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北京大学学报（医学版） ›› 2024, Vol. 56 ›› Issue (6): 972-979. doi: 10.19723/j.issn.1671-167X.2024.06.005

• 论著 • 上一篇    下一篇

抗合成酶综合征重叠类风湿关节炎患者的免疫学特征

赵亮1, 史成龙1,2, 马柯3, 赵静1, 王潇4, 邢晓燕1, 莫万星1, 练益瑞1, 高超1, 李玉慧1,3,*()   

  1. 1. 北京大学人民医院风湿免疫科，北京 100044
    2. 北京大学肿瘤医院暨北京市肿瘤防治研究所消化肿瘤内科，北京 100142
    3. 北京大学人民医院青岛医院风湿免疫科，山东青岛 266111
    4. 西双版纳傣族自治州人民医院血液风湿免疫科，云南西双版纳 666100
  • 收稿日期:2024-07-25 出版日期:2024-12-18 发布日期:2024-12-18
  • 通讯作者: 李玉慧 E-mail:liyuhui84@163.com
  • 作者简介:第一联系人：

    * These authors contributed equally to this work

  • 基金资助:
    国家自然科学基金(82371804);北京市自然科学基金(L222017);北京大学人民医院研究与发展基金(RDX2023-03);北京大学人民医院研究与发展基金(RZ2024-02)

Immunological characteristics of patients with anti-synthetase syndrome overlap with rheumatoid arthritis

Liang ZHAO1, Chenglong SHI1,2, Ke MA3, Jing ZHAO1, Xiao WANG4, Xiaoyan XING1, Wanxing MO1, Yirui LIAN1, Chao GAO1, Yuhui LI1,3,*()   

  1. 1. Department of Rheumatology and Immunology, Peking University People' s Hospital, Beijing 100044, China
    2. Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
    3. Department of Rheumatology and Immunology, Peking University People' s Hospital, Qingdao, Qingdao 266111, Shandong, China
    4. Department of Hematology and Rheumatology, the People' s Hospital of Xishuangbanna Dai Nationality Autonomous Prefecture, Xishuangbanna 666100, Yunnan, China
  • Received:2024-07-25 Online:2024-12-18 Published:2024-12-18
  • Contact: Yuhui LI E-mail:liyuhui84@163.com
  • Supported by:
    the National Natural Science Foundation of China(82371804);the Beijing Natural Science Foundation(L222017);the Peking University People' s Hospital Scientific Research and Development Foundation(RDX2023-03);the Peking University People' s Hospital Scientific Research and Development Foundation(RZ2024-02)

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摘要：

目的: 探究抗合成酶综合征(anti-synthetase syndrome, ASS)重叠类风湿关节炎(rheumatoid arthritis, RA)患者的免疫学特点。方法: 回顾性分析北京大学人民医院住院的104例ASS伴有关节炎患者的资料，包括人口学资料、临床表现(皮疹、肌肉损害等)、实验室检查结果、外周血淋巴细胞亚群和治疗用药，依据患者是否重叠RA进行分组并比较。结果: 104例ASS伴有关节炎的患者中，明确诊断RA的患者占23.1%(24/104例)，ASS重叠RA组患者的快速进展型间质性肺炎(rapid progressive interstitial lung disease, RP-ILD)发生率(41.7% vs. 17.6%，P=0.032)、压痛关节数[10 (7, 14)个vs. 4 (0, 8)个，P＜0.001]、肿胀关节数[4 (2, 8)个vs. 2 (0, 4)个，P=0.012]及骨侵蚀发生率(47.8% vs. 2.5%，P＜0.001)均显著高于非RA组。实验室检查方面，血小板水平[(289.57±68.74)×103/μL vs. (247.94±77.04)×103/μL, P=0.022]、红细胞沉降率[43 (19, 59) mm/h vs. 18 (10, 44) mm/h, P=0.019]和C反应蛋白[19.20 (4.80, 55.36) mg/L vs. 5.68 (1.10, 14.96) mg/L, P=0.006] 在ASS重叠RA组的患者中显著升高。免疫学指标检查显示，与ASS合并关节炎的患者组相比，ASS重叠RA组患者的外周血CLA+Treg细胞[(11.12±4.10)% vs. (17.22±8.49)%，P=0.003]、B细胞[8.56% (4.80%, 11.90%) vs. 14.55% (8.75%, 20.29%)，P=0.025]、自然杀伤(natural killer，NK)细胞[7.56% (4.65%, 13.20%) vs. 13.25% (7.46%, 19.25%)，P=0.045] 的比例显著降低，Naïve Th细胞[(52.66±17.66)% vs. (40.76±14.96)%，P=0.033]的比例显著升高。治疗反应方面，ASS重叠RA组患者的完全临床应答率较低(16.7% vs. 43.8%, P=0.031)。结论: ASS重叠RA患者的肺部及关节受累更严重，治疗应答率低，对此类患者需早期识别并积极干预。

关键词: 抗合成酶综合征, 类风湿关节炎, 淋巴细胞亚群, 完全临床应答

Abstract:

Objective: To investigate the clinical and immunological characteristics of anti-synthetase syndrome (ASS) patients overlap with rheumatoid arthritis (RA). Methods: A retrospective analysis was conducted on ASS patients with arthritis who were treated at Peking University People' s Hospital. Data collected included demographic information, clinical manifestations, laboratory features, lymphocyte subsets in peripheral blood, and treatments. The patients with ASS were divided into two groups based on the presence or absence of RA for comparative analysis. Results: A total of 104 ASS patients with arthritis were included, among whom 23.1% (24/104) were diagnosed with RA. The ASS with RA group had a significantly higher incidence of rapidly progressive interstitial lung disease (RP-ILD) (41.7% vs. 17.6%, P=0.032), number of tender joints [10 (7, 14) vs. 4 (0, 8), P < 0.001], number of swollen joints [4 (2, 8) vs. 2 (0, 4), P=0.012], and rate of bone erosion (47.8% vs. 2.5%, P < 0.001) compared with the non-RA group. Levels of platelets [(289.57±68.74)×103/μL vs. (247.94±77.04)×103/μL, P=0.022], erythrocyte sedimentation rate (ESR) [43 (19, 59) mm/h vs. 18 (10, 44) mm/h, P=0.019], and C-reactive protein (CRP) [19.20 (4.80, 55.36) mg/L vs. 5.68 (1.10, 14.96) mg/L, P=0.006] were found significantly higher in the ASS with RA group than those in non-RA group. Analysis of immune cells in peripheral blood mononuclear cell (PBMC) showed that significantly decreased proportions of CLA+ Treg cells [(11.12±4.10)% vs. (17.22±8.49)%, P=0.003], B cells [8.56% (4.80%, 11.90%) vs. 14.55% (8.75%, 20.29%), P=0.025], and natural killer (NK) cells [7.56% (4.65%, 13.20%) vs. 13.25% (7.46%, 19.25%), P=0.045] in the overlap group compared with non-RA group. Proportion of Naïve Th cells [(52.66±17.66)% vs. (40.76±14.96)%, P=0.033)] was significantly increased in overlap group compared with non-RA group. Overlap group had lower rate of complete clinical response than non-RA group (16.7% vs. 43.8%, P=0.031). Conclusion: Among ASS patients with arthritis, those with RA have more severe lung and joint involvement and a lower treatment response rate, highlighting the need for early recognition and aggressive intervention.

Key words: Anti-synthetase syndrome, Rheumatoid arthritis, Lymphocyte subsets, Complete clinical response

中图分类号: 

  • R593.2

表1

ASS重叠RA和非RA患者的人口学特征及临床表现"

Variables ASS overlap RA (n=24) ASS with arthritis (n=80) P value
Demographic data
   Onset age/years 48.00 (40.50, 55.50) 49.00 (40.50, 57.00) 0.802
   Female 20 (83.3) 62 (77.5) 0.742
   Disease duration/months 3 (1, 28) 9 (2, 24) 0.260
General
   Fever 13 (54.2) 30 (38.0) 0.241
Mucocutaneous
   Heliotropic rash 2 (8.3) 18 (22.5) 0.212
   Gottron’s sign/papule 13 (54.2) 49 (61.2) 0.702
   V sign 3 (12.5) 19 (23.8) 0.369
   Shawl sign 0 (0) 11 (13.8) 0.123
   Mechanic’s hands 9 (37.5) 41 (51.2) 0.342
   Skin ulcer 1 (4.2) 1 (1.2) 0.948
   Periungual erythema 3 (12.5) 5 (6.2) 0.568
Interstitial lung disease
   RP-ILD 10 (41.7) 13 (17.6) 0.032
   C-ILD 14 (58.3) 55 (74.3) 0.217
Musculoskeletal
   Muscle weakness 11 (45.8) 42 (52.5) 0.734
   Myalgia 8 (33.3) 38 (47.5) 0.322
   Dysphagia 2 (8.3) 7 (9.3) >0.999
   Tender joint count 10 (7, 14) 4 (0, 8) ＜0.001
   Swollen joint count 4 (2, 8) 2 (0, 4) 0.012
   Bone erosion 11 (47.8) 2 (2.5) ＜0.001

表2

ASS重叠RA和非RA患者关节受累分布"

Joint involvement ASS overlap RA (n=24), n (%) ASS with arthritis (n=80), n (%) P value
Temporomandibular joints 1 (4.2) 2 (2.5) >0.999
Sternoclavicular joints 1 (4.2) 1 (1.2) 0.948
Shoulder 13 (54.2) 17 (21.2) 0.004
Elbow 9 (37.5) 14 (17.5) 0.073
Wrist 14 (58.3) 31 (38.8) 0.143
Metacarpophalangeal joints 13 (54.2) 33 (41.2) 0.377
Proximal interphalangeal joints 20 (83.3) 55 (68.8) 0.255
Distal interphalangeal joints 4 (16.7) 10 (12.5) 0.854
Knee 13 (54.2) 39 (48.8) 0.816
Ankle 6 (25.0) 12 (15) 0.408

表3

ASS重叠RA患者的实验室特点"

Variables ASS overlap RA (n=24) ASS with arthritis (n=80) P value
WBC/(×103/μL) 8.78 (7.21, 9.88) 7.90 (5.70, 9.94) 0.553
Lymphocyte/(×103/μL) 1.40 (1.08, 1.83) 1.60 (1.15, 2.30) 0.576
Platelet/(×103/μL) 289.57±68.74 247.94±77.04 0.022
CK/(U/L) 166.0 (37.5, 1 074.0) 210.0 (80.5, 1 020.5) 0.386
ESR/(mm/h) 43 (19, 59) 18 (10, 44) 0.019
CRP/(mg/L) 19.20 (4.80, 55.36) 5.68 (1.10, 14.96) 0.006
Elevated ferritina 3 (27.3) 11 (28.9) >0.999
Anti-CCP positivity 18 (75.0) 1 (1.2) ＜0.001
RF positivity 19 (79.2) 6 (7.5) ＜0.001
AKA positivityb 2 (28.6) 1 (5.9) 0.396
APF positivityc 11 (52.4) 0 (0) ＜0.001
HRF positivityd 1 (5.0) 0 (0) 0.753
GPI positivityc 4 (19.0) 1 (2.6) 0.093
Anti-MCV positivitye 7 (58.3) 3 (11.1) 0.007
Anti-Ro-52 positivityf 14 (66.7) 45 (73.8) 0.731
Anti-Jo-1 positivityg 13 (56.5) 48 (60.8) 0.902
Anti-PL-7 positivityg 0 (0) 13 (16.5) 0.084
Anti-PL-12 positivityg 6 (26.1) 11 (13.9) 0.289
Anti-EJ positivityg 3 (13.0) 9 (11.4) >0.999
Anti-OJ positivityg 0 (0) 1 (1.3) >0.999

表4

ASS重叠RA和非RA患者外周血淋巴细胞亚群对比"

Variables ASS overlap RA (n=16) ASS with arthritis (n=45) P value
CD3+ total T/% 75.90 (66.64, 83.87) 68.80 (60.11, 75.55) 0.083
CD3+ total T/(/μL) 1 108.43±385.28 1 156.27±532.71 0.757
CD4+ helper T/% 46.30±18.23 40.78±11.39 0.270
CD4+ helper T/(/μL) 650.00 (357.00, 947.00) 610.00 (393.00, 984.50) 0.849
CD8+ cytotoxic T/% 24.35 (18.11, 32.66) 23.30 (16.84, 31.30) 0.887
CD8+ cytotoxic T/(/μL) 279.00 (254.00, 477.00) 377.20 (233.50, 500.80) 0.414
CD4+/CD8+ T ratio 1.85 (1.34, 2.63) 1.78 (1.31, 2.92) 0.758
CD4+CD25highCD127low Treg/% 7.90 (4.65, 9.75) 8.20 (6.35, 10.00) 0.463
CD4+CD25highCD127lowCD161+Treg/% 10.90 (8.60, 15.45) 11.50 (7.20, 13.25) 0.487
CD4+CD25highCD127lowCLA+Treg/% 11.12±4.10 17.22±8.49 0.003
CD4+CXCR5+PD-1+ pTfh/% 1.10 (0.80, 2.35) 2.60 (1.60, 3.10) 0.053
CD4+CD45RA- Naïve Th/% 52.66±17.66 40.76±14.96 0.033
CD4+CD25highFoxP3+ Treg/% 6.14 (4.04, 7.66) 7.00 (5.46, 8.78) 0.220
CD4+Foxp3-Teff/% 93.00 (91.60, 95.45) 91.20 (89.15, 93.30) 0.078
CD19+B/% 8.56 (4.80, 11.90) 14.55 (8.75, 20.29) 0.025
CD56+CD16+ NK/% 7.56 (4.65, 13.20) 13.25 (7.46, 19.25) 0.045
Th1 (TNF-α)/% 33.04±12.31 32.85±10.97 0.963
Th1 (IFN-γ)/% 6.88 (5.51, 9.70) 8.70 (6.65, 13.21) 0.257
Th1 (IL-2)/% 46.52±11.50 44.57±14.24 0.694
Th2 (IL-4)/% 1.54±0.69 1.63±0.86 0.774
Th-17 (IL-17)/% 1.18±0.69 1.38±0.56 0.358

表5

ASS重叠RA和非RA患者的药物治疗对比"

Variables ASS overlap RA (n=24), n (%) ASS with arthritis (n=80), n (%) P value
Glucocorticoids 24 (100.0) 80 (100.0) >0.999
CTX 9 (37.5) 34 (42.5) 0.842
MMF 3 (12.5) 16 (20.0) 0.594
CSA 12 (50.0) 25 (31.2) 0.150
TAC 5 (20.8) 7 (8.8) 0.207
AZA 0 (0) 7 (8.8) 0.300
MTX 2 (8.3) 5 (6.2) >0.999
LEF 0 (0) 1 (1.2) >0.999
IVIG 9 (37.5) 10 (12.5) 0.013
Tocilizumab 1 (4.2) 5 (6.2) >0.999
Rituximab 2 (8.3) 2 (2.5) 0.485
TOF 1 (4.2) 2 (2.5) >0.999
Monotherapy (glucocorticoids) 2 (8.3) 5 (6.2) >0.999
Glucocorticoids+immunosuppressants 20 (83.3) 67 (83.8) >0.999
Glucocorticoids+biologics 0 (0) 1 (1.2) >0.999
Glucocorticoids+immunosuppressants+biologics 2 (8.3) 7 (8.8) >0.999

图1

ASS重叠RA和非RA患者完全临床应答率比较"

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doi: 10.1016/S0140-6736(08)60453-5
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ISSN 1671-167X
CN 11-4691/R
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