托珠单抗治疗难治性全身型幼年特发性关节炎25例回顾性分析

Successful treatment of refractory systemic＇ onset juvenile idiopathic arthritis with tocilizumab： a retrospective analysis of 25 cases

目的研究观察生物制剂托珠单抗治疗难治性全身型幼年特发性关节炎（SoJIA）的疗效和安全性。方法2005年5月至2016年2月收住院并长期门诊随诊的难治性SoJIA患儿25例，患儿均应用过NSAIDs、激素、甲氨蝶呤或环孢素A、注射用重组人Ⅱ型肿瘤坏死因子受体．抗体融合蛋白（益赛普）等治疗均不能控制病情，CRP、ESR、铁蛋白等炎性指标反复升高，关节肿痛反复发生，对存在活动性SoJIA（病程≥6个月，且对NSAIDs和糖皮质激素应答不佳）的患儿予以生物制剂托珠单抗治疗（体质量≥30kg者剂量8nlg／kg；体质量〈30kg者剂量12mg／kg；每4周1次给药）。对其中22例患儿治疗前后的CRP、ESR、白细胞、中性粒细胞、血红蛋白、血小板、ALT、AST、LDH、球蛋白等实验室指标进行数据收集分析，比较治疗前后发热、皮疹、肝脾肿大、关节肿痛等临床症状的改善情况，并长期随访，观察激素用量的改变。采用，检验或方差分析进行数据分析。结果22例患儿经托珠单抗治疗后第24周与治疗前对比，CRP[（8．7±2．2）mg／L和（111．6±74．4）mg／L，F=5．192，P=0．002]、ESR[（6．4±6．3）mm／1b）和（65．6±24.3）mm／1h，F=50．393，P〈0.01]、白细胞[（8．4±2．5）×10^9／L和（17．6±8．6）×10^9／L，F=9．321，P〈0．01]、中性粒细胞[（4．9±2．4）×10^9／L和（14．4±8．7）×10^9／L，F=10．541，P〈0．01]、血小板[（269．5±79．2）×10^9／L和（405．4±145．3）×10^9／L，F=5．704，P〈0．01]、球蛋白[（19．2±4．1）g／L和（30．1±3．8）g／L，F=22．896，P〈0．01]等实验室指标迅速下降，血红蛋白[（118．3±9．0）g／L和（108．5±9．8）g／L，F=4．693，P=0．002]明显升高；发热、皮疹、肝脾肿大、关节肿痛明显好转,激素用量[（1．25±3．8）mg·kg-1·d-1和（16．2±12．8）mg·kg-1·d-1，F=8．21，P〈0．01]明显减少，治疗前后比较，差异具有统计学意义（P〈0．05）；治疗后ACR Pedi30／50／70／90获得改善；25例患儿中有3例出现不良反应，未纳入统计。结论生物制剂托珠单抗治疗难治性SoJIA具有较好的临床疗效。药物不良反应包括感染、过敏反应、中性粒细胞减少、转氨酶水平升高等，但发生率低，临床应用比较安全。但由于病例数还较少，有待进一步研究。

Objective To investigate the efficacy and safety of tocilizumab inpatients with refractory systemic＇onset juvenile idiopathic arthritis （SoJIA）, and to provide a new option for the treatment of this severe disease. Methods We retrospectively studied 25 cases of hospitalized patients with refractory SoJIA treated withtocilizumab, of whom 22 had data that fit for analysis, from May 2005 to February 2016. Data of 22 cases were collected retrospectively from physicians in charge of the patients. Children with SoJIA were treated with nonsteroidal antiinflammatory drugs （NSAIDs）, Glucocorticoid （GC）, methotrexate, cyclosporin A, etanerceptetc before, but still in high disease activity due to inadequate response were involved. Weretrospective analyzedthe laboratory test results like Creactive protein （CRP）, Erythrocyte sedimentation rate （ESR）, Ferritin and other inflammatory index. Improvement of pain,fever, rash, hepatosplenomegaly and lymphadenectasis of active SoJIA （disease course ≥6 months, and inadequate response to NSAIDs and GC） after tocilizumab treatment （Body weight ≥30 kg, 8 mg/kg; Body weight〈30 kg, 12 mg/kg, per 4 weeks） were analyzed. Safety data of 22 cases were collected throughout the treatment period including neutropenia, infections, anaphylaxis and elevated liver enzymes etc. We also retrospectively analyzedthe dose change of GC and the long＇ term effect. Dichtomous paramenters were compared teween groups using the X2 test. Continuous parameters were compared using the analysis of uariance. Results In comparison to the indices before the treatment, the level of CRP [（8.7±2.2） mg/L vs （111.6±74.4） mg/L, F=5.192, P=0.002], ESR [（6.4±6.3） mm/1 h） vs （65.6±24.3） mm/1 h, F=50.393, P=0.000], white blood cell （WBC） [（8.4±2.5）×109/L vs （17.6±8.6）×109/L, F=9.321, P=0.000], Neutrophil count [（4.9±2.4）×109/L vs （14.4±8.7）×109/L, F=10.541, P=-0.000], blood platelet （PLT） [（269.5±79.2）×109/L vs （405.4± 145.3）×109/L, F=5.704, P=0.000] and globulin [（19.2±4.1） g/L vs （30.1±3.8） g/L, F=22.896, P=0.000] decreased rapidly and hemoglobin [（118.3±9.0） g/L vs （108.5±9.8） g/L, F=4.693, P=0.002] increased significantly at 24 weeks after Tocilizumab （TCZ） treatment. Clinical manifestationssuch as fever, rash, hepatosplenomegaly, joint swelling and pain were significantly improved. GC dose [（1.25±3.8） mg·kg-1·d-1 vs （16.2±12.8） mg·kg-1·d-1, F=8.21, P=0.000] were significantly reduced after TCZ treatment （P〈0.05）; American College of Rheumatology （ACR） Pedi 30/50/70/90 was improved after TCZ treatment. Adverse events occurred in 3 cases of 25 children, who were not included in the statistical analysis group. Conclusion This retrospective case series has demonstrated the efficacy of tocilizumab in SoJIA, low incidence of adverse reactions. Further studies are needed to be developed because this case series haslimited sample size.