摘要目的 观察托珠单抗联合甲氨蝶呤治疗难治性AOSD的疗效和安全性,并初步探讨病情控制后托珠单抗减量的可能性.方法 28例难治性AOSD患者,接受托珠单抗(8 mg/kg,每4周1次静脉滴注,病情缓解后第6个月,减量为每8周静脉滴注8 mg/kg),联合甲氨蝶呤(每周12.5 mg口服)治疗,观察治疗前及治疗后2、4、8、12、24、36、48周时体温、皮疹、关节肿痛、肝脾肿大、血常规、ESR、CRP、血清铁蛋白、激素使用剂量的改善情况,记录治疗期间不良反应的发生.采用x2检验和重复测量方差分析进行统计学分析.结果 与治疗前相比,托珠单抗治疗AOSD患者8周后所有患者体温正常、皮疹及关节肿痛消失,48周时病情维持缓解,CRP[(125.4±48.3)mg/L,(6.1±2.5)mg/L和(4.9±1.8)mg/L,F=77.034,P<0.01]、ESR[(103±31)mm/1 h,(17±7)mm/1 h和(16±4)mm/1 h,F=55.73,P<0.01]、白细胞[(18.1±5.3)×109/L,(8.2±2.9)×109/L和(7.2±2.1)×109/L,F=24.71,P<0.01]、中性粒细胞[(16.7±4.9)×109/L,(6.1±2.2)×109/L和(4.9±2.3)×109/L,F=35.295,P<0.01]、血小板[(312±83)×109/L,(199±40)×109/L)和(204±47)×109/L,F=7.139,P<0.01]、血红蛋白[(100±9)g/L,(116±9)g/L和(119±8)g/L,F=9.852,P<0.01]、铁蛋白[(3542±1313)ng/ml),(2342±923)ng/ml和(277±102)ng/ml,F=34.232,P<0.01]明显改善,第12、24、36、48周临床症状及实验室检查持续改善.治疗2周后,泼尼松使用剂量从(71.4±20.7)mg/d减量至(55.0±11.1)mg/d(P<0.05),后泼尼松剂量持续减少,48周时为(3.3±2.1)mg/d(P<0.05),治疗36周后有5例(17.9％)患者停用泼尼松,48周时7例(25％)患者停用泼尼松.无严重不良反应发生.结论 托珠单抗能迅速并显著改善难治性AOSD患者的临床症状及实验室检查,并有助于激素的减量、停用,减量后病情仍维持稳定,且安全性良好.

abstractsObjective To observe the efficacy and safety of tocilizumab combined with methotrexate (MTX) in the treatment of refractory adult-onset Still's disease (AOSD), and to explore whether it is possible to reduce the dose of tocilizumab when disease is under control. Methods Twenty-eight patients with refractory AOSD received the treatment of tocilizumab (8 mg/kg, Intravenous infusion every 4 weeks, and reduced to 8 mg/kg every 8 weeks after 6 months of remission) combined with MTX (12.5 mg oral intake per week). The clinical efficacy, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin level and dose change of glucocorticoid (GC) were observed prior to treatment initiation and 2, 4, 8, 12, 24, 36, 48 weeks after treatment. All adverse reactions were recorded. The Chi-square test and repetitive measure analysis of variance were used for statistical analysis. Results Compared with the baseline levels, our results showed that after 8-weeks of treatment with tocilizumab all patients had normal body temperature, while skin rash, joint swelling and pain disappeared. CRP [(125.4 ±48.3) mg/L, (6.1 ±2.5) mg/L vs (4.9 ±1.8) mg/L , F=77.034, P<0.01], ESR [(103±31) mm/1 h, (17±7) mm/1 h vs (16±4) mm/1 h, F=55.73, P<0.01], white blood cells count [(18.1± 5.3)×109/L, (8.2±2.9)×109/L vs (7.2±2.1)×109/L, F=24.71, P<0.01], neutrophils count [(16.7±4.9)×109/L, (6.1± 2.2)×109/L vs(4.9±2.3)×109/L, F=35.295, P<0.01], blood platelets [(312±83)×109/L, (199±40)×109/L vs (204± 47)×109/L, F=7.139, P<0.01], hemoglobin [(100±9) g/L, (116±9) g/L vs (277±102) g/L, F=9.852, P<0.01], ferritin level [(3542±1313) ng/ml, (2342±923) ng/ml vs (277±102) ng/ml), F=34.232, P<0.01] were improved significantly, clinical symptoms and laboratory tests continued to improve at week 12, 24, 36 and 48, the doseof prednisone was reduced from (71.4±20.7) mg/d to (55.0±11.1) mg/d (P<0.05) After 2 weeks, and the dosage was gradually reduced to 3.3±2.1 mg/d (P<0.05) at the end of 48 weeks. Five (17.9％) patients discontinued prednisone after 36 weeks, and 7 (25％) patients at week 48, no serious adverse events were found during the treatment. Conclusion Tocilizumab can rapidly and significantly improve clinical symptoms and laboratory tests of patients with refractory AOSD and it also can help with the reduction of GC dosage. In addition, the disease remains stable after the dose reduction of tombuzumab. The safety profile is good.