【ACR2015】持续临床缓解的RA患者能停用TNF拮抗剂吗？

标签: 类风湿关节炎; 药物减停;
生物制剂; 减停后复发

荷兰一项随机对照试验显示,
已获持续6个月临床缓解或低疾病活动度的RA患者在停用TNFi的6个月内约三分之一病情复发

Moghadam HG, et al.
ACR 2015. Abstract ID: 1042.

背景与目的:
TNF拮抗剂(TNFi)是RA的有效治疗手段。目前尚不清楚已获临床缓解或稳定的低疾病活动度(LDA)的患者是否需要继续使用TNFi,
多药合用以及TNFi的高药费使得探讨这一问题变得非常重要。本研究旨在阐明, 如果RA患者停用TNFi并且因此而出现病情复发,
是否可以安全、有效的重新启动TNFi治疗。

方法:
这是一项探讨治疗范式的多中心、开放标签、随机对照临床试验。入组标准如下,
患者符合ACR 1987分类标准, 应用TNFi至少1年, 最近6个月DMARDs剂量稳定且
DAS28＜3.2。按2:1的比例将患者随机分入TNFi停药组或TNFi继续应用组。病情复发的定义:
DAS28≥3.2且较前次评估相比的增幅≥0.6。如果TNFi停药组患者复发,
经风湿病医生评估后可重新启动TNFi治疗。

结果:
来自47各中心的共817例患者入组,
按2:1的比例随机分入TNFi停药组(531例, 65%)和继续治疗组(286   例,
35%)。6月间病情复发情况为TNFi停药组212/531例(31.5%),
继续治疗组36/286例(9.8%)。12月间,
TNFi停药组病情复发有267/531例(50.3%), 继续治疗组有52/286例(18.2%)。TNFi停药组和继续治疗组的复发风险之比为3.41(95%CI:
  2.53-4.59)。在整个随访过程中, TNFi停药组DAS28均值升高,
与继续治疗组相比有统计学显著意义(p<0.001)。195例TNFi停药组患者在停药26周内重启TNFi,
其中165例患者(84.6%)在重治6个月内再获LDA,   再获LDA的平均疗程为12周(95%
CI: 10.8-13.2).

分析严重不良事件(SAE)发现,
TNF继续治疗组有1例死亡(0.3%), 而停药组为零;  
因感染而住院的例数分别为TNFi停药组11例(2%)、继续治疗组4例(1.4%)。停药组患者重启TNFi后未发生过敏反应。

结论:
对于已获临床缓解或稳定的低疾病活动度的RA患者,
停用TNFi治疗的复发风险显著高于继续接受TNFi治疗的患者。

图1.
分析12月间无复发的Kaplan-Meier生存曲线

[注:
以下图片是ACR2015年会现场演讲拍照。现场演讲所示1年间TNFi停药组和继续治疗组的复发率分别为：272/531(51.2%),
  52/286(18.2%, p<0.001),
即现场演讲所示TNFi停药组1年复发率有别于ACR官网之前录入的文摘报道。]

 
     
     
     
 

图2.
12月间TNFi停药组与继续治疗组的DAS28均值与HAQ-DI均值的变化

原文如下。

Pragmatic Multicenter Open-Label Randomized
 Controlled Trial of   Stopping
TNF-Inhibitors in Rheumatoid Arthritis Patients in
Remission or   Stable Low Disease Activity in the
Netherlands

Sunday, November 8,
2015: 5:15 PM

Presentation Number:
1042

Marjan Ghiti
Moghadam¹, Harald
E. Vonkeman¹, Peter M. ten Klooster²,
  Janneke Tekstra³, Dirkjan van
Schaardenburg⁴, Mirian  
Starmans-kool⁵, Elisabeth Brouwer⁶, Reinhard
Bos⁷,   Willem F. Lems⁸,
Edgar Colin⁹, Cornelia F. Allaart¹⁰,
  Inger L. Meek¹¹, Robert B.M.
Landewé¹²,
Hein J. Bernelot Moens¹³,   Piet van
Riel¹¹, Mart A.F.J. van de Laar¹, Tim
Jansen¹⁴ and   on
behalf of the Dutch National POET Collaboration.

¹Medisch
Spectrum Twente - Arthritis Center Twente,  
Enschede, Netherlands, ²University of
Twente, Enschede,  
Netherlands,³University Medical Center Utrecht, Utrecht,
  Netherlands,⁴Jan van Breemen Research
Institute, Amsterdam,  
Netherlands, ⁵Orbis Medical Center,
Geleen-Sittard,  
Netherlands, ⁶University Medical center
Groningen, Groningen,  
Netherlands, ⁷Medical Center
Leeuwarden, Leeuwarden,  
Netherlands, ⁸Amsterdam Rheumatology
and immunology Center,   VU University medical
center, Amsterdam,
Netherlands, ⁹Erasmus
  MC, Rotterdam,
Netherlands, ¹⁰Department of
Rheumatology,   Leiden Universitary Medical
Center, Leiden, Netherlands,¹¹Radboud  
University Nijmegen Medical Centre, Nijmegen,
Netherlands, ¹²Amsterdam
  Rheumatology Center, Amsterdam,
Netherlands, ¹³Ziekenhuisgroep
  Twente, Almelo,
Netherlands, ¹⁴VieCuri Medical Center,
Venlo,   Netherlands

Background/Purpose: TNF-inhibitors
  (TNFi) are effective treatments of rheumatoid
arthritis (RA). It is not clear   if patients in
remission or stable low disease activity need to continue
  their TNFi. Issues of polypharmacy and the
relatively high costs of TNFi make   it important
to examine whether patients in remission or stable low disease
  activity can stop their TNFi. If patients stop
TNFi and consequently flare,   it is unclear
whether TNFi can be restarted effectively and safely.

Methods: Pragmatic
multicenter   open-label randomized controlled
trial. Inclusion criteria: patients   diagnosed
with RA according to the ACR 1987 criteria, patients using a TNFi
  for at least 1 year with stable dose DMARDs over
the last 6 months, DAS28   <3.2 over the last 6
months. Patients were randomized to either stop or
  continue their current TNFi in a 2:1 ratio.
Flare was defined as DAS28 ≥3.2 with an
increase ≥0.6   compared to the previous DAS28. In
case of flare in the stop group, TNFi   could be
restarted at the discretion of the treating
rheumatologist.

Results: In
total 817 patients from   47 centers were
included: 531 patients (65%) in the stop group and 286
  patients (35%) in the continuation group. At 6
months, significantly more   patients in the stop
group (212/531 [31.5%]) had experienced a flare than in
  the continuation group (36/286 [9.8%],
p<0.001). At 12 months these were   267/531
[50.3%] vs 52/286 [18.2%], respectively (p<0.001). The hazard
  ratio for flare after stopping TNFi was 3.41
(95% CI: 2.53–4.59). Mean DAS28
scores in the stop group were   significantly
increased throughout the follow-up period compared with the
  continuation group (p<0.001). Of the 195
patients that restarted TNFi   within 26 weeks,
165 (84.6%) had regained low disease activity (DAS28 <
  3.2) 6 months later and median time to regained
low disease activity was 12   weeks (95% Cl:
10.8-13.2).

SAEs
in stop vs. continuation groups: Deaths  0
 vs. 1 (0.3%)   and
hospitalization due to infections 11 (2%) vs. 4 (1,4%),
respectively.   There were no allergic reactions
among the patients in the stop group that  
restarted TNFi.

Conclusion: Stopping
TNFi   treatment in RA patients in remission or
stable low disease activity results   in
substantially more flares than continuing.