托珠单抗对难治性幼年特发性关节炎全身型的治疗效果

Tocilizumab for refractory systemic juvenile idiopathic arthritis

目的 观察托珠单抗对难治性幼年特发性关节炎全身型的治疗效果和不良反应.方法 前瞻性自身病例对照研究.分析2013年12月至2016年6月在首都儿科研究所住院的符合难治性幼年特发性关节炎全身型患儿给予托珠单抗注射液（8~12 mg/kg,每2周1次静脉滴注）治疗前后的资料.检测患儿治疗前后血常规、C反应蛋白（CRP）、红细胞沉降率（ESR）、白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）等在血清中的水平,并详细记录症状、体征及临床表现.采用t检验及χ2检验对治疗前后数据进行统计学比较.结果 共入组40例患儿,年龄（6.6±3.7）岁,女25例、男15例.40例患儿应用托珠单抗前均有中等热度以上发热,其中38例应用托珠单抗后24~48 h体温降至正常.17例有关节炎的患儿应用托珠单抗4周后,13例关节症状消失,其余4例好转.10例用药前有皮疹的患儿应用托珠单抗后9例随体温下降至正常皮疹亦消退,未再反复出现,无色素沉着;1例体温正常、关节症状消失后仍然间断出现皮疹.40例患儿中38例对托珠单抗耐受性良好,2例发生皮疹、寒战等药物不良反应,经对症、抗过敏治疗后很快好转.40例患儿均未出现因治疗引起的严重感染.患儿应用托珠单抗2周后白细胞（×109/L）、CRP（mg/L）和ESR（mm/1 h）水平均明显低于治疗前,差异均有统计学意义（12.1±1.2比16.5±1.8、47±8比67±9、21±5比57±6,t=2.75、3.98、5.22,P=0.009、0、0）;血清IL-6、TNF-α浓度[ng/L,中位数（四分位间距）]差异均无统计学意义[65（207）比45（137）、14（6）比17（19）,Z=-1.247、-1.285,P=0.212、0.199].结论 托珠单抗对难治性幼年特发性关节炎全身型治疗效果较好并有一定安全性,部分患儿可发生药物不良反应.

Objective To evaluate the efficacy and side effects of tocilizumab for the treatment of systemic juvenile idiopathic arthritis. Method In this prospective self case-control study, the children diagnosed with refractory systemic juvenile idiopathic arthritis admitted to Department of Rheumatism and Immunology of Children＇＇s Hospital Affiliated to Capital Institute of Pediatrics from December 2013 to June 2016 were enrolled and information before and after treatment of tocilizumab was analyzed. The tocilizumab was introvenously guttae in a dose of 8-12 mg/kg every 2 weeks. Complete blood count, C-reactive protein （CRP）, erythrocyte sedimentation rate （ESR）, interleukin-6 （IL-6） and tumor necrosis factor-α（TNF-α） were tested before and after the application of tocilizumab. Detailed clinical manifestations were recorded. All results were analyzed byχ2 test and t test. Result Forty patients with a median age of （6.6±3.7） years were enrolled, including 15 males and 25 females. All of the patients presented with fever and 38 patients got normal temperature 24-48 hours after treatment with tocilizumab. Symptoms disappeared in 13 and improved in 4 patients after treatment among the 17 patients who presented with arthritis. Within the 10 patients who manifested with rashes, 9 patients＇＇ rashes disappeared without relapse accompanied by the normalization of temperature after the treatment of tocilizumab. One patient got normal temperature butintermittently emerged rashes after symptoms of arthritis improved. In the 40 patients, 38 well tolerated tocilizumab while 2 showed rashes and chill which disappeared shortly after antianaphylaxis treatment. No severe treatment-related infection was found in any patients. According to the study, the white blood cell counts（× 109/L）, CRP（mg/L） and ESR（mm/1h） tested 2 weeks after the treatment with tocilizumab were significantly lower than that before treatment（12.1±1.2 vs. 16.5±1.8, 47±8 vs. 67±9, 21±5 vs. 57±6,t=2.75, 3.98, 5.22,P=0.009, 0, 0, respectively）. No significant changes were found in concentration of IL-6 and TNF-α （65（207）vs. 45（137）ng/L, and 14（6） vs. 17（19）ng/L,Z=-1.247 and-1.285,P=0.212 and 0.199 respectively）. Conclusion Tocilizumab is a treatment with good efficacy and safety for refractory systemic juvenile idiopathic arthritis. Adverse effects would be found in some patients.