Tocilizumab-induced organizing pneumonia in a patient with systemic sclerosis-associated interstitial lung disease
Tocilizumab-induced organizing pneumonia in a patient with systemic sclerosis-associated interstitial lung disease
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系统性硬化症相关间质性肺病患者托珠单抗诱导的机化性肺炎
DOI：
10.1093/rheumatology/keac435
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Sato S.
中科院分区：
文献类型：
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作者：
Kuzumi A;Yoshizaki A;Mitsuo S;Miyake T;Sato S.
亲爱的编辑，托珠单抗（TCZ）是一种针对IL-6受体的人源化mAb，已成为SSc相关间质性肺病（SSc-ILD）的新治疗选择，具有良好的安全性[1，2]。在此，我们报告了1例导致SSc-ILD患者停止治疗的TCZ诱导机化性肺炎病例。一名26岁的日本女性被转介到我们的医院与1年的历史劳力性呼吸困难。她在14岁时被诊断为SSc，表现为指硬症、RP和抗Topo I抗体阳性。19岁时，高分辨率CT（HRCT）显示ILD。计划进行进一步调查，但由于搬到另一个城市，她失去了定期随访。她唯一的药物是美沙芬，她已经服用了6个月。就诊时，患者干咳，胸部听诊吸气性湿罗音。在实验室检查中，血清Krebs von den Lungen-6（KL-6; 982 U/ml，正常< 464 U/ml）和表面活性蛋白D（SP-D; 512.2 ng/ml，正常< 110.0 ng/ml）水平升高。ANA血清学检测呈阳性，滴度为1：160，呈均匀斑点状。抗Topo I抗体为763 U/ml（正常值<10.0U/ml）。HRCT显示网状阴影、牵拉性支气管扩张和以基底和外周为主的蜂窝样改变，与SSc-ILD一致（图1）。肺功能检查显示用力肺活量（FVC）和一氧化碳弥散量（DLco）的绝对值和%预测值分别为1.92 l（62.5%）和9.00 ml/min/mmHg（41.3%）。超声心动图显示无肺动脉高压迹象。在获得知情同意后，在东京大学医学研究生院伦理委员会批准的开放性研究中开始每月iv TCZ（8 mg/kg）。在第四次TCZ给药前3个月随访时，她主诉持续咳嗽。进行HRCT显示多发片状毛玻璃影，伴潜在纤维化（图1）。在肺功能检查中，FVC和DLco分别为1.83 l（60.0%）和8.24 ml/min/mmHg（37.2%），与TCZ治疗前基本相当。血清KL-6和SP-D水平分别升高至1251 U/ml和614.2 ng/ml。痰培养和支气管刷检细胞学均为阴性。由于肺功能受损，未进行支气管肺泡灌洗。通过（1，3）-b-D葡聚糖、曲霉菌抗原和CMV抗原的血清学试验进一步排除感染。进一步的调查显示，没有证据表明恶性肿瘤，血管炎或共存的其他自身免疫性疾病。在与肺科、风湿科和感染科进行多学科讨论后，怀疑TCZ诱导的机化性肺炎，并停用TCZ。TCZ停药后2周，磨玻璃样阴影自发改善（图1）。开始口服泼尼松龙40 mg/天（0.6 mg/kg/天），3周后，磨玻璃样阴影几乎消退（图1）。FVC和DLco分别改善至2.06 l（67.5%）和9.53 ml/min/mmHg（44.0%）。此外，血清KL-6和SP-D水平分别降至1026 U/ml和497.5 ng/ml。咳嗽的频率也减少了。临床病史支持TCZ诱导的机化性肺炎的诊断。在接下来的2个月里，泼尼松龙平稳地逐渐减少到10 mg/天。CRP水平在整个临床过程中均为阴性。机化性肺炎是TCZ的一种罕见并发症，文献中仅报道了少数病例[3，4...
DEAR EDITOR, Tocilizumab (TCZ), a humanized mAb against the IL-6 receptor, has been emerging as a new therapeutic option for SSc-associated interstitial lung disease (SSc-ILD) with a favourable safety profile [1, 2]. Here, we report a case of TCZ-induced organizing pneumonia that led to treatment discontinuation in a patient with SSc-ILD. A 26-year-old Japanese woman was referred to our hospital with a 1-year history of exertional dyspnoea. She was diagnosed with SSc at the age of 14years, after presenting with sclerodactyly, RP and positive anti-topo I antibody. ILD was noted on high-resolution CT (HRCT) at the age of 19years. Further investigation was planned, but she was lost to regular follow-up due to moving to another city. Her only medication was dextromethorphan, which she had been taking for the past 6months. At presentation, she had a dry cough with inspiratory crackles on chest auscultation. On laboratory examination, serum levels of Krebs von den Lungen-6 (KL-6; 982 U/ml, normal< 464 U/ml) and surfactant protein D (SP-D; 512.2 ng/ml, normal< 110.0 ng/ml) were elevated. Serological tests were positive for ANA at a titre of 1: 160 with a homogeneous and speckled pattern. Anti-topo I antibody was positive at 763U/ml (normal< 10.0 U/ml). HRCT showed reticular opacities, traction bronchiectasis, and honeycombing with basal and peripheral predominance, which were consistent with SSc-ILD (Fig. 1). Pulmonary function tests revealed that the absolute and% predicted values of forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) were 1.92 l (62.5%) and 9.00 ml/min/mmHg (41.3%), respectively. Echocardiography showed no evidence of pulmonary artery hypertension. After obtaining informed consent, monthly iv TCZ (8mg/kg) was started in an open study approved by the ethics committee of the University of Tokyo Graduate School of Medicine. At 3-month follow-up before the fourth administration of TCZ, she complained of persistent cough. HRCT was performed to show multiple patchy ground-glass opacities with underlying fibrosis (Fig. 1). On pulmonary function tests, FVC and DLco were 1.83 l (60.0%) and 8.24 ml/min/mmHg (37.2%), respectively, which were largely comparable to those prior to TCZ treatment. Serum KL-6 and SP-D levels elevated to 1251 U/ml and 614.2 ng/ml, respectively. Sputum cultures and bronchial brush cytology were negative. Bronchoalveolar lavage was not performed due to the impaired lung function. Infection was further ruled out by serological tests for (1, 3)-b-D glucan, aspergillus antigen and CMV antigen. Further investigation revealed no evidence of malignancy, vasculitis or coexistence of other autoimmune diseases. Following multidisciplinary discussion with pulmonary, rheumatology and infectious disease departments, TCZ-induced organizing pneumonia was suspected, and TCZ was discontinued. Two weeks after the discontinuation of TCZ, ground-glass opacities improved spontaneously (Fig. 1). Oral prednisolone 40mg/day (0.6 mg/kg/day) was started, and 3weeks later, ground-glass opacities almost resolved (Fig. 1). FVC and DLco improved to 2.06 l (67.5%) and 9.53 ml/min/mmHg (44.0%), respectively. In addition, serum KL-6 and SP-D levels declined to 1026 U/ml and 497.5 ng/ml, respectively. The frequency of cough was also decreased. The clinical history supported the diagnosis of TCZ-induced organizing pneumonia. Over the next 2months, prednisolone was uneventfully tapered to 10mg/day. CRP levels were negative throughout the clinical course. Organizing pneumonia is a rare complication of TCZ, with only a few cases reported in the literature [3, 4 …