重组人Ⅱ型肿瘤坏死因子受体-抗体Fc融合蛋白对幼年特发性关节炎患者细胞因子和骨代谢的影响

Effect of recombinant human tumor necrosis factor receptor type Ⅱ - Fc fusion protein antibody on cytokines and bone metabolism in patients with juvenile idiopathic arthritis

目的 观察重组人Ⅱ型肿瘤坏死因子受体-抗体Fc融合蛋白对幼年特发性关节炎（JIA）患者细胞因子和骨代谢的影响.方法 采用前瞻性、非随机、对照、开放研究.纳入自2006年12月至2009年6月广东省人民医院诊治的活动性JIA患者,共31例,年龄平均（12.7±2.3）岁.研究第1阶段（0～3个月）,根据患者经济情况分别纳入实验组和对照组治疗.两组患者在病程、年龄、性别等方面匹配.试验组的给药方案为重组人Ⅱ型肿瘤坏死因子受体-抗体Fc融合蛋白（益赛普）0.4 mg/kg,皮下注射,2次/周,患者共18例,其中附着点炎型15例,多关节炎型2例,全身型1例 对照组给药方案为甲氨蝶呤10 mg·m-2·周-1,2例不能耐受者换用柳氮磺胺吡啶（SASP）30～50mg·kg-1·d-1,患者共13例（附着点炎型9例,多关节炎型2例,全身型2例）,两组多关节炎型和全身型患者允许使用稳定剂量的非甾类抗炎药（NSAID）或小剂量糖皮质激素.第2阶段（3～6个月）,有效者继续原治疗,试验组益赛普减量为0.4 mg·kg-1·周-1,合并外周关节炎或治疗无效者可以加用SASP.分别在治疗前和1、3及6个月随访.观察肿瘤坏死因子-α（TNF-α）、基质金属蛋白酶-3（MMP-3）、白细胞介素-1β（IL-1β）、骨钙素、β-胶原分解片断（β-CTx）、碱性磷酸酶（ALP）、红细胞沉降率（ESR）、C反应蛋白（CRP）和骨密度的动态变化.结果 两组ALP、腰椎正侧位骨密度随治疗明显升高,TNF-α、IL-1β、ESR、CRP随治疗延长明显下降（P〈0.05）.治疗1个月后两组间ESR分别为（16±8）mm/h比（60±38）mm/h,CRP分别为（10±7）mg/L比（47±37）mg/L,β-CTx分别为2.1±0.8 vs 1.1±0.9μg/L,差异有统计学意义.两组骨钙素逐渐增加,且试验组高于对照组 MMP-3有下降趋势,但组间和各时间点的差异无统计学意义.股骨Ward＇s三角区和前臂骨骨密度均无明显变化.其中1例骨折不愈合达2年者经益赛普治疗6个月后复查X线已愈合并拆除内固定钢板.结论 益赛普和传统DMARD均能明显降低TNF-α、IL-1β、ESR、CRP水平,同时提升腰椎骨密度和ALP水平达到控制炎症的作用,益赛普治疗对急性时相指标及骨代谢指标的改善早于传统DMARD,从而更早改善病情,减少骨破坏.

Objective To evaluate the influence of the recombinant human type Ⅱ tumor necrosis factor receptor-antibody Fc fusion protein （rhTNFR：Fc） on cytokines and bone metabolism in patients with juvenile idiopathic arthritis （JIA）.Methods This was a prospective,non-randomized,controlled and openlabel study.Thirty-one patients with JIA in active state were enrolled at our hospital from December 2006 to June 2009.The mean age was 12.7±2.3 years.Exclusive criteria included infection with tuberculosis and hepatitis B etc.,abnormal renal or hepatic function.Study consists of two phases.During the first phase （0-3 months）,according to the economic status,all JIA patients were divided into treatment and control groups.The treatment group consisted of 18 patients （enthesitis-related arthritis,n = 15 polyarticular-onset arthritis,n =2 systemic-onset type,n = 1 ） on a regimen of rhTNFR：Fc 0.4 mg/kg,subcutaneously injected twice weekly.The control group contained 13 patients （enthesitis-related arthritis,n = 9 polyarticular-onset arthritis,n=2 systemic-onset type,n =2） on a regimen of MTX 10 mg·m-2·w-1 Two intolerance patients were given suffasalazine （SASP） 30-50 mg·kg-1·d-1.During the second phase （3-6 months）,the responding patients continued the original therapy.The rhTNFR：Fc group received a reduced dosage of 0.4 mg·kg- 1 ·w-1.All patients of both groups who became complicated with peripheral arthritis or were non-responding had the addition of SASP.Follow-up was conducted at baseline,1 month,3months and 6 months.And TNF-α,MMP-3,IL-1β,osteocalcin （BGP）,β-collagen fragment （β-CTx）,alkaline phosphatase,erythrocyte sedimentation rate （ESR）,c-reactive protein （CRP） and bone mineral density dynamic changes were examined respectively in the treatment process.Results Alkaline pbosphatase and lumbar spine bone mineral density increased while TNF-α,IL-1β,ESR and CRP decreased significantly in two groups （P〈0.05）.ESR were 16±8.0 mm/h vs 60±38 mm/h,CRP 10±7 mg/L vs 47 ±37 mg/Land β-CTx 2.1±0.8 vs 1.1±0.9 μg/L at 1 month in two groups respectively with statistic difference （ P〈0.05）.BGP increased and MMP-3 decreased in both groups with no statistic difference.Femur Ward＇s triangular area and forearm bone mineral density had no statistic difference between two groups.Interestingly,one case with bone fracture for two years has healed after a 6-month therapy of rhTNFR：Fc as proved by X-ray.Conclusion Both rhTNFR：Fc and traditional DMARDs both can reduce the levels of TNF-α,IL-1β,ESR and CRP and increase lumbar spine bone mineral density and ALP significantly.RhTNFR：Fc improves the acute phase index and bone metabolism index earlier than the traditional therapy.Thus disease and bone destruction are controlled more earlier.