小剂量甲基泼尼松龙联合静脉丙种球蛋白治疗静脉丙种球蛋白无反应型川崎病的疗效分析
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摘要
背景用标准方案治疗静脉丙种球蛋白(IVIG)无反应型川崎病存在部分患儿治疗无效的问题,此部分患儿形成冠脉瘤的风险增加,给予生物制剂或大剂量甲基泼尼松龙冲击治疗,经济压力及不良反应大,需要制定更为有效的治疗方案。目的观察小剂量甲基泼尼松龙联合IVIG治疗IVIG无反应型川崎病的疗效和安全性。方法于2013年1月—2017年1月,采用随机数字表法将114例IVIG无反应型川崎病患儿分为对照组和观察组,每组57例。对照组给予第2次IVIG冲击治疗,观察组在第2次IVIG冲击治疗的同时加用小剂量甲基泼尼松龙治疗。比较两组患儿的治疗有效率,第2次IVIG治疗前及治疗后72 h血清C反应蛋白(CRP)、白介素6(IL-6)、肿瘤坏死因子-α(TNF-α)水平,第2次IVIG治疗前及治疗后1、3、6、12个月时冠状动脉损伤率及药物不良反应。结果观察组患儿的治疗有效率为91.2%(52/57),高于对照组的75.4%(43/57),差异有统计学意义(P<0.05)。第2次IVIG治疗前两组患儿血清CRP、IL-6、TNF-α水平及冠状动脉损伤率比较,差异无统计学意义(P>0.05);第2次IVIG治疗后72 h观察组CRP、IL-6、TNF-α水平低于对照组,差异有统计学意义(P<0.05);第2次IVIG治疗后1、3个月时冠状动脉损伤率观察组低于对照组,差异有统计学意义(P<0.05);治疗后6、12个月时两组冠状动脉损伤率比较,差异无统计学意义(P>0.05)。观察组5例出现低体温、1例出现窦性心动过缓,2～3 d自行恢复正常。结论小剂量甲基泼尼松龙联合IVIG治疗IVIG无反应型川崎病,可以明显提高临床疗效,降低炎性反应,促进损伤冠状动脉恢复,且具有较高的安全性。
Background Some children with Kawasaki disease(KD) unresponsive to intravenous immunoglobulin(IVIG) also show no response to standard therapy,resulting in a higher risk of developing coronary aneurysm. Biologic drug therapy or high-dose intravenous methylprednisolone pulse therapy(IMPT) is effective,but it is high-cost and induces severe side effects. Thus it is necessary to develop highly effective,yet inexpensive treatments. Objective To investigate the clinical efficacy and safety of low-dose methylprednisolone combined with IVIG in the treatment of KD unresponsive to IVIG. Methods From January 2013 to January 2017,by use of the random number table method,114 cases of KD unresponsive to IVIG were evenly divided into the observation group and control group,receiving a second IVIG with low-dose methylprednisolone,a second IVIG,respectively. Serum C-reactive protein(CRP),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α) levels before and at 72 hours after this round of treatment were measured for evaluating the treatment response. And the incidence of coronary artery injury before and at 1,3,6,12 months after this round of treatment as well as adverse drug reactions during the treatment were measured for evaluating the treatment safety. Results The response rate of the observation group was much higher than that of the control group[91.2%(52/57) vs 75.4%(43/57)](P<0.05). Before the treatment,the serum CRP,IL-6,and TNF-α levels were similar in both groups(P>0.05),but they were much lower in the observation group than those of the control group at 72 hours after the treatment(P<0.05). The incidence of coronary artery injury was similar in both groups before the treatment(P>0.05),but it decreased significantly in the observation group at 1,3 months after treatment(P<0.05),then became similar in both groups at 6,12 months after treatment(P>0.05). Five cases had hypothermia and one case had sinus bradycardia in the observation group,but they recovered without treatment within 2 to 3 days after onset. Conclusion For patients with KD unresponsive to IVIG,low-dose methylprednisolone combined with IVIG can significantly improve the clinical efficacy,reduce inflammatory response,and promote the recovery of injured coronary artery with high safety.
Background Some children with Kawasaki disease(KD) unresponsive to intravenous immunoglobulin(IVIG) also show no response to standard therapy,resulting in a higher risk of developing coronary aneurysm. Biologic drug therapy or high-dose intravenous methylprednisolone pulse therapy(IMPT) is effective,but it is high-cost and induces severe side effects. Thus it is necessary to develop highly effective,yet inexpensive treatments. Objective To investigate the clinical efficacy and safety of low-dose methylprednisolone combined with IVIG in the treatment of KD unresponsive to IVIG. Methods From January 2013 to January 2017,by use of the random number table method,114 cases of KD unresponsive to IVIG were evenly divided into the observation group and control group,receiving a second IVIG with low-dose methylprednisolone,a second IVIG,respectively. Serum C-reactive protein(CRP),interleukin-6(IL-6),and tumor necrosis factor-alpha(TNF-α) levels before and at 72 hours after this round of treatment were measured for evaluating the treatment response. And the incidence of coronary artery injury before and at 1,3,6,12 months after this round of treatment as well as adverse drug reactions during the treatment were measured for evaluating the treatment safety. Results The response rate of the observation group was much higher than that of the control group[91.2%(52/57) vs 75.4%(43/57)](P<0.05). Before the treatment,the serum CRP,IL-6,and TNF-α levels were similar in both groups(P>0.05),but they were much lower in the observation group than those of the control group at 72 hours after the treatment(P<0.05). The incidence of coronary artery injury was similar in both groups before the treatment(P>0.05),but it decreased significantly in the observation group at 1,3 months after treatment(P<0.05),then became similar in both groups at 6,12 months after treatment(P>0.05). Five cases had hypothermia and one case had sinus bradycardia in the observation group,but they recovered without treatment within 2 to 3 days after onset. Conclusion For patients with KD unresponsive to IVIG,low-dose methylprednisolone combined with IVIG can significantly improve the clinical efficacy,reduce inflammatory response,and promote the recovery of injured coronary artery with high safety.
引文
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[6]Research Committee of the Japanese Society of Pediatric Cardiology,Cardiac Surgery Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease.Guidelines for medical treatment of acute Kawasaki disease:report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery(2012 revised version)[J].Pediatr Int,2014,56(2):135-158.DOI:10.1111/ped.12317.
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[8]中华医学会儿科学分会心血管学组,中华医学会儿科学分会免疫学组.川崎病冠状动脉病变的临床处理建议[J].中华儿科杂志,2012,50(10):746-749.DOI:10.3760/cma.j.issn.0578-1310.2012.10.008.Cardiology Group of Chinese Academy of Pediatrics,Immunology Group of Chinese Academy of Pediatrics.Recommendations for clinical management of Kawasaki disease coronary artery disease[J].Chinese Journal of Pediatrics,2012,50(10):746-749.DOI:10.3760/cma.j.issn.0578-1310.2012.10.008.
[9]尤灿,胡彬,周舟,等.川崎病患儿血清IL-4、IL-17和TNF-α水平变化的研究[J].中国医师杂志,2012,14(1):121-123.DOI:10.3760/cma.j.issn.1008-1372.2012.01.046.YOU C,HU B,ZHOU Z,et al.Changes of serum levels of IL-4,IL-17 and TNF-αin children with Kawasaki disease[J].Journal of Chinese Physician,2012,14(1):121-123.DOI:10.3760/cma.j.issn.1008-1372.2012.01.046.
[10]YE Q,GONG F Q,SHANG S Q,et al.Intravenous immunoglobulin treatment responsiveness depends on the degree of CD8+T cell activation in Kawasaki disease[J].Clin Immunol,2016,171(10):25-31.DOI:10.1016/j.clim.2016.08.012.
[11]WANG Y,WANG W,GONG F,et al.Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease[J].Arthritis Rheum,2013,65(3):805-814.DOI:10.1002/art.37815.
[12]STAHN C,BUTTGEREIT F.Genomic and nongenomic effects of glucocorticoids[J].Nat Clin Pract Rheumatol,2008,4(10):525-533.DOI:10.1038/ncprheum089.
[13]WANG J,ZHOU N,WU S,et al.Changes in 11β-hydroxysteroid dehydrogenase and glucocorticoid receptor expression in Kawasaki disease[J].Korean Circ J,2017,47(3):377-382.DOI:10.4070/kcj.2016.0257.
[14]MIURA M,OHKI H,YOSHIBA S,et al.Adverse effects of methylprednisolone pulse therapy in refractory Kawasaki disease[J].Arch Dis Child,2005,90(10):1096-1097.DOI:10.1136/adc.2004.062299.
[15]F?RSTER C,KAHLES T,KIETZ S,et al.Dexamethasone induces the expression of metalloproteinase inhibitor TIMP-1in the murine cerebral vascular endothelial cell line cEND[J].J P h y s i o l,2 0 0 7,5 8 0(P t 3):9 3 7-9 4 9.D O I:10.1113/jphysiol.2007.129007.
[16]CHEN S,DONG Y,KIUCHI M G,et al.Coronary artery complication in Kawasaki disease and the importance of early intervention:a systematic review and meta-analysis[J].JAMAPediatr,2016,170(12):1156-1163.DOI:10.1001/jamape diatrics.2016.2055.
[17]WARDLE A J,CONNOLLY G M,SEAGER M J,et al.Corticosteroids for the treatment of Kawasaki disease in children[J].Cochrane Database Sys Rev,2017,1:CD011188.DOI:10.1002/14651858.CD011188.pub2.
[2]SLEEPER L A,MINICH L L,MCCRINDLE B M,et al.Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance[J].J Pediatr,2011,158(5):831-835.DOI:10.1016/j.jpeds.2010.10.031.
[3]杨珊,贾文.甲基泼尼松龙治疗静脉丙种球蛋白无反应型川崎病的疗效观察[J].临床合理用药杂志,2017,10(5):21-22.DOI:10.15887/j.cnki.13-1389/r.2017.05.010.YANG S,JIA W.Curative effect observation of methylprednisolone on IVIG non-responsiveness Kawasaki disease[J].Chinese Journal of Clinical Rational Drug Use,2017,10(5):21-22.DOI:10.15887/j.cnki.13-1389/r.2017.05.010.
[4]高文珺,范晓晨.丙球无反应性川崎病的诊断及治疗进展[J].安徽医学,2017,38(7):951-954.DOI:10.3969/j.issn.1000-0399.2017.07.045.GAO W J,FAN X C.Progress in diagnosis and treatment of globus C nonreactive Kawasaki disease[J].Anhui Medical Journal,2017,38(7):951-954.DOI:10.3969/j.issn.1000-0399.2017.07.045.
[5]胡坚.川崎病急性期治疗进展[J].中国实用儿科杂志,2015,30(1):1-4.DOI:10.7504/ek2015010601.HU J.Treatment progress of Kawasaki disease at acute stage[J].Chinese Journal of Practical Pediatrics,2015,30(1):1-4.DOI:10.7504/ek2015010601.
[6]Research Committee of the Japanese Society of Pediatric Cardiology,Cardiac Surgery Committee for Development of Guidelines for Medical Treatment of Acute Kawasaki Disease.Guidelines for medical treatment of acute Kawasaki disease:report of the Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery(2012 revised version)[J].Pediatr Int,2014,56(2):135-158.DOI:10.1111/ped.12317.
[7]MCCRINDLE B W,ROWLEY A H,NEWBURGER J W,et al.Diagnosis,treatment,and long-term management of Kawasaki disease:a scientific statement for health professionals from the American Heart Association[J].Circulation,2017,135(17):e927-999.DOI:10.1161/CIR.0000000000000484.
[8]中华医学会儿科学分会心血管学组,中华医学会儿科学分会免疫学组.川崎病冠状动脉病变的临床处理建议[J].中华儿科杂志,2012,50(10):746-749.DOI:10.3760/cma.j.issn.0578-1310.2012.10.008.Cardiology Group of Chinese Academy of Pediatrics,Immunology Group of Chinese Academy of Pediatrics.Recommendations for clinical management of Kawasaki disease coronary artery disease[J].Chinese Journal of Pediatrics,2012,50(10):746-749.DOI:10.3760/cma.j.issn.0578-1310.2012.10.008.
[9]尤灿,胡彬,周舟,等.川崎病患儿血清IL-4、IL-17和TNF-α水平变化的研究[J].中国医师杂志,2012,14(1):121-123.DOI:10.3760/cma.j.issn.1008-1372.2012.01.046.YOU C,HU B,ZHOU Z,et al.Changes of serum levels of IL-4,IL-17 and TNF-αin children with Kawasaki disease[J].Journal of Chinese Physician,2012,14(1):121-123.DOI:10.3760/cma.j.issn.1008-1372.2012.01.046.
[10]YE Q,GONG F Q,SHANG S Q,et al.Intravenous immunoglobulin treatment responsiveness depends on the degree of CD8+T cell activation in Kawasaki disease[J].Clin Immunol,2016,171(10):25-31.DOI:10.1016/j.clim.2016.08.012.
[11]WANG Y,WANG W,GONG F,et al.Evaluation of intravenous immunoglobulin resistance and coronary artery lesions in relation to Th1/Th2 cytokine profiles in patients with Kawasaki disease[J].Arthritis Rheum,2013,65(3):805-814.DOI:10.1002/art.37815.
[12]STAHN C,BUTTGEREIT F.Genomic and nongenomic effects of glucocorticoids[J].Nat Clin Pract Rheumatol,2008,4(10):525-533.DOI:10.1038/ncprheum089.
[13]WANG J,ZHOU N,WU S,et al.Changes in 11β-hydroxysteroid dehydrogenase and glucocorticoid receptor expression in Kawasaki disease[J].Korean Circ J,2017,47(3):377-382.DOI:10.4070/kcj.2016.0257.
[14]MIURA M,OHKI H,YOSHIBA S,et al.Adverse effects of methylprednisolone pulse therapy in refractory Kawasaki disease[J].Arch Dis Child,2005,90(10):1096-1097.DOI:10.1136/adc.2004.062299.
[15]F?RSTER C,KAHLES T,KIETZ S,et al.Dexamethasone induces the expression of metalloproteinase inhibitor TIMP-1in the murine cerebral vascular endothelial cell line cEND[J].J P h y s i o l,2 0 0 7,5 8 0(P t 3):9 3 7-9 4 9.D O I:10.1113/jphysiol.2007.129007.
[16]CHEN S,DONG Y,KIUCHI M G,et al.Coronary artery complication in Kawasaki disease and the importance of early intervention:a systematic review and meta-analysis[J].JAMAPediatr,2016,170(12):1156-1163.DOI:10.1001/jamape diatrics.2016.2055.
[17]WARDLE A J,CONNOLLY G M,SEAGER M J,et al.Corticosteroids for the treatment of Kawasaki disease in children[J].Cochrane Database Sys Rev,2017,1:CD011188.DOI:10.1002/14651858.CD011188.pub2.