重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白剂量递减联合改善病情的抗风湿药治疗外周型活动性强直性脊柱炎的临床评价

Tapering of recombinant human tumor necrosis factor receptor-Fc fusion protein dosage combined with DMARDs in the treatment of peripheral joints involvement of ankylosing spondylitis

目的评价重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白（rhTNFR—Fc）剂量递减联合改善病情的抗风湿药（DMARDs）治疗外周型活动性强直性脊柱炎（AS）的临床疗效和安全性。方法第一阶段，即开始后的头8周，将60例纳入研究的AS患者按年龄、病程、病情、疾病活动性配对，然后随机纳入rhTNFR—Fc正常推荐剂量（25mg，每周2次×16次，皮下注射）作为对照组和rhTNFR—Fc剂量递减（25mg，每周1次×4次；随后改为12．5mg，每周1次×4次；再改为12．5mg，每10d1次×6次；后改为12．5mg，每15d1次×4次，皮下注射）＋甲氨蝶呤（MTX）（7．5mg，每周1次，口服）＋柳氮磺砒啶（SASP）（1g，每日2次，口服）＋沙利度胺（100mg，每晚1次，口服）联合治疗为受试组。第二阶段即第9．24周为开放研究，在原有30例的基础上新纳入42例，全部采用受试组治疗方案治疗。全部病例在第0、4、8、16、24周进行临床和实验室评价。结果在第一阶段到达4周时，总体疗效评价达到AS疗效评价标准20％（ASAS20）改善标准者2组均为100％，达到ASAS50改善标准者对照组为97％（29／30），受试组为83％（25／30）；当第8周时，2组达到ASAS20改善标准者均为100％，达到ASAS50改善标准者对照组为100％（13／13例），受试组为97％（29／30例）；差异均无统计学意义（P〉0.05）。在第二阶段72例纳入开放研究，16周时，72例全部获得ASAS20改善标准，63例（88％）获得ASAS50改善标准；24周时，72例（100％）均保持ASAS20改善标准，71例（99％）获得ASAS50改善标准。安全性和耐受性均佳，2组患者中各有1例出现感染，1例转氨酶轻度升高，受试组中有2例白细胞轻度降低，对照组中2例有注射部位的皮肤反应。结论rhTNFR—Fc剂量递减联合DMARDs治疗外周型活动性AS是一种高效、优价、安全、具有良好耐受性和依从性的好方法，少数病例出现转氨酶轻度升高、白细胞轻度降低和感染增加，需予关注。

Objective To evaluate the clinical efficacy and safety of tapering the dosage of recombinant human tumor necrosis factor receptor-Fc fusion protein （rhTNFR-Fc） combined with DMARDs in the treatment of peripheral joints involvement of ankylosing spondylitis. Methods Sixty patients who met the classification criteria of ankyloding spondylitis were enrolled. Meanwhile, all patients had one or more of the following joint involvement： hip, knee, ankle, and shoulder. Their BASDAI was higher than 4, joint pain VAS ≥4, ESR≥30 mm/lh and CRP≥8 mg/L. Tuberculosis, hepatitis B, hepatitis C infection or other microorgan-isms infections were excluded. All enrolled patients had no serious heart,liver, kidney, or other internal organ involvement. During the first stage （The first eight weeks patients were matched by age and, disease activity, then randomly divided into the rhTNFR-Fc （the control group） treatment group in which patients were treated with 25 mg rhTNFR-Fc subcutaneous injection twice per Week for 4 months） and rhTNFR-Fe dosage tapering group in which 25 mg rhTNFR-Fc were subcutaneously injected once per week for 4 weeks and then followed by 12.5 mg per week for 4 weeks, then once every 10 days for 6 times. Then the dosage of rhTNFR-Fc dosage of the dosage tapering group （the experimental group） was changed to 12.5 mg subcutaneous injection once every 15 days for another 4 times combined with methotrexate 7.5 mg per week and Salfasalazine 2 g daily and thalidomide 100 mg per night. The second stage started from week 9 to 24. In addition to the 30 cases at the first stage, 42 cases were included based on the same inclusion criteria for stage one. Patients＇ clinical and laboratory parameters were evaluated at week 0, 4, 8, 16 and 24. Results During the first four weeks, all patients of both control group and experimental group reached ASAS20, 97% （29/30） patients reached ASAS50 in the control group, 83% （25/30） patients reached ASAS50 in the experimental group. At week 8, patients in both groups maintained at 100% ASAS20 improvement, 100% （13/13） patients in the control group reached ASAS50, and that of the experimental group was 97% （29/30）, the differences between the two groups were not statistically significant （P〉0.05）. In the second stage, 72 cases （100%） could achieve ASAS20, 63 cases （88%） achieved ASAS50 at week 16. At week 24, 72 cases （100%） remained to achieve ASAS20, 71 cases （99%） achieved ASAS50. The safety and compliance of the two groups were good. Two cases developed infection, one patient had mild elevation of serum transaminase. Conclusion Tapering the dosage combined with DMARDs is an effective and safe approach in the treatment of peripheral joints involvement of ankylosing spondylitis. The compliance of this strategy is good and only few patients have serum transaminase elevation. But attention should be paid to the increased rate of infection.