Methotrexate And Cyclophosphamide Treatment Of Ankylosing Spondylitis, Clinical And Experimental Research,

Part I:Clinical study of Methotrexate plus Cyclophosphamide in Active Ankylosing SpondylitisObjective:1. To evaluate the efficacy and safety of methotrexate(MTX), cyclophosphamide(CTX) and MTX plus CTX in active ankylosing spondylitis (AS) of 24 weeks.2. To investigate the parameters predicting the clinical response to these treatment programs in AS.Methods:1. This was a randomized, controlled, monocentric, prospective clinical study lasting 24 weeks. 85 patients of active AS eligible for this study were to be adults with a diagnosis of definite AS, as defined by the 1984 Modified New York Criteria. They were randomized to receive a kind of treatment programs of MTX, CTX and MTX plus CTX. The primary efficacy end point was a response on the assessments in AS 20% response(ASAS20) at weeks 0, 6, 12, 24. The secondary end points were responses on the ASAS40 and 50% improvement of Bath AS disease activity index(BASDAI50) improvement criteria. The change of every assessed parameters were analysed.2. The safety of 72 patients of AS(including 61 patients finishing assessment of clinical efficacy, 4 patients withdrawing from treatment for adverse effects and 7 patients withdrawing for unknown reasons) were evaluated at 24 weeks.3. The parameters predicting the clinical response were analysed with ASAS40 and BASDAI50 as responder by Logistic regression likelihood ratio tests at 24 weeks.Rusults:1. Efficacy Results1) At week 6, 13.64%~32.00% of patients in three groups reached the primary end point of ASAS20. At week 24, the percent of patients achieving ASAS20 in the MTX plus CTX group were significantly higher than that of MTX or CTX group (P<0.01~0.05). The percent of patients achieving ASAS40 in the MTX plus CTX group were significantly higher than that of CTX group (P<0.05).2) The improvements at week 24 of Bath AS metrology index(BASMI) and chest expansion were not statistically significant. At week 24, the improvement of BASDAI, Bath AS functional index(BASFI), night pain scores and enthesis index(EI) in MTX plus CTX group were significantly higher than that of MTX or CTX group (P<0.01~0.05). While the improvement of patient's assessment of pain, total arthritis swelling index and erythrocyte sedimentation rate(ESR) in MTX plus CTX group were significantly higher than that of CTX group (P<0.01～0.05). There was no statistical difference in the improvement of BASMI and chest expansion among three groups (P>0.05).2. Safety ResultsThere were no serious adverse events. In the MTX, CTX and MTX plus CTX groups, the incidence of treatment related adverse events was 28.00%, 22.73% and 32.00% respectively. There was no statistical difference among three groups (P>0.05). The most frequently occuring in three groups were gastrointestinal complaint. The secondary occuring was elevated liver enzyme levels. Most treatment-related adverse events were mild to moderate in severity. There was no statistical difference in all adverse events among three groups (P>0.05).3. Predicting Parameters Analysis Results Logistic regression analysis showed all of demographic parameters and baseline AS activity parameters were not evaluated at week 0 including ESR, disease duration etc were predictive of the degree of improvement.Conclusions:Combination therapy with MTX and low dose CTX resulted in significant improvement in patients with active AS. The efficacy of combination therapy was better than MTX or CTX monotherapy. It ? was also safe and well tolerated compared with monotherapy. All of demographic parameters and baseline AS activity parameters were not predictors of major clinical response to our therapy in active AS. Part II: Changes of IL-6 and MMP-3 in ankylosing spondylitis after treatment with Methotrexate plus CyclophosphamideObjectiveTo investigate the changes of serum interleukin(IL)-6 and matrix metalloproteinase(MMP)-3 level before and after MTX, CTX or MTX plus CTX treatments of ankylosing spondylitis(AS) and to explor their meaning in diseases activity and possible link to therapy response.MethodsPeripheral bloods were collected from 34 patients with AS who randomly received a kind of treatment programs of MTX, CTX or MTX plus CTX respectively and 10 healthy controls. Serum IL-6 level and MMP-3 level were measured before and after treatment by sandwich enzyme-linked immunosorbent assay(ELISA).Results1. Serum level of IL-6 and MMP-3 were detected by ELISA. IL-6 level increased obviously in AS (P<0.01) compared with healthy group and MMP-3 level was no statistical difference between AS and healthy group.2. IL-6 level was statistical difference between MTX plus CTX and monotherapy groups at 24 weeks(P=0.010). MMP-3 level decreased statistically after treatment with MTX plus CTX.3. Baseline serum IL-6 level showed correlation with inflammation and ESR. Baseline serum MMP-3 level showed correlation with AS disease activity index BASDAI, BASMI and ESR.Conclusion1. Serum IL-6 level and MMP-3 level had correlation with AS disease activity.2. The combination therapy of MTX and CTX can effectively cut down the IL-6 level and MMP-3 level in AS patients than monotherapy. This is likely to be a relevant mechanism for the clinical efficacy of this therapy.