Development of vasculitis in a case with severe asthma treated with benralizumab and low-dose corticosteroid
Development of vasculitis in a case with severe asthma treated with benralizumab and low-dose corticosteroid
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使用贝那利珠单抗和低剂量皮质类固醇治疗的严重哮喘病例中出现血管炎
DOI：
10.1016/j.alit.2022.08.004
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发表时间：
2023
影响因子：
6.8
通讯作者：
Yasuda Shinsuke
中科院分区：
文献类型：
--
作者：
Umezawa Natsuka;Sasaki Hirokazu;Furusawa Haruhiko;Kawata Daisuke;Hata Chiina;Yasuda Shinsuke
嗜酸性肉芽肿病伴多血管炎是一种小血管炎，以严重哮喘或嗜酸性鼻窦炎为首发症状。EGPA的病理表现以嗜酸性粒细胞浸润和肉芽肿性血管炎为特征，其中IL-5在嗜酸性粒细胞的增殖和存活中起关键作用。美泊利珠单抗1和贝那利珠单抗2分别是靶向IL-5和IL-5受体（IL-5 R）的单克隆抗体，已被批准作为重症哮喘的二线治疗药物。此外，美泊利珠单抗被证明可作为EGPA的辅助治疗，3被批准用于难治性病例。在此，我们报告一例哮喘患者在接受贝那利珠单抗和低剂量皮质类固醇治疗期间发生血管炎，但组织中无嗜酸性粒细胞和嗜酸性粒细胞浸润。虽然我们不能诊断她与EGPA，我们的情况下教我们的临床特点EGPA样血管炎已被修改的IL-5阻断。一名62岁女性，患有难治性哮喘，2周前因发热、虚弱和腿部感觉迟钝入院。她在49岁时被诊断出患有支气管哮喘，并患有严重发作和复发性嗜酸性粒细胞性肺炎（EP），需要持续口服皮质类固醇治疗。在她的发作期间，外周血嗜酸性粒细胞的数量已升高至2240/ml。在55岁时开始使用美泊利珠单抗（100 mg/4周）治疗难治性哮喘。尽管美泊利珠单抗使她的发作不那么严重，并将皮质类固醇的剂量减少到泼尼松龙（PSL）10 mg/天，但在入院前10个月，为了更好地控制哮喘，将其转换为贝那利珠单抗（30 mg/8周）。即使在入院前6个月将PSL剂量降至8 mg/天后，她仍未发生哮喘发作。血清IgE水平逐渐升高，随后出现肌无力和发热。入院时，她大腿抓痛，由于双侧肌肉无力，无法自行行走。未发现呼吸道症状或皮疹。实验室数据显示白色血细胞（WBC）计数升高（13，000/ml），但嗜酸性粒细胞比率为0%。对PBMC的进一步分析显示，CCR 6-CXCR 3-Th 2细胞在CD 45 RO + CD 3 + CD 4 + Th细胞中的比例增加（58%）。4 C-反应蛋白、肌酸激酶和总IgE的血清水平升高至10.3 mg/dL（参考文献0 e0）。2）、1322 IU/L（参考40 e120）和4991 IU/L（参考0 e173）。髓过氧化物酶和蛋白酶3抗中性粒细胞胞浆抗体均为阴性。尿检和胸部X线检查结果正常。她下肢肌肉的磁共振成像显示T2序列中弥漫性高信号。腿部神经传导速度检查显示多发性单神经病。肌肉活检显示小动脉坏死性血管炎，白细胞浸润主要由组织细胞和淋巴细胞组成，但无嗜酸性粒细胞密集浸润（图1）。在检查的标本中发现很少的嗜酸性粒细胞。没有类似于炎性肌病的发现，如坏死纤维伴肌内膜细胞浸润。她的临床表现和病理结果表明存在活动性血管炎（伯明翰血管炎活动评分[BVAS] 5为14）。因为她没有表现出嗜酸性粒细胞增多和嗜酸性粒细胞的密集浸润的组织，我们不能诊断她与EGPA根据分类标准EGPA。6，7另一方面，她有EGPA的一些特征，包括成人发作的哮喘...
Eosinophilic granulomatosis with polyangiitis (EGPA) is a small vessel vasculitis preceded by severe asthma or eosinophilic rhinosinusitis. Pathological findings of EGPA are characterized by the infiltration of eosinophils and granulomatous vasculitis, where IL-5 plays a crucial role for the proliferation and survival of eosinophils. Mepolizumab 1 and benralizumab, 2 which are monoclonal antibodies targeting IL-5 and IL-5 receptor (IL-5R) respectively, have been approved as the second-line treatment for the severe asthma. In addition, mepolizumab was proven to be useful as an add-on therapy in EGPA, 3 approved for refractory cases. Herein, we report a case with asthma who developed a vasculitis without eosinophilia and eosinophil infiltration into the tissues during the treatment with benralizumab and low-dose corticosteroid. While we could not diagnose her with EGPA, our case taught us the clinical features of EGPA-like vasculitis which had been modified by IL-5 blockade. A 62-year-old woman with refractory asthma admitted because of fever, weakness and dysesthesia on her legs from 2 weeks ago. She had been diagnosed with bronchial asthma at the age of 49 and had been suffered from severe attacks and relapsing eosinophilic pneumonia (EP) requiring continuous treatments with oral corticosteroids. The number of peripheral eosinophils had been elevated up to 2240/ml during her attacks. Mepolizumab (100 mg/4 weeks) was started for the refractory asthma at the age of 55. Whereas mepolizumab made her attacks less severe and decreased the dose of corticosteroid to prednisolone (PSL) 10 mg/day, it was switched to benralizumab (30 mg/8 weeks) for better control of asthma ten months before the admission. Even after the dose of PSL was reduced to 8 mg/day six months before the admission, she had been free from asthma attacks. Serum levels of IgE were gradually elevated followed by the development of muscle weakness and fever. On admission, she had grab pain on her thigh and could not walk by herself due to bilateral muscle weakness. No respiratory symptom or skin rash was found. Laboratory data showed the elevated white blood cell (WBC) count (13,000/ml) but the rate of eosinophils was 0%. Additional analysis with PBMCs revealed that increased ratio of CCR6-CXCR3-Th2 cells (58%) among CD45RO+ CD3+ CD4+ Th cells. 4 The serum levels of C-reactive protein, creatine kinase and total IgE were elevated to 10.3 mg/dL (ref. 0e0. 2), 1322 IU/L (ref. 40e120) and 4991 IU/L (ref. 0e173) respectively. Both of myeloperoxidase and proteinase 3 antineutrophilic cytoplasmic antibodies were negative. Urine test and chest X-ray showed normal findings. Magnetic resonance imaging of her lower extremity muscles showed the diffuse hypersignal in T2 sequence. Mononeuropathy multiplex was revealed with nerve conduction velocity test on her legs. Muscle biopsy revealed necrotizing vasculitis on small arteries with leukocyte infiltrations mainly comprising of histiocytes and lymphocytes, but without dense infiltration of eosinophils (Fig. 1). Few eosinophils were found in examined specimens. There were no findings resembling to inflammatory myopathy such as necrotic fibers with endomysial cell infiltration. Her clinical presentation and pathological findings indicated the existence of active vasculitis (Birmingham Vasculitis Activity Score [BVAS] 5 was 14). Because she did not demonstrate eosinophilia and dense infiltration of eosinophils in the tissues, we could not diagnose her with EGPA according to classification criteria for EGPA. 6, 7 On the other hands, she had some characteristics of EGPA including adult-onset asthma …