Fulminant capillary leak syndrome in a patient with systemic sclerosis treated with imatinib mesylate.
Fulminant capillary leak syndrome in a patient with systemic sclerosis treated with imatinib mesylate.
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接受甲磺酸伊马替尼治疗的系统性硬化症患者发生暴发性毛细血管渗漏综合征。
DOI：
10.1093/rheumatology/kew245
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Varga,John
中科院分区：
文献类型：
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作者：
Hinchcliff,MoniqueE;Lomasney,Jon;Johnson,JulieA;Varga,John
主席先生，一项甲磺酸伊马替尼的开放标签多中心单臂临床试验(格列卫，诺华，瑞士巴塞尔)招募了27名早期dcSSc受试者。受试者的书面同意是根据赫尔辛基宣言获得的，西北大学机构审查委员会批准了这项研究。试验的初步结果给出了[1]。伊马替尼与水肿症有关[1]。我们希望报告一例使用伊马替尼治疗的自发性硬化症患者发生暴发性毛细血管渗漏综合征并最终导致心源性死亡的病例。1例52岁女性，有8个月的dcSSc病史(核仁膜RP+ANA，scl-70抗体，改良Rodnan皮肤评分(MRSS)=36，无肢体水肿)进入甲磺酸伊马替尼临床试验。超声心动图显示左心功能和肺动脉压正常，有少量心包积液。在服用伊马替尼1个月(每天400 mg)后，她出现了新的面部和下肢水肿，碱性磷酸酶升高，207U/L(正常)，其他肝功能检查正常。伊马替尼服药4周，水肿消退后，每日服用200 mg恢复治疗。在重新启动伊马替尼的4周内，出现弥漫性水肿和7.7公斤(17磅)的体重增加。肝功能检查显示血清白蛋白降低(1.6g/dl)，其他结果正常，尿检显示微量蛋白尿。停用伊马替尼，但全身水肿加重，并出现大量胸膜和心包积液。尽管有利尿和心包穿刺术，但出现了大量的血管紧张症，随后出现了需要血管加压剂支持的低血压。患者在停用伊马替尼26天后死于急性心肌梗死。尸检显示为扩张型心肌病，伴有四腔扩大，并有证据表明近期有心肌梗死，尽管有轻微的动脉粥样硬化。显微镜检查显示弥漫性心内膜下纤维化，没有炎症或血管变化(图1)。甲磺酸伊马替尼是一种酪氨酸激酶抑制剂，最初用于治疗费城染色体阳性的慢性髓细胞白血病(CML)。伊马替尼针对野生型(c-Abl)和突变(bcr-abl)酪氨酸激酶，但也显示出对PDGF受体和其他非受体酪氨酸激酶的抑制活性[1]。此外，伊马替尼可阻断由转化生长因子-1诱导的纤维化反应，促使人们将其用于治疗包括SSc在内的纤维化疾病[1]。由于10名慢性粒细胞白血病患者在服用伊马替尼后发生充血性心力衰竭[2]，有潜在心脏受累证据的受试者被排除在我们的临床试验之外。水肿是伊马替尼在慢性粒细胞白血病和其他恶性肿瘤患者中常见的副作用，但当它发生时，它的特点是对利尿治疗、减少剂量或停药有反应。伊马替尼相关性水肿症的发病机制仍不十分清楚。PDGF受体在平滑肌和内皮细胞的动态平衡和修复以及维持从毛细血管到真皮内间质的流体静力梯度方面发挥重要作用[3]。在烧伤和损伤期间，间质液体压力(IFP)降低会导致间质液体流入增加，导致组织水肿。血管周围基质细胞
SIR, An open-label multicentre single-arm clinical trial of imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) enrolled 27 subjects with early dcSSc. The subjects’ written consent was obtained according to the Declaration of Helsinki, and the Northwestern Institutional Review Board approved the study. Preliminary results from the trial were presented [1]. Imatinib has been associated with oedema [1]. We wish to report a case of fulminant and treatmentresistant capillary leak syndrome culminating in cardiac death in an SSc patient treated with imatinib. A 52-year-old woman with an 8-month history of dcSSc (RP,+ ANA against the nucleolar membrane, Scl-70 antibodies and modified Rodnan skin score (mRSS)= 36 without lower extremity oedema) entered into an imatinib mesylate clinical trial. Echocardiogram revealed normal left ventricular function and pulmonary artery pressures and a small pericardial effusion. After 1 month of imatinib (400 mg daily) she developed new facial and lower extremity oedema and elevated alkaline phosphatase of207U/l (normal< 104) with otherwise normal liver function tests. Imatinib was held for 4 weeks, and following resolution of oedema, resumed at 200mg daily. Within 4 weeks of restarting imatinib, diffuse oedema and 7.7 Kg (17 lb) weight gain developed. Liver function tests showed decreased serum albumin (1.6 g/dl) with otherwise normal results, and urinalysis showed trace proteinuria. Imatinib was stopped, but total body oedema progressed, and large pleural and pericardial effusions developed. Despite diuresis and pericardiocentesis, massive anasarca developed and hypotension requiring vasopressor support ensued. The patient died of an acute myocardial infarction 26 days after stopping imatinib. Autopsy showed a dilated cardiomyopathy with four-chamber enlargement, and evidence of recent myocardial infarction despite minimal atherosclerosis. Microscopic examination revealed diffuse subendocardial fibrosis without inflammation or vascular changes (Fig. 1).Imatinib mesylate is a tyrosine kinase inhibitor originally developed for the treatment of Philadelphia chromosomepositive chronic myelogenous leukaemia (CML). Imatinib targets both wild-type (c-Abl) and mutated (Bcr-abl) tyrosine kinases, but also demonstrates inhibitory activity against PDGF receptors and other non-receptor tyrosine kinases [1]. Furthermore, imatinib blocks fibrotic responses induced by TGF-, prompting interest in its use for the treatment of fibrotic conditions including SSc [1]. Because 10 patients with CML developed congestive heart failure after taking imatinib [2], subjects with evidence of underlying cardiac involvement were excluded from our clinical trial. Oedema is a common side effect of imatinib in patients with CML and other malignancies, but when it occurs, it characteristically responds to diuretic therapy, dose reduction or drug discontinuation. The mechanisms underlying imatinib-associated oedema remain poorly understood. PDGF receptors play an important role in smooth muscle and endothelial cell homeostasis and repair, as well as in maintaining a hydrostatic fluid gradient from the capillaries to the interstitium within the dermis [3]. Lowering of the interstitial fluid pressure (IFP), as occurs during burns and injuries, results in increased interstitial fluid influx, causing tissue oedema. Perivascular stromal cells