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.     

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.     

Radiologic progression in early rheumatoid arthritis treated with methotrexate

OBJECTIVE: To evaluate radiologic progression in patients with early rheumatoid arthritis (RA) receiving methotrexate (MTX) as the first slow acting drug. METHODS: An open, prospective study of 29 patients with RA (21 F, 8 M, mean age 48.5+/-15.4 yrs). The mean duration of RA was 6.6 (2-60) months; and rheumatoid factor was present in 11 cases. Clinical, biological, and radiographic evaluations were done before the start of MTX treatment and after 13+/-3.8 months. Radiographs of hands and wrists were blindly studied by 2 physicians, using Larsen's and modified Sharp's methods. There was a significant correlation for the scores of the 2 physicians evaluated by kappa coefficient. Radiographic evolution was defined as an increase of 15 points in the radiologic score by each method used. RESULTS: Patients showed significant clinical improvement after one year of MTX treatment. Despite clinical and biological improvement, significant mean radiographic progression was noted, with Larsen's method (p = 0.001) and Sharp's method (p = 0.034), without reaching the maximum score. However, using the definition of radiographic progression, the radiologic scores indicated stabilization in 23 patients with Larsen's method and in 24 patients with Sharp's method. CONCLUSION: This study revealed mild radiographic progression in early RA patients treated with MTX for one year. Further controlled studies are needed.     

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.     

Comparative studies of quality and bioavailability of methotrexate in Thai patients with rheumatoid arthritis

The bioavailability of the two generic methotrexate oral preparations (Emtrexate, Pharmachemie Company, Holland and Methotrexate Remedica, Remedica, Cyprus as the test preparations), were compared to the innovator (Methotrexate Lederle, Lederle, U.S.A. as the reference) in 10 patients with rheumatoid arthritis. A single 7.5 mg oral dose of each preparation was given to the subjects in a randomized, double-blind, three-period crossover design with a 1 week washout period. Serum methotrexate concentrations were determined by using Fluorescence Polarization Immunoassay (Abbott TDx). No significant differences in pharmacokinetic parameters (AUC, Cmax, and Tmax) were observed between the test and reference preparations. The mean and 90 per cent CI of the ratio Emtrexate/Methotrexate Lederle and Methotrexate Remedica/Methotrexate Lederle of the Cmax, AUC0-8, and AUC0-alpha were 0.93 (0.87-1.00), 0.9 (0.82-0.98), 0.88 (0.79-0.99) and 0.97 (0.93-1.02), 0.95 (0.90-0.99), 0.94 (0.86-1.02), respectively. These values were well within the acceptable bioequivalence range of 0.8-1.25. The mean and 90 per cent CI of Tmax difference between Emtrexate-Methotrexate Lederle and Methotrexate Remedica-Methotrexate Lederle also overlapped the stipulated bioequivalence range of the Tmax differences of +/- 0.25 hour. Thus, Emtrexate and Methotrexate Remedica were considered bioequivalent to the reference Methotrexate Lederle regarding the rate of absorption and the extent of absorption.     

Treatment of rheumatoid arthritis of senile onset with methotrexate

Elderly onset rheumatoid arthritis is a not rare disease with relevant social implications. The most important question is represented by the therapeutic choice, in relation to the typical problems of the elderly patients and to the frequent coexistence of other diseases. In this work, we evaluated the practicability and the efficacy of methotrexate therapy, at the dose of 5 mg/week, in 27 patients affected by elderly onset rheumatoid arthritis (mean age 73.76 +/- 3.39 years, range 70-83). Low dose prednisone was associated in order to control painful symptoms. Also sulindac was allowed. Frequent clinical and hematochemical controls were made in order to precociously evaluate the appearance of side effects. All the 27 patients completed the first year of treatment; during this period there was no drop out. Sixteen patients finished the second year too; during this year one patient dropped out because of significant hypertransaminasemia and another patient did not respect the follow-up. Clinical and hematochemical parameters were monitored. A significant improvement of all data was observed from the third month. A further amelioration was recorded in the following months. Our data suggest the efficacy and the safety of low dose methotrexate in the treatment of elderly onset rheumatoid arthritis. A careful evaluation of side effects is obviously necessary.     

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.     

Pneumocystis carinii pneumonia in rheumatoid arthritis patients treated with methotrexate. A report of two cases

OBJECTIVE: The induction and repair of DNA single-strand breaks (SSBs) were measured in primary cultured infant rat lens epithelial cells (RLECs) following hydrogen peroxide (HP) exposure, and the influential factors were detected. METHODS: Utilizing nick translation methodology which utilizes incorporation of labeled nucleotides at the sites of DNA SSBs to sensitively quantitate the damage, we studied the effects of temperature, doses of HP and trace amount of selenium on cell survival. RESULTS: The number of DNA SSBs at 37 degrees was higher than that at 4C (P < 0.01). Significant numbers of SSBs were detected after being insulted by as low as 36.4 mumol/L hydrogen peroxide for 12 minutes 4 degrees (P < 0.05). Repair rapidly initiated and almost completed in 60 minutes after mild damage, and it was unable to repair when the DNA damage was induced by HP at toxic concentration. Trace selenium was added to the culture and incubated for 24 hours, then the number of SSBs was significantly decreased (P < 0.01). CONCLUSIONS: At 37 degrees HP may induce DNA SSBs in RLECs. HP induces the SSBs in a dose dependent manner. The DNA SSBs can not be repaired after severe damage. Trace selenium can decrease the degree of susceptibility to oxidative damage in infant RLECs.     

Ankle arthrodesis in patients with rheumatoid arthritis

The results of 26 ankle arthrodeses performed for rheumatoid arthritis on 21 patients were reviewed. Tibiotalar arthrodesis was performed in 14 ankles, and tibiotalocalcaneal arthrodesis was performed in 12. External fixation was used in 20 ankles, and internal fixation was used in six. Followup was available in 24 of 26 ankles (19 patients), and averaged 5 years (range, 2-8 years). There was no pain experienced in 19 ankles; mild, occasional pain was experienced in four ankles; and moderate, daily pain was experienced in one ankle. Daily activities were limited in five patients and recreational activities were limited in 11. All patients reported some difficulty walking on uneven terrain. Nearly all patients were satisfied; two were satisfied with reservations and two were dissatisfied. Union was achieved in 25 of 26 (96%) ankles. Ankle arthrodesis is an effective operation in patients with rheumatoid arthritis. Unlike previous reports, union and complication rates in this series were comparable with rates for arthrodesis for posttraumatic and degenerative arthritis.     

HLA-DM polymorphisms in patients with rheumatoid arthritis

OBJECTIVE: To investigate the contribution of HLA-DMA and DMB genes, which play a crucial role in the HLA class II restricted antigen presentation pathway, in susceptibility to rheumatoid arthritis (RA). METHODS: The distribution of DMA and DMB alleles was examined in patients with RA and in healthy subjects by oligotyping of PCR amplified genomic DNA with sequence specific oligonucleotide probes. RESULTS: There were no significant differences in the prevalence of DMA and DMB alleles in patients with RA as compared to healthy controls. In addition, no significant differences in frequencies of DMA and DMB alleles were observed in RA susceptibility epitope positive RA patients and controls. CONCLUSION: DMA and DMB genes do not appear to play a role in susceptibility to RA.     

Chloroquine retinopathy in patients with rheumatoid arthritis

The paper presents data on the differential fertility of schizophrenics and controls, and the fertility of their siblings. This study used several methodological procedures in the study of schizophrenia reproduction, which strengthens the validity of the findings. Firstly, both male and female rates were examined. Secondly, the method of selection of a control avoided the biases introduced by using census data or other non-matched controls. Third, a diagnostic criterion was used which minimizes the possibility of the inclusion of other psychiatric illnesses. The results obtained support prior reports of the lowered reproductive rates of schizophrenics. Further, the siblings of schizophrenics were found not to have a reproductive advantage when contrasted to control siblings. The failure to find a reproductive advantage conflicts with a hypothesis of a balanced polymorphism as the mechanism maintaining an apparent constant rate of schizophrenia.     

Lymphocyte depletion in patients with rheumatoid arthritis

Sixteen patients with severe rheumatoid arthritis, marked inflammation of the synonvial membrane and high rheumatoid titer were cannulated by the thoracic duct for a period rangin between 82 up to 100 days. The patients being not under any medication during that time. Quantitative and qualitative analysis of the lymphocytes were performed, as well as responses to mitogens, rheumatoid factor, circulating antibodies and delayed hypersensitivity. By the 14th day nearly all the patients had a partial or almost complete remission of their disease. No complications were observed. These results will be discussed.     

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.     

Hypothalamo-pituitary-thyroid system in patients with rheumatoid arthritis]

OBJECTIVE: To determine the effect on the uptake of breast screening of a personalized letter from the general practitioner recommending mammography, sent to coincide with an invitation from the NHS breast screening programme. DESIGN: Randomised control trial with stratification of prognostic variables. SETTING: A group practice in Hackney, east London. SUBJECTS: 473 women invited for breast screening by the City and East London Breast Screening Service. OUTCOME MEASURE: Attendance for mammography. RESULTS: All women in the randomised trial were followed up; 134 of 236 (57%) randomly allocated to receive the prompting letter attended for mammography compared with 120 of 234 (51%) controls This difference was not significant (chi 2 = 1.43, p = 0.23) CONCLUSION: Personal recommendation by a letter prompting attendance for mammography from the general practitioner known best to women due to be screened did not improve uptake of breast screening in this east London practice. Other strategies are needed to increase uptake of mammography in inner cities.