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NEJM:辉瑞这款老牌关节炎药物,还能治疗“毁容性”的皮肤结节病

偶数 偶数 来源:医药魔方Pro
2019-01-08
NEJM
原文

说起托法替尼(tofacitinib),可能很多患类风湿关节炎的人都知道。托法替尼是FDA批准的首个用于治疗类风湿关节炎的JAK抑制剂,也是10年来FDA批准的首个可改善病情的口服抗风湿药,其疗效可比肩药王“修美乐(humira)”。

 

此外,托法替尼潜力巨大,除了治疗风湿性关节炎外,还被批准用于治疗溃疡性结肠炎。另外,银屑病和银屑病关节炎的适应症也处于审批阶段。近日,耶鲁大学的研究人员发现,托法替尼还可以用来治疗“毁容性”结节病。

 

 

说起结节病,很多人可能并不了解。但是具体说到,甲状腺结节、肺结节、乳腺结节,可能大家就比较明白了。结节病是一种可能影响多个器官的炎症性疾病。有些患者可以自愈,无需治疗,但是仍有一部分患者会产生肺、心脏、淋巴结、皮肤及其他器官损伤。它还会导致堪称“毁容性”的皮肤病变。比如下图这样的......


 

迄今为止,科学家对于结节病的了解非常少。结节病的确切原因尚不清楚。很多科学家猜测它可能是一种与异常免疫反应相关的自身免疫性疾病,但引发这种反应的原因尚不确定。结节病如何从身体的一部分扩散到另一部分也仍在研究中。

 

此外,由于其非特异性的症状,比如咳嗽、体重减轻、皮疹、关节疼痛和肿胀、心悸、呼吸困难、头痛或视力丧失,这些临床表现可能出现在很多别的疾病中,医生们也没有办法确切地诊断结节病。据该研究的作者耶鲁大学医学院Nkiruka Emeagwali博表示,目前只能通过使用类固醇或甲氨蝶呤之类的抗炎药物予以缓解。然而,研究人员指出,这两种方法都没有可靠的效果,而且两者都会造成严重的副作用。

 

如此棘手的一种疾病,确实需要一种有力的武器来予以应对,但是作为类风湿性关节炎的经典药物,托法替尼是怎么被科学家拐上结节病“这艘船”的呢?

 

故事就要从2017年开始说起。当时,《科学报告》上发表了一篇文章,内华达大学雷诺分校的研究人员基于健康对照组、结节病患者、难治性结节病患者的外周血单核细胞(PBMC)中microRNA和蛋白质编码基因表达的数据,鉴定出了46个microRNA和1559个基因,在不同严重程度的结节病患者(健康对照组→无并发症结节病患者→难治性结节病患者)体内差异化表达。通过对这些调控异常的microRNA-mRNA进行分析,研究人员证明了Jak-STAT信号通路在结节病的发病机制中发挥作用。

 

这项研究启发了耶鲁大学的Brett King博士。他进行了一次大胆的尝试:使用类风湿性关节炎药物托法替尼治疗皮肤结节病。研究人员选择了一名48岁女性难治性皮肤结节病患者,有长达8年的疾病史,在这8年中患者已经接受了多种抗炎药物治疗,包括口服类固醇和甲氨蝶呤八年,没有任何症状改善。

 

在此次试验中,这名女性口服托法替尼,每日两次。经过10个月的治疗,皮肤结节几乎消失了。研究人员进一步评估了治疗前后,患者皮肤标本进行组织学和免疫组化检测结果,可以证明实现了临床及组织学上的缓解。另外,研究人员还对皮肤标本进行了RNA测序。结果证实,在皮肤结节病消失的同时,不会激活Jak-STAT通路。另外,研究人员在论文中写道:抑制Jak-STAT通路可能对于其他类型的结节病有效。

 

这项研究开创了一种治疗结节病的新思路。共同作者Nkiruka Emeagwali表示,“计划评估超过200名患有肺部和多器官结节病的患者的肺液和血液中Jak-STAT通路的激活,这是解开多年来一直成谜的结节病的重要一步。”

 

耶鲁大学的研究小组目前正在进行新的临床试验,进一步验证这些发现。研究作者King称,如果得到证实,这将是结节病患者的重大突破。据了解, King博士此前还进行了Jak抑制剂治疗治疗包括白癜、斑秃和湿疹在内的其他难治性皮肤病的研究。

 

原文:Tofacitinib Treatment and MolecularAnalysis of Cutaneous Sarcoidosis

作者:William Damsky, Durga Thakral

机器翻译

Speaking of tofacitinib, many people with rheumatoid arthritis may know.Tofatinib is the first FDA-approved JAK inhibitor for rheumatoid arthritis and the first FDA-approved oral antirheumatic drug to improve the condition in 10 years.

In addition, tofacitinib has great potential and is approved for the treatment of ulcerative colitis in addition to rheumatoid arthritis.In addition, the indications for psoriasis and psoriatic arthritis are also in the approval stage.Recently, researchers at Yale University found that tofacitinib can also be used to treat "disfiguring" sarcoidosis.

Speaking of sarcoidosis, many people may not understand it.But specifically speaking, thyroid nodules, pulmonary nodules, breast nodules, may be more clear to everyone.Sarcoidosis is an inflammatory disease that may affect multiple organs.Some patients can heal themselves without treatment, but there are still some patients with lung, heart, lymph nodes, skin and other organ damage.It can also lead to what can be called "disfiguring" skin lesions.Like the picture below.

To date, scientists know very little about sarcoidosis.The exact cause of sarcoidosis is not known.Many scientists speculate that it may be an autoimmune disease associated with an abnormal immune response, but the cause of this response is uncertain.How sarcoidosis spreads from one part of the body to another is still under investigation.

In addition, because of its non-specific symptoms, such as cough, weight loss, rash, joint pain and swelling, palpitations, dyspnea, headache, or vision loss, these clinical manifestations may appear in many other diseases, and physicians have no way to accurately diagnose sarcoidosis.According to the study's author, Nkiruka Emeagwali, Yale University School of Medicine, it can only be alleviated by the use of anti-inflammatory drugs such as steroids or methotrexate.However, the researchers pointed out that neither method has reliable results, and both can cause serious side effects.

A disease that is so intractable does require a powerful weapon to deal with, but how did tofacitinib, a classic drug for rheumatoid arthritis, get abducted by scientists to the "ship" of sarcoidosis?

The story starts in 2017.At that time, an article was published in the Scientific Report. Researchers at the University of Nevada, Renault, based on data on microRNA and protein-coding gene expression in peripheral blood mononuclear cells (PBMC) from healthy controls, sarcoidosis patients, and refractory sarcoidosis patients, identified 46 microRNAs and 1559 genes that were differentially expressed in patients with sarcoidosis of varying severity (healthy controls → patients with uncomplicated sarcoidosis → patients with refractory sarcoidosis).By analyzing these dysregulated microRNA-mRNAs, the researchers demonstrated that Jak-STAT signaling plays a role in the pathogenesis of sarcoidosis.

This study inspired Dr. Brett King of Yale University.He made a bold attempt to treat cutaneous sarcoidosis with the rheumatoid arthritis drug tofacitinib.The researchers selected a 48-year-old woman with refractory cutaneous sarcoidosis who had a disease history of up to 8 years during which the patient had been treated with a variety of anti-inflammatory drugs, including oral steroids and methotrexate for eight years, without any symptomatic improvement.

In this trial, this woman received tofacitinib orally twice daily.After 10 months of treatment, the skin nodules almost disappeared.The researchers further evaluated the results of histological and immunohistochemical examination of patient skin samples before and after treatment, which could prove to achieve clinical and histological remission.In addition, the researchers also performed RNA sequencing of skin specimens.The results confirmed that Jak-STAT pathway is not activated while cutaneous sarcoidosis disappears.In addition, the researchers wrote in the paper: Inhibition of Jak-STAT pathway may be effective for other types of sarcoidosis.

This study pioneered a new idea for the treatment of sarcoidosis.Co-author Nkiruka Emeagwali stated that "it is planned to evaluate the activation of Jak-STAT pathway in the lung fluid and blood of more than 200 patients with pulmonary and multi-organ sarcoidosis, an important step in unraveling sarcoidosis that has been enigmatic for many years."

The Yale team is currently conducting new clinical trials to further validate these findings.The study author King said that if confirmed, this will be a major breakthrough for patients with sarcoidosis.It is understood that Dr. King also previously conducted Jak inhibitor therapy for the treatment of other refractory skin diseases including white peony, alopecia areata and eczema.

Original: Tofacitinib Treatment and Molecular Analysis of Cutaneous Sarcoidosis

Author: William Damsky, Durga Thakral

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