目 的

        肿瘤坏死因子拮抗剂(TNFi)生物制剂是一种治疗类风湿性关节炎(RA)的有效手段，但尚不清楚对于已经达到缓解或维持稳定的低疾病活动度的RA患者而言，是否需要继续使用TNFi。本研究评估了已经缓解或维持稳定低疾病活动度的RA患者是否能够有效、安全地停止使用TNFi治疗。

方 法

        本研究是一项实用性多中心非盲随机对照试验，入选标准包括：根据美国风湿病学会1987年分类标准诊断为RA、使用TNFi和稳定剂量的注射病症缓解性抗风湿药物至少1年并在实验开始前六个月内28处关节疾病活动度评分(DAS28)小于3.2。患者按照2:1的比例随机选择停止或继续他们目前的TNFi治疗。若患者在接下来12个月的实验期内DAS28大于或等于3.2，并且DAS28超过其基线的值大于或等于0.6时，则视作疾病复发。

结 果

        共计531名患者被分配到停止使用TNFi组，另外286名患者被分配到继续使用TNFi组。在12个月的实验期内，停止用药组的531人中有272人复发，占总人数51.2%;而继续用药组286人中有52人疾病复发，占总人数18.2%(P<0.001)，复发率小于停止用药组。停止使用TNFi后疾病复发的危险比为3.50(95%置信区间为2.60-4.72)。停止用药组的DAS28均值在实验期内显著高于继续用药组(P<0.001)。在195名在停止用药后26周内疾病复发并重新开始TNFi治疗的患者中，165人(84.6%)在随后6个月内DAS28重新回落到3.2以下，而DAS28回落到3.2以下的中位时间为12周(95%置信区间为10.7-13.3)。停止用药组的住院率(6.4%)高于继续用药组(2.4%)。

结 论

        已经达到缓解或维持稳定低疾病活动度的RA患者若停止使用TNFi治疗，其疾病复发率将会远高于继续使用TNFi治疗的同类患者。

原 文

Stopping Tumor Necrosis Factor Inhibitor Treatment in Patients With Established Rheumatoid Arthritis in Remission or With Stable Low Disease Activity: A Pragmatic Multicenter, Open-Label Randomized Controlled Trial

        Ghiti Moghadam M1, Vonkeman HE1, Ten Klooster PM1, Tekstra J2, van Schaardenburg D3, Starmans-Kool M4, Brouwer E5, Bos R6, Lems WF3, Colin EM7, Allaart CF8, Meek IL9, Landewé R10, Bernelot Moens HJ7, van Riel PL9, van de Laar MA1, Jansen TL11; Dutch National POET Collaboration.

        Author information

        1 Arthritis Center Twente Medical Spectrum Twente and University of Twente, Enschede, The Netherlands.

        2 University Medical Center Utrecht, Utrecht, The Netherlands.

        3 VU University Medical Center and Reade Medical Center, Amsterdam, The Netherlands.

        4 Atrium Medical Center, Heerlen, The Netherlands, and Orbis Medical Center, Sittard-Geleen, The Netherlands.

        5 University Medical Center Groningen, Groningen, The Netherlands.

        6 Medical Center Leeuwarden, Leeuwarden, The Netherlands.

        7 Hospital Group Almelo, Almelo, The Netherlands, and Hengelo Twente Hospital Group, Hengelo, The Netherlands.

        8 Leiden University Medical Center, Leiden, The Netherlands.

        9 Radboud University Medical Center, Nijmegen, The Netherlands.

        10 Academic Medical Center Amsterdam, Amsterdam, The Netherlands.

        11 VieCuri Medical Center, Rheumatology, Venlo, The Netherlands.

ABSTRACT

Objective

        Tumor necrosis factor inhibitor (TNFi) biologic agents are an effective treatment for rheumatoid arthritis (RA). It is unclear whether patients whose disease is in remission or who have stable low disease activity need to continue use of TNFi or can stop this treatment. This study was undertaken to assess whether patients with established RA who are in remission or have stable low disease activity can effectively and safely stop their TNFi therapy.

Methods

        The study was designed as a pragmatic multicenter, open-label randomized controlled trial. Inclusion criteria were a diagnosis of RA according to the American College of Rheumatology 1987 classification criteria, as well as use of a TNFi for at least 1 year along with a stable dose of disease-modifying antirheumatic drugs and a Disease Activity Score in 28 joints (DAS28) of <3.2 over the 6 months preceding trial inclusion. Patients were randomized in a 2:1 ratio to either stop or continue treatment with their current TNFi. Flare was defined as a DAS28 of≥3.2 during the 12-month follow-up period and an increase in score of≥0.6 compared to the baseline DAS28.

Results

        In total, 531 patients were allocated to the stop group and 286 to the TNFi continuation group. At 12 months, more patients had experienced a flare in the stop group (272 [51.2%] of 531) than in the continuation group (52 [18.2%] of 286; P < 0.001). The hazard ratio for occurrence of a flare after stopping TNFi was 3.50 (95% confidence interval [95% CI] 2.60-4.72). The mean DAS28 in the stop group was significantly higher during the follow-up period compared to that in the continuation group (P < 0.001). Of the 195 patients who restarted TNFi treatment after experiencing a flare and within 26 weeks after stopping, 165 (84.6%) had regained a DAS28 of <3.2 by 6 months later, and the median time to a regained DAS28 of <3.2 was 12 weeks (95% Cl 10.7-13.3). There were more hospitalizations in the stop group than in the continuation group (6.4% versus 2.4%).

Conclusion

        Stopping TNFi treatment results in substantially more flares than does continuation of TNFi in patients with established RA in remission or with stable low disease activity.