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ABSTRACT: To study whether the reported superior effect of methotrexate (MTX) compared to azathioprine (AZA) in retarding radiologic progression after one year in rheumatoid arthritis was sustained at 2 and 4 years.
All 64 patients enrolled in the original randomized double blind study were invited for an open extension of followup to 4 years including 4-monthly clinical and laboratory assessments and radiographs of hands, wrists, and feet at 2 and 4 years.
After 4 years, 18 patients (58%) from the MTX group and 7 patients (21%) from the AZA group continued the initial study drug. During followup more patients (n = 21) switched from AZA to MTX than vice versa (n = 5). In an intention-to-treat analysis improvement of clinical and laboratory variables at 4 years was more pronounced in the MTX group. Mean radiologic scores increased in both treatment groups during followup. According to an intention-to-treat analysis increase in erosion score at one and 2 years in the MTX group was significantly lower than in the AZA group: after one year MTX group 1.8 versus AZA group 5.3 (p = 0.002); after 2 years MTX 3.5 versus AZA 6.5 (p = 0.05). After 4 years there was a trend toward less progression in the MTX group: MTX 6.8 versus AZA 10.8 (p = 0.09). For the total score, progression in the MTX group was less after one and 2 years. After 4 years marked radiologic progression was observed more often in the AZA group.
Drug continuation after 4 years of followup was better for MTX than for AZA. In an intention-to-treat analysis the beneficial effect of MTX on radiologic progression compared with AZA was sustained after 2 years of followup. Thereafter differences between treatment groups leveled off, probably mainly due to the greater number of switches from AZA to MTX than vice versa.
The Journal of Rheumatology 06/2000; 27(5):1148-55. · 3.69 Impact Factor
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ABSTRACT: Purine enzyme activities may predict the effectiveness of azathioprine treatment and be associated with increased deaths from infectious diseases. In rheumatoid arthritis, patients show variable responses to azathioprine and a higher percentage of death is caused by infections. The aim of the study was to investigate possible rheumatoid arthritis associated abnormalities of purine enzyme activities by measuring several of these enzymes in patients with recent onset rheumatoid arthritis before treatment with disease modifying antirheumatic drugs or prednisone.
23 patients with recent onset rheumatoid arthritis and 28 healthy controls were studied. Activities of the enzymes 5'-nucleotidase, purine nucleoside phosphorylase (PNP), hypoxanthine guanine phosphoribosyltransferase (HGPRT), and thiopurine methyltransferase (TPMT) were measured. Assessment of disease activity and blood sampling for routine measurements and HLA typing were done simultaneously.
Purine enzyme activities did not differ between patients and healthy controls. Enzyme activities had no significant relations with indices of disease activity or rheumatoid factor titre or with the rheumatoid arthritis associated HLA types. Activity of 5'nucleotidase decreased with age (P < or = 0.05) and was lower by about 27% (P = 0.007) in males than in females.
In rheumatoid arthritis patients, neither the variability in azathioprine effectiveness nor the increased death rate from infections can be explained by pre-existing abnormalities in the activities of the purine enzymes 5'-nucleotidase, PNP, HGPRT, or TPMT at an early stage of the disease, before disease modifying antirheumatic drugs or prednisone treatment. Besides adjustment for age, results of studies involving purine 5' nucleotidase activity should also be adjusted for sex.
Annals of the Rheumatic Diseases 10/1996; 55(10):733-8. · 8.73 Impact Factor
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ABSTRACT: We studied the infection rate in patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX) in a 6-year open prospective study and in a 12-month randomized double blind trial comparing MTX with azathioprine (AZA) that was followed by a 3-year open prospective study. The literature on infections during low dose MTX in RA was reviewed. We also did a search for therapy-related opportunistic infections in RA and in MTX-treated psoriasis and psoriatic arthropathy patients. In our studies the infection rate during MTX treatment was higher in severe RA than in moderate RA. In severe RA there were often 2 infections simultaneously. The majority of the infections occurred in the first 1.5 years of treatment. There was no difference in the infection rate of MTX and AZA in the comparative trial. In the literature the infection rate was highest in short-term double-blind studies. Opportunistic infections are increasingly reported in RA treated with MTX and rarely with AZA, cyclosporine A, and cyclophosphamide or in MTX treated psoriasis and psoriatic arthropathy. In RA it appears that the initial period of treatment with MTX is the most vulnerable phase for infections, with the exception of opportunistic infections, which are not limited to a certain treatment period. Probably there are more MTX-associated infections in severe RA than in moderate RA.
Seminars in Arthritis and Rheumatism 07/1995; 24(6):411-21. · 4.97 Impact Factor
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ABSTRACT: To study the correlation between antiperinuclear factor (APF) titer and disease activity variables in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) or azathioprine (AZA) and to investigate whether changes are dependent on the drug used.
Serial measurements of APF titers (2-fold dilutions) and disease activity variables in a 48-week double blind trial comparing MTX and AZA in 64 patients with RA. APF titers at baseline and during followup, and correlations between APF titers and disease activity variables and their changes from baseline were studied in the patient group as a whole and in the 2 treatment groups.
The prevalence of the APF at baseline in the MTX group and in the AZA group with undiluted serum was 15/31 (48%) and 19/33 (58%), respectively. With serum diluted 1:10 this was about 25% higher. The APF titer ranged from 1/10 to 1/640. No sustained changes in APF titers were observed during followup. Statistically significant correlations were found between APF titers and 2 of the 4 disease activity variables, as well as for their changes from baseline at some time points and were most pronounced in the AZA group. However, no consistent correlation between APF titers and disease activity variables could be established. APF changed from negative to positive during followup in 4 patients (6.3%) and from positive to negative in 4 (6.3%). Changes in APF titer between 2 consecutive measuring points did not exceed 2 dilution steps.
The APF titer showed no sustained change during the followup period. There was no consistent correlation between APF titer and disease activity variables. We conclude that serial measurements of the APF in longitudinal studies do not give additional information.
The Journal of Rheumatology 01/1995; 21(12):2190-4. · 3.69 Impact Factor
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ABSTRACT: In the past 22 years, 113 patients with severe psoriasis have been treated with low-dose methotrexate (MTX) in our department. The maximum weekly dosage was 15 mg (Weinstein schedule), the estimated mean cumulative dose was 4803 mg, and the estimated mean duration of therapy was 8 years and 11 months. In 81% of the patients, prolonged clearance or near clearance was achieved, indicating the potent and sustained potential of MTX in the treatment of both the pustular and erythematosquamous variants of psoriasis. Eighty-three patients (73%) had side-effects, most frequently abnormal liver function tests, nausea and gastric complaints. Apart from hair loss in seven patients, there were no mucocutaneous side-effects, probably because of the low-dose treatment schedule. In 71 patients MTX therapy was discontinued; in 33 patients because of side-effects. In 55 patients one or more liver biopsies were performed. Fibrosis was seen in seven of these patients (13%) and cirrhosis in two (4%). There was no relation between liver biopsy classification and cumulative dosage or duration of MTX therapy, nor was there any relation between liver histology and abnormal liver function tests. During this 22-year period, there were no deaths or life-threatening side-effects attributable to MTX treatment. We conclude that low-dose MTX (< or = 15 mg/week) is a relatively safe therapy for severe psoriasis, if patients are carefully selected beforehand, and regular monitoring for side-effects and drug interactions is performed during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
British Journal of Dermatology 02/1994; 130(2):204-10. · 3.67 Impact Factor
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ABSTRACT: To assess whether circulating concentrations of soluble tumor necrosis factor receptors (sTNFR; p55 and p75), soluble interleukin-2 receptors (sIL-2R), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6) reflect clinical response and whether changes are dependent on the drug used in rheumatoid arthritis (RA) patients taking methotrexate (MTX) or azathioprine (AZA).
These cytokines and soluble receptors were assessed in 20 control subjects and serially for up to 48 weeks in 61 RA patients, by bioassay (IL-6) and immunoassays (sTNFR, sIL-2R, TNF alpha, and IL-6).
Concentrations of p55 and p75, sIL-2R, and TNF alpha (but not IL-6) were significantly higher in RA patients than in controls. Significant decreases in sIL-2R and p55 concentrations were associated with clinical improvement and were observed in patients treated with MTX, but not AZA. Both treatments induced decreases in IL-6 concentrations, but circulating AZA (or its metabolites) appears to interfere with the measurement of IL-6 bioactivity. TNF alpha and p75 levels did not show significant changes.
Measurement of circulating sIL-2R, p55, and IL-6 may be useful in the evaluation of RA disease activity and response to therapy. Interference by circulating levels of drugs must be ruled out when bioassays are used to evaluate cytokine levels.
Arthritis & Rheumatism 09/1993; 36(8):1070-9. · 7.87 Impact Factor
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ABSTRACT: We conducted a double-blind, randomized trial comparing azathioprine (AZA) and methotrexate (MTX) in the treatment of patients with rheumatoid arthritis in whom parenteral gold and/or D-penicillamine treatment had been unsuccessful. Patients were randomly assigned to receive either AZA (100 mg daily) or oral MTX (7.5 mg weekly). After 8 weeks, the dosage was increased depending on the clinical improvement. Sixty-four patients were followed up for 48 weeks (33 AZA, 31 MTX). Comparison of values at week 24 with baseline values revealed significant improvement in 12 of 13 disease variables in the MTX group and in 6 of 13 in the AZA group. Comparison between the 2 treatment groups at 24 weeks, by area-under-the-curve analysis, showed significantly more improvement in the MTX group in terms of the swollen joint count, pain score, erythrocyte sedimentation rate, C-reactive protein level, hemoglobin level, thrombocyte level, and disease activity score. A significant overall clinical improvement (disease activity score) was found in 7 of 20 patients treated with AZA and 18 of 30 patients treated with MTX after 24 weeks of therapy, and in 6 of 12 AZA-treated patients and 19 of 25 MTX-treated patients after 48 weeks. The number of withdrawals due to side effects was significantly higher in the AZA group. After 48 weeks, only 12 patients from the AZA group (36%), but 25 from the MTX group (81%), were still using the initial drug. These results demonstrate MTX to be superior to AZA in the treatment of rheumatoid arthritis, with a more rapid clinical improvement which is sustained after 1 year, accompanied by a lower rate of serious adverse reactions.
Arthritis & Rheumatism 09/1991; 34(8):961-72. · 7.87 Impact Factor
