Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open, retrospective, observational study

A total of 453 rheumatoid arthritis (RA) patients were followed up for 35.2 +/- 27.9 months (range 3-106). The clinical parameters decreased significantly after 6 months. Twenty-eight patients were in remission (6.4%). Rheumatoid factor (RF) positivity was less common in the group of patients in remission, with a higher frequency of visits and methotrexate (MTX) onset after 65 yr. There was a significant degradation of radiographic lesions (n = 60). A total of 101 patients (23.1%) stopped MTX, for toxicity (n = 61) and failure (n = 20). The onset of MTX after 65 yr, a low number of visits and the occurrence of side-effects were predictive of MTX withdrawal. A total of 259 patients (59.3%) had side-effects. A Ritchie's index < or = 10, a lower polymorphonuclear cell count and the absence of RF were predictive of side-effects. The probability of being on MTX at 5 yr was 73%. This study confirms the high efficacy of MTX in RA.     

Lack of interaction between bromfenac and methotrexate in patients with rheumatoid arthritis

OBJECTIVE: To compare the pharmacokinetics of methotrexate (MTX) and bromfenac administered separately or coadministered in patients with rheumatoid arthritis (RA). METHODS: Patients received their usual weekly oral dose of MTX on Days 1 and 8 and bromfenac 50 mg every 8 h from Days 4 to 9. On Days 1 and 8 serial blood and urine samples were collected to study the pharmacokinetics of MTX and 7-hydroxymethotrexate (7-OHMTX). Bromfenac pharmacokinetics were studied on Days 7 and 8. Concentrations of the analytes were assayed using validated high performance liquid chromatography methods. RESULTS: Nine patients, 5 women and 4 men, completed the study. No statistically significant changes were observed in any of the pharmacokinetic variables evaluated for bromfenac with or without MTX. Bromfenac also did not alter the pharmacokinetics of low dose MTX. However, some significant changes were observed in the pharmacokinetics of 7-hydroxymethotrexate: a 30% increase in dose normalized area under the serum concentration time curve (mean +/- SD) to 3102 +/- 1397 micrograms.h/l and a 16% decrease in renal clearance to 10.0 +/- 6.7 ml/h/kg. Eight patients had mild or moderate adverse events: most were considered unrelated to the study drug by the investigator. One patient did not complete the study because of moderate hypertension. No patient had clinically important abnormal laboratory test results. CONCLUSION: No clinically significant changes in MTX pharmacokinetics were detected in patients with RA when bromfenac was added to MTX therapy. Although 7-OHMTX concentrations were elevated, the changes were small and unlikely to be of clinical significance. MTX did not alter the pharmacokinetics of bromfenac.     

Adverse effects of low-dose methotrexate therapy in rheumatoid arthritis]

To analyze the possible adverse effects of low dose methotrexate (MTX) therapy, 276 patients with rheumatoid arthritis (RA) were examined retrospectively. One hundred and seven patients (39%) experienced 113 adverse events : 57 showed liver dysfunction, 24 gastrointestinal complaints, 13 cutaneous symptoms, 6 respiratory symptoms, and 6 malignancies. Interestingly, 3 patients developed a dry cough without infiltration nor interstitial shadow on chest X-ray. The cough was rapidly resolved by discontinuation of MTX, but it recurred in 1 patient when MTX was re-administered. This finding might suggest a close association between MTX administration and the occurrence of dry cough. Of the 6 patients with malignancies diagnosed during MTX therapy, 2 showed malignant lymphoma, 2 lung cancer, 1 breast cancer and 1 colon cancer. MTX might have an oncogenic potential in RA because the coincidence rate, especially with respect to lymphoma, was significantly higher than estimated in a normal population.     

Up-regulation of neuropeptide Y-Y2 receptors in an animal model of temporal lobe epilepsy

OBJECTIVE: To clarify the incidence and background of clinical relapse (escape phenomenon) during low-dose methotrexate therapy for rheumatoid arthritis. METHODS: Seventy one patients with rheumatoid arthritis (RA) were analyzed. They were started on therapy with methotrexate (MTX) between April 1, 1991 and May 30, 1995. Among them, 60 patients showed clinical improvement within 6 months after the start of the therapy and were subjected to the analysis for clinical relapse (escape phenomenon). RESULTS: Twelve patients showed an initial improvement followed by a relapse with increased serum CRP and number of painful joints despite the MTX therapy was continued. Two types of the relapses were seen; (1) early, escape (relapse after an initial brief improvement) in 7 patients, and (2) late escape (relapse after a long-term improvement with MTX therapy) in 5 patients. The early escape was seen at 9.0 +/- 0.7 months after the start of therapy while the late escape was seen at 23.3 +/- 4.8 months. Patients with both types of escape phenomenon had the longer duration of the disease and more advanced stage. There was no relationship between clinical relapse and age, baseline RA activity, MTX dose, or concurrent use of corticosteroids and other disease modifying anti-rheumatic drugs. The efficacy of MTX for RA was restored by increasing dose of MTX in 11 patients. CONCLUSION: These results suggest that clinical relapse is not rare in RA patients during low-dose methotrexate therapy, but could be improved by increasing dose.     

Clinical characteristics of patients with rheumatoid arthritis and methotrexate induced pneumonitis

OBJECTIVE: To determine the clinical features of methotrexate (MTX) pneumonitis in patients treated for rheumatoid arthritis (RA). METHODS: The medical records of 284 patients with RA who had been treated with oral MTX (mean followup 33.2 mo) were reviewed retrospectively. RESULTS: MTX induced interstitial pneumonitis developed in 6 patients (2.1%). The affected patients were significantly older than those without MTX pneumonitis (67.3 +/- 9.8 vs 52.4 +/- 12.6 yrs, respectively; p < 0.005). The cumulative MTX dose ranged from 65 to 580 mg at the time pneumonitis developed. Five of the patients (83%) had preexisting interstitial abnormalities, while only 29 of the 278 patients without MTX pneumonitis (10%) had such abnormalities (p < 0.001). The frequency of adverse effects due to previous treatment with disease modifying antirheumatic drugs (DMARD) was 66.7% in MTX pneumonitis patients and 14.3% in the other 278 patients (p < 0.01). CONCLUSION: Advanced age, preexisting interstitial abnormalities, and previous adverse reactions to DMARD may be associated with MTX pneumonitis. Patients with these characteristics require careful monitoring during MTX therapy.     

The effects of food on methotrexate absorption

OBJECTIVE: To determine the effects of food on methotrexate (MTX) absorption in patients receiving MTX for the treatment of rheumatoid arthritis (RA). METHODS: Standard pharmacokinetic variables were determined in patients with RA after their usual maintenance dose of MTX, under fasting conditions and after they ate a standard breakfast. RESULTS: No significant differences in area under the serum concentration versus time curve, maximal MTX concentration after dosing (Cmax), time to Cmax), bioavailability, urinary MTX, renal clearance of MTX, or creatinine clearance were observed between the 2 dosing conditions. CONCLUSION: We observed no significant effect of food on MTX absorption or bioavailability. Patients may consume MTX without regard to meals.     

Methotrexate in juvenile rheumatoid arthritis. Evidence of age dependent pharmacokinetics

Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5-16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg.kg-1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.     

Intrathecal granuloma complicating chronic spinal infusion of morphine. Report of three cases

OBJECTIVE: To assess the frequency of methotrexate (MTX)-induced pancytopenia in rheumatoid arthritis (RA). METHODS: A MEDLINE literature search was conducted to identify articles published during the last 15 years (1980-1995) that presented data on MTX-associated pancytopenia. Two case reports of our own experience are also presented. In addition, articles that examined risk factors associated with MTX-related pancytopenia were identified. RESULTS: A total of 70 patients with pancytopenia related to MTX therapy were identified (68 reported in the literature, 2 from our own experience). Sixty-one of the patients were described in published case reports, 7 patients were from 5 long-term prospective studies. In many of these cases, predisposing factors for the development of pancytopenia were described. The 5 long-term prospective studies reported toxicity data on patients who had been treated with MTX for at least 13 weeks. A total of 511 patients were included in the prospective trials, yielding an overall incidence of pancytopenia of 1.4% (7 of 511). Of the 70 cases reported, 12 patients died (17%). Most of them had impaired renal function, hypoalbuminemia, concurrent infection, and/or concomitant medication with more than 5 drugs. The minimal cumulative MTX dose leading to fatal pancytopenia was 10 mg, observed in one of our patients. CONCLUSION: Pancytopenia is not an uncommon side effect of low-dose pulse MTX therapy in RA. It can lead to serious complications, including death.     

Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment

Although long-term clinical studies have shown no excessive risk of lymphoma in rheumatoid arthritis (RA) patients treated with methotrexate (MTX), an increasing number of reports of this association continue to appear. We describe two cases, review the cases in the world's literature, and summarize their important characteristics. Possible oncogenic mechanisms are discussed. Most lymphoproliferation cases presented here have features of immunosuppression-associated lymphoma. The immunosuppressed state is attributable to a combination of factors, such as RA itself and the actions of MTX. The risk factors for RA patients to develop lymphoma while on MTX include severe disease, intense immunosuppression, genetic predisposition, and an increased frequency of latent infection with prooncogenic viruses such as Epstein-Barr virus (EBV). The spontaneous remission of lymphomas in eight RA patients after MTX was stopped highlights the likely causative role of the drug in the development of these malignancies. If the clinical situation permits, a period of observation for spontaneous remission after MTX is stopped is advisable. The physicians caring for RA patients on MTX should maintain a high surveillance for signs and symptoms suggestive of lymphoma.     

Methotrexate therapy in rheumatoid arthritis: a life table review of 587 patients treated in community practice

To determine whether methotrexate (MTX) maintains its effectiveness in rheumatoid arthritis (RA) in the setting of community based private rheumatology practice we used life table analysis to review the combined experience of a group of these practices. Of 587 patients with RA who started to take MTX, total termination rate at 70 months was 24.4% with most terminations prompted by drug toxicity. Older age (greater than 65 years) was associated with higher rates of toxicity. Treatment termination rates varied substantially between rheumatologists. We conclude that MTX therapy for RA is well tolerated and maintains effectiveness for at least 70 months.     

Long-term treatment of destructive rheumatoid arthritis with methotrexate

OBJECTIVE: To evaluate the tolerability and efficacy of methotrexate (MTX) treatment in patients with longstanding, progressive, active rheumatoid arthritis (RA) who had failed one or more disease modifying antirheumatic drugs (DMARD). METHODS: Two hundred seventy-one consecutive patients with RA in whom MTX treatment was introduced were followed at regular intervals for up to 108 months. Evaluations included the number of swollen joints, grip strength, patient assessment of pain and mobility, erythrocyte sedimentation rate (ESR), and hemoglobin. Radiographs of hands and feet were taken once a year and 32 joints were evaluated according to a modified Larsen score. RESULTS: Of the 271 patients, 269 had prior treatment with one DMARD, primarily parenteral gold, and 58% with 2 or more DMARD. MTX was started parenterally in all patients in doses between 15 and 25 mg weekly and continued by oral medication in most of the cases. Eighty-three percent of patients complained of adverse events. The most common side effects were nausea, hair loss, transaminase increase, and stomatitis. In 45 patients (16.5%), MTX was withdrawn because of side effects, mostly during the first year. Sixteen patients (5.9%) died during followup, mainly due to myocardial infarction, heart failure, stroke, or cancer. After one year, 78.7% and after 5 years 60.3% of the patients were still taking MTX. Number of swollen joints, ESR, grip strength, patient assessment of pain, and mobility improved significantly at all measurement points. Improvement in the swollen joint count and the ESR of over 50% was seen in more than 50% of patients. Inactivation of the disease, defined as < 2 swollen joints, ESR < 20 mm, and no concomitant steroid use, occurred in 8-14% of patients. Steroid intake was significantly reduced. In spite of clinical improvement the modified Larsen score showed a progression in the vast majority of patients. CONCLUSION: Even in patients with longstanding, active, destructive RA who failed one or more DMARD, MTX treatment is well tolerated and improves clinical and biochemical disease activity significantly, while radiographic progression is still present.     

Bayesian calculation of methotrexate clearance after low dose intramuscular administration in patients with rheumatoid arthritis

OBJECTIVE: To determine a pharmacokinetic procedure (Bayesian method) for estimation of methotrexate (MTX) clearance, using only 2 blood samples, in outpatients with rheumatoid arthritis treated with low dose intramuscular (i.m.) MTX. METHODS: Population pharmacokinetic parameters were obtained by the weighted least squares (WLSQ) method in plasma samples from 14 patients with rheumatoid arthritis (RA). In each patient, 11 samples were measured by fluorescence polarization immunoassay, at Time 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24 h after i.m. administration. These measures were validated by pharmacokinetic studies in 20 other patients with RA. Individual total body clearance of MTX was calculated using only 2 plasma samples (at 0.5 and 2 h after i.m. injection) by the Bayesian method using the population pharmacokinetic parameters. The clearance measures obtained by the Bayesian method were compared with those obtained by the WLSQ method. RESULTS: The pharmacokinetic variables (clearance, half-life, area under the curve) of 14 patients were determined, as well as the covariance and the mean values necessary to apply the Bayesian method. No significant difference was found between clearance values obtained by the Bayesian method compared to the WLSQ method, confirming the validity of the Bayesian values. CONCLUSION: The present population pharmacokinetic parameters allowed the determination of individual clearance of MTX with only 2 plasma samples (0.5 and 2 h after administration) in patients treated with low dose im MTX. Individual clearance is used to modulate MTX administration in patients presenting adverse reactions in spite of good clinical response. Individual determination of MTX pharmacokinetics in patients at risk for adverse MTX reactions could be useful for adjustment of the drug regimen.     

How Canadian and US rheumatologists treat moderate or aggressive rheumatoid arthritis: a survey

OBJECTIVE: To determine which second line agents Canadian and US rheumatologists use to treat patients with active rheumatoid arthritis (RA). METHODS: A one page survey was sent by fax or mail to all 263 members of the Canadian Rheumatology Association and 320 members of the American College of Rheumatology (10% random sample weighted by region) known to practice adult rheumatology. The survey asked for first and second treatment preferences in patients with (1) aggressive RA; (2) moderate RA; and (3) aggressive RA failing a trial of methotrexate (MTX) 25 mg. RESULTS: Altogether 231 (87.8%) Canadian and 230 (71.7%) US rheumatologists responded, and 214 responses in each survey were analyzable. In aggressive RA. MTX was the drug of first choice of most Canadian (68.7%) and US (78.5%) rheumatologists. Intramuscular gold was a drug of first choice for 14.5 and 1.9% of Canadians and Americans, respectively. 93.9% of Canadian and 90.2% of US respondents preferred single agents for the treatment of moderate RA. Among US rheumatologists. no clear leader emerged as a single agent alternative for the management of aggressive RA unresponsive to MTX. Most said they would use combination (38.3%) or triple (23.8%) therapy involving MTX plus sulfasalazine and/or hydroxychloroquine. 52.3% of Canadians preferred single agent therapy, with 34.6% choosing gold as an alternative to MTX. CONCLUSION: Canadian and US rheumatologists preferred MTX for the treatment of aggressive RA. Canadian rheumatologists saw a small but significant role for intramuscular gold. No single agent emerged as a clear alternative to MTX among US rheumatologists.     

Pharmacology and pharmacokinetics of methotrexate in rheumatic disease. Practical issues in treatment and design

Methotrexate (MTX) is among the most effective drugs for treatment of rheumatoid arthritis and has been proven valuable in the treatment of multiple other disorders of immune regulation. MTX has been administered at a wide range of doses and dose intervals, in conjunction with multiple other drugs, and in patients with a broad range of concomitant disorders. To design a safe and effective MTX treatment plan for an individual patient, the provider must have knowledge of the pharmacology and drug interactions of this effective but potentially dangerous medication. The first section of the article reviews MTX structure, pharmacology pharmacokinetics, and mechanisms of action in rheumatic disease. The second section examines factors that can be used to increase MTX efficacy and decrease toxicity.     

Elderly rheumatoid arthritis patients on steroid treatment tolerate physical training without an increase in disease activity

The effects of physical training on elderly, fragile patients with rheumatoid arthritis (RA) who are on low-dose steroids were investigated. The controlled study included 24 patients who had been treated with low-dose steroids for 2 years. Each patient was assigned either to a treatment group receiving training or to an untrained control group. The training took place over a 3-month period and was based on a protocol using progressive interval training consisting of bicycle exercises, heel lifts, and step-climbing. The exercises were performed twice weekly for 45 minutes. Comparison of the two groups showed that disease activity did not increase in the trained group and that fewer, but not significantly fewer, swollen joints were observed in this group (p = 0.06). No significant changes were noticed in erythrocyte sedimentation rate, tender joints, or morning stiffness. The work capacity of the trained patients were doubled and the numbers of repetitions increased 76%. Individually adapted exercise programs can therefore be recommended for elderly rheumatoid arthritis patients on steroid treatment.     

Percutaneous absorption and disposition studies of methotrexate in rabbits and rats

The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5.9 +/- 2.8 ng mL-1) which appeared at approximately 2 h postdose and declined with the elimination half-life of 4.48 +/- 1.74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49.0 +/- 19.8 micrograms g-1), muscle (12.7 +/- 3.3 ng g-1), and SF (19.2 +/- 10.1 ng g-1) underneath the dosed stifle joint were significantly higher (p < 0.05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (approximately 59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1.8 and 2.6 times higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26.3 +/- 8.3 and 48.8 +/- 5.2 mg, respectively. A significant enhancer effect of N,N-diethyl-n-toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed (p < 0.05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a linear calibration curve (r > 0.999) over the range of 2-50 ng mL-1. quantitation limit of 0.5 ng mL-1, and mean recovery of approximately 87% was used for the quantitation of MTX in the tissue and fluid samples.     

Lack of immunosuppressive effect of low-dose oral methotrexate on lymphocytes in rheumatoid arthritis

Whether methotrexate (MTX) is effective in rheumatoid arthritis (RA) because of immunosuppressive and/or anti-inflammatory mechanisms of action is controversial. Many lines of investigation point to the latter. We evaluated DNA synthesis in peripheral blood lymphocytes (PBL) from 33 RA patients on oral MTX (7.5-15 mg/wk) and in 30 healthy controls by flow cytometric cell cycle analysis (CCA). DNA synthesis was also evaluated with a thymidilate synthetase activity assay (TSA) (3H-deoxyuridine incorporation) in 12 patients and 21 controls (12 on MTX and NSAID, and 9 healthy subjects). The patients had taken MTX for at least 3 months and were in different stages of clinical activity. There were no significant differences in TSA or in the cell cycle phase distributions (especially the S phase) between treated RA patients and controls. These data suggest that low-dose oral MTX does not inhibit DNA synthesis and therefore does not have an immunosuppressive effect on lymphocytes from patients with RA.     

Regulation of beta-chemokine mRNA expression in adult rat astrocytes by lipopolysaccharide, proinflammatory and immunoregulatory cytokines

Methotrexate (MTX) is one of the most widely prescribed drugs in the treatment of rheumatoid arthritis (RA). The mechanism by which MTX exerts its anti-rheumatic effect has not yet been defined. The aim of the present study was to investigate the effect of MTX treatment (7.5-15 mg/week) on synovial tissue in RA. For this purpose, synovial biopsies were taken from 11 RA patients before and 16 weeks after initiation of MTX therapy. Immunohistochemistry was performed using monoclonal antibodies (MAb) specific for CD3, CD4, CD8, CD22, CD25, CD38, CD68, MAb67, Ki67, interferon gamma (IFN-gamma), interleukin (IL)-1alpha, IL-1beta, tumour necrosis factor alpha (TNF-alpha), E-selectin, ICAM-1 and VCAM-1. All parameters for disease activity improved during the period of treatment. Immunohistochemical analysis revealed a statistically significant decrease in scores for CD3, CD8, CD38, CD68, Ki67, IL-1beta, TNF-alpha and the adhesion molecules E-selectin and VCAM-1. The observed decrease in synovial scores for inflammatory cells, monokines and adhesion molecules suggests that the anti-inflammatory effect of MTX is, in part, dependent on a reduction in monokine-inducible vascular adhesion molecules and subsequent reduction of cell traffic into joints.     

Pulmonary manifestations of rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common of the classic connective tissue diseases. Its manifestations in the chest are varied as the pleura, lung parenchyma, airways, and pulmonary vasculature can all be involved. The approach to a patient with RA and respiratory complaints, radiographic findings, or physiologic abnormalities requires a broad understanding of these manifestations. Moreover, the potential for therapy-related toxicity adds further complexity to the pulmonary evaluation of these patients.     

Pulmonary function in patients with trophoblastic disease treated with low-dose methotrexate

The Sheffield Trophoblastic Disease Centre treats about 25 patients with persistent trophoblastic disease each year. A total of 75% of patients are classified as low risk according to the Charing Cross Hospital prognostic scoring system and receive methotrexate (MTX) 50 mg, i.m., on days 1, 3, 5, 7 with folinic acid 7.5 mg orally 24 h after each methotrexate injection. There is a 7-day rest between treatment cycles. Remission is achieved in 85% of cases. Approximately 20% of patients experienced pleuritic chest pain and dyspnoea. We have evaluated prospectively lung function in 16 low-risk patients receiving methotrexate. All patients had pulmonary function tests [spirometry-forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), and transfer factor - TLCO, kCO] performed before and after completed treatment. A mean of 7.5 cycles of MTX were administered (range 4-11). There was a significant reduction in the mean TLCO (mean pre/post 8.15/7.38 mmol min-1 kPa-1, P = 0.01), but there were no other statistically significant changes. Three patients experienced respiratory symptoms and were found to have a 39%, 28%, and 11% reduction in TLCO from baseline, improving on follow up to pretreatment levels. Low-dose MTX is an effective therapy but may cause troublesome pulmonary toxicity.