甲氨蝶呤联合环磷酰胺治疗强直性脊柱炎的临床与实验研究
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摘要
第一部分甲氨蝶呤联合环磷酰胺治疗强直性脊柱炎的临床研究
目的:
1.评价甲氨蝶呤(MTX)、环磷酰胺(CTX)及二者联合(MTX+CTX)治疗强直性脊柱炎(AS)的临床疗效和安全性;
2.探讨该组治疗对AS达到临床疗效的预测因素。
方法:
1.进行一项为期24周的随机、对照、单中心、前瞻性临床研究。85例纳入研究的AS患者均符合1984年修订的纽约标准,并处于疾病活动期,随机接受MTX、CTX和MTX+CTX中的任何一种治疗方案。分别在试验的0、6、12、24周进行随访,以强直性脊柱炎疗效评价标准20反应(ASAS20)为主要疗效指标,Bath强直性脊柱炎疾病活动指数改善50%(BASDAI50)和ASAS40为次要疗效指标对各组病情进行评估,并分析具体指标的变化。
2.在研究终点时对72例患者(包括完成疗效评估的61例、因不良反应退出研究的4例和研究过程中失访的7例)的安全性进行评估。
3.临床试验完成后,以BASDAI50和ASAS40作为疗效指标,采用Logistic回归分析对完成试验的61例患者疗效影响因素进行探索性分析。
结果:
1.疗效评估结果:
1)治疗6周后,各组有13.64%～32.00%的患者达到ASAS20改善。24周时MTX+CTX组达ASAS20改善的患者比例(73.91%)明显高于MTX(45.45%)及CTX组(25.00%),差异有统计学意义(P<0.01～0.05)。24周时MTX+CTX组达ASAS40改善的患者比例高于CTX组(P<0.05),与MTX组之间差异尚无统计学意义(P>0.05)。
2)治疗24周后MTX组和MTX+CTX组各项评价除Bath强直性脊柱炎测量指数(BASMI)和扩胸度以外其它指标均低于基线水平(P<0.01～0.05),CTX组仍有肿胀关节指数、夜间痛和ESR与基线时相比差异未达到统计学意义(P>0.05);24周时比较不同治疗组间的改善程度,MTX+CTX组BASDAI、Bath强直性脊柱炎功能指数(BASFI)、夜间痛和肌腱末端指数(EI)的改善高于MTX组和CTX组(P<0.01～0.05),病人总体评估(PGA)、肿胀关节指数和血沉(ESR)的改善程度与MTX组接近(P>0.05),高于CTX组(P<0.01～0.05);各治疗组在BASMI和扩胸度两个指标的改善方面差别尚未达到统计学意义(P>0.05)。
2.安全性评估结果:无严重不良事件发生。在各治疗组与药物直接相关的不良反应发生率分别为MTX组28.00%、CTX组22.73%、MTX+CTX组32.00%,差异无统计学意义(P>0.05)。胃肠道症状是各组最为常见的不良反应,在各组中的发生率为13.64%～24.00%。各组均有患者发生肝酶异常,发生率在13.64%～16.00%之间,丙氨酸转氨酶(ALT)升高均在正常值的2倍以内。其它不良事件包括白细胞减低、脱发、口腔溃疡、乏力等,各组间差异无统计学意义(P>0.05)。
3.疗效影响因素分析结果:以24周时达到ASAS40和BASDAI50为疗效标准, Logistic多因素分析显示:所有参数均未显示能预测患者在经过治疗后达到BASDAI50和ASAS40疗效标准。
结论:
MTX+CTX联合治疗可以缓解AS的脊柱关节病变,改善症状,优于单用药;安全耐受性较好,与单用药相比,联合治疗并不增加不良反应的发生率;基线时的人口学参数、疾病活动性的临床和实验室指标不能预测疗效。
第二部分甲氨蝶呤联合环磷酰胺治疗对AS患者血清IL-6、MMP-3的影响
目的:
通过检测AS患者血清中细胞因子白介素(IL)-6和基质金属蛋白酶(MMP)-3的表达水平及分析其与AS患者疾病活动的相关性,进一步研究MTX、CTX及两者联合治疗前后AS患者血清细胞因子IL-6和MMP-3的变化,探讨MTX+CTX发挥作用的可能机制。
方法:
分别在治疗0周、24周时留取本研究临床研究中34例AS患者(MTX组11例、CTX组11例、联合用药组12例)及10例正常健康对照者空腹血清,应用酶联免疫吸附试验(ELISA)测定IL-6和MMP-3水平。
结果:
1.ELISA方法检测34例AS患者治疗前血清IL-6、MMP-3,结果显示:AS患者血清IL-6水平高于正常人(P<0.01),MMP-3水平与正常对照之间差异无显著性(P=0.054)。
2.进一步用ELISA方法检测各组AS患者经过治疗24周时血清IL-6、MMP-3,结果显示:24周时,MTX+CTX组IL-6水平显著下降(P=0.010),与MTX组和CTX组比较差异均有统计学意义(P<0.05);MTX+CTX组MMP-3水平与基线时比较差异有统计学意义(P<0.05)。
3.相关分析显示:基线时IL-6水平与脊柱炎症及ESR显著相关(P<0.05),MMP-3水平BASDAI、BASMI及ESR显著相关(P<0.05)。
结论:
1.IL-6和MMP-3是AS发病机制中重要的细胞因子,与病情活动性相关。
2.MTX联合CTX较单用药组更能降低患者血清IL-6和MMP-3水平,这可能是其发挥临床疗效的机制。
Part I:Clinical study of Methotrexate plus Cyclophosphamide in Active Ankylosing Spondylitis
Objective:
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 Results
1) 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 Results
There 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 Cyclophosphamide
Objective
To 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.
Methods
Peripheral 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).
Results
1. 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.
Conclusion
1. 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.
目的:
1.评价甲氨蝶呤(MTX)、环磷酰胺(CTX)及二者联合(MTX+CTX)治疗强直性脊柱炎(AS)的临床疗效和安全性;
2.探讨该组治疗对AS达到临床疗效的预测因素。
方法:
1.进行一项为期24周的随机、对照、单中心、前瞻性临床研究。85例纳入研究的AS患者均符合1984年修订的纽约标准,并处于疾病活动期,随机接受MTX、CTX和MTX+CTX中的任何一种治疗方案。分别在试验的0、6、12、24周进行随访,以强直性脊柱炎疗效评价标准20反应(ASAS20)为主要疗效指标,Bath强直性脊柱炎疾病活动指数改善50%(BASDAI50)和ASAS40为次要疗效指标对各组病情进行评估,并分析具体指标的变化。
2.在研究终点时对72例患者(包括完成疗效评估的61例、因不良反应退出研究的4例和研究过程中失访的7例)的安全性进行评估。
3.临床试验完成后,以BASDAI50和ASAS40作为疗效指标,采用Logistic回归分析对完成试验的61例患者疗效影响因素进行探索性分析。
结果:
1.疗效评估结果:
1)治疗6周后,各组有13.64%～32.00%的患者达到ASAS20改善。24周时MTX+CTX组达ASAS20改善的患者比例(73.91%)明显高于MTX(45.45%)及CTX组(25.00%),差异有统计学意义(P<0.01～0.05)。24周时MTX+CTX组达ASAS40改善的患者比例高于CTX组(P<0.05),与MTX组之间差异尚无统计学意义(P>0.05)。
2)治疗24周后MTX组和MTX+CTX组各项评价除Bath强直性脊柱炎测量指数(BASMI)和扩胸度以外其它指标均低于基线水平(P<0.01～0.05),CTX组仍有肿胀关节指数、夜间痛和ESR与基线时相比差异未达到统计学意义(P>0.05);24周时比较不同治疗组间的改善程度,MTX+CTX组BASDAI、Bath强直性脊柱炎功能指数(BASFI)、夜间痛和肌腱末端指数(EI)的改善高于MTX组和CTX组(P<0.01～0.05),病人总体评估(PGA)、肿胀关节指数和血沉(ESR)的改善程度与MTX组接近(P>0.05),高于CTX组(P<0.01～0.05);各治疗组在BASMI和扩胸度两个指标的改善方面差别尚未达到统计学意义(P>0.05)。
2.安全性评估结果:无严重不良事件发生。在各治疗组与药物直接相关的不良反应发生率分别为MTX组28.00%、CTX组22.73%、MTX+CTX组32.00%,差异无统计学意义(P>0.05)。胃肠道症状是各组最为常见的不良反应,在各组中的发生率为13.64%～24.00%。各组均有患者发生肝酶异常,发生率在13.64%～16.00%之间,丙氨酸转氨酶(ALT)升高均在正常值的2倍以内。其它不良事件包括白细胞减低、脱发、口腔溃疡、乏力等,各组间差异无统计学意义(P>0.05)。
3.疗效影响因素分析结果:以24周时达到ASAS40和BASDAI50为疗效标准, Logistic多因素分析显示:所有参数均未显示能预测患者在经过治疗后达到BASDAI50和ASAS40疗效标准。
结论:
MTX+CTX联合治疗可以缓解AS的脊柱关节病变,改善症状,优于单用药;安全耐受性较好,与单用药相比,联合治疗并不增加不良反应的发生率;基线时的人口学参数、疾病活动性的临床和实验室指标不能预测疗效。
第二部分甲氨蝶呤联合环磷酰胺治疗对AS患者血清IL-6、MMP-3的影响
目的:
通过检测AS患者血清中细胞因子白介素(IL)-6和基质金属蛋白酶(MMP)-3的表达水平及分析其与AS患者疾病活动的相关性,进一步研究MTX、CTX及两者联合治疗前后AS患者血清细胞因子IL-6和MMP-3的变化,探讨MTX+CTX发挥作用的可能机制。
方法:
分别在治疗0周、24周时留取本研究临床研究中34例AS患者(MTX组11例、CTX组11例、联合用药组12例)及10例正常健康对照者空腹血清,应用酶联免疫吸附试验(ELISA)测定IL-6和MMP-3水平。
结果:
1.ELISA方法检测34例AS患者治疗前血清IL-6、MMP-3,结果显示:AS患者血清IL-6水平高于正常人(P<0.01),MMP-3水平与正常对照之间差异无显著性(P=0.054)。
2.进一步用ELISA方法检测各组AS患者经过治疗24周时血清IL-6、MMP-3,结果显示:24周时,MTX+CTX组IL-6水平显著下降(P=0.010),与MTX组和CTX组比较差异均有统计学意义(P<0.05);MTX+CTX组MMP-3水平与基线时比较差异有统计学意义(P<0.05)。
3.相关分析显示:基线时IL-6水平与脊柱炎症及ESR显著相关(P<0.05),MMP-3水平BASDAI、BASMI及ESR显著相关(P<0.05)。
结论:
1.IL-6和MMP-3是AS发病机制中重要的细胞因子,与病情活动性相关。
2.MTX联合CTX较单用药组更能降低患者血清IL-6和MMP-3水平,这可能是其发挥临床疗效的机制。
Part I:Clinical study of Methotrexate plus Cyclophosphamide in Active Ankylosing Spondylitis
Objective:
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 Results
1) 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 Results
There 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 Cyclophosphamide
Objective
To 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.
Methods
Peripheral 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).
Results
1. 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.
Conclusion
1. 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.
引文
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[12] Keller C, Webb A, Davis J. Cytokines in the seronegative spondyloarthropathies and their modification by TNF blockade: a brief report and literature review. Annals of theRheumatic Diseases, 2003, 62(12): 1128~1132.
[13] Gratacos J, Collado A, Filella X, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol, 1994, 33: 927~931.
[14] Gratacos J, Collado A, Pons F, et al. Significant loss of bone mass in patients with early, active ankylosing spondylitis: a followup study. Arthritis Rheum, 1999, 42: 2319~2324.
[15] Keller C, Webb A, Davis J.et al. Cytokines in the seronegative spondyloarthropathies and their modification by TNF blockade: a brief report and literature review. Ann Rheum Dis, 2003, 62: 1128~1132.
[16]杨春花,黄烽.基质金属蛋白酶3和巨噬细胞集落刺激因子与强直性脊柱炎疾病活动性及发病机制的研究. [D].中国人民解放军军医进修学院, 2005.
[17] van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum, 1984, 27: 361~368.
[18] Garrett S, Jenkinson T, Kennedy LG, et al. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol, 1994, 21: 2286~2291.
[19] Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol, 1994, 21: 2281~2285.
[20] Jenkinson TR, Mallorie PA, Whitelock HC, et al. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol, 1994, 21:1694~1698.
[21] Mander M, Simpson JM, McLellan A, et al. Studies with an enthesis index as a method of clinical assessment in ankylosing spondylitis. Ann Rheum Dis, 1987, 46: 197~202.
[22] Scott DL, Panayi GS, van Riel PL, et al. Disease activity in rheumatoid arthritis: preliminary report of the Consensus Study Group of the European Workshop for Rheumatology Research. Clin Exp Rheumatol, 1992, 10: 521~525.
[23] Anderson JJ, Baron G, van der Heijde D, et al. Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum, 2001, 44: 1876~1886.
[24]黄烽.从循证医学角度看强直性脊柱炎的治疗.中华风湿病学杂志, 2006, 10(5): 257~260.
[25] Pérez-Guijo VC, Cravo AR, Castro Mdel C. Increased efficacy of infliximab associated with methotrexate in ankylosing spondylitis. Joint Bone Spine, 2007, 74(3): 254~258.
[26] Sampaio-Burros P, Costallat L, Bertolo M, et al. Methotrexate in the treatment ofankylosing spondylitis[J]. ScandJRheumatol, 2000, 29(3): 160~162.
[27]黄烽,李胜光,刘泽星.中国新药杂志. 2001, 10(9): 689~692.
[28] Gonzalez-Lopez L, Garcia-Gonzalez A, et al. Efficacy of methotrexate in ankylosing spondylitis: a randomized, double blind, placebo controlled trial. J Rheumatol, 2004, 31: 1568~ 1574.
[29]赵福涛,丁元晶,赵浩等.甲氨蝶呤治疗强直性脊柱炎髋关节病变.中华风湿病学杂志, 2007, 11(4): 213~216.
[30] Boonen A, de Vet H, van der Heijde D, et al. Work status and its determinants among patients with ankylosing spondylitis. A systematic literature review. J Rheumatol, 2001, 28: 1056~1062.
[31] Bostan EE, Borman P, Bodur H, et al. Functional disability and quality of life in patients with ankylosing spondylitis. Rheumatol Int, 2003, 23: 121~126.
[32] Rudwaleit M, Listing J, Brandt J, et al. Prediction of a major clinical response (BASDAI50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis, 2004, 63: 665~670.
[33] Rudwaleit M, Brandt J, Braun J, et al. Is there a role for MRI in predicting the clinical response to TNF alpha blockers in ankylosing spondylitis? Ann Rheum Dis, 2003, 62: 97.
[34]张莉芸,黄烽.抗肿瘤坏死因子单克隆抗体infliximab治疗强直性脊柱炎的临床及实验研究[D].中国人民解放军军医进修学院, 2005.
[35] Dougados M, van der Heijde D. Ankylosing spondylitis: how should the disease be assessed? Best Pract Res Clin Rheumatol, 2002, 16: 605~618.
[36] Spoorenberg A, van der Heijide D, deklerk, et al. Relative value of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis. J Rheumatal, 1999, 26(4): 980~984.
[37] Rouf J, Stucki G. Validity aspects of erythrocyte sedimentation rate and C-reactive protein in ankylosing spodylitis: a literature review. J Rheumatol, 1999, 26(4): 966~970.
[38] Beutler BA. The role of tumor necrosis factor in health and disease. J Rheumatol Suppl, 1999, 57: 16~21.
[39] Falkenbach A, Herold M. In ankylosing spondylitis serum interleukin-6 correlates with the degree of mobility restriction, but not with short-term changes in the variables for mobility. Rheumatol Int, 1998, 18: 103~106.
[40] Brandt J, Haibel H, Cornely D, et al. Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab. Arthritis Rheum, 2000, 43: 1346~1352.
[41] Li Jnen H.R. Elements of the fibrinolytic systerm. Ann N Y Acad Sci, 2001, 936: 226~236.
[1] FitzGerald O, Bresnihan B. Synovial membrane cellularity and vascularity. Ann Rheum Dis, 1995, 54: 511~515.
[2] Ostergaard M, Hansen M, Stoltenberg M et al. Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis. Arthritis Rheum, 1999, 42: 918~929.
[3] Firestein GS. Starving the synovium: angiogenesis and inflammation in rheumatoid arthritis. J Clin Invest, 1999, 103: 3~4.
[4] del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum, 2001, 44: 2737~2745.
[5] Koch A. Angiogenesis as a target in rheumatoid arthritis. Ann Rheum Dis, 2003, 62(Suppl): 60~67.
[6] Achen MG, Stacker SA. The vascular endothelial growth factor family; proteins which guide the development of the vasculature. Int J Exp Pathol, 1998, 79: 255~265.
[7] Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J, 1999, 13: 9~22.
[8] Mason JC, Lidington EA, Yarwood H, Lublin DM, Haskard DO. Induction of endothelial cell decay-accelerating factor by vascular endothelial growth factor: a mechanism for cytoprotection against complement-mediated injury during inflammatory angiogenesis. Arthritis Rheum, 2001, 44: 138~150.
[9] Berse B, Hunt JA, Diegel RJ et al. Hypoxia augments cytokine (transforming growth factor-beta (TGF-beta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. Clin Exp Immunol, 1999, 115: 176~182.
[10] Giatromanolaki A, Sivridis E, Maltezos E et al. Upregulated hypoxia inducible factor-1alpha and–2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther, 2003, 5: R193~201.
[11]戴辰程.缺氧诱导因子-1与类风湿关节炎.国外医学免疫学分册, 2005, 28: 298~302.
[12] Ballara S, Taylor PC, Reusch P Marme D, Maini RN, Paleolog E. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor in inflammatory arthritis. Arthritis Rheum, 2001, 44: 2055~2064.
[13] Fraser A, Fearon U, Reece R, Emery P, Veale DJ. Matrix metalloproteinase 9, apoptosis, and vascular morphology in early arthritis. Arthritis Rheum, 2001, 44: 2024~2028.
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[19] Hurlimann D, Forster A, Noll G et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation, 2002, 106: 2184~2187.
[20] Booth AD, Jayne DR, Kharbanda RK et al. Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation, 2004, 109: 1718~1723.
[21] Qvistgaard E, Rogind H, Torp-Pedersen S, Terslev L, Danneskiold-Samsoe B, Bliddal H. Quantitative ultrasonography in rheumatoid arthritis: evaluation of inflammation by Doppler technique. Ann Rheum Dis, 2001, 60: 690~693.
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[24] Taylor PC, Steuer A, Gruber J et al. Measurement of synovitis and joint vascularity by ultrasonography in a randomised, placebo-controlled study of infliximab therapy in early rheumatoid arthritis. Arthritis Rheum, 2004, 50: 1107~1116.
[25] Walther M, Harms H, Krenn V, Radke S, Kirschner S, Gohlke F. Synovial tissue of the hipat power Doppler US: correlation between vascularity and power Doppler US signal. Radiology, 2002, 225: 225~231.
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[27] Szkudlarek M, Court-Payen M, Strandberg C, Klarlund M, Klausen T, Ostergaard M. Contrast-enhanced power Doppler ultrasonography of the metacarpophalangeal joints in rheumatoid arthritis. Eur Radiol, 2003, 13: 163~168.
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[1] Sieper J, Rudwaleit M, Khan MA, et dl. Concepts and epidemiology of spondyloarthritis. Best Pract Res Clin Rheumatol, 2006, 20:401~417.
[2] Brown MA. Nonmajor-histocompatibility-complex genetics of ankylosing spondylitis. Best Pract Res Clin Rheumatol, 2006, 20:611~621.
[3] Smith JA, Marker-Hermann E, Colbert RA. Pathogenesis of ankylosing spondylitis: current concepts. Best Pract Res Clin Rheumatol, 2006, 20:571~591.
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[6] Krarup NH, Poulsen SH, Baandrup U, et al. Aorto-mitral inflammation in rheumatological disease: transoesophageal echocardiographic presentation. Eur J Echocardiogr, 2007, 8:346~351.
[7] Huffer LL, Furgerson JL. Aortic root dilatation with sinus of valsalva and coronary artery aneurysms associated with ankylosing spondylitis. Tex Heart Inst J, 2006, 33:70~73.
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[22] Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation, 2001, 104:1108~1113.
[23] van Halm VP, van Denderen JC, Peters MJ, et al. Increased disease activity is associated with a deteriorated lipid profile in patients with ankylosing spondylitis. Ann Rheum Dis, 2006, 65:1473~1477.
[24] Brophy, James M. Cardiovascular effects of cyclooxygenase-2 inhibitors. Gastroenterology, 2007, 23:617~624.
[25] Spanakis E, Sidiropoulos P, Papadakis J et al. Modest but sustained increase of serum high density lipoprotein cholesterol levels in patients with inflammatory arthritides treated with infliximab. J Rheumatol, 2006, 33:2440-2446.
[26] Patel TN, Shishehbor MH, Bhatt DL. A review of high-dose statin therapy: targeting cholesterol and inflammation in atherosclerosis. Eur Heart J, 2007, 28:664-672.
[27] van Denderen JC, Peters MJ, van Halm VP, et al. Statin therapy might be beneficial for patients with ankylosing spondylitis. Ann Rheum Dis, 2006, 65:695~696.
[2] Boonen A, Chorus A, Miedema H, et al. Employment, work disability, and work days lost in patients with ankylosing spondylitis: a cross sectional study of Dutch patients. Ann Rheum Dis, 2001, 60: 353~358.
[3] Dougados M, Dijkmans B, Khan M, et al. Conventional treatments for ankylosing spondylitis. Annals of the Rheumatic Diseases, 2002, 61: iii40~iii50.
[4] Sadowska-Wroblewska M, Garwolinska H, Maczynska-Rusiniak B. A trial of cyclophosphamide in ankylosing spondylitis with involvement of peripheral joints and high disease activity. Scand J Rheumatol, 1986, 15(3): 259~264.
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[6]张莉芸,黄烽.生物制剂治疗强直性脊柱炎研究进展.中华风湿病学杂志, 2005, 9: 112~115.
[7] Malaviya AN, Kapoor S, Garg S. A new strategy of drug treatment in NSAID -unresponsive ankylosing spondylitis: combination of pamidronate and methylprednisolone monthly intravenous infusions on the background of a combination of disease modifying drugs sulfasalazine and methotrexate. J Assoc Physicians India, 2007, 55: 193~197.
[8] Darmawan J, Nasution AR, Chen SL. Excellent endpoints from step-down bridge combination therapy of 5 immunosuppressants in NSAID-refractory ankylosing spondylitis: 6 year international study in Asia-WHO-ILAR COPCORD stage II treatment of the autoimmune diseases, 2006, 33(12): 2484~2492.
[9] Willkens RF, Sharp JT, Stablein D, et al. Comparison of azathioprine, azathioprine, and the combination of the two in the treatment of rheumatoid arthritis. Arthritis Rheum, 1995, 38: 1799~1806.
[10] van der Heijde D, van der Linden S, et al. Which domains should be included in a core set for endpoints in ankylosing spondylitis? Introduction to the ankylosing spondylitis module of OMERACTIV. J Rheumatol, 1999, 26: 945~947.
[11] Calin A, Nakache JP, Gueguen A, et al. Outcome variables in ankylosing spondylitis: evaluation of their relevance and discriminant capacity. J Rheumatol, 1999, 26: 975~979.
[12] Keller C, Webb A, Davis J. Cytokines in the seronegative spondyloarthropathies and their modification by TNF blockade: a brief report and literature review. Annals of theRheumatic Diseases, 2003, 62(12): 1128~1132.
[13] Gratacos J, Collado A, Filella X, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol, 1994, 33: 927~931.
[14] Gratacos J, Collado A, Pons F, et al. Significant loss of bone mass in patients with early, active ankylosing spondylitis: a followup study. Arthritis Rheum, 1999, 42: 2319~2324.
[15] Keller C, Webb A, Davis J.et al. Cytokines in the seronegative spondyloarthropathies and their modification by TNF blockade: a brief report and literature review. Ann Rheum Dis, 2003, 62: 1128~1132.
[16]杨春花,黄烽.基质金属蛋白酶3和巨噬细胞集落刺激因子与强直性脊柱炎疾病活动性及发病机制的研究. [D].中国人民解放军军医进修学院, 2005.
[17] van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum, 1984, 27: 361~368.
[18] Garrett S, Jenkinson T, Kennedy LG, et al. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol, 1994, 21: 2286~2291.
[19] Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol, 1994, 21: 2281~2285.
[20] Jenkinson TR, Mallorie PA, Whitelock HC, et al. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol, 1994, 21:1694~1698.
[21] Mander M, Simpson JM, McLellan A, et al. Studies with an enthesis index as a method of clinical assessment in ankylosing spondylitis. Ann Rheum Dis, 1987, 46: 197~202.
[22] Scott DL, Panayi GS, van Riel PL, et al. Disease activity in rheumatoid arthritis: preliminary report of the Consensus Study Group of the European Workshop for Rheumatology Research. Clin Exp Rheumatol, 1992, 10: 521~525.
[23] Anderson JJ, Baron G, van der Heijde D, et al. Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum, 2001, 44: 1876~1886.
[24]黄烽.从循证医学角度看强直性脊柱炎的治疗.中华风湿病学杂志, 2006, 10(5): 257~260.
[25] Pérez-Guijo VC, Cravo AR, Castro Mdel C. Increased efficacy of infliximab associated with methotrexate in ankylosing spondylitis. Joint Bone Spine, 2007, 74(3): 254~258.
[26] Sampaio-Burros P, Costallat L, Bertolo M, et al. Methotrexate in the treatment ofankylosing spondylitis[J]. ScandJRheumatol, 2000, 29(3): 160~162.
[27]黄烽,李胜光,刘泽星.中国新药杂志. 2001, 10(9): 689~692.
[28] Gonzalez-Lopez L, Garcia-Gonzalez A, et al. Efficacy of methotrexate in ankylosing spondylitis: a randomized, double blind, placebo controlled trial. J Rheumatol, 2004, 31: 1568~ 1574.
[29]赵福涛,丁元晶,赵浩等.甲氨蝶呤治疗强直性脊柱炎髋关节病变.中华风湿病学杂志, 2007, 11(4): 213~216.
[30] Boonen A, de Vet H, van der Heijde D, et al. Work status and its determinants among patients with ankylosing spondylitis. A systematic literature review. J Rheumatol, 2001, 28: 1056~1062.
[31] Bostan EE, Borman P, Bodur H, et al. Functional disability and quality of life in patients with ankylosing spondylitis. Rheumatol Int, 2003, 23: 121~126.
[32] Rudwaleit M, Listing J, Brandt J, et al. Prediction of a major clinical response (BASDAI50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis, 2004, 63: 665~670.
[33] Rudwaleit M, Brandt J, Braun J, et al. Is there a role for MRI in predicting the clinical response to TNF alpha blockers in ankylosing spondylitis? Ann Rheum Dis, 2003, 62: 97.
[34]张莉芸,黄烽.抗肿瘤坏死因子单克隆抗体infliximab治疗强直性脊柱炎的临床及实验研究[D].中国人民解放军军医进修学院, 2005.
[35] Dougados M, van der Heijde D. Ankylosing spondylitis: how should the disease be assessed? Best Pract Res Clin Rheumatol, 2002, 16: 605~618.
[36] Spoorenberg A, van der Heijide D, deklerk, et al. Relative value of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis. J Rheumatal, 1999, 26(4): 980~984.
[37] Rouf J, Stucki G. Validity aspects of erythrocyte sedimentation rate and C-reactive protein in ankylosing spodylitis: a literature review. J Rheumatol, 1999, 26(4): 966~970.
[38] Beutler BA. The role of tumor necrosis factor in health and disease. J Rheumatol Suppl, 1999, 57: 16~21.
[39] Falkenbach A, Herold M. In ankylosing spondylitis serum interleukin-6 correlates with the degree of mobility restriction, but not with short-term changes in the variables for mobility. Rheumatol Int, 1998, 18: 103~106.
[40] Brandt J, Haibel H, Cornely D, et al. Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab. Arthritis Rheum, 2000, 43: 1346~1352.
[41] Li Jnen H.R. Elements of the fibrinolytic systerm. Ann N Y Acad Sci, 2001, 936: 226~236.
[1] FitzGerald O, Bresnihan B. Synovial membrane cellularity and vascularity. Ann Rheum Dis, 1995, 54: 511~515.
[2] Ostergaard M, Hansen M, Stoltenberg M et al. Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis. Arthritis Rheum, 1999, 42: 918~929.
[3] Firestein GS. Starving the synovium: angiogenesis and inflammation in rheumatoid arthritis. J Clin Invest, 1999, 103: 3~4.
[4] del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum, 2001, 44: 2737~2745.
[5] Koch A. Angiogenesis as a target in rheumatoid arthritis. Ann Rheum Dis, 2003, 62(Suppl): 60~67.
[6] Achen MG, Stacker SA. The vascular endothelial growth factor family; proteins which guide the development of the vasculature. Int J Exp Pathol, 1998, 79: 255~265.
[7] Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J, 1999, 13: 9~22.
[8] Mason JC, Lidington EA, Yarwood H, Lublin DM, Haskard DO. Induction of endothelial cell decay-accelerating factor by vascular endothelial growth factor: a mechanism for cytoprotection against complement-mediated injury during inflammatory angiogenesis. Arthritis Rheum, 2001, 44: 138~150.
[9] Berse B, Hunt JA, Diegel RJ et al. Hypoxia augments cytokine (transforming growth factor-beta (TGF-beta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. Clin Exp Immunol, 1999, 115: 176~182.
[10] Giatromanolaki A, Sivridis E, Maltezos E et al. Upregulated hypoxia inducible factor-1alpha and–2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther, 2003, 5: R193~201.
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