| BackgroundRheumatoid arthritis(RA) is a immune disease that can lead to serious disability. The best approach for RA is early diagnosis and combined treatment. However, the combination treatment with disease-modifying antirheumatic drugs (DMARDs) is commonly used. However, there is unsatisfied,efficacy. Further investigation is required to determine the most effective regimen to combination therapy. According to the successful experience of combined chemotherapy in leukocythemia, we first combined methotrexate (MTX) with low dose cyclophosphamide (CTX) to treat RA patients. MTX as prototype agent in RA is a cell cycle special stage agent, while CTX is a cell cycle nonspecial stage agent. During the last decade, the new combination regimen had been proved more effective and safetive through we carried on clinical practice.Objective:(1) To evaluate the efficacy of methotrexate (MTX), cyclophosphamide (CTX) and therapeutic alliance (MTX+CTX) in patients with RA.(2) To evaluate the safety of MTX, CTX and MTX+CTX in patients with RA.Methods:This was a multi-center, randomized, controlled and single-blind clinical trial lasting 48 weeks.105 patients of RA received a kind of treatment programs of MTX, CTX and MTX+CTX. The primary efficacy end point was proportion of modified 20% improvement of American College of Rheumatology (ACR20) responder. The secondary end point was proportion of ACR50, ACR70 responders. The disease activity was assessed by European League Against Rheumatism (EULAR) criteria. The efficacy and safety were assessed.Results1. Efficacy Assessment 1) At week 48,, the percentage of patients achieving ACR20 in the MTX+CTX group(87 %)was significantly higher than that of MTX(78.2%) group or CTX(27.2%)group (P<0.05-0.01). The percentage of patients achieving ACR50 in MTX,CTX and MTX+CTX group were 45.2%,13.1% and 66.7% respectively.. There were statistical difference among three groups at week 48(P<0.05).2) At week 24, the percent of patients achieving the EULAR response in MTX+CTX group. (62.5%) was significantly higher than that of MTX (41.7%) group or CTX (33.3%) group (P<0.05). DAS28 score were significant reduction at week 24 compared with base-line (P<0.01). DAS28 score were significant reduction in MTX+CTX group than MTX or CTX group (P<0.05) at week 48 compared with base-line (P<0.01).3) At week 48, Tender joint counts, patient's assessment of pain, ESR were significant improved compared with base-line values in MTX+CTX group than that of MTX or CTX group (P<0.05). Tender joint counts, swollen joint counts, patient's assessment of pain, PGA, physician's global assessment, HAQ and ESR were significant improved in MTX+CTX group than that of MTX, CTX group (P<0.05)2. Safety AssessmentThere were no serious adverse reactions. There was no difference for the incidence of treatment related adverse events in three groups. The most frequently treatment related adverse events were gastrointerstinal complaint and upper respiratory tract infection in three groups. The second was slightly elevated liver enzyme levels. Other adverse events included reduction of the total leukocyte number, alopecie, fatigue, menstrual disorders. The intensity of other adverse events was rated as mild or moderate during the whole study. There was no significant difference in all adverse reactions in three groups.Conclusion1. Therapeutic alliance with MTX and CTX (MTX+CTX) resulted in significant improvement in patients with active RA. The efficacy of combination therapy group was significant improvement than that of MTX or CTX therapy group.2. Therapeutic alliance with MTX+CTX was safe and well tolerated., MTX+CTX therapy was not associated with an increase the rate of adverse events, compared with MTX and LEF.
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