丝裂原细胞外激酶抑制剂致垂头综合征文献病例分析

Literature analysis of dropped head syndrome induced by mitogen-activated extracellular signal regulated kinase inhibitors

目的探讨丝裂原细胞外激酶(MEK)抑制剂相关垂头综合征(DHS)的临床特点。方法检索PubMed和Embase数据库(截至2020年12月20日),收集报道MEK抑制剂致DHS的临床研究和病例报告类文献,提取患者相关信息(性别、年龄、原发病、MEK抑制剂应用情况、DHS发生时间、临床表现、治疗与转归等)进行描述性统计分析。结果纳入分析的患者共7例,美国4例,法国2例,德国1例;男性4例,女性3例;年龄56~76岁;原发病为黑色素瘤者6例,Erdheim-Chester病1例;所用MEK抑制剂为司美替尼者3例,考比替尼2例,比美替尼和曲美替尼各1例。首次用药至发生DHS的时间为0.5~20个月,中位时间1(1,2)个月;主要症状为颈部疼痛、颈伸肌无力和抬头受限,可伴有颈部僵硬,疼痛可扩散至肩部、头枕部,个别表现为肩胛间疼痛。诊断DHS时7例患者血清肌酸激酶(CK)水平均升高(150~1011 U/L)。诊断DHS后,5例患者停服MEK抑制剂,DHS症状缓解或消失;2例患者加用糖皮质激素治疗1~4周,DHS症状未缓解,停服MEK抑制剂,DHS症状改善。7例患者DHS症状缓解、血清CK恢复正常的时间为停药后14~30 d。3例患者减量再次用药,1例DHS未复发;2例DHS轻度复发,可自行缓解或维持病情稳定。结论MEK抑制剂相关DHS多发生在用药1个月内,伴有血清CK升高。及时停药,DHS症状可缓解或消失,血清CK水平可恢复正常。

Objective To explore the clinical features of dropped head syndrome(DHS)related to mitogen-activated extracellular signal regulated kinase inhibitors.Methods Case reports of dropped head syndrome caused by MEK inhibitors were collected by searching PubMed and Embase databases as of December 20,2020.The following information of patients including gender,age,primary diseases,use of MEK inhibitors,occurrence time and clinical symptoms of DHS,and treatments and outcomes were extracted and analyzed descriptively.Results A total of 7 patients were entered;4 from the United States,2 from France,and 1 from Germany.There were 4 males and 3 females,aged from 56 to 76 years.The primary diseases were metastatic melanoma in 6 patients and Erdheim-Chester disease in 1 patient.Of them,3 patients were treated with selumetinib,2 were with cobimetinib,and 1 was with binimetinib and trametinib respectively.Time from the first application of MEK inhibitors to the onset of DHS was from 0.5 to 20 months with a median time of 1(1,2)month.Major symptoms of DHS were neck pain,neck extensor weakness,and limited head lifting,which might be accompanied by neck stiffness in some patients.The pain on the neck could spread to the shoulders and occipital region,and a few patients might only have interscapular pain.At the time of diagnosis of DHS,the serum concentration of creatine kinase(CK)was elevated(150~1011 U/L).After the diagnosis of DHS,5 patients stopped taking MEK inhibitors and DHS symptoms were relieved or disappeared;2 patients were treated with glucocorticoids for 1 to 4 weeks,but DHS symptoms were not relieved,then they stopped taking MEK inhibitors and DHS symptoms were improved.In total,the symptoms of DHS in the 7 patients were relieved after 14-30 days of MEK inhibitors withdrawal,with serum CK returning to within normal range.Three patients rechallenged MEK inhibitors with reduced doses;1 patient had no recurrence of DHS and the remaining 2 patients had mild recurrences of DHS,which could resolve spontaneously or stay a stable condition.Conclusions DHS related to MEK inhibitors usually occurs within 1 month of medication,accompanied by an increase in CK level.The symptoms can be relieved or disappear after stopping medication in time and CK level will return to normal.