泌尿肿瘤免疫检查点抑制剂相关性肌炎的临床特征

doi:10.19723/j.issn.1671-167X.2022.04.010

摘要/Abstract

摘要：

目的: 分析泌尿肿瘤免疫检查点抑制剂(immune checkpoint inhibitor, ICI)相关性肌炎的临床特征及治疗转归。方法: 选择2018年3月—2022年3月北京大学第一医院泌尿外科诊治的8例泌尿肿瘤ICI治疗后免疫相关性肌炎患者的临床资料进行回顾性分析，对人口学特征、用药方案、临床症状、实验室指标、肌电图检查、病理表现、治疗转归等信息进行分析。结果: 8例患者包含女性2例、男性6例，中位年龄68岁，均因泌尿肿瘤接受ICI治疗，包括2例上尿路尿路上皮癌(upper tract urothelial carcinoma，UTUC)、3例肾细胞癌(renal cell carcinoma，RCC)和3例膀胱癌(bladder cancer, BCa)。首次ICI治疗至发现免疫相关性肌炎的中位时间为39.5 d，中位疗程为2个疗程。主要症状为肌肉酸痛乏力，5例伴眼睑下垂，3例继发横纹肌溶解，5例合并心肌炎，1例合并重症肌无力，1例合并肠炎。发现合并免疫相关性心肌炎的患者首次接受ICI治疗至肌炎起病的间隔时间更短(P=0.042)。8例患者均有转氨酶及肌酶谱指标显著升高，5例患者出现自身抗体阳性。3例患者完善了肌肉活检，表现出典型的骨骼肌炎性肌病样病理改变，伴CD3⁺、CD4⁺、CD8⁺、CD20⁺淋巴细胞和CD68⁺巨噬细胞浸润。诊断免疫相关性肌炎后8例患者均立即停用ICI治疗，使用甲泼尼龙单独或合并丙种球蛋白静脉注射后病情均好转。结论: ICI治疗后免疫相关性肌炎是具有独特临床及病理特征的免疫相关不良反应(immune-related adverse events, irAEs)，常见合并心血管不良反应，立即停用ICI并开始糖皮质激素治疗可以及时改善患者病情。

关键词: 免疫检查点抑制剂, 泌尿肿瘤, 肌炎, 心肌炎

Abstract:

Objective: Immune checkpoint inhibitors (ICI) have significantly improved the treatment efficacy of a variety of malignant tumors. However, patients may experience a series of special side effects during treatments with ICI. Immune-related myositis after ICI treatment is characterized by autoimmune rheumatic and musculoskeletal damage, which is relatively rare. To analyze the clinical characteristics and outcomes of ICI-associated myositis in urological tumors, we summarized the clinical manifestations, electrophysiological and pathological characteristics, treatments and outcomes in 8 patients. Methods: The clinical data of the 8 patients with immune-related myositis after ICI treatment for urological tumors treated in the Department of Urology, Peking University First Hospital from March 2018 to March 2022 were retrospectively analyzed for demographic characteristics, drug regimen, clinical symptoms, laboratory indices, electromyography examination, pathological manifestations and outcomes. Results: The eight patients included 2 females and 6 males with a median age of 68 years, all treated with ICI for urological neoplasms, including 2 upper tract urothelial carcinoma (UTUC), 3 renal cell carcinoma (RCC), and 3 bladder cancer (BCa). The median time between the first ICI treatment and the detection of immune-related myositis was 39.5 days, and the median duration of treatment was 2 sessions. The main symptoms were muscle pain and weakness, 5 cases with ptosis, 3 cases with secondary rhabdomyolysis, 5 cases with myocarditis, 1 case with myasthenia gravis, and 1 case with enterocolitis. Among them, patients with immune-related myocarditis had a shorter interval from the first anti-programmed cell death protein-1 (PD-1) therapy to the onset of immune-related myositis (P=0.042) compared with patients without myocarditis. The 8 patients had significant elevation of transaminases and muscle enzyme profile indexes, and 5 patients showed positive auto-antibodies. 3 patients had perfected muscle biopsies and showed typical skeletal muscle inflammatory myopathy-like pathological changes with CD3⁺, CD4⁺, CD8⁺, CD20⁺ lymphocytes and CD68⁺ macrophage infiltration. After the diagnosis of immune-related myositis, all the 8 patients immediately discontinued ICI therapy and improved after intravenous administration of methylprednisolone alone or in combination with gamma-globulin. Conclusion: Immune-related myositis after ICI treatment is an immune-related adverse reactions (irAEs) with unique clinical and pathological features, commonly combined with cardiovascular adverse reactions. Immediate discontinuation of ICI and initiation of glucocorticoid therapy may improve the patient's condition in a timely manner.

Key words: Immune checkpoint inhibitors, Urological cancer, Myositis, Myocarditis

中图分类号:

R737

应沂岑,唐琦,杨恺惟,米悦,范宇,虞巍,宋毅,何志嵩,周利群,李学松. 泌尿肿瘤免疫检查点抑制剂相关性肌炎的临床特征[J]. 北京大学学报（医学版）, 2022, 54(4): 644-651.

Yi-cen YING,Qi TANG,Kai-wei YANG,Yue MI,Yu FAN,Wei YU,Yi SONG,Zhi-song HE,Li-qun ZHOU,Xue-song LI. Clinical features of immune checkpoint inhibitor-related myositis in patients with urological cancer[J]. Journal of Peking University (Health Sciences), 2022, 54(4): 644-651.

图/表 5

表1

表2

表3

表4

ICI治疗后免疫相关性肌炎患者症状、诊断及治疗转归"

Case	Symptoms	Immune-related complications	ECG	UCG	Electro-myography	Initial treatment	Outcomes
1	Palpitation, choking, dyspnea, dizziness, blurred vision, edema in both eyes, right lipomatosis ptosis	Myocarditis; Myasthenia gravis	Atrial premature beats; Ⅲ° atrioventricular block; Complete right bundle branch conduction block; TⅢ, aVF, V3, V4, V5, V6 hypoplasia; QRSⅢ, aVF abnormal Q waves	EF=82.3%; Ventricular septum thickening; Abnormal left ventricular diastolic function (grade Ⅱ); Mildly elevated pulmonary artery systolic pressure (36.3 mmHg)	Normal	MP 120 mg qd, IVIG 20 g qd	Improved; glucocorticoid reduction; Died of tumor progression
2	Vomiting, weakness, right lipomatosis ptosis, diplopia, deepening of urine color	Myocarditis; Rhabdomyolysis	Atrial premature beats; Premature ventricular contractions	EF=78.1%; Mildly elevated pulmonary artery systolic pressure；Stellate hyperechogenicity of the ventricular septum is seen	Nerve conduction slowed down	MP 120 mg qd, IVIG 30 g qd	Improved; Glucocorticoid reduction
3	Weakness of limbs, lipomatosis ptosis, muscle pain, chest tightness, palpitation, headache, difficulty in chewing and seeing	Myocarditis	Atrial premature beats; Premature ventricular contractions; ST partial Ⅰ, Ⅱ, Ⅲ, aVF, V4, V5, V6 inferior shift; T partial V3, V4, V5, V6 hypoplasia, inversion	EF=62.4%	Normal	IVIG 25 g qd	Improved; Glucocorticoid reduction
4	Right lipomatosis ptosis, muscle pain, shortness of breath after activity	None	Sinus tachycardia	EF=84.9%；Left ventricular wall thickening	Nerve conduction slowed down; Neurogenic damage	MP 80 mg qd	Improved; Complete radical cystectomy
5	General weakness	Myocarditis	Atrial fibrillation; Premature ventricular contractions; Right bundle branch conduction block; ST most Ⅰ, Ⅱ, aVF, V4, V5, V6 inferiorly displaced	Basal thickening of the ventricular septum；EF=76.7%	Nerve conduction slowed down; Neurogenic damage	MP 80 mg qd	Improved; Glucocorticoid reduction; Died of tumor progression
6	Generalized myalgia, left lipomatosis ptosis, deepening of urine color	Myocarditis；Rhabdomyolysis	Premature ventricular contractions; ST partial Ⅲ, aVF downshift	EF=72.9%	Nerve conduction slowed down; Myogenic damage	MP 120 mg qd IVIG 30 g qd	Improved; Complete radical cystectomy
7	Generalized myalgia, deepening of urine color, severe abdominal pain and diarrhea with blood in the stool	Enterocolitis；Rhabdomyolysis	Episodic premature ventricular contractions	EF=61.7%；Ascending aortic widening	Nerve conduction slowed down	MP 120 mg qd	Improved; Glucocorticoid reduction
8	Slight muscle pain and weakness in both lower limbs	None	Normal	NA	NA	Unused	Restart ICI after symptomatic treatment

表4

图1

参考文献 20

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Case	Gender	Age/years	Tumor	Complications	Surgical procedure	pTNM stage	Grade	Post-operative treatment	Recurrence/Metastasis
1	F	67	UTUC	HBP CHD	RNU	pT3N0	G3	None	None
2	M	72	RCC	ILD	RN	pT3aN0	G2-G3	None	Retroperitoneal recurrence with peritoneal metastasis
3^*	F	66	RCC	DM	RN	NA	NA	None	Pancreas metastases
4	M	73	UTUC	HBP	RNU	pT1N0	G2-G3	None	Bladder recurrence
5^*	M	72	BCa	DM	TUR-Bt	NA	G3	GC regimen and intravesical chemotherapy	Liver metastases
6	M	69	BCa	DM	TUR-Bt	pT1	G2	None	Bladder recurrence
7	M	61	RCC	DM	NSS	pT1bN0	G2	Radiotherapy	Mediastinal and liver metastases
8	M	38	BCa	HBP	TUR-Bt	PT1	G1-G2	Intravesical chemotherapy	Bladder recurrence

Case	ICI	Dosage/mg	Combined chemotherapy	Treatment period	Duration of immunotherapy/d
1	Nivolumab	240	None	2	25
2	Pembrolizumab	200	None	1	15
3	Pembrolizumab	200	None	2	37
4	Tislelizumab	200	Gemcitabine and carboplatin	2	54
5	Toripalimab	240	None	2	29
6	Tislelizumab	200	Gemcitabine and cisplatin	2	47
7	Pembrolizumab	200	None	3	58
8	Sintilimab	200	None	2	42

Case	ALT/(IU/L)	AST/(IU/L)	CK/(IU/L)	LDH/(IU/L)	HBDH/(IU/L)	CK-MB/(μg/L)	cTnI/(g/L)	hs-TnI/(g/L)	hs-CRP/(mg/L)	BNP/(ng/L)	FT3/(pmol/L)	FT4/(pmol/L)	TSH/(mIU/L)	IgM/(g/L)	Auto-antibodies
1	142	223	4 859	844	759	140.4	2.483	NA	6.63	105	NA	NA	NA	NA	AchE.Ab; Titin.Ab; RyR.Ab
2	167	377	5 587	730	605	153.2	NA	1 428.1	45.25	29	4.24	17.66	2.75	NA	NA
3	110	81	1 291	601	556	96.7	NA	17.0	1.49	11	5.35	24.3	0.2	0.41	TPOAb; TgAb; ANA; SS-A; AMA-M2
4	269	327	7 251	1 389	1 206	276.6	0.118	NA	29.98	NA	NA	NA	NA	NA	NA
5	147	265	4 295	822	709	107.8	1.010	NA	90.47	98	3.42	16.28	4.52	NA	TPOAb; TgAb
6	186	363	7 590	970	851	145.9	NA	2 588.2	15.73	30	4.15	10.69	0.38	0.57	ANA; AMA-M2; Titin.Ab; LRP4.Ab
7	96	136	2 622	469	405	58.9	NA	171.6	NA	NA	6.80	23.94	0.05	0.35	LRP4.Ab
8	63	40	595	238	190	9.5	NA	27.7	NA	NA	NA	NA	NA	NA	NA

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