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Journal of Southern Medical University logoLink to Journal of Southern Medical University
. 2021 May 20;41(5):633–639. [Article in Chinese] doi: 10.12122/j.issn.1673-4254.2021.05.01

强直性脊柱炎患者减停TNF-α抑制剂后的复发情况及预测因素：52周前瞻性临床随访

Relapse of ankylosing spondylitis and its predictors after withdrawal of tumor necrosis factor-α inhibitors: a 52-week follow-up study

Cuiping TANG 1, Feilong CHEN 2, Songyuan ZHENG 1, Lisheng WU 2, Shixian CHEN 1, Junqing ZHU 1, Juan LI 1,2,*
PMCID: PMC8214974  PMID: 34134948

Abstract

Objective

To investigate the recurrence of ankylosing spondylitis (AS) that has been relieved by standard-dose adalimumab (ADA) after dose reduction or withdrawal of tumor necrosis factor-α inhibitor (TNFi) and explore the factors that predict AS occurrence.

Methods

This study was conducted among 63 patients with AS who reduced the dose of or discontinued TNFi after completing at least 12 treatment cycles with ADA (40 mg/2 weeks) to achieve ASAS20 improvement with a BATH disease activity index (BASDAI) < 4 for more than 8 weeks. The patients were followed up every 12 weeks for a total of 52 weeks, and the recurrence of AS, changes of BASDAI, C-reactive protein (CRP)-based disease activity score (ASDASCRP), low back pain (LBP) score, Bath Ankylosing Spondylitis Metrology Index (BASMI), CRP and ESR were recorded and analyzed. Cox regression model and ROC curve analyses were performed to analyze the risk factors of AS relapse after dose reduction or discontinuation of TNFi.

Results

Of the 63 patients enrolled, 57 completed the follow-up study, among whom 22 (38.6%) patients experienced AS relapse within 52 weeks, with a median clinical recurrence time of 31 weeks. The recurrence rate of AS was significantly higher in patients with complete withdrawal of medications (89.0%) than in those with TNFi dose reduction and TNFi discontinuation (P < 0.001), and did not differ significantly between the latter two groups of patients (χ2= 0.071, P=0.791). The Cox regression model showed that a high baseline LBP score (HR=1.438, P=0.027) and a high BASMI score (HR=1.29, P=0.049) were the risk factors for AS recurrence after TNFi dose reduction or discontinuation, while maintenance of medication during follow-up was a protective factor (HR=0.209, P=0.001). ROC curve analysis showed that the combination of baseline LBP score, BASMI and medication during follow-up had a good predictive value for AS relapse (AUC=0.819) with a sensitivity of 0.772 and a specificity of 0.718.

Conclusion

Dose reduction or discontinuation of TNFi is associated with a high recurrence rate of AS that has been relieved by TNFi treatment. A high LBP score, a high BASMI score and discontinuation of maintenance medication are the risk factors for AS recurrence in patients after dose reduction or withdrawal of TNFi.

Keywords: ankylosing spondylitis, tumor necrosis factor-α inhibitor, recurrence, risk factors

强直性脊柱炎(AS)是常见的一种慢性炎症性疾病，以慢性腰背痛为主要临床表现，若不能积极有效控制病情，后期可导致骶髂关节和脊柱融合强直畸形[1]，最终导致终身残疾[2]，严重影响患者的生活质量。非甾体类抗炎药(NSAIDs)是AS治疗的一线药物[3]，当有外周关节受累时可考虑联合柳氮磺吡啶(SSZ)，肿瘤坏死因子-α抑制剂(TNFi)则被国际脊柱关节炎评估协会与欧洲抗风湿病联盟(ASAS-EULAR)及国内专家推荐用于对NSAIDs疗效不佳持续高疾病活动的患者[4-5]，其在改善患者症状、延缓骨破坏及骨赘形成上均有疗效[6]，2016年由ASAS/EULAR联合制定的中轴脊柱关节炎(axSpA)指南推荐在持续缓解的患者中可考虑TNFi减量[4]，目前在临床中常用的减量方法为延长TNFi给药间隔。

减量TNFi如能够长期维持疗效，无疑能减轻AS患者经济负担。然而TNFi减停后部分患者疾病活动度升高、病情复发是医生和患者需要面对的现实问题[7-8]。台湾一项对类风湿关节炎和强直性脊柱炎患者在减停TNFi治疗后健康生活质量变化的研究结果显示[9]，AS患者减量或停用TNFi后，超过50%的AS患者出现病情复发，生活质量相关问卷评分下降。Landewé R.et报道[10]AS患者病情缓解后，停用阿达木单抗(ADA)组有53%的患者在48周内出现复发，高于足量维持治疗组复发率。现有的临床随机对照实验对经TNFi治疗缓解的AS患者停用TNFi的研究报道，停用TNFi后一年内，50%~69%的患者出现病情复发[11-12]。而对复发的患者再次使用TNFi，达缓解所需时间可能更久，也有部分患者出现对再次引入TNFi治疗无应答，反复的病情复发增加了治疗难度，并且给患者带来了沉重的经济、心理负担，这均提示临床工作者在减停TNFi时需要谨慎，因为可能存在某些复发高危因素的患者达临床缓解减停TNFi治疗后容易复发，而目前的研究对诸如骶髂关节X线片分级高、椎体骨赘形成或基线高疾病活动度等复发危险因素的探讨尚无一致定论，缺乏真实世界、尤其是中国人减停TNFi后复发情况及危险因素的研究报道。为此，我们观察了真实世界中经ADA治疗达病情缓解而减停TNFi的AS患者63例，评估其52周内病情复发情况，并分析探讨患者病情复发的危险因素，进而为临床更好的治疗、控制AS患者病情带来更多的证据。

1. 资料和方法

1.1. 研究设计

本研究为前瞻性观察研究，已通过南方医科大学南方医院伦理委员会批准，病例对象来源于2017年9月~ 2018年9月就诊于南方医科大学南方医院风湿门诊及住院部的AS患者，所有纳入研究对象均为自愿参与并签署知情同意书。每隔12周随访一次，共随访52周，无复发患者在随访52周时结束观察，复发患者随访至复发时结束观察，记录复发时间、缓解维持时间。缓解定义为Bath强直性脊柱炎疾病活动指数(BASDAI) < 4[13]；复发定义为：与基线期相比BASDAI增加≥2且BASDAI≥4[14]。

1.2. 纳入及排除标准

纳入标准：符合1984年修订的AS纽约分类标准[15] 诊断为AS；接受标准方案ADA治疗(40 mg/2周)12次以上，ASAS20改善且BASDAI < 4并维持8周以上；因治疗方案的调整或患者个人原因等因素，停用或减量使用TNFi治疗。

排除标准：妊娠、哺乳、伴发其他慢性疾病、急性期及慢性期各种感染、肿瘤、确诊伴有免疫缺陷综合征的患者；合并其他风湿免疫系统疾病、前期治疗及随访期使用TNFi以外的生物制剂或小分子靶向药物的患者。

1.3. 观察指标

(1) 一般临床资料：年龄、性别、身高、体质量、病程、骶髂关节X线片分级；(2)腰背痛评分(LBP)、BASDAI、Bath强直性脊柱炎功能指数(BASFI)、Bath强直性脊柱炎测量指数(BASMI)、基线期及复发时红细胞沉降率(ESR)、C反应蛋白(CRP)。

1.4. 统计学方法

数据分析采用SPSS25.0统计软件，使用R3.6.3软件进行绘图。正态分布的计量资料以均数±标准差表示，采用两独立样本t检验进行比较，非正态分布的计量资料用中位数表示，用非参数检验(Mann-Whitney U检验)进行比较；复发时间以中位数和四分位数间距表示，组间比较采用卡方检验；计数资料采用绝对数(n)和相对频率(%)描述；建立Cox回归模型并绘制受试者工作曲线(ROC曲线)分析各指标对AS复发的预测价值。所有假设检验采用双侧检验，检验水准为α=0.05。

2. 结果

2.1. 人口学特征

研究纳入63例患者，有6例失访，共57例患者完成随访。57例AS患者以男性为主(50/57，87.7%)，入组时年龄为30.91±8.64岁，病程7.04±6.66年，BMI 22.52± 2.96，骶髂关节X线片分级以3级为多见，2、3、4级患者分别为14(24.6%)、41(71.9%)、2(3.5%)例。末次随访时，AS患者LBP、BASDAI、BASFI、BASMI评分与基线时比较明显升高(P < 0.05，表 1)。

1.

AS患者一般资料及随访期病情特点

Clinical and demographic characteristics of AS patients in the study

Variables Baseline 13 weeks 26 weeks 39 weeks 52 weeks
*P < 0.05 vs baseline data at each follow-up time point; ASDAS-CRP: CRP-based disease activity score; LBP: Low back pain score; BASDAI: Bath ankylosing spondylitis disease activity index; BASFI: Bath ankylosing spondylitis functional index; BASMI: Bath ankylosing spondylitis metrology index.
Age (year) 30.91±8.64 - - - -
Male/Female 50/7 - - - -
BMI (kg/m2) 22.52±2.96 - - - -
Disease duration (years) 7.04±6.66 - - - -
HLA-B27 (+/-) 48/9 - - - -
ESR (mm/h) 6.4±5.03 7.32±5.67* 7.34±4.19* 8.81±8.29 10.57±7.44*
CRP (mg/L) 2.61±3.37 3.14±3.97 3.64±4.69 3.91±6.55 7.43±14.88*
ASDAS-CRP 1.19±0.64 1.42±0.79* 1.36±0.76* 1.56±0.90* 1.75±1.18*
LBP 1.90±1.51 2.48±2.01* 2.21±1.76* 2.59±2.14* 2.96±2.33*
BASDAI 1.65±0.96 2.15±1.41* 1.94±1.24* 2.36±1.68* 2.82±2.07*
BASFI 10.69±9.13 12.83±13.04* 11.57±11.51 14.66±14.04* 14.42±14.71*
BASMI 2.51±1.30 2.65±1.44 2.43±1.26 2.59±1.08 3.51±1.32*
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2.2. 随访期治疗情况

观察到因拒绝用药全部停药而无药维持患者9例。维持药物治疗患者48例，其中TNFi停药患者22例，TNFi减量患者26例，在病情复发前均未改变种类和剂量(表 2)。

2.

维持药物治疗的AS患者具体用药种类及复发情况

Medications and disease recurrence in AS patients with maintenance medications

Groups Details of maintenance drugs and dosages n Recurrence [n (%)]
- +
TNFi withdrawal
Celecoxib 200 mg/d 10
Loxoprofen 60 mg/d 2
Meloxicam 7.5 mg/d 1
SSZ 1.5 g/d 2 16(72.7) 6(27.3)
MTX 10 mg/weeks+Meloxicam 7.5 mg/d 2
MTX 10 mg/weeks+Celecoxib 200 mg/d 2
SSZ 1.5 g/d+Meloxicam 7.5 mg/d 2
SSZ 1.5 g/d+Celecoxib 200 mg/d 1
TNFi reduction
Etanercept 25 mg/weeks+Leflunomide 20 mg/d 1
Etanercept 25 mg/10 d+Celecoxib 200 mg/d 11
Etanercept 25 mg/10 d+Celecoxib 200 mg/d+Leflunomide 10 mg/d 2
Etanercept 25 mg/10 d+Celecoxib 200 mg/d+SSZ 1.5 g/d 2 18(69.2) 8(30.8)
Etanercept 25 mg/10 d+Meloxicam 7.5 mg/d+SSZ1.5 g/d 1
Etanercept 25 mg/10 d 7
Inflixmab 200 mg/2 m 1
Adalimumab 40 mg/3 weeks 1
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2.3. 病情复发情况

至随访结束，共有22例(38.6%)患者出现疾病复发，复发中位时间31周(11~40周)。完全停药无药维持组，8例(89.0%)患者出现疾病复发，复发中位时间17周(8，36周)。药物维持组，复发14例(29%)，复发中位时间35周(17，42周)。随访至第13周、26周、39周、52周，完全停药无药维持组累积复发率依次为44.4%、66.7%、77.8%、88.9%，药物维持组依次为6.3%、8.3%、16.7%、29.0%。

完全停药患者复发率(89.0%)高于TNFi减量、TNFi停药患者(P < 0.001，图 1)；而TNFi停药患者与TNFi减量患者复发率比较，差异无统计学意义(P=0.791)。

1.

1

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无药维持与TNFi减停的AS患者复发累积风险曲线

Cumulative risk curve of recurrence in AS patients with total discontinuation of medications, TNFi dose reduction and TNFi withdrawal.

2.4. 复发危险因素

复发患者基线期腰背痛、BASMI评分高于无复发患者(P < 0.05)；随访期完全停药患者复发比例高于药物维持患者(P < 0.05)；而其他临床特征，包括性别、年龄、BMI、病史、BASDAI、ASDAS-CRP、ESR及CRP差异无统计学意义(P>0.05，表 3)。

3.

复发与无复发的AS患者基线资料比较

Comparison of baseline data between AS patients with or without recurrence

Variables No recurrence Recurrence P
BASDAI: Bath ankylosing spondylitis disease activity index; LBP: Low back pain; BASFI: Bath ankylosing spondylitis function index; BASMI: Bath ankylosing spondylitis metrology index; ASDASCRP: Ankylosing spondylitis disease activity score based on C reactive protein; ESR: Erythrocyte sedimentation rate; CRP: C reactive protein; #: Indicates that it is in accordance with the normal distribution; +: Maintaining treatment; -: Drug withdrawal.
n 35 22
Gender (%)
  Female 5 (14.3) 2(9.1) 0.867
  Male 30(85.7) 20(90.9)
  #Age (year) 31.26±9.18 30.36±7.89 0.708
  #BMI (kg/m2) 22.26±2.84 22.94±3.17 0.407
  Disease duration (years) 7.00[2.00, 12.00] 4.00[2.00, 7.00] 0.098
HLAB27 (%)
  Negative 7 (20.0) 2(9.1) 0.468
  Positive 28(80.0) 20(90.9)
X-ray of sacroiliac joint (%)
  2 11(31.4) 3 (13.6)
  3 24(68.6) 17(77.3) 0.079
  4 0(0.0) 2(9.1)
  BASDAI 1.40[1.00, 2.10] 1.50[1.07, 2.50] 0.384
  LBP 1.20[0.70, 1.75] 2.30[1.20, 4.00] 0.007
  BASFI 6.00[4.00, 15.55] 8.25[4.08, 21.38] 0.301
  BASMI 2.40[1.00, 2.80] 3.00[1.89, 4.06] 0.009
  ASDASCRP 1.11[0.65, 1.40] 1.29[0.82, 1.86] 0.204
  ESR 5.00[3.00, 7.50] 4.00[3.00, 6.00] 0.457
  CRP 0.74[0.34, 2.65] 1.56[0.82, 4.56] 0.088
Treatment (%)
  - 1(2.9) 8 (36.4) 0.003
  + 34(97.1) 14(63.6)
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将腰背痛、BASMI、随访治疗纳入Cox回归模型，提示腰背痛评分、BASMI评分高是AS患者复发的危险因素(HR>1，P < 0.05)，而随访期间维持治疗是AS患者复发的保护因素(HR < 1，P < 0.05，表 4)。

4.

减停TNFi后AS患者复发的危险因素(Cox回归模型)

Risk factors for recurrence of AS in patients after TNFi dose reduction or discontinuation (Cox regression model)

Model HR 95% CI P
Univariate analysis
  LBP 1.57 1.13-2.18 0.007
  BASMI 1.3 1.02-1.56 0.032
  Treatment 0.17 0.07-0.41 < 0.001
Multivariate analysis
  LBP 1.44 1.04-1.98 0.027
  BASMI 1.30 1.00-1.66 0.049
  Treatment 0.21 0.08-0.5 0.001
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通过R软件绘制AS患者上述3个指标及三者联合的复发ROC曲线如图 2：ROC曲线中，基线腰背痛评曲线下面积大于0.7，其对病情复发有一定预测价值，而基线BASMI及随访期治疗与否对复发预测能力有限(AUC < 0.7)。另外，三者联合对预测复发最有价值(AUC=0.819，敏感度0.772，特异度0.718)，各指标预测复发的临界点见表 5。

2.

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减停TNFi后AS患者复发ROC曲线

ROC curve of AS patients with recurrence after TNFi dose reduction or discontinuation.

5.

减停TNFi后AS患者复发的危险因素(ROC曲线)

Risk factors for recurrence of AS patients after TNFi dose reduction or discontinuation (ROC curve)

Factor AUC 95% CI Cutoff Sensitivity Specificity
AUC: The area under the ROC curve; Cutoff: The cutoff point.
LBP 0.731 0.566-0.896 2.8 0.521 0.776
BASMI 0.632 0.442-0.822 1.7 0.639 0.711
Treatment 0.533 0.468-0.598 - 0.882 0.204
Combined 0.819 0.674-0.964 - 0.772 0.718
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3. 讨论

AS以炎性腰背痛为主要临床表现，外周关节及机体组织器官均可受累。TNFi的出现，极大改写了该病的治疗史。TNFi被指南推荐用于NSAIDs治疗反应不佳的AS患者，其在改善症状、降低疾病活动度方面有确切的疗效，其中ADA可有效治疗AS的关节外表现[4]。目前指南提出AS患者治疗达缓解后，可以减停TNFi[16]，但减停后可能面临高复发风险，因此需要重视AS患者缓解后的随访。

本研究57例AS患者以年青男性为主，以骶髂关节X线片分级为3级者多见(41例，71.9%)，52周随访患者复发率是38.6%，与一项停用依那西普的研究结果显示1年复发率45.7%相近[17]。本研究观察到减停TNFi后12周内就有较高复发率，这和国外研究发现高比例患者会在停药短时间内复发[18]一致。有文献报道[19-20]停用TNFi后1年内，复发集中发生于后半年。本研究对各随访区间内复发情况分析发现，复发集中于第27~52周，与上述文献结果相似，减停TNFi后1年内，较高比例患者出现复发、疾病高活动。目前已有研究表明，高疾病活动度与骨赘形成、功能损害直接相关[21-22]。因此即使在疾病缓解后也应对患者进行长程随访以早期识别疾病高活动患者并作出干预，对延缓功能损害，防止进一步残疾发生有重要意义。

尽管TNFi对AS患者有效且安全，但在过去，昂贵的费用限制了其在缓解后的长期维持应用；同时，使用TNFi治疗的个别患者在使用中可能出现感染、腹泻、注射部位局部反应、转氨酶升高、诱发心力衰竭甚至神经脱髓鞘疾病及药物诱发自身免疫疾病等不良反应[23-24]；另外，长期反复皮下注射或静脉输液给患者带来的不良体验以及公众对于生物制剂的认识不足，均使得国内许多患者不能在疾病缓解后长期维持使用TNFi，而停药后病情复发是临床医生需要面对的现实问题。目前文献报道无药维持治疗的长期缓解非常罕见[25]。一项在AS患者中比较完全停药及减量TNFi的研究结果显示，停药组复发率明显高于减量TNFi组[26]。国外一项停用TNFi的研究提示停药后复发率高[27]。此外，停用英夫利昔单抗的一项研究显示停药后58%患者出现临床复发[28]。另有对AS患者进行足量、减量及停用NSAIDs、DMARDs的研究也发现，停药组复发率高[29]。本次随访研究观察到与上述研究类似的结果，完全停药的患者比维持药物治疗的患者复发率高(P=0.003)；而维持药物患者中，TNFi减量组与TNFi停药组患者的复发率相比无统计学差异(P>0.05)，提示在病情缓解后应尽量避免无药维持。几项停用TNFi的研究提示，停用生物制剂后的远期疗效可持续到14~45周[17, 20, 30]。本研究结果显示完全停药患者的复发四分位数时间为8~36周，复发时间跨度大，可能说明TNFi临床作用持续时间在个体间存在差异，提示临床工作中在病情缓解后如果考虑TNFi减量，最佳给药间隔可能因患者而异，需要单独确定。

长时间维持TNFi控制疾病，可能会给患者带来一定的经济压力。因此临床工作中在病情缓解后可考虑TNFi减量，但减药或停用后带来的疾病复发又给患者带来沉重的健康负担，因此及早识别复发高风险患者，是临床工作者的关注点，然而目前国内外对AS复发危险因素的研究结论不一。一项研究指出，吸烟、肥胖、高疾病活动度等是axSpA影像学进展的风险因素[31]，国外一项横断面研究结果显示，高BASDAI、病程短的AS患者容易病情复发[32]。国内两项研究显示，基线高ASDAS-CRP、停止药物治疗[29]和骨赘形成、骶髂关节炎X线片分级高[33]是复发的预测因素。本研究通过Cox回归模型分析发现，缓解减停ADA时LBP、BASMI评分高是高复发率的危险因素，随访期维持用药是高复发率的保护因素，而性别、年龄、BMI、病程、BASADI、BASFI、ASDAS-CRP、ESR、CRP、骶髂关节炎X线分级等对复发没有预测价值。LBP是中轴脊柱炎症的主要临床表现[34]，诊断中轴型脊柱关节炎的条件之一[35]，被多项临床研究作为判断复发的指标之一[14]，也是病情活动性评价指标BASDAI、ASDAS的重要组成，其评分增高与影像学脊柱活动性炎症一致[36]。本研究绘制AS患者复发ROC曲线结果提示，基线LBP评分对复发预测较好(AUC=0.731，敏感度0.521，特异性0.776)，而LBP、BASMI评分及随访期治疗情况的联合因素对复发的预测能力最高(AUC=0.819，敏感度0.772，特异性0.718)，提示复发可能受多种因素共同影响。可能指导在临床工作中，对腰背痛、BASMI评分高及用药依从性差的患者做出停止TNFi治疗决策需更谨慎。

因此，AS患者减停TNFi治疗后复发率较高，应对该类AS患者进行长程随访，及时调整治疗。减停TNFi时LBP、BASMI评分及患者的药物治疗对AS的复发有一定的预测价值。

Biography

唐翠萍，硕士，主治医师，E-mail: 406354394@qq.com

Funding Statement

广东省中医药强省建设专项中医临床重点专科建设项目(粤中医函[2015]8号)

Contributor Information

唐 翠萍 (Cuiping TANG), Email: 406354394@qq.com.

李 娟 (Juan LI), Email: lijuan@smu.edu.cn.

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