对某些类风湿关节炎患者减停治疗可行

华盛顿——达拉斯Metroplex临床研究中心的Stanley Cohen博士在美国风湿病学会(ACR)年会上报告，自身抗体血清阴性可能是类风湿关节炎(RA)患者获得缓解的最佳预测因素，但患者是否能够停止治疗及何时停止治疗的问题仍有待解决。在无药情况下获得缓解是可能实现的。但获得持续缓解不太常见，不过血清阴性无疑是可能获得持续缓解的强烈预测因素。

Stanley Cohen博士

首先，Cohen博士引用了几项在生物制剂问世前进行的研究，包括一项1996年进行的随机对照研究。在该研究中，285例患者在达到“较为严格的”1981年ACR/ARA缓解定义1年后停止了非生物制剂缓解疾病抗风湿药(DMARD)治疗。在缓解1年后，患者被随机分成2组，一组接受安慰剂治疗，另一组继续接受原有治疗。52周时，安慰剂组和继续原有治疗组急性加重的患者比例分别为38%和22%(P=0.002)。该研究的作者指出，存在类风湿因子活动性[同时无环瓜氨酸肽(CCP)抗体]预示获得持续缓解的可能性较低。缓解前接受较为积极的治疗也预示获得持续缓解的可能性较低(Lancet 1996;347:347-52)。

在2009年回顾评价的莱顿早期关节炎临床试验和英国早期类风湿关节炎研究(ERAS)中也观察到类似结果。前者在454例患者中观察到的无药持续缓解率为15%，后者在895例患者中观察到的无药持续缓解率为9%。多因素分析显示，无CCP自身抗体和类风湿因子是缓解的两个独立预测因素(Arthritis Rheum. 2009;60:2262-71)。

Cohen博士指出，患有早期疾病也会影响患者停止治疗后仍获得缓解的能力。在甲氨蝶呤联合依那西普治疗活动性早期类风湿关节炎(COMET)研究中，研究者评价了甲氨喋呤联合依那西普及单用甲氨蝶呤治疗中至重度RA 3~24个月的效果。甲氨喋呤/依那西普联合治疗组111例患者在完成1年的联合治疗后在第2年停用甲氨蝶呤。与继续接受甲氨喋呤/依那西普联合治疗的患者相比，停用甲氨蝶呤的患者在第2年仍有大部分获得DAS28缓解(Arthritis Rheum. 2010;62:674-82)。因此，在许多患有极早期疾病的患者中，停止治疗或简化治疗是可行的。

不过，在病程较长的患者中，停止治疗也是可以实现。在2003年进行的一项临床注册研究的长期扩展研究中，79例病程非常长(平均病程14年)的极重度患者接受甲氨喋呤和依那西普治疗44个月(中位数)。在第3年评价的36例患者中，30例(83%)能够降低皮质激素的剂量，20例(56%)能够停止皮质激素治疗。Cohen博士表示，这与临床上观察到的做法一致。第3年时，66例患者中有41例(62%)患者降低甲氨蝶呤剂量，19例(29%)停止甲氨蝶呤治疗(Arthritis Rheum. 2003;48:1493-9)。

Cohen博士表示无与此报告相关的经济利益冲突，但其此前披露与雅培等多家公司存在联系。

爱思唯尔版权所有  未经授权请勿转载

By: DENISE NAPOLI, Internal Medicine News Digital Network

WASHINGTON – Autoantibody seronegativity may be the best predictor of which patients will achieve remission in rheumatoid arthritis, but the question of whether and when to withdraw treatment still looms.

"Drug-free remission is possible. Sustained remission is less common," Dr. Stanley Cohen said at the annual meeting of the American College of Rheumatology. "But certainly seronegativity seems to be a strong predictor of the likelihood of sustained remission."
 
First, Dr. Cohen of Metroplex Clinical Research Center, Dallas, cited several "prebiologic era" studies, including one 1996 randomized controlled trial of 285 patients who stopped nonbiological disease-modifying antirheumatic drug (DMARD) therapy after achieving the "quite stringent" 1981 ACR/ARA remission definitions for 1 year.

In that study, after the year of remission, patients were randomized to either placebo or to continue their treatment regimen: by 52 weeks, 38% of the placebo group had flared, compared with 22% of the continued therapy group (P = .002) (Lancet 1996;347:347-52).

The authors then looked at the predictors of maintaining remission.

"They determined that having rheumatoid factor activity [there were no CCP (cyclic citrullinated peptide) antibodies at that time] was a poor prognostic factor for maintaining remission," said Dr. Cohen.

"More aggressive treatment prior to remission also boded poorly for maintaining that remission," he noted.

A similar finding was seen with the Leiden Early Arthritis Clinic trial of 454 patients and the British Early Rheumatoid Arthritis Study (ERAS) of 895 patients, both reviewed in 2009.

Sustained drug-free remission was seen in 15% of the former cohort and in 9% in the latter. The absences of CCP autoantibodies and rheumatoid factor were the sole two independent predictors of remission in multivariate analysis (Arthritis Rheum. 2009;60:2262-71).

Having early disease also plays a role in the ability to withdraw treatment, Dr. Cohen said. He pointed to the COMET trial (Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis), which looked at etanercept plus methotrexate versus methotrexate alone in moderate-to-severe rheumatoid arthritis for a duration of 3-24 months.

"What I’m interested in is year 2," Dr. Cohen said, when 111 patients who were on methotrexate plus etanercept in year 1 stopped methotrexate (Arthritis Rheum. 2010;62:674-82).

"Compared to the group that continued etanercept plus methotrexate, the majority continued to be in DAS28 remission without methotrexate" at 2 years, he said. "So, in patients with very early disease, it looks like we can withdraw or simplify the therapy in a significant number of those patients."

Treatment withdrawal, however, also can be achieved in patients with more longstanding disease.

Dr. Cohen cited a 2003 long-term extension of a clinical registration trial in which 79 patients with very long and very severe disease (mean duration of disease, 14 years) received etanercept and methotrexate for a median of 44 months (Arthritis Rheum. 2003;48:1493-9).

Among the 36 patients assessed at 3 years, 30 (83%) were able to decrease their dosages of corticosteroids and 20 (56%) could stop corticosteroids altogether.

"This certainly follows what we see in the clinic, in that we can frequently lower our doses of corticosteroids or withdraw them," Dr. Cohen said.

"What about methotrexate?" he asked. At 3 years, the dosage of methotrexate was decreased in 41 of 66 patients (62%), and methotrexate therapy was discontinued in 19 patients (29%).

"We try to wean our therapy in the majority of these patients," said Dr. Cohen. "Some are successful, some are not."

Dr. Cohen stated that he had no disclosures related to this presentation; he previously disclosed relationships with Abbott Laboratories, Amgen, Astellas, Bristol-Myers Squibb, Janssen, Pfizer, and Roche.