Tofacitinib可迅速改善RA症状和体征

《内科学年鉴》8月19日发表的一项最新研究显示，类风湿性关节炎(RA)患者每日2次口服5或10 mg的Janus激酶抑制剂tofacitinib，6个月后的应答率比最初接受安慰剂治疗、之后改为tofacitinib治疗的患者提高了至少20%。

主要研究者Joel Kremer博士总结称：联用tofacitinib(Xeljanz)和非生物性缓解疾病抗风湿药物(DMARD)，可迅速减少RA的症状和体征，改善躯体功能。不过研究者也承认，由于本项研究中的多数患者服用的是甲氨蝶呤，因此在将该研究结果外推至其他的非生物性DMARD时必须谨慎。


Joel Kremer博士

研究者还指出，该研究结果进一步支持了既往研究中的发现：tofacitinib联合甲氨蝶呤方案表现出色。其中包括今年早些时候发表在《柳叶刀》上的一项研究(Lancet 2013 [doi:10.1016/S0140-6736(12)61424-X])。这项研究与本次发表的研究一样，都是由辉瑞赞助的。

本项研究的入组标准为：年龄≥18岁，RA诊断符合1987年美国风湿病学会标准，对至少1种非生物性DMARD应答不充分。这些患者被要求在整个研究过程中继续使用至少1种非生物性DMARD。其中服用甲氨蝶呤的患者必须在研究开始前使用该药至少4个月并且达到稳定剂量至少6周。允许使用小剂量口服皮质激素。

排除标准包括：在研究开始前1年内曾接受淋巴细胞耗竭治疗；血红蛋白、红细胞压积、白细胞或血小板计数偏低；或者有自身免疫性风湿病或癌症病史。在基线6个月内曾发生需要住院或静脉使用抗生素的感染的患者、基线2周内曾口服抗生素的患者，或者发生带状疱疹、乙型/丙型肝炎或HIV感染的患者，也被排除在外。

共有19个国家的114家医院、792例患者参加了本项研究。这些患者被随机分为tofacitinib 5 mg 2次/d组、tofacitinib 10 mg 2次/d组和安慰剂组。3个月时，安慰剂组的无应答患者在不知情状态下改用5或 10 mg tofacitinib治疗。3个月时无应答的tofacitinib组患者剂量不变。6个月后，所有仍在服用安慰剂的患者均在不知情状态下改用5或 10 mg tofacitinib治疗。

在入组的792例患者中只有651例(82%)完成了研究。各组患者的平均年龄为51~53岁，女性占3/4以上。67%~73%的患者在研究期间继续服用基线时的DMARD，至少有1/4的患者使用了≥2种DMARD。甲氨蝶呤是最常用的DMARD。

3个月时，安慰剂组患者半数无应答而转为5 mg(38例)或10 mg(40例)tofacitinib治疗；5 mg组有80例(26%)、10 mg组有58例(18%)无应答。根据ACR20标准，共有27%的安慰剂组患者获得了应答。

6个月时，与服用3个月安慰剂后改用tofacitinib的患者相比，正在服用5 mg tofacitinib者的应答率[定义为3个月时疼痛、水肿的关节数量改善20%(ACR20)]为21%，正在服用10 mg tofacitinib者为26%。

与安慰剂组患者相比，治疗组患者的健康评估问卷残疾指数(HAQ-DI)在3个月时改善更显著(P＜0.001)，有更多患者的28关节疾病活动度评分(DAS28-4)在6个月时＜2.6。

研究者指出，与安慰剂组相比，2个治疗组均在第2周达到了明显更高的ACR20和ACR50应答率，并且随着时间推移，DAS28-4和DAS28-4＜2.6、慢性疾病治疗功能评估-疲乏的应答率也明显更高。

不仅如此，安慰剂组的不良事件和严重不良事件发生率均高于治疗组。不过，治疗组的停药率更高。1年内，5 mg tofacitinib的不良事件发生率为172/100患者-年，10 mg tofacitinib为176/100患者-年，安慰剂转tofacitinib为342/100患者-年。Tofacitinib的最常见不良事件为上呼吸道感染和鼻咽炎。安慰剂、5 mg tofacitinib和10 mg tofacitinib的不良事件所致停药率分别为5.4/100患者-年、6.2/100患者-年和9.7/100患者-年。

研究者报告了4例治疗相关性机会感染：播散性带状疱疹和隐球菌肺炎各1例，肺结核2例。研究期间有4例患者死亡，但其中仅有1例(呼吸衰竭)被认为与治疗有关。

该试验的心血管安全性终点裁定委员会认定，有3例患者发生了重要事件：5 mg组1例短暂性脑缺血发作，5 mg组1例脑血管意外，10 mg组1例心力衰竭并最终死亡。在服用tofacitinib的患者中，研究者还观察到3个月时平均中性粒细胞计数下降和12个月时仍持续的高、低密度脂蛋白水平升高。

不过上述结果并未打动欧洲药品管理局(EMA)，后者的人用药品委员会(CHMP)在7月份重申了其在4月份提出的“tofacitinib的获益未能超过风险”的观点。CHMP建议不批准该药上市。辉瑞声称正在评估这一观点，并“将决定如何重新提交该药的上市申请”。

Kremer博士是美国风湿病研究者联合会(CORRONA)的创立者和现任主席，接受了辉瑞的资助，在辉瑞研发tofacitinib的过程中担任其顾问。数名合著者报告称接受了辉瑞提供的补助金。其他合著者为辉瑞的雇员。

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By: ALICIA AULT, Internal Medicine News Digital Network

Response rates for rheumatoid arthritis patients taking either 5 mg or 10 mg twice-daily of the oral Janus kinase inhibitor tofacitinib were at least 20% greater after 6 months than for those who started on placebo and switched to the therapy, according to a new study.

Lead investigator Dr. Joel Kremer and his colleagues concluded that tofacitinib (Xeljanz) – when taken in combination with a nonbiologic disease-modifying antirheumatic drug (DMARD) – rapidly reduced the signs and symptoms of RA and improved physical functioning. But, they added, since the majority of patients in their study were taking methotrexate, extrapolating the results to other nonbiologic DMARDs should be done with caution.

They also noted that this trial supported findings in previous studies that tofacitinib works well with methotrexate. One such study was published in the Lancet and was also funded by Pfizer (Lancet 2013 [doi:10.1016/S0140-6736(12)61424-X]).

In the trial, paid for by Pfizer and conducted at 114 centers in 19 countries, 792 patients were randomly assigned 4:4:1:1 to twice-daily treatment with 5 mg of tofacitinib; 10 mg of tofacitinib; or placebo. The study was published Aug. 19 in the Annals of Internal Medicine.

At 3 months, placebo patients who did not respond were blindly switched to the 5-mg or 10-mg dose. Patients taking tofacitinib who did not respond at 3 months continued on the same dose. After 6 months, all patients still on placebo were switched blindly to either the 5-mg or 10-mg dose.

At 6 months, the response rates – defined as 20% improvement in the tender or painful and swollen joint count at three months (ACR20) – were 21% greater for patients taking 5 mg, and 26% greater for patients taking 10 mg, when compared with patients who had been on placebo for 3 months and then switched to one of the two doses.

There was a significantly greater improvement (P less than .001) at 3 months in the Health Assessment Questionnaire Disability Index (HAQ-DI) for patients in the treatment arms, and more of those patients had a Disease Activity Score for 28 joints (DAS28-4) of less than 2.6 at 6 months than did the placebo groups.

Patients were enrolled if they were aged 18 years or older and had a rheumatoid arthritis diagnosis consistent with the 1987 American College of Rheumatology criteria, and an inadequate response to treatment with one or more nonbiologic or biologic DMARDs. They were also required to continue treatment with one or more nonbiologic DMARDs throughout the study. Those taking methotrexate had to have been receiving it for at least 4 months and at stable dosing over at least 6 weeks before the study start. Low-dose, oral corticosteroid therapy was also allowed.

Exclusion criteria included previous treatment with lymphocyte-depleting therapies within a year of the study start; a depressed hemoglobin, hematocrit, leukocyte, or platelet count; or a history of autoimmune rheumatic disease or most cancers. Patients were also excluded if they had experienced an infection requiring hospitalization or intravenous antibiotics within 6 months of baseline, oral antibiotics within 2 weeks of baseline, or infection with herpes zoster, hepatitis B or C, or HIV.

Only 651 (82%) of the 792 patients enrolled completed the study. The mean age across the four treatment groups was 51-53 years old, and at least three-quarters of the participants were female. Two-thirds to 73% of patients continued to take background DMARDs during the study, and at least a quarter received two or more DMARDs. Methotrexate was the most frequently prescribed DMARD.

At 3 months, half of the placebo patients did not have a response and were then switched to either 5 mg (38 patients) or 10 mg (40 patients) of tofacitinib. In the treatment group at 3 months, 80 (26%) patients taking 5 mg and 58 (18%) patients taking 10 mg had no response. A total of 27% of those taking placebo had a response according to the ACR20 criteria.

The authors reported statistically significant response rates for ACR20 and ACR50 by the second week for both treatment arms. DAS28-4, DAS28-4 less than 2.6, and Functional Assessment of Chronic Illness Therapy-Fatigue response rates also were statistically significant over time for the tofacitinib treatment groups when compared with placebo.

The authors reported a higher adverse event and serious adverse event rate for patients on placebo, but a higher discontinuation rate for those taking tofacitinib.

Over a year, the adverse event rate was 172/100 patient-years for tofacitinib 5 mg, 176 for the 10 mg group, and 342 for the placebo-to-tofacitinib groups. The most common adverse events in the tofacitinib groups were upper respiratory tract infections and nasopharyngitis. The discontinuation rate from adverse events was 5.4/100 patient-years for placebo, 6.2 for the 5-mg group, and 9.7 for the 10-mg group.

The authors reported four treatment-related opportunistic infections: disseminated herpes zoster, cryptococcal pneumonia, and two cases of pulmonary tuberculosis. There were four deaths during the study, but only one, respiratory failure, was deemed to be treatment related.

The trial’s Cardiovascular Safety Endpoint Adjudication Committee determined that three patients had events that were notable: a transient ischemic attack in a patient taking 5 mg, a cerebrovascular accident in a patient taking 5 mg, and heart failure in a patient taking 10 mg who eventually died.

In patients taking tofacitinib, the authors also reported decreases in mean neutrophil counts at 3 months and increases in high- and low-density lipoprotein levels that were sustained at 12 months after baseline.

These results have not impressed the European Medicines Agency. In July, the EMA’s Committee for Medicinal Products for Human Use (CHMP) reaffirmed an opinion issued in April that tofacitinib’s benefits did not outweigh its risks. The CHMP recommended against approval of the drug. Pfizer said in a release that it is evaluating the opinion and "will determine next steps to resubmit" its approval application.

Dr. Kremer is the founder and president of the Consortium of Rheumatology Researchers of America (CORRONA) registry, which receives funding from Pfizer. He received a research grant from Pfizer to conduct the study and has been a consultant to Pfizer for the development of tofacitinib. Several other authors reported receiving grants from Pfizer and performing consultant work to Pfizer in relation to the trial. Other authors are Pfizer employees.