Janus酪氨酸激酶抑制剂在皮肤科的应用

Janus酪氨酸激酶（JAK）-信号转导及转录激活子（STAT）途径是一种细胞内信号传导通路,是多种细胞因子如白细胞介素（IL）、干扰素（IFN）及其他分子进行细胞膜到细胞核信号传导的重要途径,依赖于JAK?STAT途径的可溶性炎症介质参与了很多炎症性疾病的发病。因此,应用JAK抑制剂是治疗这类炎症性及免疫性疾病的新手段。目前临床上已用于治疗骨髓纤维化、真性红细胞增多症、类风湿性关节炎等疾病,并且越来越多的病例报告及临床研究证实,JAK抑制剂治疗特应性皮炎、斑秃、银屑病、白癜风等皮肤疾病也取得良好疗效……     

Janus激酶抑制剂在皮肤病治疗中的应用前景

【摘要】 Janus激酶（JAK）和信号转导和转录激活因子（STAT）所构成的JAK-STAT信号通路是一条重要的细胞内信号通路,参与许多炎症性疾病的发病。JAK抑制剂阻断该通路已经成为治疗某些疾病的有效方法,例如类风湿关节炎、溃疡性结肠炎。然而,目前JAK抑制剂尚未被批准应用于皮肤病治疗。本文就JAK抑制剂在皮肤疾病中的应用前景进行综述。     

JAK抑制剂在皮肤科的应用进展

Janus激酶/信号转导和转录激活因子（JAK-STAT）信号转导通路与许多皮肤病的发病相关,Janus激酶（JAK）抑制剂通过抑制该通路达到治疗作用,是具有良好前景的皮肤科新型治疗药物。该文总结了JAK抑制剂在银屑病、白癜风、特应性皮炎、斑秃、扁平苔藓、皮肌炎、红斑狼疮、移植物抗宿主病、环状肉芽肿等多种皮肤科疾病中的应用进展情况,为此类药物今后的临床应用提供参考。     

Janus激酶抑制剂治疗斑秃的研究进展

斑秃是一种由免疫机制介导的非瘢痕性脱发。Janus激酶抑制剂通过阻断JAK/STAT信号转导通路减少炎性因子的生成与释放,从而减轻炎性介质对毛囊的攻击,使毛发再生。部分报道已初步证实Janus激酶抑制剂治疗斑秃的有效性和安全性,因此Janus激酶抑制剂可能成为一种治疗斑秃的新型有效方法。     

酪氨酸激酶抑制剂在恶性黑素瘤分子靶向治疗中的进展

恶性黑素瘤是一种异质性肿瘤,不同发病部位或不同组织学类型,可能存在不同的基因和信号转导途径的异常.因此,针对异常基因、信号通路的靶向治疗药物的发明和临床应用为晚期黑素瘤患者的个性化治疗提供了新的选择.中国人最常见的黑素瘤是肢端型,该型黑素瘤中最常见的异常基因是c-kit基因.针对c-kit基因的靶向药物酪氨酸激酶抑制剂在治疗晚期黑素瘤方面已有较多体外研究及临床观察.主要介绍酪氨酸激酶抑制剂中的受体酪氨酸激酶抑制剂、多靶点酪氨酸激酶抑制剂和非受体酪氨酸激酶抑制剂3类药物的药理作用机制及国内外治疗黑素瘤的研究进展,以及酪氨酸激酶抑制剂的常见不良反应.     

JAK抑制剂在难治性皮肌炎中的应用进展

JAK/STAT信号通路在皮肌炎发病中起着重要作用。JAK抑制剂能阻断依赖JAK/STAT通路相关因子的信号转导,抑制免疫细胞激活和T细胞介导的炎症性反应。目前美国食品药品监督管理局批准的JAK抑制剂适应证只有风湿性关节炎和骨髓纤维化,但已有不少应用JAK抑制剂治疗难治性皮肌炎的报道。本文综述JAK/STAT通路在皮肌...     

酪氨酸激酶及其抑制剂与免疫性皮肤病的研究进展

酪氨酸激酶是一类催化蛋白质酪氨酸残基磷酸化的酶。他们是一系列细胞反应的信号传导途径中的关键因素。近来研究表明,酪氨酸激酶与系统性硬化症、银屑病、寻常型天疱疮、大疱性类天疱疮、皮肌炎和系统性红斑狼疮等免疫性皮肤病的发病关系密切。酪氨酸激酶抑制剂为这些患者提供了一类新的治疗方法。本文就与免疫性皮肤病密切相关的酪氨酸激酶信号通路和酪氨酸激酶抑制剂的临床应用进展作一综述。     

霉酚酸酯在皮肤病治疗中的应用

霉酚酸酯是一种新型免疫抑制剂,它可选择性地抑制T、B淋巴细胞中的次黄嘌呤核苷酸脱氢酶而发挥免疫抑制效应,口服后迅速水解为霉酚酸,不良反应效轻微。近年来霉酚酸酯已被用来治疗银屑病、寻常型天疱疮、大疱性类天疱疮及狼疮性肾炎等免疫性皮肤病,并取得了可喜的疗效。     

免疫抑制剂和细胞毒药物在皮肤病治疗中的应用

细胞毒和免疫抑制剂通常用于治疗增殖性、免疫介导炎症性疾病和某些皮肤肿瘤。甲氨蝶呤、硫唑嘌呤、霉酚酸莫非替、环孢菌素、环磷酰胺、苯丁酸氨芥和其他相关药物在严重和／或顽固的风湿性皮肤病的治疗中有潜在疗效。此类药物的治疗窗较狭窄，主要用于致死性皮肤病或固醇类替代药物。     

皮肤病治疗学的进展

近10余年来皮肤病治疗学有很大的进步,使某些皮肤病的治疗达到了新的水平,本文介绍了1、感染性皮肤病治疗,对疱疹病毒感染性皮肤病用阿昔洛韦治疗相当于用青霉素治疗细菌性感染,新的还有缬昔洛韦和泛昔洛韦,真菌感染的治疗以甲癣治疗最有成效,可采用伊曲康唑冲击疗法或特比萘芬连续口服,细菌感染要特别注意杀灭鼻腔内的金黄色葡萄球菌,疥疱外用5%苄氯菊脂霜已取代了林丹,2、炎症性皮肤病,异位性皮炎可外用他克莫司治疗。银屑病治疗有了一定的进展,采用维生素D3衍生物钙泊三醇软膏治疗效果好,采用顺序疗法既可加快治疗效果。减少刺激性,缓解时间较长。3、痤疮的治疗可口服四环素及其衍生物,异构维甲酸可采用间断治疗方法。对女性痤疮病人可采用三合一炔醚片剂治疗。     

The effectiveness of Janus kinase inhibitors in treating atopic dermatitis: A systematic review and meta‐analysis

Primary studies have presented conflicting results on the efficacy of Janus kinase (JAK) inhibitors in treating atopic dermatitis. Hence, it is important to determine the summary effect of JAK inhibitors in order to guide the clinical application of this potentially beneficial drug. To determine the efficacy of JAK inhibitors in treating atopic dermatitis in all age groups. A systematic review with meta‐analyses of randomized controlled trials (RCTs) reporting on the effect of JAK inhibitors on the signs and symptoms of atopic dermatitis were conducted. Six electronic databases, registries, and search engines (PubMed, Cochrane Central Register of Controlled Trials [CENTRAL], Google Scholar, ScienceDirect, Clinical.gov, and WHO ICTRP) were searched from inception to September, 2019. The search terms include “atopic dermatitis,” “eczema,” and “Janus kinase inhibitor.” The search was restricted to humans. A total of 413 studies were identified through the database search and hand‐searching. After the selection process, five RCTs were included in this systematic review. A meta‐analysis of three studies showed that JAK inhibitors were effective in reducing Eczema Area and Severity Index (P = .0001) and pruritus scores (P = .0001). JAK inhibitors appear to be effective in treating atopic dermatitis. Future studies should aim to evaluate its cost‐effectiveness and availability to patients especially in developing countries.     

The role of Janus kinase inhibitors in the treatment of alopecia areata: A systematic review

Alopecia areata (AA) is a non‐scarring alopecia, which often carries a major impact on patients' quality of life. Currently there is no single approved treatment that effectively induces permanent remission. Recently, the JAK–STAT signaling pathway has emerged as a possible therapeutic target leading to increased interest in the use of Janus kinase (JAK) inhibitors (JAKis) in the treatment of this pathology. This review of the literature summarizes information on patients with AA who underwent treatment with JAKis and discusses the current evidence on the efficacy and safety of its use. A literature search was conducted in different databases to identify clinical trials and case reports published in January 2019. Several clinical studies have shown very promising results in the treatment of AA with oral formulas of JAKis. These agents, however, need chronic administration to maintain response. Topical formulations did not show satisfactory responses. The safety profile of these agents appears to be favorable. Current evidence is promising regarding the efficacy and safety of oral JAKis. However, the data obtained are of low quality, originating predominantly from reports of clinical cases. Further studies are needed to confirm these data and to optimize its long‐term efficacy and safety.     

The use of Janus kinase inhibitors and narrowband ultraviolet B combination therapy in non-segmental vitiligo

Vitiligo is a depigmentation disorder of the skin that occurs secondary to the destruction of melanocytes by an immune-mediated process. Vitiligo clinically presents with depigmented macules and patches, most commonly on the face, acral sites, and genitalia. It can be characterized as generalized or localized based on distribution. The localized form can be further divided into segmental (linear, band-like, or Blaschkoid) and non-segmental vitiligo. The classical treatment of vitiligo includes topical steroids, pulsed oral steroids in unstable vitiligo, phototherapy, a combination of steroid therapy and phototherapy, surgical grafting, as well as intentional depigmentation therapy in severe cases. However, recent advances in understanding the immune mechanisms implicated in the pathogenesis of vitiligo have led to the use of an FDA-approved topical Janus kinase (JAK) inhibitors for vitiligo. Despite this novel therapy advancement, we recommend the addition of narrowband ultraviolet B (NB-UVB) to JAK inhibitors in patients with extensive and progressive lesions, or those not fully responsive to JAK inhibitor monotherapy.     

Newer treatments of psoriasis regarding IL‐23 inhibitors,phosphodiesterase 4 inhibitors,and Janus kinase inhibitors

The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult‐to‐treat disease. IL‐23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL‐23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL‐23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL‐23). Phosphodiesterase inhibitors exert an anti‐inflammatory action and their most common group is the PDE4 family. PDE4 inhibits cAMP, which reduces the inflammatory response of the pathway of Th helper lymphocytes, Th17, and type 1 interferon which modulates the production of anti‐inflammatory cytokines such as IL‐10 interleukins. The Janus kinase (JAK) signaling pathway plays an important role in the immunopathogenesis of psoriasis. Tofacitinib suppresses the expression of IL‐23, IL‐17A, IL‐17F, and IL‐22 receptors during the stimulation of lymphocytes. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 kinases and the JAK‐STAT signaling pathway. This article is a review of the aforementioned drugs as described in the latest available literature.     

Recommendations for risk minimization when using Janus kinase inhibitors for the treatment of chronic inflammatory skin diseases

In accordance with article 20 of Regulation (EC) No 726/2004, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has re-evaluated the safety of Janus kinase inhibitors for the treatment of inflammatory diseases and formulated safety information deviating from the previous indications in the respective summary of product characteristics of the products concerned. These refer to the consideration of a possibly increased risk of venous thromboembolic or severe cardiovascular events, an increased infection rate and an increase in the prevalence of skin cancer across drugs and indications. Therefore, in patients with independent risk factors (age 65 years and older, smokers or former smokers, patients with oral contraception or hormone replacement therapy and other risk factors), it is recommended to use Janus kinase inhibitors therapeutically only if there are no suitable treatment alternatives. To facilitate a pragmatic and thorough detection of high-risk patients in everyday clinical practice, an interdisciplinary checklist was developed that is suitable as a working tool from the perspective of the dermatologist.