免疫介导坏死性肌病的临床和病理特征分析

doi:10.19723/j.issn.1671-167X.2019.06.002

摘要/Abstract

摘要：

目的比较不同肌炎特异性自身抗体(myositis specific antibodies,MSAs)类型的免疫介导坏死性肌病(immune-mediated necrotizing myopathies,IMNM)的临床和病理特征。方法从中日友好医院2008—2018年住院期间所有行肌肉活检的特发性炎性肌病患者中选取符合以下任一条件的IMNM患者104例:(1)抗信号识别颗粒(signal recognition particle,SRP)抗体阳性;(2)抗3-羟基-3-甲基戊二酰辅酶A 还原酶(3-hydroxy-3-methylglutaryl-coenzyme A reductase,HMGCR)抗体阳性;(3)血清MSAs阴性且病理符合2004年欧洲神经肌肉病中心定义的IMNM病理诊断标准。回顾性收集患者的临床、实验室检查和肌肉病理等信息,比较各组临床及病理特征的差异。结果所有104例IMNM患者中,肌无力(92.3%)、肌酸激酶升高(92.3%)是IMNM的最常见临床表现,此外,33.7%的IMNM患者合并吞咽困难,46.5%的患者合并间质性肺病(interstitial lung diseases,ILD)。抗HMGCR阳性患者较抗SRP阳性和MSAs阴性患者更容易出现V形疹(30.4% vs. 4.3%和5.9%,P<0.01),抗SRP阳性患者合并ILD发生率高于抗HMGCR阳性和MSAs阴性患者(64.4% vs. 34.8%和29.0%,P<0.01),MSAs阴性患者合并其他结缔组织病更多见(32.4% vs. 8.5%和4.3%,P<0.01)。3组IMNM患者肌肉病理中均可见肌细胞坏死(94.2%)、吞噬(65.4%)和再生(67.3%),肌细胞膜表达主要组织相容性复合物-Ⅰ分子上调(78.8%),肌内膜CD4 ⁺T细胞(68.3%)和CD68 ⁺巨噬细胞(65.7%)浸润。结论抗SRP抗体阳性、抗HMGCR抗体阳性和MSAs阴性的IMNM患者存在异质性,在临床上开展MSAs检测和肌肉病理检查对区分不同类型的IMNM有指导价值。

关键词: 肌炎, 自身免疫病, 信号识别颗粒, 羟甲基戊二酰基CoA还原酶, 病理学

Abstract:

Objective: To investigate the clinical and pathological features of immune-mediated necro-tic myopathies (IMNM) with different myositis-specific antibodies (MSAs).Methods: In the study, 104 IMNM patients who met any of the following three criteria were selected from idiopathic inflammatory myopathy patients who had MSAs results and underwent muscle biopsy from 2008 to 2018 in China-Japan Friendship Hospital: (1) Anti-signal recognition particle (SRP) antibody positive; (2) Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibody positive; (3) MSAs negative and consistent with the pathological diagnostic criteria of IMNM defined by the European Neuromuscular Centre in 2004. The clinical, laboratory and muscle pathological information of the IMNM patients were retrospectively collected and compared in anti-SRP, anti-HMGCR and MSAs negative groups.Results: Of 104 IMNM patients, 47 patients (45.2%) were positive for anti-SRP antibody, 23 (22.1%) were positive for anti-HMGCR antibody, and 34 (32.7%) were negative for MSAs. The common symptoms of IMNM patients were muscle weakness (92.3%), elevated serum creatine kinase level (92.3%), dysphagia (33.7%) and interstitial lung diseases (ILD) (49.5%). The anti-HMGCR-positive patients were more frequent to have “V” sign (30.4% vs. 4.3% and 5.9%, P<0.01) as compared with the anti-SRP-positive and MSAs-negative patients. The incidence of ILD in the anti-SRP-positive patients was higher than that in the anti-HMGCR-positive and MSAs negative patients (64.4% vs. 34.8% and 29.0%, P<0.01). The prevalence of the patients combined with other connective tissue diseases in MSAs-negative IMNM was higher than that in the other two groups (32.4% vs. 8.5% and 4.3%, P<0.01). 93.3% of the anti-SRP-positive patients were found with antinuclear antibody positivity, higher than those of the anti-HMGCR-positive and MSAs-negative patients (93.3% vs. 36.4% and 58.8%, P<0.001). The common pathological features of IMNM were muscle fibre necrosis (94.2%), regeneration (67.3%) and phagocytosis (65.4%), overexpression of major histocompatibility complex-1 on sarcolemma (78.8%), infiltration of CD4 ⁺ T cells (81.7%) and CD68 ⁺ macrophage (79.8%) and expression of membrane attack complex (MAC) (77.8%). The endomysial infiltration of CD4 ⁺ T cells and CD68 ⁺ macrophage and MAC expression on sarcolemma in the MSAs-negative group were more common than that in the anti-SRP and anti-HMGCR groups (88.2% vs. 57.4% and 60.9%, 91.2% vs. 59.1% and 38.1%, 76.5% vs. 45.5% and 42.9%, respectively, P<0.01).Conclusion: There is heterogeneity in anti-SRP-positive, anti-HMGCR-positive or MSAs-negative patients. The detection of MSAs and performing of muscle biopsy are useful for distinguishing different types of IMNM.

Key words: Myositis, Autoimmune diseases, Signal recognition particle, Hydroxymethylglutaryl CoA reductases, Pathology

中图分类号:

R593.26

杨红霞,田小兰,江薇,李文丽,刘青艳,彭清林,王国春,卢昕. 免疫介导坏死性肌病的临床和病理特征分析[J]. 北京大学学报（医学版）, 2019, 51(6): 989-995.

Hong-xia YANG,Xiao-lan TIAN,Wei JIANG,Wen-li LI,Qing-yan LIU,Qing-lin PENG,Guo-chun WANG,Xin LU. Clinical and pathological characteristics of immune mediated necrotizing myopathy[J]. Journal of Peking University(Health Sciences), 2019, 51(6): 989-995.

图/表 4

表1

表2

IMNM不同抗体组实验室特征比较"

Features ^a	IMNM (n=104)	Anti-SRP (n=47)	Anti-HMGCR (n=23)	MSAs negative (n=34)	P
Anti-Ro-52	25 (24.0)	16 (34.0)	1 (4.3)	8 (23.5)	0.024
ANA	74/101 (73.3)	42/45 (93.3)	8/22 (36.4)	20/34 (58.8)	<0.001^*
Peak CK/(IU/L)	5 100 (2 749, 9 916)	5 070 (2 975, 9 994)	5 728 (3 320, 11 435)	4 827 (1 324, 9 831)	0.546
ALT (0-40 U/L)	96 (51, 208)	120 (55, 221)	93 (51, 209)	92 (38, 154)	0.500
AST (0-40 U/L)	62 (36, 127)	83 (37, 151)	64 (36, 124)	54 (29, 114)	0.306
LDH (100-250 IU/L)	522 (317, 770)	587 (339, 783)	569 (330, 836)	387 (258, 615)	0.113
CK (26-200 IU/L)	2 157 (810, 4 645)	1 753 (771, 4 241)	2 157 (861, 5 481)	2 326 (612, 4 709)	0.956
CRP (<8 mg/L)	2.9 (1.9, 5.5)	2.9 (1.9, 5.2)	4.3 (2.2, 8.6)	2.6 (1.6, 5.2)	0.198
ESR (<20 mm/h)	8 (4, 16)	9 (4, 20)	8 (4, 20)	6 (3, 13)	0.466
Fet (11.0-306.8 μg/L)	123.0 (48.9, 231.1)	120.0 (58.9, 218.2)	172.0 (109.9, 716.7)	86.0 (22.0, 205.0)	0.126
IgG (6.94-16.20 g/L)	10.50 (8.28, 14.13)	11.60 (8.73, 15.65)	8.59 (6.03, 11.28)	10.50 (8.87, 13.40)	0.033^#
IgA (0.68-3.78 g/L)	1.67 (1.17, 2.35)	1.86 (1.35, 2.58)	1.32 (1.03, 1.92)	1.56 (0.09, 2.54)	0.105
IgM (0.60-2.63 g/L)	1.12 (0.79, 1.45)	1.19 (0.82, 1.76)	0.88 (0.66, 1.21)	1.18 (0.84, 1.42)	0.109
C3 (0.70-1.28 g/L)	0.86 (0.75, 1.01)	0.87 (0.77, 0.99)	0.88 (0.78, 1.05)	0.82 (0.71, 1.03)	0.336
C4 (0.16-0.47 g/L)	0.18 (0.15, 0.22)	0.19 (0.15, 0.23)	0.20 (0.17, 0.24)	0.17 (0.12, 0.20)	0.067
T cell (1 000-3 000 cell/mL)	2 060 (1 555, 2 650)	1 870 (1 480, 2 240)	1 990 (1 370, 2 350)	2 620 (1 570, 3 350)	0.027^△
CD3⁺ T cell (808-2 072 cell/mL)	1 500 (1 038, 1 877)	1 400 (999, 1 686)	1 458 (903, 1 978)	1 767 (1 125, 2 378)	0.760
CD4⁺ T cell (380-1 280 cell/mL)	853 (608, 1 283)	817 (604, 1 114)	758 (456, 1 123)	1 767 (1 125, 2 378)	0.042
CD8⁺ T cell (229-982 cell/μL)	493 (375, 761)	477 (378, 678)	653 (345, 797)	554 (348, 812)	0.586

表2

表3

图1

参考文献 19

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Features	IMNM(n=104)	Anti-SRP(n=47)	Anti-HMGCR(n=23)	MSAs negative(n=34)	P
Female	73 (70.2)	38 (80.9)	13 (56.5)	22 (64.7)	0.078
Age/years	46.24±15.38	47.49±15.76	46.09±18.08	44.62±12.02	0.712
Age of onset/years	44.63±16.03	46.11±16.21	44.13±20.83	42.91±11.82	0.671
Duration/months	20.85±27.79	19.01±25.08	25.5±35.03	10.23±26.36	0.652
Chronic progression (>12 months)	59 (56.7)	28 (59.6)	12 (52.2)	19 (55.9)	0.836
Fever	5 (4.8)	3 (6.4)	1 (4.3)	1 (2.9)	0.763
Loss of weight	31 (29.8)	14 (29.8)	4 (17.1)	13 (32.8)	0.241
Muscle weakness	96 (92.3)	44 (93.6)	21 (91.3)	31 (91.1)	0.902
Severe muscle weakness	48 (46.2)	22 (46.8)	9 (39.1)	17 (50.0)	0.716
Muscle atrophy	15/73(20.5)	5/33 (15.6)	4/17 (23.5)	6/24 (25.0)	0.651
Myalgia	29 (27.9)	13 (27.7)	8 (34.8)	8 (23.5)	0.649
Arthritis	10 (9.6)	4 (8.5)	1 (4.3)	5 (14.7)	0.404
Skin involvement	27 (26.0)	12 (25.5)	8 (34.8)	7 (20.6)	0.485
Heliotrope rash	7 (7.7)	3 (6.4)	2 (8.7)	3 (8.8)	0.902
Gottron’s sign	2 (1.9)	1 (2.1)	0	1 (2.9)	0.723
“V” sign	11 (10.6)	2 (4.3)	7 (30.4)	2 (5.9)	0.002^*
Shawl sign	6 (5.8)	2 (4.3)	4 (17.4)	0	0.018
Raynaud phenomenon	4 (3.8)	3 (6.4)	0	1 (2.9)	0.404
ILD	46/99 (46.5)	29/45 (64.4)	7/23 (30.4)	10/31 (29.0)	0.004^#
Cough	2/46 (4.3)	2/29 (6.9)	0/7	0/10	0.542
Dyspnea	4/46 (8.7)	3/29 (10.3)	0/7	1/10 (10.0)	0.675
Asymptomatic	41/46 (89.1)	25/29 (86.2)	7/7 (100.0)	9/10 (90.0)	0.572
Dysphagia	35 (33.7)	17 (36.2)	8 (34.8)	10 (29.4)	0.576
Cancer	4 (3.8)	3 (6.4)	1 (4.3)	0	0.334
With other CTD	16 (15.4)	4 (8.5)	1 (4.3)	11 (32.4)	0.003^△
Death	5 (4.8)	3 (6.4)	1 (4.3)	1 (2.9)	0.769

Features	IMNM (n=104)	Anti-SRP (n=47)	Anti-HMGCR (n=23)	MSAs negative (n=34)	P
Muscle fibre
Necrosis	98 (94.2)	43 (91.5)	21 (91.3)	34 (100.0)	0.213
Regeneration	70 (67.3)	33 (70.2)	11 (47.8)	26 (76.5)	0.066
Phagocytosis	68 (65.4)	27 (57.4)	14 (60.9)	27 (79.4)	0.107
Connective tissue proliferation	36 (34.6)	17 (36.2)	8 (34.8)	11 (32.4)	0.938
MHC-Ⅰ expression on sarcolemma	82 (78.8)	35 (74.5)	17(73.9)	30 (88.2)	0.263
Partial expression	56 (53.8)	24 (51.1)	11 (47.8)	21 (61.8)	0.512
Diffuse expression	26 (25.0)	11 (23.4)	6 (26.1)	9 (26.5)	0.953
Inflammation infiltration
CD4⁺T cell	85 (81.7)	35 (74.5)	18 (78.3)	32 (94.1)	0.045
Endomysial	71 (68.3)	27 (57.4)	14 (60.9)	30 (88.2)	0.009^*
Perivascular	30 (28.8)	17 (36.2)	6 (26.1)	7 (20.6)	0.295
CD8⁺T cell	57 (54.8)	21 (44.7)	11 (47.8)	25 (73.5)	0.027^#
Endomysial	48 (46.2)	17 (36.2)	8 (34.8)	23 (67.6)	0.009^*
Perivascular	17 (16.3)	8 (17.0)	4 (17.4)	5 (14.7)	0.951
CD20⁺B cell	7 (6.7)	2 (4.3)	1 (4.3)	4 (11.8)	0.361
Endomysial	4 (3.8)	1 (2.1)	0	3 (8.8)	0.168
Perivascular	3 (2.9)	1(2.1)	1 (4.3)	1 (2.9)	0.124
CD68⁺ macrophage	79/99 (79.8)	35/44 (79.5)	11/21 (52.4)	32 (94.1)	0.002^△
Endomysial	65/99 (65.7)	26/44 (59.1)	8/21 (38.1)	31 (91.2)	<0.001^*
Perivascular	24/99 (24.2)	18/44 (40.9)	3/21 (15.0)	3 (8.8)	0.003^#
MAC	77/99 (77.8)	34/44 (77.3)	11/21 (52.4)	32 (94.1)	0.001^△
Sarcolemma	55/99 (55.6)	20/44 (45.5)	9/21 (42.9)	26 (76.5)	0.015^*
Sarcoplasm	18/99 (18.2)	8/44 (18.2)	3/21 (14.3)	7 (20.6)	0.841
Capillaries	31/99 (31.3)	19/44 (43.2)	4/21 (19.0)	8 (23.5)	0.070