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北京大学学报（医学版） ›› 2023, Vol. 55 ›› Issue (6): 1013-1021. doi: 10.19723/j.issn.1671-167X.2023.06.009

• 论著 • 上一篇    下一篇

艾拉莫德联合托法替布治疗难治性中重度类风湿关节炎的疗效

邹雪1,2,白小娟1,张丽卿1,*()   

  1. 1. 山西医科大学附属汾阳医院, 山西省汾阳医院风湿免疫科, 山西汾阳 032200
    2. 苏州永鼎医院消化内科, 江苏苏州 215100
  • 收稿日期:2023-08-24 出版日期:2023-12-18 发布日期:2023-12-11
  • 通讯作者: 张丽卿 E-mail:zhanglq828@sohu.com
  • 基金资助:
    山西省汾阳医院科技攻关重点项目(2021-2022-03)

Effectiveness of tofacitinib combined with iguratimod in the treatment of difficult-to-treat moderate-to-severe rheumatoid arthritis

Xue ZOU1,2,Xiao-juan BAI1,Li-qing ZHANG1,*()   

  1. 1. Department of Rheumatology and Immunology, Fenyang Hospital Affiliated to Shanxi Medical University, Shanxi Province Fenyang Hospital, Fenyang 032200, Shanxi, China
    2. Department of Gastroenterology, Suzhou Yongding Hospital, Suzhou 215100, Jiangsu, China
  • Received:2023-08-24 Online:2023-12-18 Published:2023-12-11
  • Contact: Li-qing ZHANG E-mail:zhanglq828@sohu.com
  • Supported by:
    the Key Science and Technology Program of Shanxi Province Fenyang Hospital(2021-2022-03)

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摘要：

目的: 探讨艾拉莫德联合托法替布在难治性中重度类风湿关节炎(rheumatoid arthritis, RA)患者中的疗效和安全性。方法: 选择2021年9月至2022年6月规律就诊于山西省汾阳医院风湿免疫科的难治性中重度活动性RA患者30例进行前瞻性临床研究，其中，23例患者采用≥2种传统合成改善病情抗风湿药(disease modifying anti-rheumatic drugs，DMARDs)(至少包括甲氨蝶呤或来氟米特)治疗6个月以上，7例患者采用传统合成DMARDs联合肿瘤坏死因子拮抗剂治疗。将DMARDs调整为艾拉莫德联合托法替布，共治疗12周，收集患者治疗前，治疗4周、8周及12周时的临床资料：肿胀关节数(swollen joints count，SJC)、疼痛关节数(tender joints count，TJC)、晨僵时间、临床疾病活动指数(clinical disease activity index，CDAI)、健康状况评估问卷(health status assessment questionnaire，HAQ)、28个关节计数的疾病活动评分(28-joint disease activity score，DAS28)。记录患者的红细胞沉降率(erythrocyte sedimentation rate, ESR)、C反应蛋白(C-reactive protein, CRP)、血小板(platelet, PLT)、类风湿因子(rheumatoid factor, RF)、球蛋白、抗环瓜氨酸肽(cyclic citrullinated peptide, CCP)抗体等实验室检查结果，记录患者的用药情况，比较患者疾病活动指标的变化情况，记录药物不良反应。结果: 比较治疗前后的ESR、CRP、RF、PLT、SJC、TJC、基于ESR的DAS28(DAS28-ESR)、晨僵时间、HAQ、CDAI、抗CCP抗体，差异均有统计学意义(P < 0.05)，而治疗前后的球蛋白比较差异无统计学意义(P>0.05)。艾拉莫德联合托法替布治疗期间，所有患者均未发生白细胞减少、肝酶明显升高、过敏、血栓栓塞等严重不良反应。结论: 艾拉莫德联合托法替布治疗难治性中重度RA，可通过降低炎性指标改善患者的近期临床症状，且安全性良好。

关键词: 类风湿关节炎, 艾拉莫德, 托法替布, 治疗结果, 安全

Abstract:

Objective: To investigate the efficacy and safety of iguratimod combined with tofacitinib in patients with difficult-to-treat moderate-to-severe rheumatoid arthritis (RA). Methods: In this prospective clinical study, 30 patients with difficult-to-treat moderate-to-severe RA who attended the Department of Rheumatology and Immunology of Shanxi Province Fenyang Hospital from September 2021 to June 2022 were selected. Twenty-three patients enrollment had been treated with 2 or more conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) for more than 6 months. At least, methotrexate or leflunomide was included. Seven patients were treated with conventional synthetic DMARDs combined with tumor necrosis factor antagonists. Because all the patients had not reached the target of treatment, the combination treatment regimen of DMARDs was changed to iguratimod and tofacitinib. The observation period was 12 weeks. Clinical data were collected before and after treatment. At the end of 4 weeks, 8 weeks and 12 weeks, the clinical data were collected such as swollen joints count (SJC), tender joints count (TJC), time of morning stiffness, clinical disease activity index (CDAI), health status assessment questionnaire (HAQ), and 28-joint disease activity score (DAS28) were included. We collected laboratory indicators, recorded the patient's medication, and observed some changes to see if any adverse drug reactions occurred during the treatment. Results: There were significant differences in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), platelet (PLT), SJC, TJC, DAS28 based on ESR(DAS28-ESR), time of morning stiffness, HAQ, CDAI, and anti-cyclic citrullinated peptide antibody before and after treatment. The differences had statistical significance (P < 0.05). There was no statistical differences in globulin before and after treatment (P>0.05). During the treatment of iguratimod combined with tofacitinib, there was no serious adverse reactions such as leukopenia, significant elevation of liver enzymes, allergy or thromboemblolic events that occurred in all the patients. Conclusion: Iguratimod combined with tofacitinib in the treatment of difficult-to-treat moderate-to-severe RA may have efficacy. The machanism was improving the patients' recent clinical symptoms by reducing inflammatory indexes. This combination treatment regimen with iguratimod and tofacitinib has a good safety profile.

Key words: Rheumatoid arthritis, Iguratimod, Tofacitinib, Treatment outcome, Safety

中图分类号: 

  • R593.22

表1

患者入组前的用药情况(n=30)"

Usage of drugs n (%)
Two csDMARDs 21 (70.00)
    MTX and HCQ 6 (20.00)
    MTX and SSZ 9 (30.00)
    MTX and IGU 3 (10.00)
    LEF and IGU 2 (6.67)
    LEF and HCQ 1 (3.33)
Three csDMARDs 2 (6.66)
    MTX, HCQ and SSZ 1 (3.33)
    LEF, HCQ and SSZ 1 (3.33)
csDMARDs and bDMARDs 7 (23.34)
    MTX and etanercept 3 (10.00)
    MTX and adalimumab 1 (3.33)
    LEF and etanercept 2 (6.64)
LEF and adalimumab 1 (3.33)
Prednisone (≤10 mg/d) 22 (73.33)
NSAIDs 18 (60.00)

表2

治疗前后疾病活动相关指标的比较(n=30)"

Project Before treatment, M (P25, P75) After treatment, M (P25, P75) Wald χ2 P
4 weeks 8 weeks 12 weeks
ESR/(mm/h) 60.00 (42.75, 82.75) 30.05 (16.5, 53.00) 17.50 (10.05, 30.50) 9.00 (4.25, 13.50) 134.183 <0.001*
CRP/(mg/L) 22.97 (11.81, 43.89) 6.94 (2.20, 15.86) 3.45 (1.03, 6.41) 1.30 (0.33, 3.10) 37.586 <0.001*
RF/(IU/mL) 82.30 (22.43, 308.70) 53.00 (19.38, 202.50) 39.50 (13.40, 111.63) 18.50 (7.23, 59.83) 15.759 0.001*
PLT/(×109/L) 316.50 (234.50, 394.50) 250.50 (210.50, 308.00) 242.50 (213.00, 283.00) 242.00 (213.00, 313.50) 19.278 <0.001*
Globulin/(g/L) 31.60 (25.42, 34.02) 28.05 (24.72, 33.05) 27.30 (23.62, 32.55) 5.648 0.130
DAS28-ESR 4.77 (4.13, 5.60) 3.67 (2.75, 4.10) 1.83 (1.08, 2.94) 1.14 (0.72, 2.62) 393.417 <0.001*
Morning stiffness/min 90.00 (57.50, 120.00) 52.50 (27.50, 120.00) 20.00 (10.00, 41.25) 5.00 (0.00, 16.25) 122.857 <0.001*
SJC 8.50 (5.75, 12.00) 5.00 (2.00, 8.00) 2.50 (1.00, 4.00) 1.00 (0.00, 3.00) 129.482 <0.001*
TJC 9.51 (6.00, 14.25) 7.00 (4.00, 10.00) 3.00 (2.00, 6.00) 2.00 (2.00, 5.50) 153.105 <0.001*
CDAI 32.00 (22.75, 43.00) 24.00 (13.50, 28.00) 9.50 (5.00, 15.00) 5.00 (1.75, 9.75) 211.187 <0.001*
HAQ 10.00 (7.00, 17.00) 6.50 (4.00, 10.00) 5.00 (2.75, 7.25) 2.00 (1.75, 9.75) 141.037 <0.001*
ACPA/(IU/mL) 246.00 (153.75, 294.75) 138.00 (106.50, 232.50) 56.986 <0.001*

表3

治疗前后疾病活动指标比较(经广义估计方程模型分析，以治疗前为对照进行时间效应多重比较)"

Project Group β(95%CI) Wald χ2 P
ESR Before treatment
4 weeks -27.867 (-36.365, -19.368) 41.302 <0.001*
8 weeks -40.433 (-49.870, -30.997) 70.524 <0.001*
12 weeks -50.600 (-59.823, -41.377) 115.614 <0.001*
CRP Before treatment
4 weeks -24.367 (-36.299, -12.435) 16.020 <0.001*
8 weeks -30.088 (-42.632, -17.543) 22.100 <0.001*
12 weeks -32.867 (-45.684, -20.049) 25.257 <0.001*
RF Before treatment
4 weeks -42.168 (-69.685, -14.652) 9.022 0.003*
8 weeks -86.759 (-131.934, -41.584) 14.169 <0.001*
12 weeks -139.566 (-222.283, -56.849) 10.936 0.001*
PLT Before treatment
4 weeks -49.900 (-79.813, -19.987) 10.690 <0.001*
8 weeks -56.833 (-83.675, -29.991) 17.221 <0.001*
12 weeks -60.933 (-88.237, -33.630) 19.132 <0.001*
SJC Before treatment
4 weeks -3.733 (-4.595, -2.872) 72.147 <0.001*
8 weeks -6.567 (-7.701, -5.433) 128.777 <0.001*
12 weeks -7.833 (-9.219, -6.447) -15.346 <0.001*
TJC Before treatment
4 weeks -4.000 (-5.205, -2.795) 42.353 <0.001*
8 weeks -6.700 (-8.216, -5.184) 75.053 <0.001*
12 weeks -8.933 (-10.429, -7.438) 137.104 <0.001*
DAS28-ESR Before treatment
4 weeks -1.286 (-1.553, -1.020) 89.469 <0.001*
8 weeks -2.893 (-3.228, -2.557) 285.404 <0.001*
12 weeks -3.459 (-3.801, -3.117) 392.627 <0.001*
Morning stiffness Before treatment
4 weeks -21.000 (-29.333, -12.667) 24.395 <0.001*
8 weeks -57.267 (-68.908, -45.625) 92.962 <0.001*
12 weeks -73.833 (-87.535, -60.132) 111.545 <0.001*
HAQ Before treatment
4 weeks -4.300 (-5.201, -3.399) 87.446 <0.001*
8 weeks -6.700 (-7.877, -5.523) 124.579 <0.001*
12 weeks -8.900 (-10.394, -7.406) 136.386 <0.001*
CDAI Before treatment
4 weeks -11.217 (-13.516, -8.917) 91.402 <0.001*
8 weeks -21.650 (-25.044, -18.256) 156.323 <0.001*
12 weeks -26.350 (-30.079, -22.621) 191.827 <0.001*
ACPA Before treatment
After treatment -68.267 (-85.991, -50.542) 56.986 <0.001*

表4

治疗期间疾病活动构成比的比较(n=30)"

Items Remission, n (%) Low disease activity, n (%) Moderate disease activity, n (%) High disease activity, n (%) Z P
Before treatment 0 (0) 0 (0) 16 (53.33) 14 (46.67)
4 weeks 7 (23.33) 3 (10.00) 15 (50.00) 5 (16.67) -3.491 <0.05*
8 weeks 15 (50.00) 10 (33.33) 3 (10.00) 2 (6.67) -5.828 <0.05*
12 weeks 21 (70.00) 7 (23.33) 2 (6.67) 0 (0) -6.704 <0.05*

表5

治疗4、8、12周时疾病活动指标与治疗前比较(t检验)"

Items ESR CRP RF PLT DAS28-ESR Morning stiffness SJC TJC CDAI HAQ ACPA
4 weeks t -7.51 -5.23 -1.54 -4.18 -8.16 -3.81 -7.31 -6.61 -8.10 -8.58
P <0.05* <0.05* 0.12 <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05*
8 weeks t -10.91 -6.46 0.002 -4.77 -18.35 -10.40 -12.86 -11.08 -15.64 -15.64
P <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05*
12 weeks t -13.65 -7.06 -5.12 -5.11 -21.95 -12.86 -15.34 -14.77 -19.04 -19.04 -7.42
P <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05* <0.05*

图1

治疗前后DAS28-ESR评分构成比的比较(n=30)"

表6

治疗前后常规实验室检查指标比较(n=30)"

Project Before treatment, M (P25, P75) After treatment, M (P25, P75) Wald χ2 P
4 weeks 8 weeks 12 weeks
WBC/(×109/L) 7.35 (6.48, 8.84) 6.74 (5.57, 7.90) 6.39 (5.08, 7.73) 6.07 (5.43, 7.56) 5.090 0.165
RBC/(×1012/L) 4.27 (4.09, 4.67) 4.40 (4.17, 4.65) 4.51 (4.25, 4.90) 4.49 (4.26, 4.83) 15.936 0.001*
HGB/(g/L) 125.50 (111.75, 137.25) 122.00 (114.75, 129.25) 126.50 (114.75, 142.50) 132.00 (121.00, 141.75) 10.300 0.016*
ALT/(U/L) 17.00 (15.00, 27.00) 18.50 (14.00, 23.25) 17.00 (15.00, 24.00) 18.50 (15.75, 25.75) 9.138 0.028*
AST/(U/L) 18.50 (15.00, 25.25) 18.50 (14.00, 23.00) 19.50 (15.00, 24.00) 18.50 (15.00, 28.00) 1.905 0.592
GGT/(U/L) 19.00 (14.00, 31.50) 18.00 (14.75, 22.50) 15.50 (12.75, 23.50) 15.00 (12.00, 22.50) 2.727 0.436
Total protein/(g/L) 74.00 (71.87, 76.62) 76.00 (69.20, 77.85) 73.25 (70.75, 77.47) 73.30 (70.00, 82.22) 2.417 0.490
Albumin/(g/L) 43.95 (41.60, 46.15) 44.70 (42.92, 47.35) 45.55 (42.77, 47.52) 45.65 (43.30, 47.45) 5.845 0.119
Cr/(μmol/L) 62.50 (56.75, 72.50) 65.00 (59.00, 76.30) 67.00 (56.75, 73.50) 66.00 (58.75, 77.00) 5.149 0.161
BUN/(mmol/L) 4.40 (3.70, 5.02) 4.60 (4.20, 5.45) 4.70 (4.40, 6.10) 4.65 (4.37, 5.32) 8.214 0.042*

表7

治疗前后常规检测指标的比较(n=30)"

Project Group β(95%CI) Wald χ2 P
RBC Before treatment
4 weeks 0.369 (0.022, 0.717) 4.334 0.037*
8 weeks 0.261 (0.063, 0.460) 6.674 0.010*
12 weeks 0.532 (0.234, 0.831) 12.227 <0.001*
HGB Before treatment
4 weeks -2.433 (-9.203, 4.336) 0.496 0.481
8 weeks 2.300 (-3.816, 8.416) 0.543 0.461
12 weeks 6.500 (-1.942, 14.942) 2.277 0.131
ALT Before treatment
4 weeks -4.933 (-8.176, -1.690) 8.890 0.003*
8 weeks -3.633 (-7.479, 0.212) 3.429 0.064*
12 weeks -2.333 (-6.553, 1.886) 1.175 0.278
BUN Before treatment
4 weeks 0.297 (-0.124, 0.717) 1.911 0.167
8 weeks 4.237 (-0.886, 9.359) 2.628 0.105
12 weeks 0.360 (0.037, 0.683) 4.766 0.029*
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