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北京大学学报(医学版), 2023, 55(6): 958-965 doi: 10.19723/j.issn.1671-167X.2023.06.002

论著

抗Jo-1抗体在特发性炎性肌病临床分层及疾病谱中的意义

李嘉辰1, 赖展鸿1, 邵苗1, 金月波1, 高小娟2, 张科3, 侯儆4, 张燕英5, 栗占国,1, 李玉慧,1

1. 北京大学人民医院风湿免疫科, 北京 100044

2. 宁德师范学院附属宁德市医院风湿免疫科, 福建宁德 352199

3. 中国人民解放军第80集团军医院内分泌科, 山东潍坊 261000

4. 张家口市第一医院肾内科, 河北张家口 075041

5. 深圳市中医院风湿病科, 深圳 518033

Significance of anti-Jo-1 antibody's clinical stratification in idiopathic inflammatory myopathy and disease spectrum

LI Jia-chen1, LAI Zhan-hong1, SHAO Miao1, JIN Yue-bo1, GAO Xiao-juan2, ZHANG Ke3, HOU Jing4, ZHANG Yan-ying5, LI Zhan-guo,1, LI Yu-hui,1

1. Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing 100044, China

2. Department of Rheumatology and Immunology, Ningde Hospital Affiliated to Ningde Normal University, Ningde 352199, Fujian, China

3. Department of Endocrinology, 80th Group Army Hospital of Chinese PLA, Weifang 261000, Shandong, China

4. Department of Nephrology, Zhangjiakou First Hospital, Zhangjiakou 075041, Hebei, China

5. Department of Rheumatology, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen 518033, China

收稿日期: 2023-08-19  

基金资助: 国家自然科学基金(82371804)
北京市自然科学基金海淀原始创新联合基金项目(L222017)
北京大学人民医院研究与发展基金(RDX2023-03)

Corresponding authors: LI Zhan-guo, e-mail, li99@bjmu.edu.cnLI Yu-hui, e-mail, liyuhui84@163.com

Received: 2023-08-19  

Fund supported: the National Natural Science Foundation of China(82371804)
Beijing Natural-Science Foundation(L222017)
Peking University People's Hospital Research and Development Foundation(RDX2023-03)

Abstract

Objective: To investigate the significance of anti-histidyl tRNA synthetase (Jo-1) antibody in idiopathic inflammatory myopathies (IIM) and its diseases spectrum. Methods: We enrolled all the patients who were tested positive for anti-Jo-1 antibody by immunoblotting in Peking University People's Hospital between 2016 and 2022. And the patients diagnosed with anti-synthetase antibody syndrome (ASS) with negative serum anti-Jo-1 antibody were enrolled as controls. We analyzed the basic information, clinical characteristics, and various inflammatory and immunological indicators of the patients at the onset of illness. Results: A total of 165 patients with positive anti-Jo-1 antibody were enrolled in this study. Among them, 80.5% were diagnosed with connective tissue disease. And 57.6% (95/165) were diagnosed with IIM, including ASS (84/165, 50.9%), immune-mediated necrotizing myopathy (7/165, 4.2%) and dermatomyositis (4/165, 2.4%). There were 23.0% (38/165) diagnosed with other connective tissue disease, mainly including rheumatoid arthritis (11/165, 6.7%), undifferentiated connective tissue disease (5/165, 3.0%), interstitial pneumonia with autoimmune features (5/165, 3.0%), undifferentiated arthritis (4/165, 2.4%), Sjögren's syndrome (3/165, 1.8%), systemic lupus erythematosus (3/165, 1.8%), systemic vasculitis (3/165, 1.8%), and so on. Other cases included 3 (1.8%) malignant tumor patients, 4 (2.4%) infectious cases and so on. The diagnoses were not clear in 9.1% (15 /165) of the cohort. In the analysis of ASS subgroups, the group with positive serum anti-Jo-1 antibody had a younger age of onset than those with negative serum anti-Jo-1 antibody (49.9 years vs. 55.0 years, P=0.026). Clinical manifestations of arthritis (60.7% vs. 33.3%, P=0.002) and myalgia (47.1% vs. 22.2%, P=0.004) were more common in the ASS patients with positive anti-Jo-1 antibody. With the increase of anti-Jo-1 antibody titer, the incidence of the manifestations of arthritis, mechanic hands, Gottron sign and Raynaud phenomenon increased, and the proportion of abnormal creatine kinase and α-hydroxybutyric dehydrogenase index increased in the ASS patients. The incidence of myalgia and myasthenia were significantly more common in this cohort when anti-Jo-1 antibody-positive ASS patients were positive for one and more myositis specific antibodies/myositis associated autoantibodies (P < 0.05). Conclusion: The disease spectrum in patients with positive serum anti-Jo-1 antibody includes a variety of diseases, mainly ASS. And anti-Jo-1 antibody can also be found in many connective tissue diseases, malignant tumor, infection and so on.

Keywords： Anti-histidyl tRNA synthetase antibody; Anti-synthetase syndrome; Connective tissue disease

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李嘉辰, 赖展鸿, 邵苗, 金月波, 高小娟, 张科, 侯儆, 张燕英, 栗占国, 李玉慧. 抗Jo-1抗体在特发性炎性肌病临床分层及疾病谱中的意义[J]. 北京大学学报(医学版), 2023, 55(6): 958-965 doi:10.19723/j.issn.1671-167X.2023.06.002

LI Jia-chen, LAI Zhan-hong, SHAO Miao, JIN Yue-bo, GAO Xiao-juan, ZHANG Ke, HOU Jing, ZHANG Yan-ying, LI Zhan-guo, LI Yu-hui. Significance of anti-Jo-1 antibody's clinical stratification in idiopathic inflammatory myopathy and disease spectrum[J]. Journal of Peking University (Health Sciences), 2023, 55(6): 958-965 doi:10.19723/j.issn.1671-167X.2023.06.002

特发性炎性肌病(idiopathic inflammatory myo-pathies，IIM)是一组以横纹肌和皮肤慢性炎症为特征的异质性疾病[1]，包括皮肌炎、抗合成酶综合征(anti-synthetase antibody syndrome，ASS)、免疫介导坏死性肌病(immune-mediated necrotizing myopathy，IMNM)、包涵体肌炎和多肌炎[2]。IIM发病机制尚不完全清楚，患者机体对自身抗原的异常反应是发病的主要原因之一[3-4]。在血清学方面，抗组氨酰tRNA合成酶(histidyl tRNA synthetase, Jo-1)抗体是ASS最常见的抗体，能在约30%的ASS患者体内测出[5]。既往文献表明，不仅IIM患者抗Jo-1抗体阳性，很多其他结缔组织病(connective tissue disease，CTD)及非CTD患者的血清中也可以检测到该抗体，如类风湿关节炎、系统性红斑狼疮等[6-10]，但多为个案报道或针对单一疾病的报道，目前缺乏归纳抗Jo-1抗体疾病谱的系统性大样本研究。

抗Jo-1抗体可以影响患者的临床特征，研究发现抗Jo-1抗体造成器官损伤可能与循环中的Jo-1、肌肉内皮细胞中的补体密切相关[11-12]，既往文献描述，抗Jo-1抗体阳性IIM患者临床主要表现为关节炎、肌肉受累和间质性肺病(interstitial lung disease，ILD)[13-14]，但抗Jo-1抗体在其他疾病中的作用并不完全清楚。本研究旨在通过大样本真实世界研究，分析抗Jo-1抗体阳性患者的临床表现和实验室检查数据，探究抗Jo-1抗体阳性患者的疾病谱及临床特点。

1 资料与方法

1.1 一般资料

纳入2016—2022年于北京大学人民医院检测肌炎谱的患者中所有抗Jo-1抗体阳性患者，记录患者起病的基本信息[起病年龄、性别，初次就诊时血常规、肌酸激酶(creatine kinase，CK)、乳酸脱氢酶(lactate dehydrogenase，LDH)、α-羟丁酸脱羧酶(α-hydroxybutyric dehydrogenase，α-HBD)等]、临床诊断、临床表现以及多种炎症指标、免疫学指标。IIM的诊断符合美国风湿病学会及欧洲抗风湿病学联盟分类标准[15]；ASS的诊断符合Solomon标准[16]，即抗合成酶抗体阳性同时合并任意2种主要指标或1种主要指标及2种次要指标[主要指标：①排除其他原因的间质性肺病，②符合Bohan和Peter标准的皮肌炎或多肌炎；次要指标：①关节炎，②雷诺现象(Raynaud phenomenon)，③技工手]；IMNM的诊断符合国际共识[17]。此外，本研究同时纳入45例同期于北京大学人民医院诊断为抗Jo-1抗体阴性的ASS患者[抗异亮氨酰tRNA合成酶(isoleucyl tRNA synthetase，OJ)抗体、抗甘氨酰tRNA合成酶(glycyl tRNA synthetase，EJ)抗体、抗苏氨酰tRNA合成酶(threonyl tRNA synthetase，PL-7)抗体或抗丙氨酸tRNA合成酶(alanine tRNA synthetase，PL-12)抗体阳性]作为对照，对照组ASS患者符合Solomon标准[16]。

在免疫学指标方面，检测了肌炎相关抗体(myositis associated antibodies，MAAs)和肌炎特异性抗体(myositis specific antibodies，MSAs)，包括抗核小体重塑-去乙酰化酶复合物组成成分(component of the nucleosome remodeling-deacetylase complex，Mi-2)、抗转录中介因子1γ(transcriptional intermediary factor 1γ，TIF-1γ)、小泛素样修饰激活酶(small ubiquitin like modifier activating enzyme，SAE)、黑色素瘤分化相关基因5(melanoma differentiation associated gene 5，MDA5)、核基质蛋白2(nuclear matrix protein 2，NXP2)、信号识别颗粒(signal recognition particle，SRP)、Ro-52、Ku、PM-Scl、抗PL-7、抗PL-12、抗EJ、抗OJ抗体和抗核抗体(anti-nuclear antibody，ANA)。

在其他实验室检查方面，我们定义C反应蛋白(C-reaction protein，CRP)>10 mg/L为CRP升高，男性红细胞沉降率(erythrocyte sedimentation rate，ESR)>15 mm/h、女性ESR>20 mm/h为ESR升高，CK>165 U/L为CK升高，LDH>245 U/L为LDH升高，α-HBD>182 U/L为α-HBD升高。

1.2 检测方法

抗Jo-1抗体的检测应用免疫印迹法，带有天然Jo-1(利用亲和层析法从小牛和兔胸腺中纯化)的试纸孵育后，用EUROLineScan软件进行判读，+、++、+++分别表示抗体滴度的低、中、高。

1.3 统计学处理

本研究采用SPSS 23.0进行统计学分析。符合正态分布的计量资料用均数±标准差表示，采用t检验进行统计分析；不符合正态分布的计量资料用中位数(25%分位数，75%分位数)表示，采用Wil-coxon秩和检验进行统计分析；分类变量用例数(百分数)表述，使用卡方检验及Fisher’s精确概率检验进行统计分析。在分析临床特征与抗Jo-1抗体滴度相关性时使用Spearman秩相关分析，P < 0.05为差异有统计学意义。

2 结果

2.1 抗Jo-1抗体阳性患者疾病谱

研究纳入165例抗Jo-1抗体阳性患者，包括120例女性和45例男性，平均年龄(48.04±14.24)岁；其中CTD共133例(80.6%)，分为IIM及除外IIM的CTD患者：(1)IIM共95例(57.6%)，其中ASS 84例(50.9%)、IMNM 7例(4.2%)、皮肌炎4例(2.5%)；(2)除外IIM的CTD共38例(23.0%)，其中类风湿关节炎11例(6.7%)、未分化结缔组织病5例(3.0%)、具有自身免疫特征的间质性肺炎5例(3.0%)、未分化关节炎4例(2.5%)、干燥综合征3例(1.8%)、系统性红斑狼疮3例(1.8%)、系统性血管炎3例(1.8%)、系统性硬化症2例(1.2%)、抗磷脂综合征1例(0.6%)、风湿性多肌痛1例(0.6%)。此外，未诊断CTD的患者包括恶性肿瘤3例(1.8%，样本中患恶性肿瘤患者共6例，另外3例合并CTD)、感染性疾病4例(2.4%，支原体感染1例、EB病毒感染1例、乙型肝炎1例及未明确病原体感染1例)、骨关节炎2例、免疫性血小板减少性紫癜2例及脊柱关节炎、痛风、多系统萎缩、神经性皮炎、周围神经病和溃疡性结肠炎各1例。有15例(9.1%)患者未明确临床诊断(图 1)。

图1

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图1   抗Jo-1抗体阳性患者疾病分布

Figure 1   Disease distribution in patients with positive anti-Jo-1 antibody

ASS, anti-synthetase syndrome; IMNM, immune-mediated necrotizing myositis; DM, dermatomyositis; RA, rheumatoid arthritis; UCTD, undifferentiated connective tissue disease; IPAF, interstitial pneumonia with autoimmune features; UA, undifferentiated arthritis; SS, Sjögren's syndrome; SLE, systemic lupus erythematosus; SV, systemic vasculitis; SSc, systemic sclerosis; APS, antiphospholipid syndrome; PMR, polymyalgia rheumatica; Non-CTD, non-connective tissue disease.


2.2 抗Jo-1抗体阳性和阴性ASS患者比较

本研究纳入的抗Jo-1抗体阳性及阴性的ASS患者分别为84例和45例，后者包括抗PL-7抗体阳性15例、抗PL-12抗体阳性14例、抗EJ抗体阳性15例、抗OJ抗体阳性3例。将抗Jo-1抗体阳性及阴性的ASS患者进行比较发现，抗Jo-1抗体阳性的ASS患者的起病年龄更低(49.9岁vs. 55.0岁，P=0.026)，更多表现为关节炎(60.7% vs. 33.3%，P=0.002)和肌痛(47.1% vs. 22.2%，P=0.004)，抗Jo-1抗体阴性的ASS患者ESR升高的比例显著高于阳性患者(50.0% vs. 71.1%，P=0.010，表 1)。

表1   抗Jo-1抗体阳性与阴性ASS患者临床特征及实验室数据对比

Table 1  Comparison of clinical features and laboratory data in ASS with positive and negative anti-Jo-1 antibody

ItemsAnti-Jo-1 (+) (n=84)Anti-Jo-1 (-) (n=45)t/Z/χ2P
Clinical features
  Age of onset/years49.9±12.855.0±11.92.2470.026
  Female64 (76.2)33 (73.3)0.1280.720
  ILD72 (85.7)43 (95.6)2.9330.087
  Arthritis51 (60.7)15 (33.3)8.7920.003
  Myalgia40 (47.1)10 (22.2)7.9620.005
  Myasthenia45 (53.6)21 (46.7)0.5590.455
  Dysphagia5 (6.0)6 (13.3)2.0470.153
  Mechanic hands45 (53.6)23 (51.1)0.0710.790
  Gottron sign68 (81.0)39 (86.7)0.6760.411
  Raynaud phenomenon11 (13.1)8 (17.8)0.8420.474
  Neurologic abnormality4 (4.8)00.297a
  Malignancy2 (2.4)1 (2.2)>0.999a
Laboratory data
  ANA+44 (52.4)29 (64.4)1.7360.188
  Anti-Ro-52 (+)63 (75.0)36 (80.0)0.4100.522
  Anti-PM-Scl 75/100 (+)5 (6.0)00.156a
  Anti-Mi-2 (+)2 (2.4)1 (2.2)>0.999a
  Anti-SAE (+)1 (1.2)0>0.999a
  Anti-MDA5 (+)1 (1.2)0>0.999a
  Anti-NXP2 (+)00
  Anti-TIF-1γ (+)01 (2.2)0.349a
  Anti-SRP (+)1 (1.2)0>0.999a
  ESR/(mm/h)20.0 (8.0, 44.0)32.0 (16.0, 58.0)-2.0670.039
  Elevated ESR42 (50.0)32 (71.1)5.3400.021
  CRP/(mg/L)4.3 (0.6, 27.0)13.2 (1.5, 27.0)-1.6480.099
  Elevated CRP51 (60.7)24 (53.3)0.6560.418
  CK/(U/L)230.0 (93.0, 1 059.0)131.0 (69.0, 413.0)-1.7330.083
  Elevated CK46 (54.8)19 (42.2)1.8430.175

Data are expressed as n(%), $\bar x \pm s$ or median (0.25 quantile, 0.75 quantile). a, analyzed by Fisher’s exact test. Elevated ESR: male>15 mm/h, female>20 mm/h; Elevated CRP: CRP>10.0 mg/L; Elevated CK: CK>165 U/L. Anti-Jo-1, anti-histidyl tRNA synthetase antibody; ASS, anti-synthetase syndrome; ILD, interstitial lung disease; ANA, antinuclear antibodies; Mi-2, component of the nucleosome remodeling-deacetylase complex; SAE, small ubiquitin like modifier activating enzyme; MDA5, melanoma differentiation associated gene 5; NXP2, nuclear matrix protein 2; TIF-1γ, transcriptional intermediary factor 1γ; SRP, signal recognition particle. SRP, signal recognition particle; ESR, erythrocyte sedimentation rate; CRP, C-reaction protein; CK, creatine kinase.

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2.3 抗Jo-1抗体滴度与临床特点

依据抗Jo-1抗体滴度+、++、+++将患者分为低、中、高三组，其中低滴度组15例(25.0%)，中等滴度组15例(38.5%)，高滴度组54例(81.8%)，图 2展示了抗Jo-1抗体不同滴度组的疾病分布。将抗Jo-1抗体滴度与ASS患者临床特点进行Spearman秩相关分析发现，在临床表现方面，关节炎、技工手、雷诺现象、Gottron征的发生率均随抗体滴度的升高而升高(P < 0.05)；在实验室检查方面，随着抗Jo-1抗体滴度升高，患者CK和α-HBD升高的发生率增加(P＜0.05，表 2)，抗Jo-1抗体滴度低、中、高组的CK值依次为67.0(40.0，284.0) U/L、186.0(83.0，494.0) U/L和414.0(121.0，1 288.5) U/L，α-HBD值依次为247.5(144.3，287.0) U/L、234.0(159.0，293.0) U/L和275(201.5，367.0) U/L。

图2

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图2   抗Jo-1抗体滴度与疾病分布(前五种)

Figure 2   The top five diseases with high, median and low anti-Jo-1 antibody titer

Abbreviations as in Figure 1 and Table 1.


表2   抗Jo-1抗体滴度与ASS患者临床特征及实验室数据的相关性分析

Table 2  Correlation analysis between anti-Jo-1 antibody titer and clinical features and laboratory data of ASS patients

ItemsAnti-Jo-1 (+) (n=15)Anti-Jo-1 (++) (n=15)Anti-Jo-1 (+++)(n=54)rP
Clinical features
  Fever5 (33.3)4 (26.7)9 (16.7)-0.1630.140
  ILD12 (80.0)13 (86.7)47 (87.0)0.0620.576
  Arthritis4 (26.7)7 (46.7)40 (74.1)0.385< 0.001
  Myalgia6 (40.0)11 (73.3)24 (44.4)-0.0710.521
  Myasthenia6 (40.0)8 (53.3)32 (59.3)0.1360.218
  Dysphagia005 (9.3)0.1830.096
  Mechanic hands4 (26.7)8 (53.3)33 (61.1)0.2330.033
  Raynaud phenomenon01 (2.6)10 (15.2)0.2230.041
  Gottron sign9 (60.0)12 (80.0)47 (87.3)0.2360.031
  Malignancy1 (6.7)01 (1.9)-0.0740.504
  Neurologic abnormality1 (6.7)03 (5.6)0.0280.797
Laboratory data
  Elevated WBC7 (46.7)10 (66.7)38 (70.4)0.1620.141
  Decreased lymphocyte8 (53.3)9 (60.0)31 (57.4)0.0160.887
  Elevated neutrophil10 (66.7)11 (73.3)38 (70.4)0.0130.905
  Elevated ESR7 (46.7)4 (26.7)31 (57.4)0.1590.151
  Elevated CRP7 (46.7)1 (6.7)24 (44.4)0.0870.445
  Decreased albumin13 (86.7)10 (66.7)40 (74.1)-0.0580.600
  Elevated CK4 (26.7)8 (53.3)34 (63.0)0.2630.016
  Elevated LDH13 (86.7)10 (66.7)43 (79.6)0.0020.958
  Elevated α-HBD10 (66.7)9 (60.0)47 (87.0)0.2550.021

Data are expressed as n(%). Elevated WBC: WBC>9.50×109/L; Decreased lymphocyte: Lymphocyte < 1.10×109/L; Elevated neutrophil: Neutrophil>6.3×109/L; Decreased albumin: Albumin < 40 g/L; Elevated LDH: LDH>245 U/L; Elevated α-HBD: α-HBD >182 U/L; WBC, white blood cell; LDH, lactate dehydrogenase; α-HBD, α-hydroxybutyric dehydrogenase. Other abbreviations and explanations as in Figure 1 and Table 1.

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2.4 单一抗Jo-1抗体阳性与抗Jo-1抗体合并其他MAAs/MSAs阳性ASS患者对比

将抗Jo-1抗体阳性ASS患者分为单一抗Jo-1抗体阳性组(20例)和抗Jo-1抗体合并其他MAAs/MSAs阳性组(64例)，两组比较发现，单一抗Jo-1抗体阳性组表现出肌痛(25.0% vs. 56.3%，P=0.015)、肌无力(35.0% vs. 61.0%，P=0.042)的比例显著低于抗Jo-1抗体合并其他MAAs/MSAs阳性组，其他临床表现及实验室指标两组间差异无统计学意义(表 3)。

表3   单一抗Jo-1抗体与抗Jo-1抗体合并其他MAAs/MSAs阳性ASS患者临床特征及实验室数据对比

Table 3  Comparison of clinical features and laboratory data in ASS patients with positive anti-Jo-1 antibody only and ASS patients positive for anti-Jo-1 antibody combined with other MAAs/MSAs

ItemsIsolated anti-Jo-1 (+)
(n=20)		Coexistence of anti-Jo-1 (+) and MAAs/MSAs (+)
(n=64)		t/Z/χ2P
Clinical features
  Age of onset/years45.60±10.1549.94±13.60-0.1020.919
  Female15 (75.0)49 (76.6)< 0.001>0.999
  Fever5 (25.0)13 (20.3)0.0180.894
  Myalgia5 (25.0)36 (56.3)5.9560.015
  Myasthenia7 (35.0)39 (61.0)4.1380.042
  Dysphagia05 (7.8)0.332a
  Gottron sign15 (75.0)53 (82.8)0.2030.652
  Raynaud phenomenon2 (10.0)9 (14.1)0.0080.928
  ILD17 (85.0)55 (85.9)< 0.001>0.999
  Mechanic hands9 (45.0)36 (56.3)0.7750.379
  Arthritis11 (55.0)40 (62.5)0.3590.549
  Neurologic abnormality1 (5.0)3 (4.7)>0.999a
  Malignancy1 (5.0)1 (1.6)0.422a
Laboratory data
  ESR/(mm/h)15.5 (7.5, 31.5)22.0 (8.0, 56.0)-1.0760.282
  Elevated ESR9 (45.0)33 (51.6)0.3310.565
  CRP/(mg/L)7.1 (0.5, 12.4)4.3 (0.6, 32.2)-0.9520.341
  Elevated CRP8 (40.0)24 (37.5)0.0460.836
  CK/(U/L)155.0 (80.0, 756.0)237.0 (100.0, 1153.0)-0.7990.425
  Elevated CK10 (50.0)36 (56.3)0.3130.576

Data are expressed as n(%), $\bar x \pm s$ or median (0.25 quantile, 0.75 quantile). a, analyzed by Fisher’s exact test. MAAs, myositis associated antibodies; MSAs, myositis specific antibodies. Other abbreviations and explanations as in Table 1 and Table 2.

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此外，在95例IIM患者中，抗Jo-1抗体与其他三种MAAs同时存在的情况见图 3，其中单一抗Jo-1抗体阳性者占13.7%，抗Jo-1抗体同时合并Ro-52抗体和ANA阳性患者最多见，占总体的42.1%。

图3

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图3   IIM患者中抗Jo-1抗体与抗Ro-52抗体、抗PM-Scl 75/100抗体及抗核抗体合并存在情况

Figure 3   Condition of anti-Jo-1 antibody with anti-Ro-52, anti-PM-Scl 75/100 and ANA in IIM patients

The red part represents the anti-Jo-1 antibody-positive samples, the blue part represents the anti-Ro-52 antibody-positive samples, the purple part represents the anti-PM-Scl 75/100 antibody-positive samples, the green part represents the antinuclear antibody-positive samples, and the overlap part represents the patients with two or more positive antibodies at the same time.


3 讨论

抗Jo-1抗体是肌炎特异性抗体之一，本研究结果显示抗Jo-1抗体阳性患者的疾病多样，有57.6%的患者最终诊断为IIM，50.9%诊断为ASS，除外IIM的CTD患者占23.6%。在除外IIM的CTD中，类风湿关节炎是最多的诊断，以往研究显示，ASS在疾病早期往往不会表现出经典的关节炎、肌炎、ILD三联征，可只表现出关节症状，导致部分ASS在早期被诊断为类风湿关节炎，也有部分病例最终被认为是ASS与类风湿关节炎重叠[7]，因此，这部分诊断为非肌炎CTD的患者需继续随访观察。本研究有31例患者未被诊断为CTD，Mielnik等[18]的研究表明，部分IIM患者在表现出肌炎相关症状前可以检测到抗Jo-1抗体阳性，因此本研究中部分未被诊断为CTD的患者可能是IIM早期，最终可能分化进展为肌炎。与以往研究[19]相比，本研究诊断IIM的比例较低，推测在未诊断为IIM的患者中有部分未表现出典型症状者可能被遗漏掉，需密切随访观察。

在ASS患者的亚组分析中，抗Jo-1阳性的ASS患者发病年龄更早，更多表现为肌痛和关节炎，而ESR升高的发生率更低。在抗Jo-1抗体阴性的ASS亚组中，其他抗合成酶抗体(抗EJ、OJ、PL-7、PL-12抗体)的阳性率相应更高，Ge等[20]的研究提示，抗OJ抗体阳性ASS患者ESR高于抗Jo-1抗体阳性ASS患者，这与本研究抗Jo-1阳性ASS患者ESR升高比例低于阴性组的结果相一致。既往研究表明，抗Jo-1抗体阳性与技工手、ILD、肌炎、关节炎、雷诺现象等症状有关[21]，在Aggarwal等[19]的研究结果中，抗Jo-1抗体阴性ASS患者组与阳性组相比起病年龄更晚，常无典型肌炎表现，更多表现出ILD、肺动脉高压等肺部受累表现，而肺部受累患者普遍预后差、死亡率高。本研究结果在起病年龄和肌肉受累方面与既往结果类似，与抗Jo-1抗体阳性ASS患者相比，抗Jo-1抗体阴性ASS患者的ILD比例更高，但未发现统计学意义，尚需加大样本量进一步探究。

本组84例抗Jo-1抗体阳性的ASS患者中，随着抗Jo-1抗体滴度的升高，关节炎、技工手、Gottron征、雷诺现象更加多见，且CK及α-HBD异常的比例升高。Liu等[22]的研究表明，抗Jo-1抗体阳性患者多存在白细胞、ESR、CRP、CK、LDH等指标水平的升高，Zhao等[23]的研究提示，血清抗Jo-1抗体水平与疾病活动度相关，本研究发现大量结缔组织受累表现和肌肉损害相关指标与抗Jo-1抗体的抗体滴度相关，表明抗Jo-1抗体可能介导机体某些炎症反应及肌肉组织损伤，后续研究可以就抗Jo-1抗体水平能否作为预测患者疾病活动和预后的指标进行探究。本研究发现随着抗Jo-1抗体滴度升高，诊断为ASS的比例也随之升高，由前可知随着抗Jo-1抗体的升高，Gottron征、技工手、关节炎及肌炎相关指标升高的发生率更高，因此，我们认为高滴度的抗Jo-1抗体可能对ASS更有诊断价值。

值得注意的是，本研究结果中抗Jo-1抗体阳性患者白细胞升高大多以中性粒细胞为主，淋巴细胞绝对值多正常甚至下降，Zhang等[24]的研究曾发现，抗Jo-1抗体可促进中性粒细胞胞外诱捕网的功能，这与肌炎的发病以及ILD的加重有关，可以解释本研究中中性粒细胞升高的结果。Kryštůfková等[25]的研究发现抗Jo-1抗体可以与肿瘤坏死因子家族B细胞活化因子相互作用促进炎症反应，Ascherman等[26]的研究结果提示T细胞与抗Jo-1抗体的作用机制相关，这均与本研究中淋巴细胞普遍降低的结果不一致。抗Jo-1抗体与免疫细胞亚群的相互作用还需要被进一步研究。

恶性肿瘤是IIM较为常见的合并症，以往研究表明，抗合成酶抗体是IIM合并恶性肿瘤的保护因素[27]，这与本研究的结果相一致，但本研究中仅2例ASS患者合并肿瘤，其临床指导意义较小，抗Jo-1抗体与恶性肿瘤的关系以及作用机制尚需更深入地探究。

本研究中抗Jo-1抗体与其他肌炎抗体的组合多样，其中抗Jo-1抗体最常合并抗Ro-52抗体，与郑艺明等[28]的研究结果一致。本研究中ASS患者多集中在抗Jo-1抗体合并其他MAAs/MSAs阳性患者中，可见抗Jo-1抗体合并其他肌炎抗体阳性对于ASS的诊断有一定提示意义。抗Jo-1抗体合并其他MAAs/MSAs阳性的ASS患者出现肌痛、肌无力的比例更高，疾病表现更加严重。Marie等[29]的研究也发现合并抗Ro-52抗体阳性的抗Jo-1抗体阳性ASS患者更易损伤关节和肌肉，说明不同的肌炎抗体可能存在相互协同的关系，抗体之间的相互作用值得进一步探究。

本研究存在一定的局限性：首先，本研究为单中心横断面回顾性研究，有待扩大样本进行随访；其次，本研究所用检测抗Jo-1抗体的方法为免疫印记法，为非定量检测，期待其他检测方法应用于临床以进一步验证。

综上所述，抗Jo-1抗体阳性患者疾病谱广，以ASS为主；抗Jo-1抗体阳性ASS患者相较于阴性患者起病更早，更易累及肌肉和关节，抗Jo-1抗体阴性ASS患者更易出现ESR升高；随着抗Jo-1抗体滴度升高，ASS患者累及结缔组织的临床表现和肌肉损伤指标异常情况发生率升高，总体疾病活动度更高，病情更加严重；抗Jo-1抗体可与MAAs/MSAs同时存在，在合并其他肌炎抗体阳性时，ASS患者更多表现出肌痛、肌无力，疾病表现更重。

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