferative responses of PBMC from RA + MTX. The data demonstrate decreased PHA-induced cellular proliferation of cultured PBMC from RA + MTX compared with controls. When comparing the PBMC proliferative responses in high vs low folate medium, a significantly greater increase (P less than 0.05) in proliferation occurs in the cells from RA + MTX cultured in the high folate medium. This suggests that an in vivo folate-deficient state of the cells from RA + MTX may be corrected in vitro when a high folate medium is used in culture. We conclude that the use of 3H-UdR and a medium containing folate within the normal range of plasma folate levels eliminates artifacts associated with the use of high folate medium and 3H-TdR, which obscures the anti-proliferative effect of MTX in RA patients. | |
| 1977391 | The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Result | 1990 Oct | We performed 2 metaanalyses of placebo-controlled and comparative clinical trials to examine the relative efficacy and toxicity of methotrexate (MTX), injectable gold, D-penicillamine (DP), sulfasalazine (SSZ), auranofin (AUR), and antimalarial drugs, the second-line drugs most commonly used to treat rheumatoid arthritis (RA). For the efficacy study, we applied a set of inclusion criteria and focused on trials which provided information on tender joint count, erythrocyte sedimentation rate, or grip strength. We found 66 clinical trials that contained 117 treatment groups of interest, and for each drug, we combined the treatment groups. For each outcome, results showed that AUR tended to be weaker than other second-line drugs. The results of the 3 outcome measures were synthesized into a composite measure of outcomes, and AUR was significantly weaker than MTX (P = 0.006), injectable gold (P less than 0.0001), DP (P less than 0.0001), and SSZ (P = 0.009) and was slightly, but not significantly, weaker than antimalarial agents (P = 0.11). We also found heterogeneity among antimalarial agents, in that patients treated with chloroquine did better than those treated with hydroxychloroquine. We found little difference in efficacy between MTX, injectable gold, DP, and SSZ. A power analysis showed that a trial should contain at least 170 patients per treatment group to successfully differentiate between more effective and less effective (e.g., AUR) second-line drugs. None of the reported interdrug comparative trials we reviewed were this large. For the toxicity study, our inclusion criteria captured RA trials which reported the proportion of patients who discontinued therapy because of drug toxicity and the total proportion who dropped out. We found 71 clinical trials that contained 129 treatment groups. The average proportion who dropped out and the average proportion who dropped out because of drug toxicity were computed for each drug. Overall, 30.2% of the patients in these trials dropped out; 50% of them did so because of drug toxicity. Injectable gold had higher toxicity rates (P less than 0.05) and higher total dropout rates (P less than 0.01) than any other drug; 30% of gold-treated patients dropped out because of side effects versus 15% of all trial patients. Antimalarial drugs and AUR had relatively low rates of toxicity; the rate for MTX was imprecise because of discrepancies between trials. Thus, of the commonly used second-line drugs, AUR is the weakest, and injectable gold is the most toxic. Agents introduced in the future will be compared with these drugs.(ABSTRACT TRUNCATED AT 400 WORDS) | |
| 2112243 | Second-line antirheumatic drugs in the elderly with rheumatoid arthritis: a post hoc analy | 1990 | This study assessed the relative efficacy and toxicity of second-line antirheumatic drugs in patients 65 years of age or older compared to younger counterparts. The results of three prospective, double-blind, parallel, randomized, multicenter trials were reanalyzed, stratifying outcomes by intervention and patient age. Efficacy was assessed by categorizing patient responses as follows: important improvement, no meaningful change, or progressive disease. Toxicity was analyzed by comparing withdrawal rates due to adverse effects. The three trials compared the following treatments: (1) D-penicillamine 10-12 mg/day versus azathioprine 1.25-1.5 mg/kg/day; (2) gold sodium thiomalate 50 mg intramuscularly weekly versus auranofin 6 mg/day versus placebo; and (3) pulse oral methotrexate 7.5-15.0 mg weekly versus placebo. At baseline, 103 patients age 65 or older were similar to 485 patients less than 65 years of age, with the exception of disease duration in all studies and erythrocyte sedimentation rate in one study. For patients completing each study, efficacy outcomes based on age were not significantly different. Withdrawal rates due to adverse drug reactions were also not significantly different. | |
| 2213397 | Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. | 1990 Oct | Twenty-nine children with juvenile rheumatoid arthritis were studied to determine the safety and efficacy of methotrexate therapy. The initial dose of methotrexate averaged 7.1 mg/m2/wk and was given as a single, oral weekly dose or as three divided doses, each separated by 12 hours. Current antiinflammatory medications were continued; 25 of 29 children had had lack of efficacy, and 8 of 29 had toxic effects, with one or more prior drugs such as intramuscularly or orally administered gold, hydroxychloroquine, or D-penicillamine. Intolerable corticosteroid dependency or toxic effects were present in 18 of 29 cases. Methotrexate-treated patients were examined monthly; minimum treatment duration required to assess efficacy and toxicity was 6 months. The range of treatment duration was 8 to 39 months (mean 18.5 months). Efficacy was assessed by comparing pretreatment versus posttreatment fever and rash, swollen-joint counts, articular indexes, duration of morning stiffness, functional class, hemoglobin levels, and platelet counts. Treatment with methotrexate effectively controlled fever and rash in 83% of children with systemic juvenile rheumatoid arthritis, reduced morning stiffness by 63%, eliminated recalcitrant joint restriction in 48%, and reduced numbers of swollen joints and swelling indexes by 46% and 52%, respectively. No significant toxic effects were observed. Juvenile rheumatoid arthritis of long duration, or with major erosions, was more likely to be refractory to methotrexate therapy. We recommend earlier consideration of methotrexate in place of other slow-acting antirheumatic drugs for juvenile rheumatoid arthritis not responding well to usual therapy. Future studies should address potential methotrexate toxic effects in the lungs and reproductive system, as well as outcome after discontinuation of methotrexate treatment. | |
| 2388211 | Hepatic fibrosis with the use of methotrexate for juvenile rheumatoid arthritis. | 1990 Jun | Methotrexate (MTX) is currently under study for use in juvenile rheumatoid arthritis. One complication of MTX is hepatotoxicity. Although liver function tests may be abnormal with its use, in this setting they do not correlate well with the development of hepatic fibrosis. Periodic liver biopsy is required to monitor for the hepatotoxic changes secondary to MTX. We describe and discuss the case of a 17-year-old woman who developed evidence of hepatic fibrosis after 3 years of MTX therapy. | |
| 3718568 | Methotrexate therapy in juvenile rheumatoid arthritis: a retrospective study. | 1986 Jun | Nineteen selected patients with severe, mostly systemic onset, juvenile rheumatoid arthritis were treated with methotrexate (MTX) for an average of 10.5 months. Twelve patients showed statistically significant improvement, as measured by the number of affected, swollen, tender, and functionally impaired joints, and by decreases in erythrocyte sedimentation rate and C-reactive protein and an increase in hemoglobin level. Systemic manifestations improved in 6 of 8 patients. In 10 children receiving corticosteroids, the dosage was reduced. Seven patients did not respond to MTX therapy. Six of them showed an unchanged disease course, and 1 had a relapse after 4 months of MTX treatments. Probable side effects included gastrointestinal symptoms, elevated liver enzymes, and herpes zoster infection. MTX treatment should be considered for children with life-threatening or severe disabling arthritis that is unresponsive to other therapy. | |
| 2242072 | Rescue of interleukin-1 activity by leucovorin following inhibition by methotrexate in a m | 1990 Nov | We have recently shown that methotrexate (MTX) inhibits interleukin-1 (IL-1) activity in vitro. This effect may play an important role in the rapid antiinflammatory action of MTX in rheumatoid arthritis. In the present study, we showed that the inhibition of IL-1 activity in vitro by MTX is dependent on folate pathways since, after the addition of leucovorin, the inhibitory effect of MTX was abolished. These findings may shed more light on the mechanism of action of MTX in rheumatoid arthritis. They also point to the fact that some IL-1 activities may be dependent on intracellular folate pathways. | |
| 3626435 | Combined steroid-cyclosporin treatment of chronic autoimmune diseases. Clinical results an | 1987 Aug 3 | Twenty-one patients suffering from different autoimmune diseases (14 from systemic lupus erythematosus, 4 from rheumatoid arthritis, one from Sjögren's syndrome, one from systemic hypersensitivity vasculitis, and one from diffuse proliferative glomerulonephritis) were treated with a combined immuno-suppressive regimen. Cyclosporin was given at a dose of 5 mg/kg/day together with steroids. In addition, the rheumatoid arthritis patients also received methotrexate. In all patients a kidney biopsy was performed after a treatment period of 17 to 42 months (mean duration 21.7 months). The cumulative cyclosporin dose at the time of biopsy varied from 1.071 to 4.587 mg/kg. Patients suffering from systemic lupus erythematosus and rheumatoid arthritis were assessed according to a scoring system set up for this purpose. The combined therapy proved useful in these patients as reflected in the diminution of the respective activity scores, improvement of kidney function, and diminution of proteinuria. Histological examination of the kidney biopsy specimens showed only minimal activity in patients with systemic lupus erythematosus. No unequivocal signs of renal toxicity could be detected. In the last group, the condition of the patient with Sjögren's syndrome was stabilized and the patient with systemic vasculitis improved clinically. Neither patient had signs of kidney lesions. The patient with diffuse proliferative glomerulonephritis, in whom kidney biopsy was performed before and after treatment, showed improvement of kidney function, diminution of proteinuria, and diminution of inflammatory activity within the kidney, and no signs of cyclosporin toxicity. | |
| 2735961 | Toxicity and serum levels of methotrexate in children with juvenile rheumatoid arthritis. | 1989 Jun | Twenty-three children with destructive polyarticular juvenile rheumatoid arthritis (JRA) were treated for 0.5-4.3 years (median 1.6 years) with weekly doses of methotrexate (MTX) (0.11-0.6 mg/kg/week). Serum levels of MTX at 1 hour and at 24 hours after drug administration were obtained at each dosage level and every 3 months after a stable dosage was achieved. No patient had serum levels of MTX that were in the toxic range nor evidence of hematologic, skin, mucous membrane, gastrointestinal, or pulmonary abnormalities. Ten patients had transiently elevated serum transaminase levels. Arthritis symptoms improved in 21 of these JRA patients, and the improvement was significantly associated with a mean 1-hour serum MTX level of greater than or equal to 5.8 x 10(-7)M (P = 0.008) and a dosage of greater than or equal to 0.3 mg/kg/week (P = 0.004). The 1-hour serum level of MTX was correlated with the MTX dosage (r = 0.28, P = 0.005). Our observations suggest that with close monitoring, MTX can be used safely at dosages as high as 0.6 mg/kg/week, and improvement in the symptoms of JRA will become evident when the serum levels of MTX 1 hour after administration approach 6.0 x 10(-7)M. | |
| 1930318 | Suppression of collagen-induced arthritis by combination cyclosporin A and methotrexate th | 1991 Oct | Louvain (LOU) rats were administered either methotrexate (MTX; 0.3 mg/kg/week or 0.8 mg/kg/week intraperitoneally), cyclosporin A (CSA; 4 mg/kg/day or 10 mg/kg/day continuous infusion via osmotic pump), or a combination of both agents. The rats were immunized with native type II collagen (CII) to determine the effects of these agents on collagen-induced arthritis, an animal model of rheumatoid arthritis. A significant decrease in the incidence (P less than 0.01) and severity of arthritis by clinical (P less than 0.05) and radiographic assessments (P less than 0.05) was found in recipients of combination therapy, compared with controls. Delayed-type hypersensitivity reactions to CII were measured on day 26, and production of IgG antibody to CII was measured on days 7, 14, and 26. IgG antibody was evident by day 7, and titers were near-maximal by day 14. Both delayed-type hypersensitivity and antibodies to CII were reduced in animals that received the higher dosage of CSA. Liver, kidney, and spleen specimens obtained from rats treated with CSA and MTX demonstrated no histologic abnormalities on light microscopy, compared with controls. These studies indicate that CSA and MTX in combination is a safe and effective therapy for collagen-induced arthritis and may be useful in the treatment of rheumatoid arthritis. | |
| 2674740 | Methotrexate therapy in connective tissue diseases: a review of the literature. | 1989 Aug | Low dose methotrexate (MTX) therapy is now widely used with considerable success in refractory rheumatoid arthritis. Experience with the drug in other connective tissue diseases and vasculitis has been limited. This article reviews hypotheses about the mode of action of MTX, pharmacology and pharmacokinetics, reasons to use cytotoxic agents in the different diseases, and results of MTX therapy. Risk factors, adverse reactions and drug interactions of MTX with other drugs are mentioned. Although based on a small number of patients, data about remarkable clinical improvement in polymyositis, systemic lupus erythematosus and vasculitis suggest that MTX is a potent and effective drug in connective tissue diseases other than rheumatoid arthritis. However, controlled trials are needed to assess the exact value of the drug in these diseases. | |
| 3963528 | Methotrexate in the treatment of steroid-dependent asthma. | 1986 Apr | A 63-year-old woman with refractory psoriatic arthritis and asthma, requiring intermittent steroid therapy, was treated with methotrexate (MTX). Her arthritis responded rapidly and it was noted that her asthma required no further steroid therapy. Six patients with established steroid-dependent asthma were then treated with 7.5 to 15.0 mg of MTX per week, after protocols used to treat psoriasis and rheumatoid arthritis. Five patients reduced their steroid usage while on MTX. Side effects were minimal while taking MTX. It was concluded that MTX may have a role in reducing cortisone requirements in steroid-dependent asthma. | |
| 3671132 | [Therapy with plasmapheresis and lymphoplasmapheresis combined with immunosuppressive agen | 1987 May | Two cases of JRA refractory to NSAID' steroids and long-acting drugs were successfully treated with plasmapheresis and combined lympho- and plasma-apheresis respectively. Case 1. A 8 year old female child who had been suffering from systemic JRA for 6 years received a course of three plasmapheresis followed by a 6 month cycle of azathioprine. Clinical and laboratory remission was promptly achieved and is still present after 18 months. Case 2. A 12-year old boy affected by poliarticular JRA received a course of 4 plasmapheresis followed by a 6 month cycle with azathioprine. The opportunity of performing plasma or lymphoplasmapheresis reinforced by immunosuppressive drugs such as azathioprine or methotrexate at low doses in refractory cases of JRA is discussed. | |
| 2674317 | Methotrexate pneumonitis: a case report and summary of the literature. | 1989 Sep | Methotrexate is used to treat a growing number of malignancies, severe rheumatoid arthritis, and refractory psoriatic arthritis. Pneumonitis induced by the drug occurs in a small percentage of patients and is usually associated with fever, cough, dyspnea, and restrictive pulmonary disease. Severe reactions may progress to respiratory failure. Early recognition of the toxicity is important, and discontinuation of the drug and therapy with corticosteroids usually lead to dramatic improvement. | |
| 2497256 | Serum hyaluronate as a marker for disease severity in the Lactobacillus casei model of art | 1989 Jan | Serum concentrations of hyaluronate may provide a clinically relevant, quantitative marker of disease in patients with active rheumatoid arthritis (RA). We studied the utility of serum hyaluronate in an animal model, with features reminiscent of human RA, in which LEW/N female rats were made arthritic by intraperitoneal injection of sonicated Lactobacillus casei. When serum hyaluronate was measured by an inhibition ELISA, a dose dependent correlation was found between the amount of L. casei injected and both joint score and serum hyaluronate in the chronic phase of the disease. A linear correlation between the chronic phase joint score and serum hyaluronate was observed (r = 0.69, p less than 0.001). Two orally administered compounds, flurbiprofen (20 mg/kg) and methotrexate (0.125 mg/kg), were effective in decreasing both variables. Thus, serum hyaluronate may have utility in evaluating the therapeutic efficacy of antirheumatic/antiinflammatory agents in vivo in the chronic phase of RA-like diseases. | |
| 2476134 | Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularizat | 1989 Sep | Neovascularization in the rheumatoid synovium plays an important role in the propagation of rheumatoid synovitis because the emigration of mononuclear cells and the growth of pannus are critically dependent on the development of small blood vessels. Inhibition of local vascular endothelial cell (EC) proliferation, which is essential for growth of these vessels, therefore, would have the potential to suppress rheumatoid inflammation. We investigated the effects of methotrexate (MTX), low doses of which are commonly administered to rheumatoid arthritis patients, on DNA synthesis by human umbilical vein EC in vitro and on rabbit corneal neovascularization in vivo. MTX inhibited both basal and EC growth factor-stimulated tritiated deoxyuridine (3H-UdR) incorporation into EC in a dose-dependent manner. Significant inhibition was observed at a concentration of 5 x 10(-9) M, which is that attained in the serum of treated patients. Neovascularization in vivo was also suppressed by low-dose intramuscular injections. These results suggest that MTX has an antiangiogenic effect, and may suppress rheumatoid inflammation through the reduction of synovial small blood vessels responsible for mononuclear cell infiltration and proliferation of synovial tissue. | |
| 1767078 | Current status of the medical treatment of children with juvenile rheumatoid arthritis. | 1991 Nov | Based on clinical experience and the aforementioned studies, a number of opinions can be entertained concerning the historically traditional conservative management of children with JRA. 1. Because the inflammatory changes of JRA on the bones and joints once established are irreversible in most children, there are ample theoretical reasons to start more effective therapy (if available) early. 2. Most of the currently available drugs control inflammation only partially or temporarily. 3. Most children stop taking the various SAARDS after approximately 2 years of disease because of lack of efficacy or the development of toxicity. 4. Whereas corticosteroids are the most potent and effective anti-inflammatory agents, long-term use in children, even in low dosage, is severely limited, especially by their effect on growth. 5. Methotrexate appears to be the most effective of the alternative agents and much safer than expected when used in the currently recommended protocol. 6. More effective therapy must await a better understanding of the pathogenesis of JRA, although currently available medications might be used more rationally by taking into consideration available pharmacologic studies. |