Abstract
目的
比较临床无肌病性皮肌炎(clinically amyopathic dermatomyositis, CADM)和皮肌炎(dermatomyositis, DM)的临床及免疫学特征。
方法
选择2010年1月—2019年12月在北京大学人民医院风湿免疫科住院的106例CADM和158例DM患者的病例资料进行回顾性分析，对两组患者的临床及免疫学指标进行比较，探讨肌炎抗体在CADM和DM中的的分布特点及临床意义，其中，肌炎抗体的检测采用免疫印迹法。
结果
在临床表现方面，与DM相比，CADM更多地以肺间质病变(interstial lung diseases, ILD)起病(20.7% vs. 7.6%, P=0.002)，且以急性ILD为主(58.3% vs. 26%, P < 0.001)，而在皮疹、合并其他结缔组织病和恶性肿瘤等方面, CADM与DM差异无统计学意义, CADM类风湿因子和抗核抗体的阳性率均低于DM。CADM最常见的肌炎特异性抗体(myositis specific autoantibodies, MSAs)为抗黑色素瘤分化相关基因5(melanoma differentiation related genes, MDA5, 36%)、抗PL-7(11.2%)及抗TIF-1γ(10.1%); DM最常见的MSAs为抗Jo-1(19.2%)、抗TIF-1γ(11.5%)及抗MDA5(11.5%)。抗MDA5与急性ILD及皮肤破溃相关，但在CADM中皮肤破溃与抗MDA5的滴度无关，而在DM中皮肤破溃与高滴度的抗MDA5相关。在DM中，抗TIF-1γ与向阳疹、V领/披肩征、甲周炎，以及合并恶性肿瘤相关，且合并恶性肿瘤的比例与抗TIF-1γ的滴度无关; 在CADM中，抗TIF-1γ与临床表现及合并症无明显相关性。CADM及DM中最常见肌炎相关抗体均为抗Ro-52, 抗Ro-52在CADM中与雷诺现象和慢性ILD相关，在DM中与技工手、发热，以及合并其他结缔组织病相关。
结论
与DM相比，CADM-ILD以急性为主，肌炎抗体在CADM与DM中具有不同的分布特点; 同一种肌炎抗体在CADM及DM中的临床意义也存在区别，且部分肌炎抗体的临床意义还与滴度相关。
Keywords: 皮肌炎, 临床无肌病性皮肌炎, 肌炎抗体
Abstract
Objective
To study the differences between clinically amyopathic dermatomyositis (CADM) and typical dermatomyositis (DM) on clinical and immunological features.
Methods
By collecting clinical data of 106 CADM patients and 158 DM patients from January 2010 to June 2019 in the department of Rheumatology and Immunology, Peking University People's Hospital, the clinical characteristics and immunological features in the two groups were compared, and the distribution characters and the clinical meanings of myositis autoantibodies were discussed in the two groups respectively. Myositis autoantibodies were measured by immunoblotting according to the manufacturers' instructions.
Results
In the aspects of clinical manifestations, CADM presented more with onset of interstial lung diseases (ILD) compared with DM (20.7% vs. 7.6%, P=0.002), and CADM-ILD was more likely to be acute ILD (58.3% vs. 26%, P < 0.001), and there were no differences between CADM and DM in cutaneous manifestations, accompanied with connective tissue disease (CTD) and malignancy. In CADM, the positive rate of rheumatoid factors and antinuclear antibodies was lower in DM. The most common myositis specific autoantibodies (MSAs) in CADM were anti-MDA5 (36%), anti-PL-7 (11.2%) and anti-TIF-1γ (10.1%). The most common MSAs in DM were anti-Jo-1 (19.2%), anti-TIF-1γ (11.5%) and anti-MDA5 (11.5%). Anti-MDA5 was correlated with acute ILD and skin ulceration both in CADM and DM; in CADM, skin ulceration was not associated with the titer of anti-MDA5; while in DM, skin ulceration was associated with high titer of anti-MDA5. In DM, anti-TIF-1γ was correlated with heliotrope eruption, V/shawl neck sign, perionychia erythma and malignancy, and higher rate of malignancy was seen in all titers of the anti-TIF-1γ positive patients. In CADM, anti-TIF1-γ showed no correlation with clinical manifestations. The most common myositis associated autoantibody was anti-Ro-52 both in CADM and DM. In CADM, anti-Ro-52 was associated with Raynaud's phenomenon and chronic ILD, while in DM, anti-Ro-52 was associated with mechanic's hands, noninfectious fever and accompanied CTD.
Conclusion
Compared with DM, ILD is more likely to be acute in CADM. It is different between CADM and DM about the distribution of myositis autoantibodies and the clinical significance of the same myositis antibody, and the clinical significance of some myositis antibodies is related to titers.
Keywords: Clinically amyopathic dermatomyositis, Dermatomyositis, Myositis autoantibody
皮肌炎(dermatomyositis, DM)是炎性肌病(idiopathic inflammatory myopathies, IIM)最常见的亚型，主要表现为不同程度的皮肤、肌肉和肺部受累[1-2]。临床上观察到一类并没有明显的肌肉受累表现的DM称为临床无肌病性皮肌炎(clinically amyopathic dermatomyositis, CADM)[3]。最初认为CADM为DM的一种亚型，但越来越多的研究显示，与DM相比，CADM更易出现高滴度抗抗黑色素瘤分化相关基因5(melanoma differentiation related genes, MDA5)及急进性肺间质病变(interstial lung diseases, ILD)[4-5]。目前认为, MDA5参与自身免疫反应的机制可能是RNA病毒与MDA5结合进而激发的Ⅰ型干扰素反应，与经典的DM的发病机制存在一定差异[6]，提示CADM与DM除临床表现不同外可能还存在其他差异。本研究对北京大学人民医院2010年1月—2019年12月在北京大学人民医院风湿免疫科住院的106例CADM及158例DM患者的肌炎抗体的分布及临床意义进行对比分析，以期进一步揭示两种疾病尤其是免疫学相关特征的异同。
1. 资料与方法
1.1. 研究对象
选择2010年1月—2019年12月于北京大学人民医院住院的DM和CADM患者病例资料进行回顾性分析。DM患者符合2017年欧洲抗风湿病联盟(the European League Against Rheumatism, EULAR)/美国风湿病学会(American College of Rheumatology, ACR)关于成人DM的分类标准[2]，而CADM患者满足Sontheimer等[3]或Gerami等[7]对CADM的界定，包括无肌病皮肌炎(amyopathic dermatomyositis, ADM)及低肌病皮肌炎(hypomyopathic dermatomyositis, HDM)。ADM定义为存在DM皮疹(向阳疹、Gottron征/疹)，无肌力下降的症状和体征，肌酸激酶(creatine kinase, CK)正常，肌电图、肌活检均正常。HDM定义为存在DM皮疹(向阳疹、Gottron征/疹)，肌力仅轻度下降，CK不超过正常上限的1.5倍，肌电图或肌肉活组织病理检查仅见可疑性肌炎表现。共收集到106例CADM及158例DM患者病例资料。本研究开始前获得北京大学人民医院伦理委员会审查批准(2020PHB114-01)。
1.2. 临床资料
收集患者的年龄、性别、炎性肌病的典型皮肤表现、系统表现、合并症[包括其他结缔组织病(connective tissue disease, CTD)和恶性肿瘤]，以及ILD类型等临床资料。恶性肿瘤为确诊DM或CADM前后1年内出现的且由组织病理学确诊的恶性肿瘤。ILD按照2013年美国胸科协会及欧洲呼吸病学会的定义[8]，符合以下任意一项并除外其他原因可考虑诊断。按照病情进展的程度分为急进性ILD(1个月内病情恶化)、亚急性ILD(1~3个月内病情恶化)和慢性ILD(病情缓慢进展超过3个月)，其中急进性ILD及亚急性ILD统称急性ILD。符合以下两项即考虑病情恶化：(1)劳力性呼吸困难加重、活动耐量减低; (2)高分辨CT扫描(high resolution CT, HRCT)显示肺间质病变加重; (3)肺功能恶化(肺活量下降超过10%或动脉血氧分压下降超过1.33 kPa)。
1.3. 实验室指标
收集的实验室指标包括免疫球蛋白、补体、肿瘤标志物、类风湿因子(rheumatic factor, RF)、抗核抗体(antinuclear antibodies, ANA)以及肌炎抗体谱。肿瘤标志物包括癌胚抗原(carcino-embryonic antigen, CEA)、甲胎蛋白(alpha-fetoprotein, AFP)、神经烯醇化酶(neurenolase, NSE)、细胞角蛋白片段19(cytokeratin fragment 19, CYFRA21-1)和糖链抗原19-9(carbohydrate antigen 19-9, CA19-9)。肌炎抗体谱包括抗Jo-1、抗PL-7、抗PL-12、抗EJ、抗OJ、抗Mi-2α、抗Mi-2β、抗信号识别颗粒(signal recognition particle, SRP)、抗MDA5、抗核基质蛋白(nuclear matrix protein, NXP2)、抗转录中介因子-1γ(transcriptional mediator, TIF-1γ)和抗小泛素样修饰物激活酶1(small ubiquitin-like modifier activating enzyme, SAE1)等肌炎特异性抗体(myositis specific autoantibodies, MSAs)，以及抗Ro-52、抗Ku、抗PM/Scl-75和抗PM/Scl-100等抗肌炎相关抗体(myositis associated autoantibodies, MAAs)。所有肌炎抗体均采用免疫印迹法(德国欧蒙公司)检测，结果表示为阴性(-)、低度阳性(+)、中度阳性(++)及强阳性(+++)，其中低度阳性、中度阳性及高度阳性统称为阳性。
1.4. 统计学分析
采用SPSS 23.0软件，符合正态分布的连续变量以均数±标准差表示，组间差异比较采用方差分析; 不符合正态分布的连续变量采用M(P25，P75)表示，组间差异比较采用秩和检验; 分类变量采用百分数表示，组间差异比较若所有单元格的频数均≥5采用卡方检验，若任一单元格的频数＜5则采用Fisher精确检验。肌炎抗体滴度在CADM与DM中差异采用Mantel-Haenszel卡方检验。肌炎抗体与临床表现及合并恶性肿瘤与CTD的相关性的分析采用趋势卡方检验，不同类型ILD与肌炎抗体的相关性采用Wilcoxon秩和检验以比较3个分组间有序分类指标的差异。P＜0.05认为差异具有统计学意义。
2. 结果
2.1. CADM与DM临床特点及一般实验室指标的比较
在临床表现方面(表 1)，20.8% (22/106) CADM患者以ILD起病，比例显著高于DM [7.6% (12/158)]。虽然CADM与DM合并ILD的比例无明显差异(79.2% vs. 82.9%)，但在合并ILD的患者中，CADM (58.3%)出现急性ILD显著高于DM (26.0%)，而无症状ILD在CADM (20.2%)中显著低于DM (32.8%)。实验室指标中，CEA的滴度在CADM [2.89(1.76, 5.27) μg/L (ng/mL)]中显著高于DM [2.00(1.10, 4.03) μg/L]，NSE的滴度在CADM [14.08(11.15, 17.20) μg/L]中显著低于DM [16.20(12.39, 23.47) μg/L]。CADM中RF的阳性率和ANA阳性率均低于DM。
表 1.
CADM与DM的临床表现及实验室指标比较
Comparison of clinical manifestations and laboratory parameters between CADM and DM
| Items | CADM (n=106) | DM (n=158) | F/χ2 | P |
| Values displayed as n(%), x±s, or median (P25, P75) according to their features of distribution. ILD，interstitial lung disease; CADM，clinically amyopathic dermatomyositis; DM，dermatomyositis; CTD，connective tissue disease; TAA，tumor associated antigens; CEA，carcinoembryonic antigen; AFP，alpha-fetoprotein; CYFRA21-1，cytokeratin-19 fragment; NES，neuron specific enolase; CA19-9，Carbohydrate antigen 19-9; RF，rheumatoid factors; ANA，antinuclear antibodies. *The data of RF and ANA was missing in four patients in CADM and two patients in DM. | ||||
| Age/years, x±s | 50.47±12.44 | 51.63±13.85 | 0.484 | 0.487 |
| Gender，female :male (%female) | 82 :24 (77.4) | 109 :49 (69.0) | 2.222 | 0.136 |
| Age of onset/years, x±s | 48.84±13.07 | 48.92±14.79 | 0.001 | 0.969 |
| Cutaneous manifestation | ||||
| Gottron's sign/papule, n(%) | 85 (80.2) | 115 (72.8) | 1.894 | 0.169 |
| Mechanic's hands, n(%) | 41 (38.7) | 56 (35.4) | 0.286 | 0.593 |
| Heliotrope eruption, n(%) | 59 (55.7) | 82 (51.9) | 0.361 | 0.548 |
| V shawl neck sign, n(%) | 59 (55.7) | 92 (58.2) | 0.171 | 0.679 |
| Skin ulceration, n(%) | 13 (12.3) | 17 (10.8) | 0.143 | 0.706 |
| Perionychia erythma, n(%) | 21 (19.8) | 35 (22.2) | 0.208 | 0.648 |
| Skin calcinosis, n(%) | 7 (6.6) | 8 (5.1) | 0.281 | 0.596 |
| Pulmonary involvement | ||||
| ILD, n(%) | 84 (79.2) | 131 (82.9) | 0.564 | 0.453 |
| Acute, n(%) | 49 (58.3) | 34 (26.0) | 22.640 | < 0.001 |
| Asymptomatic, n(%) | 17 (20.2) | 43 (32.8) | 4.030 | 0.045 |
| ILD onset before CADM diagnosed, n(%) | 22 (20.7) | 12 (7.6) | 9.792 | 0.002 |
| Systemic symptoms | ||||
| Noninfectious fever, n(%) | 41 (38.7) | 56 (35.4) | 0.286 | 0.593 |
| Arthralgia, n(%) | 56 (52.8) | 65 (41.1) | 3.493 | 0.062 |
| Raynaud phenomenon, n(%) | 12 (11.3) | 22 (13.9) | 0.383 | 0.536 |
| Splenomegaly, n(%) | 11 (10.4) | 10 (6.3) | 1.383 | 0.240 |
| Weight loss, n(%) | 38 (35.8) | 44 (27.8) | 1.897 | 0.168 |
| Accompanied CTD, n(%) | 20 (18.9) | 31 (19.6) | 0.023 | 0.879 |
| Accompanied malignancy, n(%) | 5 (4.7) | 14 (8.9) | 1.631 | 0.202 |
| Serum TAAs | ||||
| CEA/(μg/L), M(P25, P75) | 2.89 (1.76, 5.27) | 2.00 (1.10, 4.03) | 2.750 | 0.006 |
| AFP/(μg/L), M(P25, P75) | 2.45 (1.89, 3.17) | 2.45 (1.78, 3.46) | 0.297 | 0.767 |
| CA19-9/(U/mL), M(P25, P75) | 11.81 (4.97, 16.53) | 9.92 (5.78, 18.87) | 0.471 | 0.638 |
| CYFRA21-1/(μg/L), M(P25, P75) | 3.38 (2.05, 5.49) | 3.06 (2.36, 4.81) | 0.260 | 0.795 |
| NSE/(μg/L), M(P25, P75) | 14.08 (11.15, 17.20) | 16.20 (12.39, 23.47) | 2.848 | 0.004 |
| Immunological parameters | ||||
| RF positive, n(%)* | 11 (10.8) | 32 (20.5) | 4.203 | 0.040 |
| ANA (≥1 :80)，n(%)* | 36 (35.3) | 78 (50.0) | 6.538 | 0.011 |
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 | + | ++ | +++ | χ2 | P | χ2 | 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 | |
图 1.
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.
图 2.
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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