炎性关节炎治疗的临床及基础研究
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摘要
第一部分改善病情抗风湿药(DMARDs)治疗银屑病关节炎的临床研究
目的：
1．评价甲氨蝶呤(MTX)、来氟米特(LEF)、MTX和LEF减小剂量后联合治疗(MTX+LEF)对银屑病关节炎(PsA)关节病变的临床疗效；
2．评价MTX、LEF和MTX+LEF对PsA皮肤病变的临床疗效；
3．评价MTX、LEF和MTX+LEF治疗PsA的安全性；
4．探讨不同方案治疗对PsA达到临床疗效的预测因素；
方法：
1．进行一项为期24周的2个中心、开放、对照的临床研究。完成临床研究的46例PsA患者接受MTX、LEF、MTX+LEF中的任何一种治疗方案。以银屑病关节炎疗效标准(PsARC)作为主要疗效指标，修改的美国风湿病学会疗效标准提高20％(ACR20)作为次要疗效指标，对关节病变进行评估，并分析具体评价指标的变化。
2．以银屑病皮损面积和严重性指数提高50％、75％(PASI50、PASI75)作为银屑病皮损疗效的评价指标，对皮肤病变进行评估，并分析PASI和皮肤病生命质量指数(DLQI)的变化。
3．在研究终点时对51例患者(包括完成疗效评估的46例和因不良反应而退出研究的5例)的安全性进行评估。
4．在研究终点时以PsARC作为疗效指标，采用Logistic回归分析对疗效影响因素进行分析。
结果：
1．疗效评估结果
1)治疗4周后，各治疗组有28.6％～50％和12.5％～38.5％的患者达到主要疗效指标PsARC和次要疗效指标修改的ACR20，第8周时达到的比例迅速升高并延续至24周。24周时各组达到PsARC和ACR20改善的比例分别在68％和50％以上。在研究终点各组达到PsARC和ACR20改善比例的差异无统计学意义(P＞0.05)。
2)治疗4周时各组除ESR外的其他各项评价指标与基线相比显著改善(P＜0.05)。在研究终点时的改善程度与MTX组比较，压痛关节数、肿胀关节数、HAQ、PGA均高于LEF组，在肿胀关节数、HAQ、ESR高于MTX+LEF组(P＜0.05)。MTX+LEF组的各项具体指标均高于LEF组，但未达到统计学差异。
3)治疗4周后，各组有12.5％～50％的患者达到PASI50改善，第8周时迅速升高并延续至第24周，研究结束时各组达到PASI 50和PASI75改善的比例分别为50％、30％以上。研究结束时达到PASI50和PASI75改善的比例在LEF组显著低于MTX和MTX+LEF组(P＜0.05)。
4) 24周时MTX组和MTX+LEF组DLQI得分显著低于基线水平(P＜0.05～0.01)，而LEF组则无明显差别。24周的改善程度LEF组低于MTX组和MTX+LEF组，差异有显著统计学意义(P＜0.05)。
2．安全性评估结果
无严重不良事件发生。MTX、LEF、MTX+LEF组与药物相关的不良反应发生率分别为38.5％、38.9％、35％，差异无统计学意义(P＞0.05)。MTX组和MTX+LEF组以胃肠道症状最为常见，LEF组以肝酶轻度升高最常见。除MTX组有1例ALT升高超过正常值的5倍以上外，其他不良反应均为轻中度。各种不良反应在各组间无统计学差异。
3．疗效影响因素分析结果
Logistic分析显示脊柱炎型、年龄、肿胀关节数、PGA、ESR、DLQI为疗效PsARC的预测因素，脊柱炎型PsA、年龄大、肿胀关节数多、PGA和DLQI得分高的患者不易达到PsARC的改善，ESR高的患者易于达到PsARC的改善。
结论：
MTX和LEF减小剂量后MTX+LEF联合治疗可以迅速、显著缓解PsA的关节和皮肤病变，与单用MTX疗效相当，对皮肤病变的疗效显著高于单用LEF；安全耐受性较好，与单用LEF和MTX相比，联合治疗并不增加不良反应的发生率。
第二部分人鼠嵌合抗CD20单克隆抗体Rituximab治疗类风湿关节炎的临床及实验研究
目的：
1．评价抗CD20单克隆抗体Rituximab治疗类风湿因子(RF)阳性、活动性类风湿关节炎(RA)的临床疗效及安全性；并探讨达到临床疗效的预测因素；
2．评价Rituximab对外周血细胞和免疫球蛋白的影响；
3．探讨Rituximab治疗对T细胞功能的影响。
方法：
1．本研究为一项为期24周的开放性临床研究。纳入研究的12例RF阳性、活动性RA患者分别在试验的第1日、第15日接受静脉输注Rituximab(500mg或1000mg)，以ACR20为主要疗效指标，ACR50、ACR70为次要疗效指标，以欧洲抗风湿联盟(EULAR)疗效标准为病情活动性的评价指标，评价其疗效及安全性，并用Logistic分析达到疗效的预测因素。
2．在Rituximab输注前后、4、8、16、24周检测外周血细胞和免疫球蛋白，分析其变化；
3．分别在基线、2、8周取12例RA患者和12例正常对照者的外周血单个核细胞(PBMC)，应用酶联免疫斑点法(ELISPOT)测定抗CD3／CD28刺激后分泌IL-2、IFN-γ的T细胞数，和自发分泌TNF-α和IL-6的T细胞数，并分析Rituximab对T细胞功能的影响。
结果：
1．疗效评估结果
1)治疗24周后达到主要疗效指标ACR20的比例为75％，达到次要疗效指标ACR50、ACR70的比例分别为16.67％、8.33％。4周后达到ACR20、ACR50的比例分别为25％、8.33％；8周时达到的比例最高为83.3％、50％；16周时达到ACR20、ACR50改善仍保持高的比例为75％、50％，并出现ACR70改善者(8.3％)；在8、16、24周时达到ACR20的比例显著高于第4周(P＜0.05)，不同时间点达到ACR50、ACR70的比例差异无统计学意义(P＞0.05)。
2)在24周时达到有效、显效、病情低活动和缓解的比例分别为58.3％、8.3％、8.3％、8.3％。16周时达到有效的患者比例最高为66.7％，在8、16、24周时DAS28分数的下降与基线相比差异有统计学意义(P＜0.01)。
3)4周时肿胀关节数、患者疼痛VAS评分、医生的总体评价、PGA、HAQ显著低于基线水平(P＜0.05～0.01)，8、16、24周时所有评价指标包括肿胀关节数、压痛关节数、患者疼痛程度VAS评分、医生的总体评价、PGA、HAQ、ESR、CRP下降与基线相比差异有统计学意义(P＜0.05～0.01)。24周时慢性疾病治疗疲劳程度的功能评估(FACIT-F)评分明显低于基线水平(P＜0.05)。
3)输注Rituximab后淋巴细胞和单核细胞数显著低于治疗前水平(P＜0.01)。在4周时恢复正常；单核细胞在8周时明显高于基线水平，持续至24周，但均在正常范围。25％的患者同时出现白细胞、中性粒细胞降低，24周时恢复正常。
4)治疗后第8周免疫球蛋白(IgM、IgG、IgA)水平显著低于基线水平(P＜0.05)，在16周、24周回升至基线水平，但治疗期间均在正常范围。
2．安全性评价结果
无严重不良事件发生。Rituximab与药物相关的不良反应发生率为41.7％，所有不良事件均为轻中度、暂时性的，以上呼吸道感染最为常见。
3．疗效影响因素分析结果
Logistic回归分析发现肿胀关节数和RF滴度是ACR20的疗效影响因素。
4．Rituximab治疗对T细胞的影响
Rituximab治疗后RA患者外周血分泌IFN-r、IL-2和TNF-α的T细胞数明下降(P＜0.05)，而分泌IL-6的T细胞数无明显变化。
结论：
1．Rituximab可以迅速、显著缓解活动性RA的病情，8～16周时疗效最佳，可持续至24周；肿胀关节数少和RF滴度低可能是Rituximab影响疗效的因素。
2．Rituximab治疗活动性RA安全性较好，不增加感染的风险，出现输液相关的不良反应少；
3．在Rituximab输注后24h内可出现一过性淋巴细胞、单核细胞和免疫球蛋白下降；
4．Rituximab治疗引起B细胞缺失后可以下调RA患者外周血分泌IFN-γ、IL-2和TNF-α的T细胞数。
Objective:
1. To evaluate the efficacy of methotrexate (MTX), leflunomide (LEF) and therapeutic alliance (MTX+LEF) with lesser dosage MTX and LEF in the joint disease of psoriatic arthritis (PsA).
2. To evaluate the efficacy of MTX, LEF and MTX+LEF in the skin disease of PsA.
3. To evaluate the safety of MTX, LEF and MTX+LEF in the treatment of PsA.
4. To investigate the parameters predicting the clinical response to three treatment programs.
Methods:
1. This was a two-center, open-lable, controlled clinical trial lasting 24 weeks. 46 patients of PsA received a kind of treatment programs of MTX, LEF and MTX+LEF. The primary end point was proportion of psoriatic arthritis response criteria (PsARC ) responder, the secondary end point was proportion of modified 20% improvement of American College of Rheumatology ( ACR20 ) responder. The efficacy of joint disease was assessed and change of every assessed parameter were analysed.
2. The efficacy of psoriatic rash wase evaluated by 50% and 70% improvement of psoriasis area and severity index scores ( PASI50 and PASI75) , and changes of PASI and dermatology life quality index (DLQI) were analysed.
3. The safety of fifty-one patients of PsA (including forty-six patients finishing assessment of clinical efficacy and five patients withdrawing from treatment due to adverse effects) were evaluated in the study end point.
4. The parameters predicting the clinical response were analysed with Logistic
regression liklihood ratio tests in the study end point by PsARC as responder. Results:
1. At week 4, 28.6%-50% and 12.5%-38.5% of patients in three groups reached the primary end point of PsARC and secondary end point of modified ACR20. The proportion of patients in three groups reaching PsARC and ACR20 showed quick improvement from week 8 to week 24. The percent of patients achieving PsARC and ACR20 were >68.8% and >50% at week 24. There was no statistical difference in achieving PsARC and ACR20 among three groups at week 24 (P >0.05 ) .
2. At week 24, various measures except ESR were improved compared with base-line values (P<0.05). Compared with improvement in the MTX group at end point, Tender joint counts, swollen joint counts, HAQ, PGA were significant low in the LEF group; swollen joint counts, HAQ, ESR were significant low in the MTX+LEF group( P<0.05). All measures were lower in the LEF group than that of MTX+LEF group, but there were no statistical significance.
3. At week 4, 12.5%-50% of patients in three groups reached improvement of PASI50. The proportion of patients in three groups reached PASI50 showed continuing improvement from week 8 to week 24. The percent of patients achieving PASI50 and PASI75 were >50% and >30% at week 24. At the end point, the percent of patients achieving PASI75 and PASI50 in the LEF group were significantly lower than that of MTX and MTX+LEF group (P<0.05) .
4. At week 24, improvement of DLQI scores over base-line were significant greater in the MTX and MTX+LEF groups (P<0.05-0.01) , whereas no difference was observed in the LEF group. The improvement in the LEF group was significant lower than that in the MTX and MTX+LEF group at week 24 (P<0.05 ).
5. There were no serious adverse reactions. In the MTX, LEF and MTX+LEF group the incidence of treatment related adverse events was 38.5%, 38.9% and 35%, respectively. There was no difference in three groups. The most frequently treatment related adverse events in the MTX and MTX+LEF group
were gastrointerstinal complaint and in the LEF group was slightly elevated liver enzyme levels. Except a MTX-treated patient with ALT elevations >5 times over the upper limit of normal, 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.
6. Logistic regression analysis showed higher ESR levels was related to a higher likelihood to response, axial arthropathy of PsA, elder, more swollen joint counts, higher score of PGA and DLQI were related to a lower likelihood to response. Conclusion:
1. Therapeutic alliance with lesser dosage MTX and LEF (MTX+LEF) resulted in rapid, significant improvement in joint and skin disease of patients with PsA, the efficacy of joint and skin involvement were equal to that of MTX. Compared with LEF, treatment with MTX+LEF significantly ameliorated the sympotoms of psoriatic rash. MTX+LEF was safe and well tolerated. Therapeutic alliance of MTX+LEF was not associated with an increase the rate of adverse events, compared with MTX and LEF.
Objective:
1. To assess the clinical efficacy and safety of anti-CD20 antibody (Rituximab) in active rheumatoid arthritis (RA) with positive rheumatoid factor (RF) and to investigate the parameters predicting the clinical response.
2. To assess the influence of rituximab on peripheral blood cell and immunoglobulin.
3. To investigate the influence of rituximab on T cell function. Methods:
1. This was a 24-week, open-lable, clinical trial. 12 patients of active RA with positive RF were treated with 500 mg or 1000 mg intravenous infusions of rituximab on days 1 and 15. The primary end point was proportion of ACR20 responders. 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. And the parameters predicting the clinical response of rituximab were analysed with Logistic regression liklihood ratio tests.
2. Peripheral blood cells and immunoglobulin were detected at after and before rituximab influsion, week 4, 8, 16, 24 and the changes of peripheral blood cells and immunoglobulin were analysed.
3. Peripheral blood mononuclear cells (PBMC) were collected from 12 patients and 12 healthy controls at baseline, week 2, 8. The number of T cells that secret interferon-γ (IFN-γ) and interleukin 2 (IL-2) after anti-CD3/anti-CD28 stimulation was detected by ELISPOT. The number of cells that spontaneously secret TNF-α and IL-6 was assayed by ELISPOT. The influence of rituximab on T cell function was analysed.
Rusults:
1. At week 24, 75% of patients of rituximab treatment reached the primary end point of ACR20. The percent of patients achieving the secondary end points of ACR50, ACR70 were 16.67% and 8.3%. The percent of patients achieving ACR20 and ACR50 were 25% and 8.3% at week 4. The peak percent of patients achieving ACR20 and ACR50 were observed at week 8, 83.3% and 50% respectively. The trend maintained to week 16, and a proportion of patients achieved ACR70 response. The rate of reaching ACR20 was significant higher at week 8, 16, 24 than week 4 (P<0.05). There were no differences in the percent of patients reaching ACR50 and ACR70 at different observed point.
2. At week 24, the percent of patients achieving the EULAR moderate, good, low disease activity and remission response were 58.3%, 8.3%, 8.3% and 8.3% respectively. The peak percentages of patients achieving the EULAR moderate response showed at week 16, DAS28 score were significant reduction at week 8, 16, 24 compared with base-line (P<0.01) .
3. Improvements over base-line values for four measures including patient's assessment of pain, physician's global assessment, PGA, HAQ were significantly decreased at week 4 (P<0.05-0.01) . Improvements over base-line values for all measures including patient's assessment of pain, physician's global assessment, PGA, HAQ, tender joint score, swollen joint score, ESR/CRP, were significantly decreased at week 8,16,24 (P<0.05-0.01) . FACIT-F score was significant reduction at week 24 compared with base-line.
4. Lymphocyte and monocyte counts were decreased significantly between after and before rituximab infusion (P<0.01), and recovered to normal levels at week 4. Monocyte counts improved significantly over base-line from week 8 to week 24 but within upper limit of normal. Leucocyte and neutrophil in 25% patients were seen transient decrease and resolved at week 24.
5. Immunoglubulin (IgM, IgG, IgA) levels decreased significantly at week 8 compared with that of base-line, and returned to base-line levels at week 16, 24. Immunoglubulin (IgM, IgG, IgA) levels were normal during the study.
6. There were no serious adverse reactions. The incidence of rituximab related adverse event was 41.7%. The intensity of all adverse events was rated as mild or moderate and transient during the whole study. The most frequently treatment related adverse events was the upper respiratory infection.
7. Logistic regression analysis showed swollen joint counts and titre of RF predicted ACR20 response.
8. After rituximab treatment, the number of T cells that secret IL-2 and IFN-γ was significantly decreased (P<0.01), the number of TNF-α secreting monocytes was decreased (P<0.05) but IL-6 secreting cells did not change significantly.
Conclusion:
1. Treatment with rituximab resulted in rapid and significant improvement in patients with active RA with positive RF. The clinical efficacy obtained to best during week 8 and 16, and maintained to week 24.
2. Rituximab was safe and well tolerated, it was not associated with an increase the risk of infection. The incidence of rituximab infusion related adverse event was seldom.
3. Transient decrease of lymphocyte, monocyte and immunoglobulin were seen within 24 hours after rituximab infusion.
4. Lower swollen joint counts and titre of RF was related to higher likelihood to response.
5. Rituximab treatment reduced the cytokine secretion from T cells and monocytes in RA patients of dramatically depleted B cells.
目的：
1．评价甲氨蝶呤(MTX)、来氟米特(LEF)、MTX和LEF减小剂量后联合治疗(MTX+LEF)对银屑病关节炎(PsA)关节病变的临床疗效；
2．评价MTX、LEF和MTX+LEF对PsA皮肤病变的临床疗效；
3．评价MTX、LEF和MTX+LEF治疗PsA的安全性；
4．探讨不同方案治疗对PsA达到临床疗效的预测因素；
方法：
1．进行一项为期24周的2个中心、开放、对照的临床研究。完成临床研究的46例PsA患者接受MTX、LEF、MTX+LEF中的任何一种治疗方案。以银屑病关节炎疗效标准(PsARC)作为主要疗效指标，修改的美国风湿病学会疗效标准提高20％(ACR20)作为次要疗效指标，对关节病变进行评估，并分析具体评价指标的变化。
2．以银屑病皮损面积和严重性指数提高50％、75％(PASI50、PASI75)作为银屑病皮损疗效的评价指标，对皮肤病变进行评估，并分析PASI和皮肤病生命质量指数(DLQI)的变化。
3．在研究终点时对51例患者(包括完成疗效评估的46例和因不良反应而退出研究的5例)的安全性进行评估。
4．在研究终点时以PsARC作为疗效指标，采用Logistic回归分析对疗效影响因素进行分析。
结果：
1．疗效评估结果
1)治疗4周后，各治疗组有28.6％～50％和12.5％～38.5％的患者达到主要疗效指标PsARC和次要疗效指标修改的ACR20，第8周时达到的比例迅速升高并延续至24周。24周时各组达到PsARC和ACR20改善的比例分别在68％和50％以上。在研究终点各组达到PsARC和ACR20改善比例的差异无统计学意义(P＞0.05)。
2)治疗4周时各组除ESR外的其他各项评价指标与基线相比显著改善(P＜0.05)。在研究终点时的改善程度与MTX组比较，压痛关节数、肿胀关节数、HAQ、PGA均高于LEF组，在肿胀关节数、HAQ、ESR高于MTX+LEF组(P＜0.05)。MTX+LEF组的各项具体指标均高于LEF组，但未达到统计学差异。
3)治疗4周后，各组有12.5％～50％的患者达到PASI50改善，第8周时迅速升高并延续至第24周，研究结束时各组达到PASI 50和PASI75改善的比例分别为50％、30％以上。研究结束时达到PASI50和PASI75改善的比例在LEF组显著低于MTX和MTX+LEF组(P＜0.05)。
4) 24周时MTX组和MTX+LEF组DLQI得分显著低于基线水平(P＜0.05～0.01)，而LEF组则无明显差别。24周的改善程度LEF组低于MTX组和MTX+LEF组，差异有显著统计学意义(P＜0.05)。
2．安全性评估结果
无严重不良事件发生。MTX、LEF、MTX+LEF组与药物相关的不良反应发生率分别为38.5％、38.9％、35％，差异无统计学意义(P＞0.05)。MTX组和MTX+LEF组以胃肠道症状最为常见，LEF组以肝酶轻度升高最常见。除MTX组有1例ALT升高超过正常值的5倍以上外，其他不良反应均为轻中度。各种不良反应在各组间无统计学差异。
3．疗效影响因素分析结果
Logistic分析显示脊柱炎型、年龄、肿胀关节数、PGA、ESR、DLQI为疗效PsARC的预测因素，脊柱炎型PsA、年龄大、肿胀关节数多、PGA和DLQI得分高的患者不易达到PsARC的改善，ESR高的患者易于达到PsARC的改善。
结论：
MTX和LEF减小剂量后MTX+LEF联合治疗可以迅速、显著缓解PsA的关节和皮肤病变，与单用MTX疗效相当，对皮肤病变的疗效显著高于单用LEF；安全耐受性较好，与单用LEF和MTX相比，联合治疗并不增加不良反应的发生率。
第二部分人鼠嵌合抗CD20单克隆抗体Rituximab治疗类风湿关节炎的临床及实验研究
目的：
1．评价抗CD20单克隆抗体Rituximab治疗类风湿因子(RF)阳性、活动性类风湿关节炎(RA)的临床疗效及安全性；并探讨达到临床疗效的预测因素；
2．评价Rituximab对外周血细胞和免疫球蛋白的影响；
3．探讨Rituximab治疗对T细胞功能的影响。
方法：
1．本研究为一项为期24周的开放性临床研究。纳入研究的12例RF阳性、活动性RA患者分别在试验的第1日、第15日接受静脉输注Rituximab(500mg或1000mg)，以ACR20为主要疗效指标，ACR50、ACR70为次要疗效指标，以欧洲抗风湿联盟(EULAR)疗效标准为病情活动性的评价指标，评价其疗效及安全性，并用Logistic分析达到疗效的预测因素。
2．在Rituximab输注前后、4、8、16、24周检测外周血细胞和免疫球蛋白，分析其变化；
3．分别在基线、2、8周取12例RA患者和12例正常对照者的外周血单个核细胞(PBMC)，应用酶联免疫斑点法(ELISPOT)测定抗CD3／CD28刺激后分泌IL-2、IFN-γ的T细胞数，和自发分泌TNF-α和IL-6的T细胞数，并分析Rituximab对T细胞功能的影响。
结果：
1．疗效评估结果
1)治疗24周后达到主要疗效指标ACR20的比例为75％，达到次要疗效指标ACR50、ACR70的比例分别为16.67％、8.33％。4周后达到ACR20、ACR50的比例分别为25％、8.33％；8周时达到的比例最高为83.3％、50％；16周时达到ACR20、ACR50改善仍保持高的比例为75％、50％，并出现ACR70改善者(8.3％)；在8、16、24周时达到ACR20的比例显著高于第4周(P＜0.05)，不同时间点达到ACR50、ACR70的比例差异无统计学意义(P＞0.05)。
2)在24周时达到有效、显效、病情低活动和缓解的比例分别为58.3％、8.3％、8.3％、8.3％。16周时达到有效的患者比例最高为66.7％，在8、16、24周时DAS28分数的下降与基线相比差异有统计学意义(P＜0.01)。
3)4周时肿胀关节数、患者疼痛VAS评分、医生的总体评价、PGA、HAQ显著低于基线水平(P＜0.05～0.01)，8、16、24周时所有评价指标包括肿胀关节数、压痛关节数、患者疼痛程度VAS评分、医生的总体评价、PGA、HAQ、ESR、CRP下降与基线相比差异有统计学意义(P＜0.05～0.01)。24周时慢性疾病治疗疲劳程度的功能评估(FACIT-F)评分明显低于基线水平(P＜0.05)。
3)输注Rituximab后淋巴细胞和单核细胞数显著低于治疗前水平(P＜0.01)。在4周时恢复正常；单核细胞在8周时明显高于基线水平，持续至24周，但均在正常范围。25％的患者同时出现白细胞、中性粒细胞降低，24周时恢复正常。
4)治疗后第8周免疫球蛋白(IgM、IgG、IgA)水平显著低于基线水平(P＜0.05)，在16周、24周回升至基线水平，但治疗期间均在正常范围。
2．安全性评价结果
无严重不良事件发生。Rituximab与药物相关的不良反应发生率为41.7％，所有不良事件均为轻中度、暂时性的，以上呼吸道感染最为常见。
3．疗效影响因素分析结果
Logistic回归分析发现肿胀关节数和RF滴度是ACR20的疗效影响因素。
4．Rituximab治疗对T细胞的影响
Rituximab治疗后RA患者外周血分泌IFN-r、IL-2和TNF-α的T细胞数明下降(P＜0.05)，而分泌IL-6的T细胞数无明显变化。
结论：
1．Rituximab可以迅速、显著缓解活动性RA的病情，8～16周时疗效最佳，可持续至24周；肿胀关节数少和RF滴度低可能是Rituximab影响疗效的因素。
2．Rituximab治疗活动性RA安全性较好，不增加感染的风险，出现输液相关的不良反应少；
3．在Rituximab输注后24h内可出现一过性淋巴细胞、单核细胞和免疫球蛋白下降；
4．Rituximab治疗引起B细胞缺失后可以下调RA患者外周血分泌IFN-γ、IL-2和TNF-α的T细胞数。
Objective:
1. To evaluate the efficacy of methotrexate (MTX), leflunomide (LEF) and therapeutic alliance (MTX+LEF) with lesser dosage MTX and LEF in the joint disease of psoriatic arthritis (PsA).
2. To evaluate the efficacy of MTX, LEF and MTX+LEF in the skin disease of PsA.
3. To evaluate the safety of MTX, LEF and MTX+LEF in the treatment of PsA.
4. To investigate the parameters predicting the clinical response to three treatment programs.
Methods:
1. This was a two-center, open-lable, controlled clinical trial lasting 24 weeks. 46 patients of PsA received a kind of treatment programs of MTX, LEF and MTX+LEF. The primary end point was proportion of psoriatic arthritis response criteria (PsARC ) responder, the secondary end point was proportion of modified 20% improvement of American College of Rheumatology ( ACR20 ) responder. The efficacy of joint disease was assessed and change of every assessed parameter were analysed.
2. The efficacy of psoriatic rash wase evaluated by 50% and 70% improvement of psoriasis area and severity index scores ( PASI50 and PASI75) , and changes of PASI and dermatology life quality index (DLQI) were analysed.
3. The safety of fifty-one patients of PsA (including forty-six patients finishing assessment of clinical efficacy and five patients withdrawing from treatment due to adverse effects) were evaluated in the study end point.
4. The parameters predicting the clinical response were analysed with Logistic
regression liklihood ratio tests in the study end point by PsARC as responder. Results:
1. At week 4, 28.6%-50% and 12.5%-38.5% of patients in three groups reached the primary end point of PsARC and secondary end point of modified ACR20. The proportion of patients in three groups reaching PsARC and ACR20 showed quick improvement from week 8 to week 24. The percent of patients achieving PsARC and ACR20 were >68.8% and >50% at week 24. There was no statistical difference in achieving PsARC and ACR20 among three groups at week 24 (P >0.05 ) .
2. At week 24, various measures except ESR were improved compared with base-line values (P<0.05). Compared with improvement in the MTX group at end point, Tender joint counts, swollen joint counts, HAQ, PGA were significant low in the LEF group; swollen joint counts, HAQ, ESR were significant low in the MTX+LEF group( P<0.05). All measures were lower in the LEF group than that of MTX+LEF group, but there were no statistical significance.
3. At week 4, 12.5%-50% of patients in three groups reached improvement of PASI50. The proportion of patients in three groups reached PASI50 showed continuing improvement from week 8 to week 24. The percent of patients achieving PASI50 and PASI75 were >50% and >30% at week 24. At the end point, the percent of patients achieving PASI75 and PASI50 in the LEF group were significantly lower than that of MTX and MTX+LEF group (P<0.05) .
4. At week 24, improvement of DLQI scores over base-line were significant greater in the MTX and MTX+LEF groups (P<0.05-0.01) , whereas no difference was observed in the LEF group. The improvement in the LEF group was significant lower than that in the MTX and MTX+LEF group at week 24 (P<0.05 ).
5. There were no serious adverse reactions. In the MTX, LEF and MTX+LEF group the incidence of treatment related adverse events was 38.5%, 38.9% and 35%, respectively. There was no difference in three groups. The most frequently treatment related adverse events in the MTX and MTX+LEF group
were gastrointerstinal complaint and in the LEF group was slightly elevated liver enzyme levels. Except a MTX-treated patient with ALT elevations >5 times over the upper limit of normal, 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.
6. Logistic regression analysis showed higher ESR levels was related to a higher likelihood to response, axial arthropathy of PsA, elder, more swollen joint counts, higher score of PGA and DLQI were related to a lower likelihood to response. Conclusion:
1. Therapeutic alliance with lesser dosage MTX and LEF (MTX+LEF) resulted in rapid, significant improvement in joint and skin disease of patients with PsA, the efficacy of joint and skin involvement were equal to that of MTX. Compared with LEF, treatment with MTX+LEF significantly ameliorated the sympotoms of psoriatic rash. MTX+LEF was safe and well tolerated. Therapeutic alliance of MTX+LEF was not associated with an increase the rate of adverse events, compared with MTX and LEF.
Objective:
1. To assess the clinical efficacy and safety of anti-CD20 antibody (Rituximab) in active rheumatoid arthritis (RA) with positive rheumatoid factor (RF) and to investigate the parameters predicting the clinical response.
2. To assess the influence of rituximab on peripheral blood cell and immunoglobulin.
3. To investigate the influence of rituximab on T cell function. Methods:
1. This was a 24-week, open-lable, clinical trial. 12 patients of active RA with positive RF were treated with 500 mg or 1000 mg intravenous infusions of rituximab on days 1 and 15. The primary end point was proportion of ACR20 responders. 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. And the parameters predicting the clinical response of rituximab were analysed with Logistic regression liklihood ratio tests.
2. Peripheral blood cells and immunoglobulin were detected at after and before rituximab influsion, week 4, 8, 16, 24 and the changes of peripheral blood cells and immunoglobulin were analysed.
3. Peripheral blood mononuclear cells (PBMC) were collected from 12 patients and 12 healthy controls at baseline, week 2, 8. The number of T cells that secret interferon-γ (IFN-γ) and interleukin 2 (IL-2) after anti-CD3/anti-CD28 stimulation was detected by ELISPOT. The number of cells that spontaneously secret TNF-α and IL-6 was assayed by ELISPOT. The influence of rituximab on T cell function was analysed.
Rusults:
1. At week 24, 75% of patients of rituximab treatment reached the primary end point of ACR20. The percent of patients achieving the secondary end points of ACR50, ACR70 were 16.67% and 8.3%. The percent of patients achieving ACR20 and ACR50 were 25% and 8.3% at week 4. The peak percent of patients achieving ACR20 and ACR50 were observed at week 8, 83.3% and 50% respectively. The trend maintained to week 16, and a proportion of patients achieved ACR70 response. The rate of reaching ACR20 was significant higher at week 8, 16, 24 than week 4 (P<0.05). There were no differences in the percent of patients reaching ACR50 and ACR70 at different observed point.
2. At week 24, the percent of patients achieving the EULAR moderate, good, low disease activity and remission response were 58.3%, 8.3%, 8.3% and 8.3% respectively. The peak percentages of patients achieving the EULAR moderate response showed at week 16, DAS28 score were significant reduction at week 8, 16, 24 compared with base-line (P<0.01) .
3. Improvements over base-line values for four measures including patient's assessment of pain, physician's global assessment, PGA, HAQ were significantly decreased at week 4 (P<0.05-0.01) . Improvements over base-line values for all measures including patient's assessment of pain, physician's global assessment, PGA, HAQ, tender joint score, swollen joint score, ESR/CRP, were significantly decreased at week 8,16,24 (P<0.05-0.01) . FACIT-F score was significant reduction at week 24 compared with base-line.
4. Lymphocyte and monocyte counts were decreased significantly between after and before rituximab infusion (P<0.01), and recovered to normal levels at week 4. Monocyte counts improved significantly over base-line from week 8 to week 24 but within upper limit of normal. Leucocyte and neutrophil in 25% patients were seen transient decrease and resolved at week 24.
5. Immunoglubulin (IgM, IgG, IgA) levels decreased significantly at week 8 compared with that of base-line, and returned to base-line levels at week 16, 24. Immunoglubulin (IgM, IgG, IgA) levels were normal during the study.
6. There were no serious adverse reactions. The incidence of rituximab related adverse event was 41.7%. The intensity of all adverse events was rated as mild or moderate and transient during the whole study. The most frequently treatment related adverse events was the upper respiratory infection.
7. Logistic regression analysis showed swollen joint counts and titre of RF predicted ACR20 response.
8. After rituximab treatment, the number of T cells that secret IL-2 and IFN-γ was significantly decreased (P<0.01), the number of TNF-α secreting monocytes was decreased (P<0.05) but IL-6 secreting cells did not change significantly.
Conclusion:
1. Treatment with rituximab resulted in rapid and significant improvement in patients with active RA with positive RF. The clinical efficacy obtained to best during week 8 and 16, and maintained to week 24.
2. Rituximab was safe and well tolerated, it was not associated with an increase the risk of infection. The incidence of rituximab infusion related adverse event was seldom.
3. Transient decrease of lymphocyte, monocyte and immunoglobulin were seen within 24 hours after rituximab infusion.
4. Lower swollen joint counts and titre of RF was related to higher likelihood to response.
5. Rituximab treatment reduced the cytokine secretion from T cells and monocytes in RA patients of dramatically depleted B cells.
引文
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7. Scarpa R, Manguso F, Oriente P, et al. Leflunomide in psoriatic polyarthritis: an Italian pilot study. Arthritis Rheum, 2001, 44: S92.
8. Liang GC, Barr WG. Long term follow up of the use of leflunomide in recalcitrant psoriatic arthritis and psoriasis. Arthritis Rheum 2001, 44: S121
9. Cuchacovich M, Soto L. Leflunomide decreases joint erosions and induces reparative changes in a patient with psoriatic arthritis. Ann Rheum Dis, 2002, 61:942-943
10. Kaltwasser JP, Nash P, Gladman D, et al. Treatment of Psoriatic Arthritis Study Group. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double blind, randomized,placebo-controlled clinical trial. Arthritis Rheum, 2004, 50:1939-1950.
11. Nash P, Thaci D, Behrens F, et al. Leflunomide Improves Psoriasis in Patients with Psoriatic Arthritis: An In-Depth Analysis of Data from the TOPAS Study. Dermatology. 2006, 212(3): 238-249.
12. Mader R, Gladman DD, Long J, et al. Does injectable gold retard radiologic evidence of joint damage in psoriatic arthritis? Clin Invest Med, 1995, 18: 139-143.
13. Lacaille D, Stein HB, Raboud J, et al. Long term therapy of psoriatic arthritis: intramuscular gold or methotrexate? J Rheumatol, 2000, 27: 1922-1927.
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26. Utset TO, Auger JA, Peace D, et al. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J Rheumatol, 2002, 29:1907-1913.
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1. Sarzi-Puttini P, Santandrea S, Boccassini L, et al. The role of NSAIDs in psoriatic arthritis: evidence from a controlled study with nimesulide. Clin Exp Rheumatol, 2001, 19 (1 Supp 1 22): S17-S20.
2. Clark DW, Coulter DM. Psoriasis associated with rofecoxib. Arch Dermatol 2003, 139:1223.
3. Pipitone N, Kingsley GH, Manzo A, et al. Current concepts and new developments in the treatment of psoriatic arthritis. Rheumatology (Oxford), 2003,42:1138-1148.
4. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study. Arthritis Rheum, 1999, 42: 2325-2329.
5. Raffayova H, Rovensky J, Malis F. Treatment with cyclosporin in patients with psoriatic arthritis: results of clinical assessment. Int J Clin Pharmacol Res, 2000, 20: 1-11.
6. Macchioni P, Boiardi L, Cremonesi T, et al. The relationship between serum-soluble interleukin-2 receptor and radiological evolution in psoriatic arthritis patients treated with cyclosporin-A. Rheumatol Int 1998, 18:27-33
7. Scarpa R, Manguso F, Oriente P, et al. Leflunomide in psoriatic polyarthritis: an Italian pilot study. Arthritis Rheum, 2001, 44: S92.
8. Liang GC, Barr WG. Long term follow up of the use of leflunomide in recalcitrant psoriatic arthritis and psoriasis. Arthritis Rheum 2001, 44: S121
9. Cuchacovich M, Soto L. Leflunomide decreases joint erosions and induces reparative changes in a patient with psoriatic arthritis. Ann Rheum Dis, 2002, 61:942-943
10. Kaltwasser JP, Nash P, Gladman D, et al. Treatment of Psoriatic Arthritis Study Group. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double blind, randomized,placebo-controlled clinical trial. Arthritis Rheum, 2004, 50:1939-1950.
11. Nash P, Thaci D, Behrens F, et al. Leflunomide Improves Psoriasis in Patients with Psoriatic Arthritis: An In-Depth Analysis of Data from the TOPAS Study. Dermatology. 2006, 212(3): 238-249.
12. Mader R, Gladman DD, Long J, et al. Does injectable gold retard radiologic evidence of joint damage in psoriatic arthritis? Clin Invest Med, 1995, 18: 139-143.
13. Lacaille D, Stein HB, Raboud J, et al. Long term therapy of psoriatic arthritis: intramuscular gold or methotrexate? J Rheumatol, 2000, 27: 1922-1927.
14. Gladman DD, Blake R, Brubacher B, et al. Chloroquine therapy in psoriatic arthritis. J Rheumatol, 1992, 19: 1724-1726.
15. Nash P, Clegg DO. Psoriatic arthritis therapy: NSAIDs and traditional DMARDs. Ann Rheum Dis, 2005, 64(Suppl II):ii74-ii77.
16. Schrader P, Mooser G, Peter RU, et al. Preliminary results in the therapy of psoriatic arthritis with mycophenolate mofetil. Z Rheumatol, 2002, 61: 545-550.
17. Takada K, Danning CL, Kuroiwa T, et al. Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects. Ann Rheum Dis, 2003, 62: 1112-1115.
18. Mease PJ, Antoni CE. Psoriatic arthritis treatment: biological response modifiers. Ann Rheum Dis, 2005, 64 (Suppl2): ii78-82.
19. Mease PJ, Kivitz AJ, Burch FX, et al. Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept. J Rheumatol, 2006, 33(4):712-721.
20. Antoni C, Kavanaugh A, Kirkham B, et al. The infliximab multinational psoriatic arthritis controlled trial (IMPACT): substantial efficacy on synovitis and psoriatic lesions with or without concomitant DMARD therapy. Arthritis Rheum, 2005 (in press).
21. Kavanaugh A, Krueger G, de Vlam K, et al. Infliximab improves arthritis and psoriasis in patients with active polyarticular psoriatic arthritis: results of the IMPACT II trial. Ann Rheum Dis, 2004, 63(suppl l):402.
22. Kavanaugh A, Antoni CE, Gladman D, et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year. Ann Rheum Dis, 2006, 65(8): 1038-1043.
23. Mease P, Gladman D, Ritchlin C, et al. Adalimumab therapy in patients with psoriatic arthritis: 24-week results of a phase III study. Arthritis Rheum, 2004,50: 4097.
24. Nikas SN, Drosos AA. Onercept. Serono. Curr Opin Investig Drugs. 2003, 4: 1369-1376.
25. Kraan MC, vanKuijk AW, Dinant HJ, et al. Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum, 2002,46: 2776-2784.
26. Utset TO, Auger JA, Peace D, et al. Modified anti-CD3 therapy in psoriatic arthritis: a phase I/II clinical trial. J Rheumatol, 2002, 29:1907-1913.
27. McInnes IB, Illei GG, Danning CL, et al. IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function inpatients with psoriatic arthritis. J Immunol, 2001, 167: 4075-4082.