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Code  ›  临床无肌病性皮肌炎与皮肌炎临床及免疫学特征比较 - PMC
pubmed 皮肌炎 肌炎 抗体滴度
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745270/
小胡子的莴苣
1 年前
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Beijing Da Xue Xue Bao Yi Xue Ban. 2020 Dec 18; 52(6): 1001–1008.
Published online 2020 Nov 4. Chinese. doi: 10.19723/j.issn.1671-167X.2020.06.003
PMCID: PMC7745270
PMID: 33331305

Language: Chinese | English

临床无肌病性皮肌炎与皮肌炎临床及免疫学特征比较

Comparison of clinical and immunological features between clinically amyopathic dermatomyositis and typical dermatomyositis

甘 雨舟 , 1 李 玉慧 , 1 张 丽华 , 2 马 琳 , 3 何 文雯 , 4 金 月波 , 1 安 媛 , 1 栗 占国 , 1 and 叶 华 1, *

甘 雨舟

北京大学人民医院风湿免疫科，北京 100044, Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China

Find articles by 甘 雨舟

李 玉慧

北京大学人民医院风湿免疫科，北京 100044, Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China

Find articles by 李 玉慧

张 丽华

呼伦贝尔市人民医院风湿免疫科，内蒙古呼伦贝尔市 021008, Department of Rheumatology, Hulunbeier People's Hospital, Hulunbeier 021008, Inner Mongolia, China

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马 琳

河北省中医院风湿免疫科，石家庄 050011, Department of Rheumatology, Hebei Hospital of Traditional Chinese Medicine, Shijiazhuang 050200, China

Find articles by 马 琳

何 文雯

重庆医科大学附属第一医院内分泌内科，重庆 400016, Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China

Find articles by 何 文雯

金 月波

北京大学人民医院风湿免疫科，北京 100044, Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China

Find articles by 金 月波

安 媛

北京大学人民医院风湿免疫科，北京 100044, Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China

Find articles by 安 媛

栗 占国

北京大学人民医院风湿免疫科，北京 100044, Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China

Find articles by 栗 占国

叶 华

北京大学人民医院风湿免疫科，北京 100044, Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China 北京大学人民医院风湿免疫科，北京 100044, Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China 呼伦贝尔市人民医院风湿免疫科，内蒙古呼伦贝尔市 021008, Department of Rheumatology, Hulunbeier People's Hospital, Hulunbeier 021008, Inner Mongolia, China 河北省中医院风湿免疫科，石家庄 050011, Department of Rheumatology, Hebei Hospital of Traditional Chinese Medicine, Shijiazhuang 050200, China 重庆医科大学附属第一医院内分泌内科，重庆 400016, Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China Age/years, x ± s 50.47±12.4451.63±13.850.4840.487Gender，female :male (%female)82 :24 (77.4)109 :49 (69.0)2.2220.136Age of onset/years, x ± s 48.84±13.0748.92±14.790.0010.969Cutaneous manifestation  Gottron's sign/papule, n (%)85 (80.2)115 (72.8)1.8940.169  Mechanic's hands, n (%)41 (38.7)56 (35.4)0.2860.593  Heliotrope eruption, n (%)59 (55.7)82 (51.9)0.3610.548  V shawl neck sign, n (%)59 (55.7)92 (58.2)0.1710.679  Skin ulceration, n (%)13 (12.3)17 (10.8)0.1430.706  Perionychia erythma, n (%)21 (19.8)35 (22.2)0.2080.648  Skin calcinosis, n (%)7 (6.6)8 (5.1)0.2810.596Pulmonary involvement  ILD, n (%)84 (79.2)131 (82.9)0.5640.453  Acute, n (%)49 (58.3)34 (26.0)22.640< 0.001  Asymptomatic, n (%)17 (20.2)43 (32.8)4.0300.045  ILD onset before CADM diagnosed, n (%)22 (20.7)12 (7.6)9.7920.002Systemic symptoms  Noninfectious fever, n (%)41 (38.7)56 (35.4)0.2860.593  Arthralgia, n (%)56 (52.8)65 (41.1)3.4930.062  Raynaud phenomenon, n (%)12 (11.3)22 (13.9)0.3830.536  Splenomegaly, n (%)11 (10.4)10 (6.3)1.3830.240  Weight loss, n (%)38 (35.8)44 (27.8)1.8970.168Accompanied CTD, n (%)20 (18.9)31 (19.6)0.0230.879Accompanied malignancy, n (%)5 (4.7)14 (8.9)1.6310.202Serum TAAs  CEA/(μg/L), M ( P 25 , P 75 )2.89 (1.76, 5.27)2.00 (1.10, 4.03)2.7500.006  AFP/(μg/L), M ( P 25 , P 75 )2.45 (1.89, 3.17)2.45 (1.78, 3.46)0.2970.767  CA19-9/(U/mL), M ( P 25 , P 75 )11.81 (4.97, 16.53)9.92 (5.78, 18.87)0.4710.638  CYFRA21-1/(μg/L), M ( P 25 , P 75 )3.38 (2.05, 5.49)3.06 (2.36, 4.81)0.2600.795  NSE/(μg/L), M ( P 25 , P 75 )14.08 (11.15, 17.20)16.20 (12.39, 23.47)2.8480.004Immunological parameters  RF positive, n (%) * 11 (10.8)32 (20.5)4.2030.040  ANA (≥1 :80)， n (%) * 36 (35.3)78 (50.0)6.5380.011

此外，CADM与DM在年龄、性别、起病年龄、典型皮肤表现(Gottron征/疹、技工手、向阳疹、V领/披肩征、皮肤破溃、甲周炎和皮肤钙质沉着)、系统表现(发热、关节炎、雷诺现象、脾大和体质量下降)，以及合并恶性肿瘤和其他结缔组织病等方面差异均无统计学意义。

2.2. CADM与DM肌炎抗体的分布比较

共计89例CADM与130例DM检测了肌炎抗体( 表 2 )，CADM中最常见的3种MSAs依次为抗MDA5(36.0%)、抗PL-7(11.2%)和抗TIF-1γ(10.1%); DM中最常见的MSAs依次为抗Jo-1(19.2%)、抗TIF-1γ(11.5%)和抗MDA5(11.5%)。抗Ro-52为CADM(49.4%)及DM(53.8%)中最常见MAAs。此外，CADM患者抗MDA5和抗Ku阳性率高于DM，抗Jo-1和抗EJ阳性率明显低于DM。虽然CADM与DM中抗TIF-1γ阳性率无明显差异，但抗体滴度在两种疾病中差异具有统计学意义，即在CADM患者中抗TIF-1γ多为中低滴度，而在DM中以高滴度为主。除上述5种有差异的肌炎抗体外，其他11种肌炎抗体在CADM及DM中的阳性率及滴度分布差异无统计学意义。

表 2

肌炎抗体在CADM与DM中分布的比较

Comparison of distribution of myositis autoantibodies between CADM and DM

Items CADM ( n =89) DM ( n =130) Comparison by overall positive rate Comparison by titers
Overall + ++ +++ Overall + ++ +++ χ 2 P χ 2 P
Values are displayed as n (%). CADM，clinically amyopathic dermatomyositis; DM，dermatomyositis.
Myositis specific autoantibodies (MSAs)
Mi-2α 1 (1.1) 1 (1.1) 0 0 7 (5.4) 3 (2.3) 3 (2.3) 1 (0.8) - 0.146 3.124 0.077
Mi-2β 4 (4.5) 3 (3.4) 0 1 (1.1) 6 (4.6) 3 (2.3) 3 (2.3) 0 - 1 0.001 0.970
TIF-1γ 9 (10.1) 8 (9.0) 1 (1.1) 0 15 (11.5) 3 (2.3) 5 (3.8) 9 (6.9) 0.444 0.505 4.202 0.040
MDA5 32 (36.0) 6 (6.7) 6 (6.7) 20 (22.5) 15 (11.5) 5 (3.8) 2 (1.5) 8 (6.2) 20.65 < 0.001 18.697 < 0.001
NXP2 5 (5.6) 2 (2.2) 1 (1.1) 2 (2.2) 7 (5.4) 1 (0.8) 3 (2.3) 3 (2.3) 0.006 0.941 0.022 0.883
SAE1 3 (3.4) 0 0 3 (3.4) 1 (0.8) 0 0 1 (0.8) - 0.306 - 0.306
SRP 4 (4.5) 4 (4.5) 0 0 8 (6.2) 2 (1.5) 2 (1.5) 4 (3.1) - 0.765 2.108 0.147
Jo-1 7 (7.9) 2 (2.2) 2 (2.2) 3 (3.4) 25 (19.2) 2 (1.5) 3 (2.3) 20 (15.4) 5.47 0.019 7.255 0.007
PL-7 10 (11.2) 5 (5.6) 3 (3.4) 2 (2.25) 10 (7.7) 2 (1.5) 4 (3.1) 4 (3.1) 0.799 0.371 0.067 0.796
PL-12 7 (7.9) 1 (1.1) 1 (1.1) 5 (5.6) 7 (5.4) 3 (2.3) 0 4 (3.1) 0.543 0.461 1.034 0.309
EJ 0 (0.0) 0 0 0 10 (7.7) 1 (0.8) 1 (0.8) 8 (6.2) - 0.006 6.744 0.009
OJ 2 (2.2) 2 (2.25) 0 0 4 (3.1) 3 (2.3) 1 (0.8) 0 - 1 0.336 0.562
Myositis associated autoantibodies (MAAs)
PM-Scl100 6 (6.7) 5 (5.6) 1 (1.12) 0 5 (3.8) 1 (0.8) 1 (0.8) 3 (2.3) 0.928 0.335 0.055 0.815
PM-Scl75 6 (6.7) 3 (3.4) 1 (1.12) 2 (2.2) 9 (6.9) 2 (1.5) 4 (3.1) 3 (2.3) 0.003 0.958 0.089 0.766
Ku 9 (10.1) 4 (4.5) 2 (2.2) 3 (3.4) 4 (3.1) 2 (1.5) 1 (0.8) 1 (0.8) - 0.041 4.218 0.040
Ro-52 44 (49.4) 8 (9.0) 5 (5.6) 31 (34.8) 70 (53.8) 4 (3.1) 4 (3.1) 62 (47.7) 0 1 1.952 0.162
Both MSAs and MAAs positive 79 (88.8) - - - 112 (86.1) - - - 1.143 0.285 - -
Only MSAs positive 62 (69.7) - - - 99 (76.1) - - - 0 0.989 - -
Only MAAs positive 54 (60.1) - - - 79 (60.8) - - - 0.323 0.570 - -

2.3. 肌炎抗体在CADM与DM中的临床意义

选取在CADM及DM中的阳性率均＞10%的肌炎抗体(抗TIF-1γ、抗MDA5及抗Ro-52)，探讨它们与临床表现以及合并恶性肿瘤、其他CTD( 表 3 )和继发性肺间质病变( 表 4 )的相关性。此外，进一步探讨不同滴度的肌炎抗体患者临床表现的差异( 图 1 、 2 )。

表 3

在CADM与DM中肌炎抗体的临床表现及合并疾病的相关性的比较

Comparison of the correlation of myositis autoantibodies and clinical manifestations and accompanied diseases between CADM and DM

Items CADM DM
TIF-1γ MDA5 Ro-52 TIF-1γ MDA5 Ro-52
r P r P r P r P r P r P
CADM，clinically amyopathic dermatomyositis; DM，dermatomyositis; CTD，connective tissue disease; MDA5, melanoma differentiation related genes.
Mechanic's hands -0.058 0.524 0.117 0.275 0.101 0.344 0.004 0.961 0.058 0.509 0.196 0.026
Heliotrope eruption 0.025 0.818 0.165 0.123 -0.335 0.001 0.310 < 0.001 0.146 0.098 -0.121 0.171
V/shawl neck sign 0.111 0.302 0.014 0.893 -0.157 0.141 0.280 0.001 0.127 0.151 -0.256 0.003
Skin ulceration -0.013 0.907 0.289 0.006 -0.167 0.117 -0.022 0.805 0.310 < 0.001 0.013 0.882
Perionychia erythma 0.017 0.875 0.115 0.281 -0.148 0.167 0.287 < 0.001 0.300 0.001 0.024 0.783
Skin calcinosis -0.078 0.465 -0.169 0.112 0.063 0.560 -0.087 0.323 -0.079 0.372 -0.179 0.042
Noninfectious fever 0.012 0.912 -0.015 0.892 0.094 0.381 -0.238 0.006 -0.082 0.354 0.257 0.003
Arthralgia -0.156 0.144 0.107 0.317 0.102 0.343 -0.165 0.060 0.204 0.020 0.141 0.109
Raynaud's phenomenon -0.013 0.907 -0.106 0.322 0.246 0.020 -0.046 0.601 -0.025 0.775 0.052 0.556
Malignancy -0.070 0.516 -0.022 0.840 -0.078 0.465 0.476 < 0.001 -0.124 -0.160 -0.102 0.247
Accompanied CTD -0.089 0.407 0.073 0.498 0.066 0.540 -0.135 0.124 -0.110 0.214 0.329 < 0.001

表 4

在CADM与DM中肌炎抗体与不同类型肺间质病变相关性的比较

Comparison of the correlation of myositis autoantibodies and different types of ILD between CADM and DM

Items CADM DM
Non-ILD( n =16) Acute ILD( n =44) Chronic ILD( n =29) P Non-ILD( n =22) Acute ILD( n =27) Chronic ILD( n =81) P
*Significance comparing with patients without ILD，adjusted P ＜0.05. § Significance comparing with patients with acute ILD，adjusted P ＜0.05. ※ The correlation of anti-Jo-1 and different types of ILD was not conducted in CADM because of the low positive rate of anti-Jo-1. CADM，clinically amyopathic dermatomyositis; DM，dermatomyositis; ILD，interstitial lung disease.
TIF-1γ 3 (18.7) 5 (11.4) 1 (3.4) 0.234 8 (36.4) 0 * 9 (11.1) * 0
MDA5 3 (18.7) 22 (50.0) * 7 (24.1) § 0.027 0 8 (29.6) * 7 (8.6) § 0.002
Jo-1 ※ - - - - 1 (4.5) 7 (25.9) * 17 (21.0) * 0.039
Ro-52 4 (25.0) 21 (47.7) 19 (65.5) * § 0.018 9 (40.9) 17 (63.0) 44 (54.3) 0.415
An external file that holds a picture, illustration, etc. Object name is bjdxxbyxb-52-6-1001-1.jpg

不同滴度的肌炎抗体阳性的CADM患者临床表现的比较

Comparison of clinical manifestations among different titers of myositis autoantibodies in CADM

A，skin ulceration; B, Raynaud phenonenon. *Significance comparing with patients with a certain myositis autoantidy negative, adjusted P ＜0.05.

An external file that holds a picture, illustration, etc. Object name is bjdxxbyxb-52-6-1001-2.jpg

不同滴度肌炎抗体阳性的DM患者临床表现的比较

Comparison of clinical manifestations among different titers of myositis autoantibodies in DM

A, anti-MDA5; B, anti-TIF-1γ, C, anti-Ro-52. *Significance comparing with patients with a certain myositis autoantidy negative, adjusted P ＜0.05.

抗MDA5在CADM与DM中均与皮肤破溃及急性肺间质病变相关，且在DM中抗MDA5还与甲周炎及关节炎相关。进一步分析发现，在CADM中皮肤破溃发生率在低、中、高滴度抗MDA5阳性的患者中均明显升高( 图 1A )，但在DM中皮肤破溃、甲周炎及关节炎的发生率仅在高滴度抗MDA5阳性患者中升高( 图 2A )。

抗TIF-1γ在CADM中与皮肤表现、系统表现及合并疾病均无明显相关性:在DM中与向阳疹、V领/披肩征、甲周炎及恶性肿瘤相关，且合并恶性肿瘤的比例在不同滴度抗TIF-1γ阳性患者中均明显升高，在中、高滴度抗TIF-1γ的DM患者中V领/披肩征的比例明显升高，但向阳疹及甲周炎的发生率仅在高滴度抗TIF-1γ明显升高。此外，无ILD的DM患者抗TIF-1γ的滴度显著升高( 图 2B )。

抗Ro-52在CADM中与雷诺现象及慢性ILD相关，高滴度抗Ro-52阳性患者中雷诺现象的比例明显升高( 图 1B )。在DM中抗Ro-52与技工手、发热及合并其他CTD相关，且高滴度抗Ro-52阳性患者中技工手、发热及合并其他CTD的比例明显升高( 图 2C )。

3. 讨论

既往认为，CADM为DM的一种亚型，即CADM为肌炎轻微甚至无肌炎表现的DM [ 3 , 7 ] ，但有研究表明两者在部分临床特征上存在一定差异 [ 9 - 12 ] 。本研究选择近10年在北京大学人民医院风湿免疫科住院的106例CADM及158例DM患者，比较两者的临床表现、合并症及肌炎抗体的差异，系统地总结了两种疾病的异同。

肺间质病变是IIM最常见的系统表现，而合并ILD尤其是急进性ILD是IIM重要的预后不良因素及死亡原因 [ 13 ] ，但ILD在不同亚型的IIM中的表现并不完全一样 [ 9 , 13 - 14 ] 。本研究发现，虽然CADM与DM合并ILD的比例差异无统计学意义，但CADM中以ILD起病及急性ILD的比例明显多于DM，而DM中无症状ILD较CADM常见，提示CADM-ILD与DM-ILD存在明显差异，与文献报道基本一致 [ 9 - 10 , 15 ] 。此外, 还有研究报道CADM为IIM-ILD的预后不良因素 [ 15 - 16 ] 。以上结果提示, CADM-ILD可能较DM-ILD更严重。

肌炎抗体，尤其是MSAs在DM的诊断、分型及预后中的重要意义已被大量证实 [ 6 , 13 - 14 , 17 - 18 ] ，如抗MDA5与皮肤破溃及急性ILD相关 [ 19 - 21 ] ，抗TIF-1γ与恶性肿瘤相关 [ 12 , 22 ] 。但既往研究很少探讨同一种MSAs在DM不同亚型中的分布及临床意义。日本有研究表明CADM中抗MDA5阳性率明显高于DM，而抗TIF-1γ阳性率显著低于DM [ 12 ] ，且DM中抗TIF-1γ以高滴度为主 [ 23 ] ，与本研究结果基本一致。此外，尽管在DM中抗TIF-1γ与多种皮肌炎典型的皮肤表现及合并恶性肿瘤相关，但在CADM中抗TIF-1γ与典型的临床表现及合并症均无明显相关性; 抗MDA5在CADM仅与皮肤破溃及急性ILD相关，但在DM中还与甲周炎及关节炎相关。因此，部分MSAs在DM及CADM中可能具有不同的分布及临床意义。

近年来多种MAAs在IIM中的临床意义已逐渐受到关注，如抗PM/Scl与合并系统性硬化相关，抗u1-RNP与合并混合性结缔组织病相关 [ 6 ] 。既往研究证实抗Ro-52为最常见的MAAs，并与抗合成酶抗体以及ILD相关 [ 8 , 17 , 20 , 24 - 26 ] 。本研究发现，抗Ro-52在CADM及DM中均为最常见的肌炎抗体，在CADM中与雷诺现象及慢性ILD相关，而在DM中与技工手、发热及合并其他CTD相关，提示MAAs在CADM与DM中也可能具有不同的临床意义。

由于肌炎抗体种类较多，因此免疫印迹法仍是目前主要的批量检测方法 [ 18 , 27 ] 。但国际肌炎评估与临床研究组(International Myositis Assessment and Clinical Studies Group, IMACS)近期发布的一项全球范围内的调查发现, 酶联免疫吸附法(ELISA)已广泛用于肌炎抗体的检测 [ 28 ] ，提示了临床对肌炎抗体定量/半定量检测的需求。美国一项研究发现不同肌炎抗体可能有各自最佳的界值，如抗Jo-1抗体诊断效力最强的界值点是低滴度阳性，抗PL-7诊断效力最强的界值点是高滴度阳性 [ 29 ] 。本研究发现同一种肌炎抗体不同滴度间的临床表现也不完全相同，如在CADM中皮肤破溃发生率在低、中、高滴度抗MDA5阳性的患者中均明显升高，但在DM中皮肤破溃发生率仅在高滴度抗MDA5阳性患者中升高。抗TIF-1γ与恶性肿瘤的相关性与滴度无关，但向阳疹、甲周炎的比例仅在高滴度抗TIF-1γ的DM患者中显著升高。有学者采用ELISA定量检测抗TIF-1γ及抗Mi-2, 发现抗体滴度的升高与病情复发明显相关 [ 23 ] ，也有研究发现抗TIF-1γ的滴度与肿瘤相关性皮肌炎的转归相关 [ 30 ] ，以上研究结果提示临床中不仅需注意肌炎抗体的阳性率，还应注意滴度变化，且肌炎抗体滴度的变化在疾病预后中可能具有重要意义。

已有研究表明, 肿瘤标志物在CTD-ILD中具有重要的临床意义 [ 25 , 31 - 32 ] ，其中Jin等 [ 32 ] 发现CEA是CTD-ILD的独立危险因素。肿瘤标志物在ILD中升高的原因目前尚未阐明，推测可能与肺泡上皮细胞增殖相关 [ 33 ] 。本研究发现CEA在CADM中的水平较DM高，而CADM-ILD比DM-ILD严重，进一步提示了CEA等肿瘤标志物在IIM-ILD中可能具有重要的致病作用及预后判断价值。

综上所述，CADM与DM在肺间质病变及肌炎抗体的分布和临床意义上具有明显差异，且不同滴度的肌炎抗体有不同的临床意义。但由于本研究是一项单中心回顾性横断面研究，故存在一定的选择偏倚，另外, CADM中抗Ku阳性及抗Jo-1阳性的例数相对较少，故没有探讨它们的临床意义，因此，后续需要多中心前瞻性研究进一步探讨CADM与DM的预后和肌炎抗体的异同。

Funding Statement

国家自然科学基金(81801615、81871289、81801617)

Supported by the National Natural Science Foundation of China (81801615, 81871289, 81801617)

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Articles from Journal of Peking University (Health Sciences) are provided here courtesy of Editorial Office of Beijing Da Xue Xue Bao Yi Xue Ban, Peking University Health Science Center
 
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