Elsevier

Pharmacology & Therapeutics
药理学与治疗学

Volume 243, March 2023, 108355
第 243 卷,2023 年 3 月,108355
Pharmacology & Therapeutics

How to get rid of itching
如何摆脱瘙痒

https://doi.org/10.1016/j.pharmthera.2023.108355Get rights and content 获取权限和内容

Abstract 抽象

Itch is an unpleasant sensation arising from a variety of dermatologic, neuropathic, systemic, and psychogenic etiologies. Various itch pathways are implicated according to the underlying etiology. A variety of pruritogens, or itch mediators, as well as receptors have been identified and provide potential therapeutic targets. Recent research has primarily focused on targeting inflammatory cytokines and Janus kinase signaling, protease-activated receptors, substance P and neurokinin, transient receptor potential-vanilloid ion channels, Mas-related G-protein-coupled receptors (MRGPRX2 and MRGPRX4), the endogenous opioid and cannabinoid balance, and phosphodiesterase 4. Periostin, a newly identified pruritogen, should be further explored with clinical trials. Drugs targeting neural sensitization including the gabergic system and P2X3 are other potential drugs for chronic itch. There is a need for more targeted therapies to improve clinical outcomes and reduce side effects.
瘙痒是一种由各种皮肤病、神经性、全身性和心因性病因引起的不愉快感觉。根据潜在的病因,涉及各种瘙痒途径。已经确定了多种瘙痒原或瘙痒介质以及受体,并提供了潜在的治疗靶点。最近的研究主要集中在靶向炎症细胞因子和 Janus 激酶信号传导、蛋白酶激活受体、P 物质和神经激肽、瞬时受体电位-香草酸离子通道、Mas 相关 G 蛋白偶联受体(MRGPRX2 和 MRGPRX4)、内源性阿片类药物和大麻素平衡以及磷酸二酯酶 4。骨膜蛋白是一种新发现的瘙痒原,应通过临床试验进一步探索。靶向神经致敏的药物,包括胃蛋白系统和 P2X3 是治疗慢性瘙痒的其他潜在药物。需要更多的靶向治疗来改善临床结果并减少副作用。

Keywords 关键字

Atopic dermatitis
Cytokines
Itch
Neuroimmune
Prurigo nodularis
Pruritus

特应性皮炎细胞因子瘙痒神经免疫性结节性痒痒

Abbreviations 缩写

AD
atopic dermatitis
AhR
aryl hydrocarbon receptor
cAMP
cyclic adenosine monophosphate
CSU
chronic spontaneous urticaria
GABA
gamma-aminobutyric acid
IL
interleukin
GPCR
G-protein-coupled receptor
IL-4Rα
interleukin-4 receptor-α
JAK/STAT
Janus kinase and signal transducer and activator of transcription
KOR
kappa-opioid receptor
MC
mast cell
MRGPRX
mas-related G protein-coupled receptor-x
MMP
methylbenzylmethylbenzimidazolepiperidinylmethanone
MOR
mu-opioid receptor
NAC
N-acetylcysteine
NaV
voltage-gated sodium
NK1
neurokinin-1
NRS
Numerical Rating Scale
OSMRβ
oncostatin M receptor beta
PAR2
polymorphic protease-activated receptor 2
PGE2
prostaglandin E2
PLA2
phospholipase A2
R
receptor
S1P
sphingosine-1-phosphate
SP
substance P
TRP
transient receptor potential
TRPA1
Ankyrin 1
TSLP
thymic stromal lymphopoietin

A特应性皮炎AhRaryl 烃受体cAMP环状腺苷单磷酸CSU慢性自发性荨麻疹GABAγ-氨基丁酸IL白细胞介素GPCRG蛋白偶联受体IL-4Rα白细胞介素-4受体-αJAK/STAT肛门激酶和信号转导和转录激活剂KORkappa-阿片受体MC肥大细胞MRGPRXmas相关G蛋白偶联受体-xMMP甲基苄基甲基苯并咪唑哌啶甲酮MORmu-阿片类药物受体NACN-乙酰半胱氨酸NaVvoltage门控钠NK1neurokinin-1NRS药物评定量表OSMRβ抑菌素M受体βPAR2多态性蛋白酶激活受体2PGE2前列腺素E2PLA2磷脂酶A2R受体S1P鞘氨醇-1-磷酸SP物质PTR瞬时受体电位TRPA1锚蛋白1TSL胸腺基质淋巴细胞生成素

1. Introduction 1. 引言

Itch is defined as an unpleasant sensation that causes the desire to scratch. Severity of itch varies greatly from a mild nuisance to a debilitating symptom often instigating sleep disturbance, depression, and anxiety while interfering with optimal quality of life (Dalgard et al., 2015; Lipman & Yosipovitch, 2021; Warlich et al., 2015; Weiss, Mettang, Tschulena, & Weisshaar, 2016; Xu, Shetty, Badiger, Chan, & Yosipovitch, 2018). Secondary skin changes frequently result from scratching including excoriations, lichenification, nodules, open wounds, bleeding, and infection.
瘙痒被定义为一种令人不快的感觉,导致抓挠的欲望。瘙痒的严重程度差异很大,从轻微的滋扰到使人衰弱的症状,通常会引发睡眠障碍、抑郁和焦虑,同时干扰最佳生活质量(Dalgard 等人,2015 年;利普曼和约西波维奇,2021 年;Warlich 等人,2015 年;Weiss,Mettang,Tschulena和Weisshaar,2016;Xu,Shetty,Badiger,Chan和Yosipovitch,2018)。继发性皮肤变化通常由抓挠引起,包括脱落、苔藓形成、结节、开放性伤口、出血和感染。

Chronic itch lasts at least six weeks and is estimated to have a lifetime prevalence of 22% (Weisshaar, 2016). Causes of itch include dermatologic, neuropathic, systemic, and psychogenic etiologies (Lipman, Ingrasci, & Yosipovitch, 2021). Of these, the most heavily investigated dermatologic conditions include atopic dermatitis (an intensely pruritic, chronic, relapsing, inflammatory skin condition), psoriasis (a chronic, recurrent, immune-mediated condition of the skin and joints causing scaly, itchy plaques), and chronic urticaria (a condition characterized by recurrence of wheals, with or without angioedema). Neuropathic causes include notalgia paresthetica (an itch of the upper back) and brachioradial pruritus (an itch of the arms caused by spinal-nerve impingement). Systemic causes include chronic kidney disease, cholestatic disease, myeloproliferative disorders, and hyperthyroidism.
慢性瘙痒持续至少六周,估计终生患病率为 22%(Weisshaar,2016 年)。瘙痒的原因包括皮肤病、神经性、全身性和心因性病因(Lipman、Ingraci 和 Yosipovitch,2021 年)。其中,研究最深入的皮肤病包括特应性皮炎(一种剧烈瘙痒、慢性、复发性、炎症性皮肤病)、牛皮癣(一种慢性、复发性、免疫介导的皮肤和关节疾病,导致鳞屑、瘙痒斑块)和慢性荨麻疹(一种以风团复发为特征的疾病,伴或不伴血管性水肿)。神经性病因包括感觉异常(上背部瘙痒)和肱桡动脉瘙痒(由脊神经撞击引起的手臂瘙痒)。全身性病因包括慢性肾病、胆汁淤积性疾病、骨髓增生性疾病和甲状腺功能亢进。

Because numerous mechanisms are responsible for a wide range of conditions causing pruritus, treating itch can be a therapeutic challenge. Acute and chronic itch have multiple pathophysiologies which require different treatments. Therapies should be directed at correcting the underlying etiology when possible. When this is not possible, non-specific immune modulation with topical and systemic steroids are often utilized. These treatments may provide relief in some cases, but at the expense of various side effects. With advances in our understanding of underlying itch mechanisms, the future of treatment for pruritus is transitioning from a “one size fits all” model to more targeted therapy particular to underlying pathophysiology. In this review, we delve deeper into the specific molecules and receptors involved in various itch pathways and the novel therapeutics in development to target them (Table 1).
由于许多机制导致多种疾病引起瘙痒,因此治疗瘙痒可能是一项治疗挑战。急性和慢性瘙痒具有多种病理生理学,需要不同的治疗。如果可能,治疗应以纠正潜在病因为导向。当这是不可能的时,通常使用局部和全身类固醇的非特异性免疫调节。在某些情况下,这些治疗可能会缓解症状,但会以各种副作用为代价。随着我们对潜在瘙痒机制的理解的进步,瘙痒治疗的未来正在从“一刀切”模式过渡到针对潜在病理生理学的更有针对性的治疗。在这篇综述中,我们深入研究了参与各种瘙痒途径的特定分子和受体,以及正在开发的针对它们的新型疗法(表1)。

Table 1. Itch targets and ongoing clinical trials.
表 1.瘙痒目标和正在进行的临床试验。

Empty CellTargetDrug Names 药物名称National Clinical Trial Number
国家临床试验编号
Type 2 inflammation 2型炎症IL-4 and IL-13 IL-4 和 IL-13Dupilumab; lebrikizumab; CM310; CBP-201
度普利尤单抗;lebrikizumab;CM310型;美国海关和边境保护局-201
NCT04180488; NCT03749135; NCT03749148; NCT04146363; NCT04256759; NCT05263206; NCT05452343; NCT05649098; NCT05590585; NCT05614817
Empty CellIL-31 and Oncostatin M IL-31 和抑癌素 MVixarelimab; nemolizumab Vixarelimab;奈莫利珠单抗NCT03816891; NCT05075408 NCT03816891;NCT05075408
Empty CellIL-17SecukinumabNCT04717466
Empty CellIL-5Benralizumab; mepolizumab
贝那利珠单抗;美泊利单抗
NCT04612725; NCT03494881 NCT04612725;NCT03494881
Empty CellOX40KY1005NCT05131477
Empty CellSphingosine-1-phosphateEtrasimod; BMS-986166 依曲莫德;BMS-986166NCT04162769; NCT05014438 NCT04162769;NCT05014438
Empty CellJAK/STAT JAK/统计PF-04965842; INCB054707; ruxolitinib
PF-04965842;INCB054707;芦可替尼
NCT02780167; NCT05061693; NCT05456529
NCT02780167;NCT05061693;NCT05456529
Empty CellAryl hydrocarbon receptor
芳烃受体
TapinarofNCT05142774; NCT05014568; NCT05032859
NCT05142774;NCT05014568;NCT05032859
Empty CellPhosphodiesterase 4 磷酸二酯酶4Crisaborole; roflumilast 西硼罗;罗氟司特NCT05200403; NCT04773587; NCT04845620; NCT04973228; NCT04549870
NCT05200403;NCT04773587;NCT04845620;NCT04973228;NCT04549870
Empty CellTyrosine kinase KIT 酪氨酸激酶试剂盒BarzolvolimabNCT05368285; NCT04944862 NCT05368285;NCT04944862
Empty CellMRGPRX2EP262
Neural targets 神经靶点PARDoxycycline; minocycline 多西环素;米诺环素NCT03968562; NCT04202263 NCT03968562;NCT04202263
Empty CellTRPV3KM-001NCT05454462
Empty CellMRGPRX4EP547NCT04510090; NCT05525520 NCT04510090;NCT05525520
Neural sensitization 神经敏化Opioid imbalance 阿片类药物失衡MR13A9; naltrexone; HSK21542; difelikefalin; nalfurafine hydrochloride; nalbuphine
MR13A9型;纳曲酮;HSK21542;地非利福林;盐酸纳呋拉芬;纳布啡
NCT04711603; NCT04325802; NCT05135390; NCT05342623; NCT05356403; NCT05387707; NCT04728984; NCT03497975
Empty CellGABAPregabalinNCT04660773; NCT03928093 NCT04660773;NCT03928093
Empty CellCannabinoid receptors 大麻素受体Nabilone; cannabidiol 萘比隆;大麻二酚NCT05180968; NCT05651607 NCT05180968;NCT05651607

Abbreviations: GABA, gamma-aminobutyric acid; IL, interleukin; JAK/STAT, Janus kinase and signal transducer and activator of transcription; MRGPRX, mas-related G protein-coupled receptor-x; PAR, polymorphic protease-activated receptor; S1P, sphingosine-1-phosphate; TRP, transient receptor potential.
缩写:GABA,γ-氨基丁酸;IL,白细胞介素;JAK/STAT,Janus激酶和信号转导器和转录激活剂;MRGPRX,mas相关G蛋白偶联受体-x;PAR,多态性蛋白酶激活受体;S1P,1-磷酸鞘氨醇;TRP,瞬时受体电位。

2. The general itch pathway
2.一般瘙痒途径

The general pathway of itch signaling occurs with many similarities to the pathway of pain perception (Fig. 1; Yosipovitch, Rosen, & Hashimoto, 2018). Itch is initiated with the introduction of pruritogens, endogenous and exogeneous molecules that induce itching (Mollanazar, Smith, & Yosipovitch, 2016). The pruritogen of acute itch is histamine released by mast cells, basophils (Hashimoto, Rosen, Sanders, & Yosipovitch, 2019), and keratinocytes (Shimizu, Andoh, Yoshihisa, & Shimizu, 2015) located in the skin. Chronic itch is mediated by a diverse range of pruritogens (proteases, cytokines/chemokines, and amines) in the epidermis and dermal-epidermal junction, which will be elaborated on in this review. Through binding of their respective receptors, pruritogens activate either histamine-sensitive or histamine-insensitive neurons, which are unmyelinated type C and thinly myelinated type Aδ nerve fibers. The histaminergic and non-histaminergic pathways are distinct tracts ultimately inducing unique patterns of brain activity (Davidson et al., 2012; Dhand & Aminoff, 2014; Mu & Sun, 2022; Papoiu, Coghill, Kraft, Wang, & Yosipovitch, 2012).
瘙痒信号传导的一般通路与疼痛感知通路有许多相似之处(图1;Yosipovitch,Rosen和Hashimoto,2018)。瘙痒是通过引入瘙痒原,诱发瘙痒的内源性和外源性分子而开始的(Mollanazar,Smith和Yosipovitch,2016)。急性瘙痒的瘙痒原是由肥大细胞,嗜碱性粒细胞(Hashimoto,Rosen,Sanders和Yosipovitch,2019)和角质形成细胞(Shimizu,Andoh,Yoshihisa和Shimizu,2015)释放的组胺。慢性瘙痒是由表皮和真皮-表皮交界处的多种瘙痒原(蛋白酶、细胞因子/趋化因子和胺)介导的,本综述将对此进行详细阐述。通过结合各自的受体,瘙痒原激活组胺敏感或组胺不敏感的神经元,这些神经元是无髓鞘的 C 型和薄髓鞘化的 Aδ 型神经纤维。组胺能和非组胺能途径是不同的道,最终诱导独特的大脑活动模式(Davidson等人,2012;Dhand&Aminoff,2014年;Mu & Sun,2022 年;Papoiu,Coghill,Kraft,Wang和Yosipovitch,2012)。

Fig. 1
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Fig. 1. Pathways of itch from skin to brain.
图 1.从皮肤到大脑的瘙痒途径。

Itch originates in the epidermis and dermal–epidermal junction and is transmitted by itch-selective C nerve fibers. Some of these fibers are sensitive to histamine, but the majority are not. A complex interplay among T cells, mast cells, neutrophils, eosinophils, keratinocytes, and nerve cells (along with increased release of cytokines, proteases, and neuropeptides) leads to exacerbation of itch. The C fibers form synapses with second-order projections in the dorsal horn, and the itch signal ascends in the contralateral spinothalamic tract, with projections to the thalamus and parabrachial nucleus. From the thalamus, itch is transmitted to several regions of the brain that are involved in sensation, evaluative processes, emotion, reward, and memory.
瘙痒起源于表皮和真皮-表皮交界处,并通过瘙痒选择性 C 神经纤维传播。其中一些纤维对组胺敏感,但大多数不敏感。T 细胞、肥大细胞、中性粒细胞、嗜酸性粒细胞、角质形成细胞和神经细胞之间的复杂相互作用(以及细胞因子、蛋白酶和神经肽的释放增加)导致瘙痒加重。C纤维在背角形成具有二级突起的突触,瘙痒信号在对侧脊髓丘脑束中上行,并投射到丘脑和臂旁核。瘙痒从丘脑传播到大脑的几个区域,这些区域涉及感觉、评估过程、情绪、奖励和记忆。

The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.
该图部分使用施维雅提供的施维雅医疗艺术生成,根据知识共享署名 3.0 未本地化版本许可获得许可。

Adapted from: Yosipovitch and Bernhard, 2013. Copyright © (2022) Massachusetts Medical Society. Reprinted with permission.
改编自:Yosipovitch 和 Bernhard,2013 年。版权所有 © (2022) 马萨诸塞州医学会。经许可转载。

Various itch receptors lead to afferent neuronal activation. Two major families of receptors transmitting itch are the G-protein-coupled receptors (GPCRs) and the transient receptor potential (TRP) channels, which can be activated by the GPCRs. The GRPRs include the histamine H1 (involved in acute itch) and H4 receptors and the protease-activated receptors (PARs), mas-related G protein coupled receptors (MRGPRs), and neurokinin receptors (NKs; involved in chronic itch).
各种瘙痒感受器导致传入神经元激活。传递瘙痒的两个主要受体家族是 G 蛋白偶联受体 (GPCR) 和瞬时受体电位 (TRP) 通道,它们可以被 GPCR 激活。GRPR 包括组胺 H1(参与急性瘙痒)和 H4 受体以及蛋白酶激活受体 (PAR)、MAS 相关 G 蛋白偶联受体 (MRGPR) 和神经激肽受体 (NK;参与慢性瘙痒)。

The transient receptor potential ion channels are implicated in both acute and chronic itch as well as pain (Kittaka & Tominaga, 2017; Mahmoud, Soares, & Yosipovitch, 2023; Moore, Gupta, Jordt, Chen, & Liedtke, 2018; Shirolkar & Mishra, 2022). Transient receptor potential vanilloid 1 (TRPV1) is involved with both nociception and pruriception, widely known for detection of capsaicin found in chili peppers (Li & Wang, 2021). Ankyrin 1 (TRPA1) acts as the downstream molecule to various histamine-independent, chronic itch pathways in addition to the histaminergic pathway (Liu et al., 2021; Maglie et al., 2021). Along with GPCRs and caspsaicin, other external stimuli found to activate TRPV1 and/or TRPA1 include pH alterations, hot or cold temperatures, ATP, prostaglandins, oxidants, and allyl isothiocyanate (found in wasabi; Yosipovitch, Rosen, & Hashimoto, 2018). More recently discovered, TRPV3 is activated by warm temperatures and is implicated in atopic dermatitis and skin barrier damage related itch; TRPV4 is stimulated by hypotonicity and metabolites of the mevalonate pathway and has been shown to be elevated in chronic idiopathic pruritus (Dutta et al., 2020; Mahmoud et al., 2023; Moore et al., 2018).
瞬时受体电位离子通道与急性和慢性瘙痒以及疼痛有关(Kittaka&Tominaga,2017;马哈茂德、苏亚雷斯和约西波维奇,2023 年;Moore,Gupta,Jordt,Chen和Liedtke,2018;Shirolkar 和 Mishra,2022 年)。瞬时受体电位香草素1(TRPV1)与伤害感受和瘙痒有关,因检测辣椒中发现的辣椒素而广为人知(Li&Wang,2021)。锚蛋白 1 (TRPA1) 除了组胺能途径外,还充当各种组胺非依赖性慢性瘙痒途径的下游分子(Liu 等人,2021 年;Maglie 等人,2021 年)。除了 GPCR 和卡普赛克星外,其他发现激活 TRPV1 和/或 TRPA1 的外部刺激包括 pH 值改变、热或冷温度、ATP、前列腺素、氧化剂和异硫氰酸烯丙酯(存在于芥末中;Yosipovitch,Rosen和Hashimoto,2018)。最近发现,TRPV3 被温暖的温度激活,并与特应性皮炎和皮肤屏障损伤相关的瘙痒有关;TRPV4 受到甲羟戊酸途径的低渗性和代谢物的刺激,并且已被证明在慢性特发性瘙痒中升高(Dutta 等人,2020 年;Mahmoud 等人,2023 年;Moore等人,2018)。

TRPV1 and TRPA1 activate Nav1.7, a voltage-gated sodium channel, in both histaminergic and nonhistaminergic itch. Nav1.7 is responsible for triggering action potentials in sensory neurons and has been implicated in itch and pain transmission (Li et al., 2022). A gain-of-function mutation of Nav1.7 leads to paroxysmal itch (Devigili et al., 2014), while blocking Nav1.7 alleviates histamine-dependent itch in mouse models (Graceffa et al., 2017; Li et al., 2022; Roecker et al., 2017; Zhang et al., 2019).
TRPV1 和 TRPA1 在组胺能和非组胺能瘙痒中激活 Nav1.7,这是一种电压门控钠通道。Nav1.7 负责触发感觉神经元中的动作电位,并与瘙痒和疼痛传递有关(Li 等人,2022 年)。Nav1.7的功能获得性突变导致阵发性瘙痒(Devigili等人,2014),而阻断Nav1.7可减轻小鼠模型中的组胺依赖性瘙痒(Graceffa等人,2017;Li 等人,2022 年;Roecker 等人,2017 年;Zhang等人,2019)。

When excited, the signal is transmitted from the C fibers to the dorsal horn of the spinal cord, where the fibers synapse with second-order neurons. Opioid modulation occurs at the level of the spinal cord. The itch signal ascends in the contralateral spinothalamic tract through the second-order neuron with projections to the thalamus and parabrachial nuclei, where it is finally transmitted to the cortical areas of the brain associated with sensation, evaluative processes, emotion, reward, and memory (Chen & Sun, 2020; Papoiu et al., 2012).
当被激发时,信号从C纤维传递到脊髓的背角,在那里纤维与二级神经元突触。阿片类药物调节发生在脊髓水平。瘙痒信号通过二阶神经元在对侧脊髓丘脑束中上升,投射到丘脑和臂旁核,最终传递到与感觉、评估过程、情绪、奖励和记忆相关的大脑皮质区域(Chen & Sun,2020 年;Papoiu等人,2012)。

Crosstalk occurs between the immune and neural systems, leading to exacerbation of itch (Yosipovitch, Rosen, & Hashimoto, 2018). The excited sensory neurons can release neuropeptides (calcitonin gene–related protein and substance P [SP]) with involvement of T cells, mast cells, neutrophils, eosinophils, keratinocytes, and macrophages, all causing the release of cytokines, proteases, and neuropeptides. This activity creates a local environment of neurogenic inflammation–local vasodilation, plasma extravasation, and mast cell degranulation (Rosa & Fantozzi, 2013).
串扰发生在免疫系统和神经系统之间,导致瘙痒加剧(Yosipovitch,Rosen和Hashimoto,2018)。兴奋的感觉神经元可以释放神经肽(降钙素基因相关蛋白和 P 物质 [SP]),参与 T 细胞、肥大细胞、中性粒细胞、嗜酸性粒细胞、角质形成细胞和巨噬细胞,所有这些都会导致细胞因子、蛋白酶和神经肽的释放。这种活动创造了神经源性炎症的局部环境 - 局部血管舒张,血浆外渗和肥大细胞脱颗粒(Rosa&Fantozzi,2013)。

3. Neuronal sensitization
3. 神经元致敏

Neuronal sensitization refers to a process wherein neurons become hyper-responsive to extracellular stimuli, enhancing itch signaling (Andersen et al., 2018; Yosipovitch, Rosen, & Hashimoto, 2018). Stimuli can include pruritogens, which under these conditions, causes an amplification of itch signaling, or they can be normally non-pruritogenic entities, but provoke itch under these conditions (such as light touch from clothing; Andersen et al., 2018). The phenomenon of alloknesis refers to the provocation of itch from a normally non-itchy stimulus, such as light touch. Neuronal sensitization can occur at multiple points within the itch pathway including within the skin, dorsal root ganglia, spinal cord, and brain (Yosipovitch, Rosen, & Hashimoto, 2018). Peripheral neuronal sensitization has been demonstrated from inflammation and can be associated with abnormal innervation, such as changes in nerve fiber density in the epidermis (Tominaga & Takamori, 2014). At the level of the spinal cord, an imbalance of endogenous opioid or attenuation of the descending inhibitory pathway can modify signaling (Ding et al., 2020; Lee & Ko, 2015). Several drugs have been developed for chronic itch which inhibit these mechanisms of neuronal sensitization.
神经元敏化是指神经元对细胞外刺激反应过度的过程,增强瘙痒信号传导(Andersen等人,2018;Yosipovitch,Rosen和Hashimoto,2018)。刺激物可以包括瘙痒原,在这些条件下,瘙痒原会导致瘙痒信号的放大,或者它们通常可以是非瘙痒性实体,但在这些条件下会引起瘙痒(例如衣服的轻触;Andersen等人,2018)。同种异体现象是指通常不瘙痒的刺激(例如轻触)引起的瘙痒。神经元敏化可以发生在瘙痒通路的多个点,包括皮肤,背根神经节,脊髓和大脑(Yosipovitch,Rosen和Hashimoto,2018)。外周神经元敏化已从炎症中得到证明,并且可能与异常神经支配有关,例如表皮中神经纤维密度的变化(Tominaga和Takamori,2014)。在脊髓水平上,内源性阿片类药物的不平衡或下降抑制途径的衰减可以改变信号传导(Ding等人,2020;Lee&Ko,2015)。已经开发了几种治疗慢性瘙痒的药物,这些药物可以抑制这些神经元致敏机制。

4. Important new clinical targets: Drugs targeting type 2 inflammation
4. 重要的新临床靶点:靶向2型炎症的药物

Chronic itch is often induced in inflammatory skin diseases in which type 2 cytokines including interleukin (IL)-4, IL-13, IL-31, IL-33, thymic stromal lymphopoietin, and periostin (an extracellular matrix protein highly associated with type 2 inflammation) are released from mast cells, keratinocytes, innate lymphoid cells 2, and type 2 T lymphocytes (Fig. 2; Garcovich et al., 2021; Ingrasci, Lipman, Hawash, Girolomoni, & Yosipovitch, 2021). They activate the sensory neurons directly or induce neuronal sensitization. The evolutionary purpose of type 2 inflammation was as a defense mechanism triggered by skin barrier disruption to protect the host from extracellular pathogens and to reinforce tissue repair and remodeling (Garcovich et al., 2021). Pathologic type 2 inflammation is implicated in atopic dermatitis, prurigo nodularis, bullous pemphigoid, scabies, parasitic diseases, urticaria, and Sézary syndrome, to name a few (Garcovich et al., 2021; Ingrasci et al., 2021).
慢性瘙痒常在炎症性皮肤病中引起,其中 2 型细胞因子包括白细胞介素 (IL)-4、IL-13、IL-31、IL-33、胸腺基质生成素和骨膜蛋白(一种与 2 型炎症高度相关的细胞外基质蛋白)从肥大细胞、角质形成细胞、先天淋巴样细胞 2 和 2 型 T 淋巴细胞中释放出来(图 2;Garcovich 等人,2021 年;Ingrasci、Lipman、Hawash、Girolomoni 和 Yosipovitch,2021 年)。它们直接激活感觉神经元或诱导神经元敏化。2型炎症的进化目的是作为皮肤屏障破坏触发的防御机制,以保护宿主免受细胞外病原体的侵害,并加强组织修复和重塑(Garcovich等人,2021)。病理性 2 型炎症与特应性皮炎、结节性痒疹、大疱性类天疱疮、疥疮、寄生虫病、荨麻疹和 Sézary 综合征有关(Garcovich 等人,2021 年;Ingrasci 等人,2021 年)。

Fig. 2
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Fig. 2. Itch signaling pathways and new drug developments.
图 2.瘙痒信号通路和新药开发。

IL-4 and IL-13 (inhibited by lebrikizumab and tralokinumab) bind to IL-4Rα (inhibited by dupilimab). IL-31 binds to the IL-31 receptor A (inhibited by nemolizumab) and oncostatin M receptor (inhibited by vixarelimub) heterodimer. IL-17 (inhibited by secukinumab and ixekizumab) binds to five different IL-17 receptors (not shown). IL-5 (inhibited by mepolizumab and reslizumab) binds to the IL-5α receptor (inhibited by benralizumab). Note that these cytokine receptors are associated with JAK/STAT signaling. S1P binds to the S1P receptor (inhibited by etrasimod), activating TRPV1 and TRPA1. Periostin directly activates nerve fibers through the αVβ3 integrin and is blocked by an integrin αVβ3 antagonist, cilengitide. The JAK/STAT inhibitors work by inhibiting STAT molecule translocation to the nucleus to alter gene expression. Phosphodiesterase-4 inhibitors work by increasing intracellular levels of cAMP. CDX-0159 is a novel humanized monoclonal antibody that inhibits tyrosine kinase KIT receptors, which are utilized by mast cells. PAR2 is activated by proteases, including tryptase from mast cells. Within the keratinocyte, PAR2 (inhibited by MMP and tetracyclines) accelerates the release of IL-8, which recruits neutrophils to inflammatory lesions. TRPV1 (inhibited by asivatrep) causes calcium influx. PAR2 also activates TRPV3 (inhibited by KM-001) on keratinocytes. The TRPA1 receptor (inhibited by GDC-0334) is also coupled with the TSLP receptor. TRPV4 is another TRPV channel which is inhibited by GSK2798745. On the mast cell, MRGPRX2-mediated degranulation is initiated by SP among other endogenous and exogenous activators. MRGPRX4 on the sensory neuron is inhibited by EP547. SP, released by the sensory nerve ending, also activates the NK1 receptor located on mast cells as well as the sensory nerve fiber itself. MOR activity increases itch, while KOR activity decreases itch. These are influenced by difelikefalin and nalbuphine. The GABA-A receptor is activated by muscimol and the GABA-B receptor is activated by baclofen, thus decreasing sensory neuron excitation. Finally, oxidative stress (inhibited by NAC), activates TRPA1. Activation of TRP channels leads to NaV1.7 activation and subsequent action potential of the neuron.
IL-4 和 IL-13(被 lebrikizumab 和 tralokinumab 抑制)与 IL-4Rα(被 dupilimab 抑制)结合。IL-31 与 IL-31 受体 A(被奈莫利珠单抗抑制)和抑癌素 M 受体(被 vixarelimub 抑制)异二聚体结合。IL-17(由司库奇尤单抗和依奇珠单抗抑制)与五种不同的IL-17受体结合(未显示)。IL-5(被美泊利单抗和瑞利珠单抗抑制)与IL-5α受体(被贝那利珠单抗抑制)结合。请注意,这些细胞因子受体与 JAK/STAT 信号转导有关。S1P与S1P受体结合(被依曲莫德抑制),激活TRPV1和TRPA1。骨膜素通过 αVβ3 整合素直接激活神经纤维,并被整合素 αVβ3 拮抗剂西仑吉肽阻断。JAK/STAT抑制剂通过抑制STAT分子易位到细胞核以改变基因表达而起作用。磷酸二酯酶-4抑制剂通过增加细胞内cAMP水平起作用。CDX-0159是一种新型人源化单克隆抗体,可抑制肥大细胞利用的酪氨酸激酶KIT受体。PAR2 被蛋白酶激活,包括来自肥大细胞的类胰蛋白酶。在角质形成细胞内,PAR2(被 MMP 和四环素抑制)加速 IL-8 的释放,IL-8 将中性粒细胞募集到炎症病变中。TRPV1(被 asivatrep 抑制)导致钙内流。PAR2 还激活角质形成细胞上的 TRPV3(被 KM-001 抑制)。TRPA1受体(被GDC-0334抑制)也与TSLP受体偶联。TRPV4 是另一个被 GSK2798745 抑制的 TRPV 通道。在肥大细胞上,MRGPRX2介导的脱颗粒由SP以及其他内源性和外源性激活剂启动。感觉神经元上的MRGPRX4被 EP547 抑制。 由感觉神经末梢释放的 SP 还激活位于肥大细胞上的 NK1 受体以及感觉神经纤维本身。MOR活性增加瘙痒,而KOR活性减少瘙痒。这些都受到地非利福林和纳布啡的影响。GABA-A受体被麝香酚激活,GABA-B受体被巴氯芬激活,从而降低感觉神经元的兴奋。最后,氧化应激(由NAC抑制)激活TRPA1。TRP 通道的激活导致神经元的 NaV1.7 激活和随后的动作电位。

Abbreviations: cAMP, cyclic adenosine monophosphate; GABA, gamma-aminobutyric acid; IL, interleukin; IL-4Rα, interleukin-4 receptor-α; JAK/STAT, Janus kinase and signal transducer and activator of transcription; KOR, kappa-opioid receptor; MRGPRX, mas-related G protein-coupled receptor-x; MMP, methylbenzylmethylbenzimidazolepiperidinylmethanone; MOR, mu-opioid receptor; NAC, N-acetylcysteine; NaV, voltage-gated sodium; NK1, neurokinin-1; OSMRβ, oncostatin M receptor beta; PAR2, polymorphic protease-activated receptor 2; PGE2, prostaglandin E2; PLA2, phospholipase A2; R, receptor; S1P, sphingosine-1-phosphate; SP, substance P; TRP, transient receptor potential; TSLP, thymic stromal lymphopoietin
缩写:cAMP,环磷酸腺苷;GABA,γ-氨基丁酸;IL,白细胞介素;IL-4Rα,白细胞介素-4受体-α;JAK/STAT,Janus激酶和信号转导器和转录激活剂;KOR, κ-阿片受体;MRGPRX,mas相关G蛋白偶联受体-x;MMP,甲基苄基甲基苯并咪唑哌啶基甲酮;MOR,μ阿片受体;NAC,N-乙酰半胱氨酸;NaV,电压门控钠;NK1,神经激肽-1;OSMRβ,抑癌素M受体β;PAR2,多态性蛋白酶活化受体2;PGE2,前列腺素E2;PLA2,磷脂酶A2;R, 受体;S1P,1-磷酸鞘氨醇;SP, 物质P;TRP,瞬时受体电位;TSLP,胸腺基质淋巴细胞生成素

4.1. Cytokines 4.1. 细胞因子

IL-4 and IL-13 are type 2 cytokines which directly stimulate sensory neurons through activation of IL-4 receptor-α (IL-4Rα), transient receptor potential channels, and Janus kinase 1 (JAK1) signaling. IL-4 and IL-13 also promote isotype class switching to IgE and act on mast cells, eosinophils, and basophils (Maurer, Khan, Elieh Ali Komi, & Kaplan, 2021). Intradermal introduction of IL-4 and/or IL-13 are sufficient to induce scratching behavior in mice (Campion et al., 2019). Subsequent studies showed that IL-4 sensitizes the neurons to previously subthreshold levels of pruritogens (i.e.., induces neuronal sensitization; Oetjen et al., 2017), thus demonstrating its importance in chronic itch.
IL-4 和 IL-13 是 2 型细胞因子,通过激活 IL-4 受体α (IL-4Rα)、瞬时受体电位通道和 Janus 激酶 1 (JAK1) 信号转导直接刺激感觉神经元。IL-4 和 IL-13 还促进同型类向 IgE 的转换,并作用于肥大细胞、嗜酸性粒细胞和嗜碱性粒细胞(Maurer、Khan、Elieh Ali Komi 和 Kaplan,2021 年)。皮内引入IL-4和/或IL-13足以诱导小鼠的抓挠行为(Campion等人,2019)。随后的研究表明,IL-4 使神经元对先前阈值以下水平的瘙痒原敏感(即诱导神经元致敏;Oetjen等人,2017),从而证明了其在慢性瘙痒中的重要性。

Dupilumab is a fully human monoclonal antibody that targets the IL-4R-alpha subunit and inhibits IL-4 and IL-13 receptor binding. It has been approved for the treatment of moderate to severe atopic dermatitis and has been studied for itch in prurigo nodularis, chronic pruritus of unknown origin, bullous pemphigoid, chronic spontaneous urticaria (CSU), cholinergic urticaria, and histaminergic itch (Lee and Simpson, 2019; NCT04180488; NCT03749135; NCT03749148). In AD, four clinical trials showed early and sustained improvements in itch intensity (Silverberg et al., 2020). The effect was seen as early as day 2 in adults and day 5 in adolescents, with steady improvement during treatment and lasting the entire treatment duration, up to 1 year. Pruritus reduction based on least-squares mean percent change from baseline for Peak Pruritus Numerical Rating Scale (NRS) scores were −47.5 to −57.3%, statistically significant versus placebo. In prurigo nodularis, a severe, chronic itch condition with heterogenous causes, two phase 3 trials (PRIME2 and PRIME) recently showed significant benefit of dupilumab that led to recent FDA-approval of dupilumab for prurigo nodularis. The primary endpoint of both studies was a clinically meaningful reduction in itch from baseline and was achieved in 60% on dupilumab versus 18% on placebo at Week 24 (PRIME) and 37% versus 22% at Week 12 (PRIME2; Yosipovitch et al., 2022a, Yosipovitch et al., 2022b). This was associated with significantly greater improvements in health-related quality of life.
度普利尤单抗是一种靶向 IL-4R-α 亚基并抑制 IL-4 和 IL-13 受体结合的全人源单克隆抗体。它已被批准用于治疗中度至重度特应性皮炎,并已研究用于治疗结节性痒疹、不明原因慢性瘙痒、大疱性类天疱疮、慢性自发性荨麻疹 (CSU)、胆碱能性荨麻疹和组胺能瘙痒(Lee 和 Simpson,2019 年;NCT04180488;NCT03749135;NCT03749148)。在 AD 中,四项临床试验显示瘙痒强度的早期和持续改善(Silverberg 等人,2020 年)。早在成人第 2 天和青少年第 5 天就观察到了效果,在治疗期间稳步改善并持续整个治疗期间,长达 1 年。瘙痒减少基于最小二乘平均百分比相对于基线的峰值瘙痒数值评定量表 (NRS) 评分为 -47.5% 至 -57.3%,与安慰剂相比具有统计学意义。在结节性痒疹(一种具有异质性原因的严重慢性瘙痒疾病)中,最近两项 3 期试验(PRIME2 和 PRIME)显示度普利尤单抗具有显着益处,导致最近 FDA 批准度普利尤单抗治疗结节性痒疹。两项研究的主要终点都是瘙痒较基线有临床意义的减少,第24周(PRIME)组比安慰剂组为60%,安慰剂组为18%,第12周(PRIME2)组为37%,22%为22%。Yosipovitch 等人,2022a,Yosipovitch 等人,2022b)。这与健康相关生活质量的显着改善有关。

Lebrikizumab is a humanized monoclonal antibody against IL-13. A preclinical study utilizing a human dorsal root ganglion model showed that lebrikizumab has a direct antipruritic effect on nerves (Miron et al., 2022). Two phase 2 clinical trials demonstrated significant antipruritic effect in atopic dermatitis (Guttman-Yassky et al., 2020; Simpson et al., 2018), which were further validated in phase 3 trials (Advocate 1 and 2). Advocate 1 demonstrated significant antipruritic effect in Week 16 (−45.75 NRS score change from baseline versus −15.24 for placebo; NCT04146363; Lilly Investors, 2021). Finally, tralokinumab is a human IgG4 monoclonal antibody that targets IL-13 and received FDA-approval for use in AD based on the efficacy and safety reported in the ECZTRA trials (Silverberg et al., 2021; Gutermuth et al., 2022; Wollenberg et al., 2021).
Lebrikizumab 是一种针对 IL-13 的人源化单克隆抗体。一项利用人类背根神经节模型的临床前研究表明,lebrikizumab 对神经具有直接的止痒作用(Miron 等人,2022 年)。两项 2 期临床试验显示对特应性皮炎有显着的止痒作用(Guttman-Yassky 等人,2020 年;Simpson等人,2018),在3期试验(倡导者1和2)中得到了进一步验证。倡导者 1 在第 16 周表现出显着的止痒效果(NRS 评分相对于基线变化 -45.75,安慰剂组为 -15.24;NCT04146363;礼来投资者,2021 年)。最后,tralokinumab 是一种靶向 IL-13 的人 IgG4 单克隆抗体,并根据 ECZTRA 试验中报告的疗效和安全性获得 FDA 批准用于 AD(Silverberg 等人,2021 年;Gutermuth 等人,2022 年;Wollenberg 等人,2021 年)。

All of these monoclonal antibodies are administered via subcutaneous injection. Common side effects include injection site erythema or pain and conjunctivitis.
所有这些单克隆抗体都是通过皮下注射给药的。常见的副作用包括注射部位红斑或疼痛和结膜炎。

IL-31 is an important mediator of itch in chronic conditions including atopic dermatitis, prurigo nodularis, scabies, skin lymphoma, and lichen amyloidosis and has been coined the “itchy cytokine” (Cedeno-Laurent et al., 2015; Kunimura & Fukui, 2021; Nattkemper et al., 2016; Tey et al., 2016). Produced by CD4+ helper T cells, macrophages, mast cells, and dendritic cells in skin, IL-31 stimulates an itch response through the IL-31 receptor heterodimer consisting of IL-31 receptor A and the oncostatin M receptor expressed in dorsal root ganglion neurons. Oncostatin M is another cytokine that induces itch by enhancing neuronal sensitization to itch-selective natriuretic polypeptide B neurons (Crunkhorn, 2022).
IL-31 是慢性疾病中瘙痒的重要介质,包括特应性皮炎、结节性痒疹、疥疮、皮肤淋巴瘤和苔藓淀粉样变性,被称为“瘙痒细胞因子”(Cedeno-Laurent 等人,2015 年;Kunimura & Fukui,2021 年;Nattkemper 等人,2016 年;Tey等人,2016)。IL-31 由皮肤中的 CD4+ 辅助性 T 细胞、巨噬细胞、肥大细胞和树突状细胞产生,通过由 IL-31 受体 A 和背根神经节神经元中表达的抑癌素 M 受体组成的 IL-31 受体异二聚体刺激瘙痒反应。抑癌素 M 是另一种细胞因子,通过增强神经元对瘙痒选择性利钠多肽 B 神经元的敏感性来诱导瘙痒(Crunkhorn,2022 年)。

Nemolizumab is a humanized IL-31 receptor A monoclonal antibody primarily developed for atopic dermatitis. Phase 2 and 3 clinical trials demonstrated that nemolizumab is safe and efficacious when used concomitantly with topical treatments (Kabashima et al., 2020; Silverberg et al., 2020; Kabashima, Matsumura, Komazaki, Kawashima and Nemolizumab JP01 andJP02 Study Group, 2022) and also appears efficacious in treating prurigo nodularis (Ständer et al., 2020). Recent data from a phase 3 trial demonstrated its significant antipruritic effect: 56% of patients received at least a 4-point NRS reduction compared to 21% in the placebo group (Galderma, 2021). Nemolizumab is subcutaneously administered. The adverse effects observed in trials were minimal nasopharyngitis and dermatitis (Kabashima, Matsumura, Komazaki, Kawashima and Nemolizumab JP01 andJP02 Study Group, 2022; Silverberg et al., 2020).
Nemolizumab 是一种人源化 IL-31 受体 A 单克隆抗体,主要用于特应性皮炎。2 期和 3 期临床试验表明,nemolizumab 与局部治疗同时使用时是安全有效的(Kabashima 等人,2020 年;Silverberg 等人,2020 年;Kabashima、Matsumura、Komazaki、Kawashima 和 Nemolizumab JP01 和 JP02 研究组,2022 年),并且在治疗结节性痒疹方面似乎也有效(Ständer 等人,2020 年)。一项 3 期试验的最新数据证明了其显着的止痒作用:56% 的患者至少降低了 4 分的 NRS,而安慰剂组为 21%(Galderma,2021 年)。Nemolizumab皮下给药。试验中观察到的不良反应是轻微的鼻咽炎和皮炎(Kabashima、Matsumura、Komazaki、Kawashima 和 Nemolizumab JP01 和 JP02 研究组,2022 年;Silverberg 等人,2020 年)。

Vixarelimab is an experimental human monoclonal antibody targeting oncostatin M receptor beta (OSMRβ), effectively inhibiting signaling of oncostatin M and IL-31. Vixarelimab has been studied in prurigo nodularis, where it is undergoing a phase 2b study currently (NCT03816891). A phase 2a clinical trial demonstrated 51% reduction in NRS compared to 29% in the placebo at Week 8 (Sofen et al., 2022).
Vixarelimab 是一种靶向抑癌素 M 受体 β (OSMRβ) 的实验性人单克隆抗体,可有效抑制抑癌素 M 和 IL-31 的信号传导。Vixarelimab 已在结节性痒疹中进行了研究,目前正在进行 2b 期研究 (NCT03816891)。一项 2a 期临床试验显示,在第 8 周时,NRS 降低了 51%,而安慰剂组降低了 29%(Sofen 等人,2022 年)。

IL-17 also has a role in itch, particularly in psoriasis (Kanda, 2021). Secukinumab and ixekizumab are two drugs which target IL-17. In an analysis of patient diaries from two phase 3 clinical trials of secukinumab, the itch severity score was markedly reduced as early as Week 2 of treatment by an average of 1.4 out of 10 (Yosipovitch et al., 2019). At Week 12, the mean change from baseline was about −5, exceeding both etanercept (−3.8) and placebo (−0.4) in terms of itch reduction.
IL-17 在瘙痒中也有作用,尤其是在牛皮癣中(Kanda,2021 年)。Secukinumab 和 ixekizumab 是两种靶向 IL-17 的药物。在对司库奇尤单抗两项 3 期临床试验的患者日记的分析中,早在治疗第 2 周,瘙痒严重程度评分就显着降低了平均 1.4 分(满分 10 分)(Yosipovitch 等人,2019 年)。在第 12 周时,相对于基线的平均变化约为 -5,在瘙痒减轻方面超过了依那西普 (-3.8) 和安慰剂 (-0.4)。

IL-5 contributes to histaminergic diseases such as chronic spontaneous urticaria and chronic inducible urticaria by directly affecting the mast cells in the skin and promoting the recruitment of eosinophils and basophils. Inhibitors include benralizumab, mepolizumab, and reslizumab which have been approved for the treatment of asthma and are prescribed off-label for the treatment of histaminergic pruritus (Maurer et al., 2021). One study in chronic spontaneous urticaria found that monthly benralizumab significantly decreased urticarial activity scores (based on pruritus intensity and the number of wheals) by −16 at Week 20 (scores range from 0 to 42 with 42 having greatest severity; Bernstein et al., 2020). No adverse events were reported, and efficacy was found to be similar to omalizumab. Further studies are underway (NCT04612725, NCT03494881).
IL-5通过直接影响皮肤中的肥大细胞并促进嗜酸性粒细胞和嗜碱性粒细胞的募集,导致组胺能疾病,如慢性自发性荨麻疹和慢性诱发性荨麻疹。抑制剂包括贝那利珠单抗、美泊利单抗和瑞利珠单抗,它们已被批准用于治疗哮喘,并被超说明书规定用于治疗组胺能性瘙痒(Maurer 等人,2021 年)。一项针对慢性自发性荨麻疹的研究发现,每月服用贝那利珠单抗可在第 20 周时将荨麻疹活动评分(基于瘙痒强度和风团数量)显著降低 -16(评分范围为 0 至 42,其中 42 分的严重程度最高;Bernstein 等人,2020 年)。未报告不良事件,疗效与奥马珠单抗相似。进一步的研究正在进行中(NCT04612725,NCT03494881)。

OX40 is a co-stimulatory molecule on T-cells that, when ligated by antigen-presenting cells or mast cells, hastens T helper 2 (Th2) effector cell differentiation (Gramaglia et al., 2000; Ishii, Takahashi, Soroosh, & Sugamura, 2010; Rogers, Song, Gramaglia, Killeen, & Croft, 2001). OX40 activation is thus linked to the type 2 inflammatory process that drives itch in conditions like atopic dermatitis. One study showed that OX40 serum levels are decreased in atopic dermatitis, the expression of OX40 by activated skin-homing CD4+ T cells is increased, and OX40+ and OX40L+ cells are co-located within the dermis (Elsner et al., 2020). A phase 2a clinical trial of intravenous GBR 830, a humanized OX40 antibody, in patients with atopic dermatitis showed a −2.7 NRS point reduction from baseline compared to −1.5 in the placebo group at 10 weeks (Guttman-Yassky et al., 2019). While the study was not powered to detect clinical efficacy, the safety profile was shown to be acceptable. A Japanese phase 2a study similarly showed promising results in KHK4083, a monoclonal antibody against OX40 (Nakagawa et al., 2020). Pruritus intensity decreased from baseline by −28% at Week 6 and further decreased by −64% from baseline by Week 22.
OX40 是 T 细胞上的共刺激分子,当被抗原呈递细胞或肥大细胞连接时,加速 T 辅助性 2 (Th2) 效应细胞分化(Gramaglia 等人,2000 年;Ishii,Takahashi,Soroosh和Sugamura,2010;Rogers,Song,Gramaglia,Killeen和Croft,2001)。因此,OX40 激活与 2 型炎症过程有关,该过程在特应性皮炎等疾病中引起瘙痒。一项研究表明,特应性皮炎患者的 OX40 血清水平降低,活化的皮肤归巢 CD4+ T 细胞增加 OX40 的表达,并且 OX40+ 和 OX40L+ 细胞位于真皮内(Elsner 等人,2020 年)。在特应性皮炎患者中静脉注射 GBR 830(一种人源化 OX40 抗体)的 2a 期临床试验显示,在 10 周时,与安慰剂组的 -1.5 相比,NRS 点较基线降低了 -2.7(Guttman-Yassky 等人,2019 年)。虽然该研究没有能力检测临床疗效,但安全性被证明是可以接受的。日本的一项 2a 期研究同样在 KHK4083(一种针对 OX40 的单克隆抗体)中显示出有希望的结果(Nakagawa 等人,2020 年)。在第 6 周时,瘙痒强度较基线下降了 -28%,到第 22 周时,瘙痒强度较基线进一步下降了 -64%。

Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that is a key mediator of the cytokine network. It modulates lymphocytic migration and trafficking through the S1P receptor, which are expressed by T cells, B cells, mast cells, macrophages, dendritic cells, and natural killer cells (Pérez-Jeldres, Alvarez-Lobos, & Rivera-Nieves, 2021). As a sphingolipid, it is also an essential structural component of the epidermis and functions as a signaling molecule to regulate keratinocytes and dendritic cells of the skin (Gray, Limberg, Bräuer, & Raap, 2022; Pérez-Jeldres et al., 2021). Modulation of S1PR has been found to be therapeutic in various immune-mediated diseases, including chronically pruritic conditions such as atopic dermatitis, where serum S1P levels are higher and ceramide and sphingosine in the stratum corneum are altered (Gray et al., 2022). A few clinical trials are currently testing S1P inhibitors in atopic dermatitis. A multicenter, randomized, double-blinded, placebo-controlled phase 2b clinical trial on etrasimod, an oral selective S1P modulator, found the 2 mg dose significantly reduced pruritus by Week 4 in patients with moderate-to-severe atopic dermatitis (NCT04162769; Arena Pharmaceuticals, 2020). Branebrutinib (BMS-986166), another oral selective S1P modulator, is currently undergoing clinical trials for atopic dermatitis as well (NCT05014438).
鞘氨醇-1-磷酸 (S1P) 是一种生物活性脂质代谢物,是细胞因子网络的关键介质。它通过S1P受体调节淋巴细胞迁移和运输,S1P受体由T细胞,B细胞,肥大细胞,巨噬细胞,树突状细胞和自然杀伤细胞表达(Pérez-Jeldres,Alvarez-Lobos和Rivera-Nieves,2021)。作为鞘脂,它也是表皮的重要结构成分,并作为信号分子调节皮肤的角质形成细胞和树突状细胞(Gray,Limberg,Bräuer和Raap,2022;Pérez-Jeldres 等人,2021 年)。已发现 S1PR 的调节可治疗各种免疫介导的疾病,包括慢性瘙痒性疾病,例如特应性皮炎,其中血清 S1P 水平较高,角质层中的神经酰胺和鞘氨醇发生改变(Gray 等人,2022 年)。目前,一些临床试验正在测试S1P抑制剂在特应性皮炎中的应用。一项关于口服选择性 S1P 调节剂 etrasimod 的多中心、随机、双盲、安慰剂对照的 2b 期临床试验发现,到 4 周,2 mg 剂量可显着减轻中度至重度特应性皮炎患者的瘙痒 (NCT04162769;Arena Pharmaceuticals,2020 年)。Branebrutinib (BMS-986166) 是另一种口服选择性 S1P 调节剂,目前正在进行特应性皮炎的临床试验 (NCT05014438)。

Periostin is an extracellular matrix protein produced by fibroblasts and keratinocytes in allergic, inflamed skin. Periostin binds to various integrins on immune and nonimmune cells (i.e., macrophages, basophils, and eosinophils), causing the release of itch mediators and IL-4 and IL-13 cytokines (Hashimoto, Mishra, Olivry, & Yosipovitch, 2021; Izuhara et al., 2019). Periostin also directly activates nerve fibers through the αVβ3 integrin (Mishra et al., 2020). TRPA1, TRPV1, or both are required for periostin-induced itch (Mishra et al., 2020).
骨膜蛋白是一种细胞外基质蛋白,由过敏性发炎皮肤中的成纤维细胞和角质形成细胞产生。骨膜素与免疫和非免疫细胞(即巨噬细胞、嗜碱性粒细胞和嗜酸性粒细胞)上的各种整合素结合,导致瘙痒介质和 IL-4 和 IL-13 细胞因子的释放(Hashimoto、Mishra、Olivry 和 Yosipovitch,2021 年;Izuhara 等人,2019 年)。骨膜素还通过αVβ3整合素直接激活神经纤维(Mishra等人,2020)。TRPA1、TRPV1 或两者都是骨膜蛋白诱导的瘙痒所必需的(Mishra 等人,2020 年)。

Under normal skin conditions, periostin is localized to the papillary dermis below the basement membrane (Jackson-Boeters, Wen, & Hamilton, 2009). Studies have shown deposition of periostin throughout the dermis in Th2 allergic diseases, such as atopic dermatitis (Masuoka et al., 2012; Mineshige et al., 2015), prurigo nodularis (Hashimoto et al., 2021), stasis dermatitis itch (Hashimoto et al., 2020a), and bullous pemphigoid (Hashimoto et al., 2020b). A significant correlation with itch intensity was noted with periostin expression in many of these conditions (Hashimoto, Mishra, et al., 2021). When the periostin-integrin pathway is blocked, chronic inflammation decreases (Masuoka et al., 2012; Mishra et al., 2020). The development of periostin and integrin αVβ inhibitors are thus potential therapeutic options.
在正常的皮肤条件下,骨膜素定位于基底膜下方的状真皮(Jackson-Boeters,温和Hamilton,2009)。研究表明,在Th2过敏性疾病(如特应性皮炎)中,骨膜蛋白在整个真皮层中沉积(Masuoka等人,2012;Mineshige等人,2015),结节性痒疹(Hashimoto等人,2021),淤滞性皮炎瘙痒(Hashimoto等人,2020a)和大疱性类天疱疮(Hashimoto等人,2020b)。在许多这些情况下,骨膜蛋白表达与瘙痒强度显着相关(Hashimoto、Mishra 等人,2021 年)。当骨膜素-整合素途径被阻断时,慢性炎症减少(Masuoka等人,2012;Mishra等人,2020)。因此,骨膜蛋白和整合素αVβ抑制剂的开发是潜在的治疗选择。

4.2. JAK/STAT pathway 4.2. JAK/STAT通路

One way in which cytokines such as IL-4, IL-13, and IL-31 exert their effects is through JAK signaling within sensory neurons (Vazquez et al., 2018). Once these cytokines bind, the intracellular portions of the cytokine receptors dimerize and interact with JAK molecules (Chovatiya & Paller, 2021). The JAK molecules then phosphorylate each other and become active, phosphorylating signal transducers and activators of transcription (STAT) molecules, which translocate to the nucleus to alter gene expression (Chovatiya & Paller, 2021).
IL-4,IL-13和IL-31等细胞因子发挥其作用的一种方式是通过感觉神经元内的JAK信号传导(Vazquez等人,2018)。一旦这些细胞因子结合,细胞因子受体的细胞内部分就会二聚化并与JAK分子相互作用(Chovatiya&Paller,2021)。然后,JAK分子相互磷酸化,成为活性的磷酸化信号转导器和转录激活因子(STAT)分子,它们易位到细胞核以改变基因表达(Chovatiya&Paller,2021)。

Four types of JAKs are known: JAK1, JAK2, JAK3, and tyrosine kinase 2 (Vazquez et al., 2018). Several murine studies have shown the importance of JAK1 in chronic itch. In one study of the imiquimod-induced mouse model of psoriasis, treatment with the JAK inhibitor tofacitinib significantly reduced expression of cytokines IL-22, IL-23, and IL-31 as well as scratching behavior (Hashimoto, Sakai, Sanders, Yosipovitch, & Akiyama, 2019).
已知有四种类型的JAKs:JAK1,JAK2,JAK3和酪氨酸激酶2(Vazquez等人,2018)。几项小鼠研究表明 JAK1 在慢性瘙痒中的重要性。在一项关于咪喹莫特诱导的银屑病小鼠模型的研究中,用JAK抑制剂托法替尼治疗显着降低了细胞因子IL-22,IL-23和IL-31的表达以及抓挠行为(Hashimoto,Sakai,Sanders,Yosipovitch和Akiyama,2019)。

JAK1 and/or JAK2 inhibitors are under extensive investigation for efficacy in chronic itch, especially in atopic dermatitis due to its Th2-predominant pathogenesis (Chovatiya & Paller, 2021). Available medications include ruxolitinib (the first with FDA approval), abrocitinib, upadacitinib, baricitinib, tofacitinib, and delgocitinib. There are topical and oral options. Several have approval outside of the United States and several have FDA-approval for other inflammatory conditions (Ständer, 2021).
JAK1 和/或 JAK2 抑制剂正在广泛研究其对慢性瘙痒的疗效,尤其是特应性皮炎,因为它以 Th2 为主的发病机制(Chovatiya & Paller,2021 年)。可用的药物包括 ruxolitinib(第一个获得 FDA 批准的药物)、abrocitinib、upadacitinib、baricitinib、tofacitinib 和 delgocitinib。有局部和口服选择。一些在美国以外的地方获得批准,一些在FDA批准用于其他炎症性疾病(Ständer,2021)。

Orally taken abrocitinib and upadacitinib, selective JAK1 inhibitors, were recently approved for treatment of moderate-to-severe atopic dermatitis (Perche, Cook, & Feldman, 2022). Numerous clinical trials have reported significant improvement in itch with abrocitinib as compared to placebo (Bieber et al., 2021; Blauvelt et al., 2022; Eichenfield et al., 2021; Gooderham et al., 2019; Reich, 2021; Silverberg et al., 2020; Simpson et al., 2020; Simpson et al., 2021). One study found that 64.3% (200 mg), 52.4% (100 mg), and 34.4% (placebo) of patients taking abrocitinib for 16 weeks had a ≥ 4-point improvement from baseline in Night Time Itch Scale severity (Thyssen et al., 2022). Another study investigating the effects of abrocitinib on itch relief in patients with moderate-to-severe atopic dermatitis pooled data from three clinical trials (one phase 2b and two phase 3 trials) and found that after 12 weeks, 57.3% (200 mg), 42.9% (100 mg), and 16.5% (placebo) of patients achieved a 4-point or greater reduction in self-reported itch (Kim et al., 2021). These studies showed abrocitinib and upadacitinib are generally well-tolerated, occasionally causing nausea and acne. Besides prednisone, abrocitinib and upadacitinib are the only oral FDA-approved treatments for AD, as the other available biologics (i.e., dupilumab) are injections.
口服 abrocitinib 和 upadacitinib 是选择性的 JAK1 抑制剂,最近被批准用于治疗中度至重度特应性皮炎(Perche、Cook 和 Feldman,2022 年)。许多临床试验报告说,与安慰剂相比,阿布罗替尼可显着改善瘙痒(Bieber 等人,2021 年;Blauvelt 等人,2022 年;Eichenfield 等人,2021 年;Gooderham 等人,2019 年;帝国,2021 年;Silverberg 等人,2020 年;Simpson等人,2020;辛普森等人,2021 年)。一项研究发现,服用阿布罗替尼 16 周的患者中有 64.3%(200 毫克)、52.4%(100 毫克)和 34.4%(安慰剂)的夜间瘙痒量表严重程度较基线≥ 4 分改善(Thyssen 等人,2022 年)。另一项研究调查了阿布罗替尼对中度至重度特应性皮炎患者瘙痒缓解的影响,汇总了三项临床试验(一项 2b 期和两项 3 期试验)的数据,发现 12 周后,57.3%(200 毫克)、42.9%(100 毫克)和 16.5%(安慰剂)的患者自我报告的瘙痒减少了 4 分或更多(Kim 等人, 2021). 这些研究表明,阿布罗替尼和乌帕替尼通常耐受性良好,偶尔会引起恶心和痤疮。除泼尼松外,阿布罗替尼和乌帕替尼是唯一经 FDA 批准的口服 AD 治疗方法,因为其他可用的生物制剂(即度普利尤单抗)是注射剂。

4.3. Aryl hydrocarbon receptor
4.3. 芳烃受体

The aryl hydrocarbon receptor (AhR) is a transcription factor which binds to exogenous and endogenous chemicals and modifies gene expression (Kim et al., 2022). It is highly expressed in all skin cell types, and its signaling is important for skin barrier maintenance, melanogenesis, and modulating host-environment interactions and inflammatory responses (Furue, Takahara, Nakahara, & Uchi, 2014; Tauchi et al., 2005). AhR signaling has both beneficial and harmful effects, leading to investigation of both agonists and antagonists. Interest in the role of AhR in psoriasis and atopic dermatitis arose with the finding that exogenous AhR ligands related to air pollution and cigarette smoking exacerbate these two chronic inflammatory skin diseases (Fadadu et al., 2021; Hidaka et al., 2017). Tapinarof is a new topical AhR agonist which has been shown to reduce the expression of pro-inflammatory cytokines in human skin (Smith et al., 2017). According to several clinical trials, tapinarof is beneficial for treating pruritus in patients with psoriasis (Lebwohl et al., 2021) and atopic dermatitis (Paller et al., 2021; Peppers et al., 2019): a phase 3 trial showed significantly reduced itch by at least four points on a 0 to 10 scale in psoriatic patients (Lebwohl et al., 2021). Tapinarof has a good safety profile and was approved by the FDA for plaque psoriasis.
芳烃受体(AhR)是一种转录因子,可与外源性和内源性化学物质结合并修饰基因表达(Kim等人,2022)。它在所有皮肤细胞类型中都高度表达,其信号传导对于皮肤屏障维持、黑色素生成和调节宿主与环境相互作用和炎症反应很重要(Furue,Takahara,Nakahara和Uchi,2014;Tauchi 等人,2005 年)。AhR 信号转导具有有益和有害作用,导致对激动剂和拮抗剂的研究。随着发现与空气污染和吸烟相关的外源性 AhR 配体加剧这两种慢性炎症性皮肤病,人们对 AhR 在牛皮癣和特应性皮炎中的作用产生了兴趣(Fadadu 等人,2021 年;Hidaka 等人,2017 年)。Tapinarof是一种新的局部AhR激动剂,已被证明可以减少人类皮肤中促炎细胞因子的表达(Smith等人,2017)。根据几项临床试验,tapinarof 有益于治疗牛皮癣(Lebwohl 等人,2021 年)和特应性皮炎(Paller 等人,2021 年;Peppers 等人,2019 年):一项 3 期试验显示,银屑病患者的瘙痒在 0 到 10 分的范围内显着降低了至少 4 分(Lebwohl 等人,2021 年)。Tapinarof 具有良好的安全性,并被 FDA 批准用于斑块状银屑病。

4.4. Phosphodiesterase 4 (PDE4)
4.4. 磷酸二酯酶4(PDE4)

PDE4 catalyzes the metabolism of cyclic adenosine 3′,5′-monophosphate (cAMP), resulting in enhanced production of proinflammatory cytokines and chemokines. Elevated cAMP levels, by inhibiting PDE4 or be utilizing a cAMP elevator, may reduce inflammation and itch in various disorders including atopic dermatitis (Yosipovitch et al., 2018; Zebda and Paller, 2018). An in vitro study of C-fiber neurons demonstrated that phosphodiesterase-4 inhibitor E6005 caused elevated intracellular levels of cAMP, which significantly decreased capsaicin-evoked (TRPV1-mediated) depolarization (Wakita, Ohkuro, Ishii, Hishinuma, & Shirato, 2015).
PDE4 催化环腺苷 3′,5′-单磷酸 (cAMP) 的代谢,从而增强促炎细胞因子和趋化因子的产生。通过抑制 PDE4 或利用 cAMP 升降机升高 cAMP 水平可以减少包括特应性皮炎在内的各种疾病的炎症和瘙痒(Yosipovitch 等人,2018 年;Zebda 和 Paller,2018 年)。C纤维神经元的体外研究表明,磷酸二酯酶-4抑制剂E6005导致细胞内cAMP水平升高,从而显着降低辣椒素诱发(TRPV1介导的)去极化(Wakita,Ohkuro,Ishii,Hishinuma和Shirato,2015)。

Topical PDE4 inhibitor crisaborole demonstrated significant and rapid antipruritic effect in atopic dermatitis, showing early improvement in 57% of patients using it versus 40% of patients using a vehicle (Yosipovitch et al., 2018). Difamilast (OPA-15406), currently used in Japan for the treatment of atopic dermatitis, has also improved patient-reported pruritis scores over the course of four weeks (Saeki, Baba, Ito, Yokota, & Tsubouchi, 2022; Saeki, Baba, Oshiden, Abe, & Tsubouchi, 2020). Roflumilast cream was recently FDA-approved for psoriasis as it rapidly and effectively reduced itch severity in plaque psoriasis, providing improvement after two weeks with a reduction in worse itch of −4 on a 10-point scale at Week 8 (Gold et al., 2021; Gooderham et al., 2021). In seborrheic dermatitis, a phase 2 trial showed that among patients with baseline Worst Itch Numeric Rating Scale score ≥ 4 (n = 184), statistically significant 4-point reduction was achieved after two weeks with roflumilast foam compared with vehicle (∼30% versus ∼15%, respectively; P ≤ .0007; Zirwas et al., 2022). Several ongoing clinical trials are investigating its effectiveness in atopic dermatitis.
局部PDE4抑制剂crisaborole在特应性皮炎中显示出显着和快速的止痒作用,使用该药的患者中有57%的患者表现出早期改善,而使用载体的患者为40%(Yosipovitch等人,2018)。目前在日本用于治疗特应性皮炎的 Difamilast (OPA-15406) 在 4 周内也改善了患者报告的瘙痒评分(Saeki、Baba、Ito、Yokota 和 Tsubouchi,2022 年;Saeki,Baba,Oshiden,Abe和Tsubouchi,2020)。罗氟司特乳膏最近被 FDA 批准用于治疗牛皮癣,因为它可以快速有效地降低斑块状银屑病的瘙痒严重程度,两周后有所改善,在第 8 周时以 10 分制将更严重的瘙痒减少 -4(Gold 等人,2021 年;Gooderham 等人,2021 年)。在脂溢性皮炎中,一项 2 期试验显示,在基线最严重瘙痒数字评定量表评分≥ 4 (n = 184) 的患者中,与载体相比,罗氟司特泡沫在两周后实现了统计学显着的 4 分降低(分别为 ∼30% 和 ∼15%;P ≤ .0007;Zirwas 等人,2022 年)。几项正在进行的临床试验正在研究其对特应性皮炎的有效性。

As for oral medications, apremilast is a PDE4 inhibitor that is currently FDA-approved for the treatment of psoriasis and psoriatic arthritis (Schafer, 2012). It showed antipruritic effect in psoriatic itch (Sobell et al., 2016), but did not demonstrate effect in atopic dermatitis (Simpson et al., 2019) and in chronic idiopathic itch (Clark, Wang, Bodet, & Kim, 2020).
至于口服药物,阿普司特是一种PDE4抑制剂,目前已被FDA批准用于治疗牛皮癣和牛皮癣关节炎(Schafer,2012)。它在银屑病瘙痒中显示出止痒作用(Sobell等人,2016),但在特应性皮炎(Simpson等人,2019)和慢性特发性瘙痒(Clark,Wang,Bodet和Kim,2020)中没有显示出效果。

4.5. Histamine 4 receptor
4.5. 组胺4受体

JNJ-39758979 is a potent and selective H4R antagonist that prevents the binding of histamine and activation of TRPV1 (Kollmeier et al., 2014; Shim et al., 2007). A randomized clinical trial found that JNJ-39758979 was effective in reducing histamine-induced pruritus at two hours and six hours after administration compared to placebo, and at six hours compared to cetirizine (Kollmeier et al., 2014). A phase 2a randomized, double-blinded trial analyzed JNJ-39758979 in the treatment of Japanese adults with moderate atopic dermatitis did not meet its primary end point (Murata et al., 2015). The study was discontinued due to drug-induced agranulocytosis in two patients. Other adverse effects reported were nausea and headache (Kollmeier et al., 2014).
JNJ-39758979 是一种有效和选择性的 H4R 拮抗剂,可防止组胺结合和 TRPV1 的激活(Kollmeier 等人,2014 年;Shim等人,2007)。一项随机临床试验发现,与安慰剂相比,JNJ-39758979 在给药后 2 小时和 6 小时以及西替利嗪 6 小时可有效减少组胺诱导的瘙痒(Kollmeier 等人,2014 年)。一项 2a 期随机、双盲试验分析了 JNJ-39758979 治疗患有中度特应性皮炎的日本成年人,但未达到其主要终点(Murata 等人,2015 年)。由于两名患者的药物诱导粒细胞缺乏症,该研究被终止。报告的其他不良反应是恶心和头痛(Kollmeier等人,2014)。

4.6. Mast cells 4.6. 肥大单元

Mast cells (MCs) are known propagators of pruritus and are upregulated in the skin of patients with CSU and prurigo nodularis. Recent efforts have been made to target MCs in the skin (Labib, Ju, Vander Does, & Yosipovitch, 2022; Maurer et al., 2021). CDX-0159 is a novel humanized monoclonal antibody that inhibits tyrosine kinase KIT receptors, which are utilized by MCs (Alvarado et al., 2022). Although data in patients with prurigo nodularis and CSU is limited, CDX-0159 administration in healthy volunteers was found to cause durable and profound MC suppression (Alvarado et al., 2022). A phase 2 randomized, double-blind, placebo-controlled study for the use of this drug in patients with CSU is currently underway (NCT05368285). Similarly, there is currently one ongoing clinical trial for the use of CDX-1059 in patients with prurigo nodularis (NCT04944862).
肥大细胞 (MC) 是已知的瘙痒增殖体,在 CSU 和结节性瘙痒症患者的皮肤中上调。最近已经努力针对皮肤中的 MC(Labib、Ju、Vander Does和 Yosipovitch,2022 年;Maurer 等人,2021 年)。CDX-0159是一种新型人源化单克隆抗体,可抑制MC利用的酪氨酸激酶KIT受体(Alvarado等人,2022)。尽管结节性痒疹和 CSU 患者的数据有限,但发现在健康志愿者中给药 CDX-0159 会导致持久和深刻的 MC 抑制(Alvarado 等人,2022 年)。目前正在进行一项针对在 CSU 患者中使用该药物的 2 期随机、双盲、安慰剂对照研究 (NCT05368285)。同样,目前有一项正在进行的 CDX-1059 用于结节性痒疹 (NCT04944862) 患者的临床试验。

5. Neural targets 5. 神经靶点

5.1. Protease-activated receptors (PAR)
5.1. 蛋白酶激活受体(PAR)

PAR-2 and PAR-4 are GPCR receptors found in sensory nerve fibers and keratinocytes (Zhao et al., 2020). Multiple pruritogens have been identified which induce itch via PAR-2 and PAR-4 including plant cowhage (which contains mucunian, a serine protease), tryptase, kallikreins, cathepsin S, trypsin, and dust mite proteases (Akiyama, Lerner, & Carstens, 2015). In times of inflammation in which proteases activate PAR-2, downstream signaling within the keratinocyte accelerates the release of IL-8, which recruits neutrophils to the inflammatory lesions.
PAR-2 和 PAR-4 是在感觉神经纤维和角质形成细胞中发现的 GPCR 受体(Zhao 等人,2020 年)。已经鉴定出多种通过PAR-2和PAR-4诱导瘙痒的瘙痒原,包括植物cowhage(含有粘蛋白酶,一种丝氨酸蛋白酶),类胰蛋白酶,激肽释放酶,组织蛋白酶S,胰蛋白酶和尘螨蛋白酶(Akiyama,Lerner和Carstens,2015)。在蛋白酶激活 PAR-2 的炎症时期,角质形成细胞内的下游信号加速 IL-8 的释放,IL-8 将中性粒细胞募集到炎症病变中。

There are currently no FDA-approved PAR2 inhibitors used for the treatment of dermatologic conditions (Rothmeier & Ruf, 2012). Currently one study testing the efficacy of a PAR2 antagonist for a condition causing chronic pruritus has been published (Cao, Tan, Kim, & Tey, 2017). In this randomized, double-blind, placebo-controlled trial, a selective PAR-2 inhibitor, methylbenzylmethylbenzimidazolepiperidinylmethanone (MMP), was tested in 16 healthy control patients and was shown to reduce itch intensity (Cao et al., 2017). Although this drug needs to be tested in patients with pruritic conditions, the results of this study demonstrate that PAR2 inhibitors hold therapeutic potential as an adjunctive treatment for patients with chronic pruritis.
目前没有FDA批准的PAR2抑制剂用于治疗皮肤病(Rothmeier&Ruf,2012)。目前,一项测试PAR2拮抗剂对引起慢性瘙痒的疾病的疗效的研究已经发表(Cao,Tan,Kim和Tey,2017)。在这项随机、双盲、安慰剂对照试验中,在 16 名健康对照患者中测试了一种选择性 PAR-2 抑制剂甲基苄基甲基苯并咪唑哌啶甲酮 (MMP),并被证明可以降低瘙痒强度(Cao 等人,2017 年)。虽然这种药物需要在瘙痒症患者中进行测试,但本研究的结果表明,PAR2抑制剂作为慢性瘙痒炎患者的辅助治疗具有治疗潜力。

Additional options include antimicrobials. Tetracyclines have anti-inflammatory properties useful for the treatment of inflammatory skin disorders. Doxycycline's and minocycline's antipruritic mechanisms are likely due to their attenuation of the PAR-2 interleukin-8 pathway (Cao, Tan, Chan, Yosipovitch, & Tey, 2018; Ishikawa, Tsuda, Konishi, Nakagawa, & Yamanishi, 2009). Doxycycline has been shown to reduce itch associated with acne vulgaris when taking a daily dose of 100 mg for six weeks. This finding was significant even after adjusting for improvement in acne, and no adverse events were reported (Cao et al., 2018). A current cross-sectional survey (NCT03968562) is analyzing the efficacy of topical doxycycline 2% emollient cream on immediate hypersensitivity allergy skin test responses, pruritus, and associated late-phase skin swelling. An interventional clinical trial (GINA3) on topical minocycline for the suppression of cutaneous allergic responses and pruritus with 0–3% minocycline cream formulations (NCT04202263) is currently underway.
其他选择包括抗菌药物。四环素类药物具有抗炎特性,可用于治疗炎症性皮肤病。多西环素和米诺环素的止痒机制可能是由于它们减弱了PAR-2白细胞介素-8通路(Cao,Tan,Chan,Yosipovitch和Tey,2018;Ishikawa,Tsuda,Konishi,Nakagawa和Yamanishi,2009)。多西环素已被证明可以减少与寻常痤疮相关的瘙痒,当每天服用 100 毫克时,持续六周。即使在调整痤疮改善后,这一发现也很重要,并且没有不良事件报告(Cao等人,2018)。当前的一项横断面调查 (NCT03968562) 正在分析外用多西环素 2% 润肤霜对速发型超敏反应过敏皮肤试验反应、瘙痒和相关晚期皮肤肿胀的疗效。目前正在进行一项关于局部米诺环素抑制皮肤过敏反应和瘙痒的 0-3% 米诺环素乳膏制剂 (NCT04202263) 的介入性临床试验 (GINA3)。

5.2. TRPV1

TRPV1 is involved in both acute and chronic itch. In acute itch, TRPV1 co-stimulation is necessary for propagation of H1R signaling (Shim et al., 2007). In murine models, histamine lessened scratching behavior in mice lacking TRPV1 or treated with a TRPV1 blocker. Because TRPV1 is stimulated by the metabolic products of lipoxygenases (LO), it's proposed that H1R activity leads to activation of the phospholipase system, producing substances such as phospholipase A2 (PLA2) and 12-hydroxyeicosatetraenoic acid that then trigger TRPV1 and subsequent Ca2+ influxes. A more recent study utilizing scratching assay in mice in vivo and Ca2+ imaging of murine sensory dorsal root ganglia neurons in vitro showed inhibiting TRPV1 reduced both H1R- and H4R-mediated pruritus (Wilzopolski et al., 2021).
TRPV1 与急性和慢性瘙痒有关。在急性瘙痒中,TRPV1共刺激对于H1R信号的传播是必要的(Shim等人,2007)。在小鼠模型中,组胺减轻了缺乏TRPV1或用TRPV1阻滞剂治疗的小鼠的抓挠行为。由于 TRPV1 受到脂氧合酶 (LO) 代谢产物的刺激,因此提出 H1R 活性导致磷脂酶系统的激活,产生磷脂酶 A2 (PLA2) 和 12-羟基二十碳四烯酸等物质,然后触发 TRPV1 和随后的 Ca2+ 流入。最近的一项研究利用小鼠体内抓挠测定和体外小鼠感觉背根神经节神经元的 Ca2+ 成像显示,抑制 TRPV1 可减少 H1R 和 H4R 介导的瘙痒(Wilzopolski 等人,2021 年)。

For chronic itch, there are several clinical trials testing TRPV1 antagonists for the treatment of atopic dermatitis, seborrheic dermatitis, and skin pruritus. One double-blind, vehicle-controlled phase 2b study tested 0.1%, 0.3%, and 1% formulations of asivatrep (PAC-14028), a non-steroidal cream that antagonizes TRPV1, in atopic dermatitis and found that all formulations of this agent improved pruritis without significant adverse effects (Lee et al., 2019). Another double-blind, vehicle-controlled phase 3 trial showed that at the end of eight weeks, atopic dermatitis patients using 1% asivatrep had significantly improved pruritus (mean visual analog scale score decrease of 2.3 on a 10-point scale) as compared to those in the vehicle group (decrease of 1.5; Park et al., 2022).
对于慢性瘙痒,有几项临床试验测试TRPV1拮抗剂用于治疗特应性皮炎、脂溢性皮炎和皮肤瘙痒。一项双盲、载体对照的 2b 期研究测试了 0.1%、0.3% 和 1% 的 asivatrep 制剂 (PAC-14028),这是一种拮抗 TRPV1 的非甾体乳膏,治疗特应性皮炎,发现该药物的所有制剂都改善了瘙痒,没有明显的不良反应(Lee 等人,2019 年)。另一项双盲、车辆对照的 3 期试验显示,在 8 周结束时,与车辆组相比,使用 1% asivatrep 的特应性皮炎患者明显改善了瘙痒(10 分制的平均视觉模拟量表评分降低 2.3 分)(减少 1.5 分;Park 等人,2022 年)。

5.3. TRPV3 5.3. TRPV3的

PAR-2 activates TRPV3, a warm temperature sensitive channel abundantly expressed in keratinocytes, and has a role in itch associated with skin barrier damage (Zhao et al., 2020). TRPV3 and PAR-2 are upregulated in atopic dermatitis (Briot et al., 2009; Larkin et al., 2021; Steinhoff et al., 2003) and gain-of-function mutations are implicated in Olmsted syndrome, a condition causing severe pruritus (Lin et al., 2012). Inhibition results in reduced inflammation and itch attenuation (Han et al., 2021; Zhao et al., 2020). Activation of TRPV3 coupled with PAR-2 leads to the release of several cytokines and chemokines, such as thymic stromal lymphopoietin, a cytokine also associated with epithelial dysfunction in itch (Seo, Kim, Kim, Chung, & Lee, 2020).
PAR-2 激活 TRPV3,这是一种在角质形成细胞中大量表达的温暖温度敏感通道,并在与皮肤屏障损伤相关的瘙痒中发挥作用(Zhao 等人,2020 年)。TRPV3 和 PAR-2 在特应性皮炎中上调(Briot 等人,2009 年;Larkin等人,2021;Steinhoff等人,2003)和功能获得性突变与奥姆斯特德综合征有关,奥姆斯特德综合征是一种导致严重瘙痒的疾病(Lin等人,2012)。抑制导致炎症减少和瘙痒减弱(Han 等人,2021 年;Zhao 等人,2020 年)。TRPV3 与 PAR-2 偶联的激活导致几种细胞因子和趋化因子的释放,例如胸腺基质淋巴细胞生成素,一种细胞因子也与瘙痒的上皮功能障碍有关(Seo、Kim、Kim、Chung 和 Lee,2020 年)。

There has been an increasing interest in developing therapeutic agents that antagonize TRPV3 (Cui, Wang, Wei, & Wang, 2018). Currently, TRPV3 antagonists are being clinically tested for lichen simplex chronicus, a localized itchy dermatosis (NCT0545454462).
人们对开发拮抗TRPV3的治疗药物越来越感兴趣(Cui,Wang,Wei和Wang,2018)。目前,TRPV3 拮抗剂正在接受慢性单纯性苔藓(一种局部瘙痒性皮肤病 (NCT0545454462))的临床测试。

5.4. TRPA1

As described earlier, TRPA1 is a downstream mediator to various GPCR signaling cascades involved in both acute (histaminergic) and chronic (histamine-independent) itch. Known modulators of TRPA1 include the TSLP receptor, the bile acid receptor TGR5, and the MRGPRs (Xie and Hu, 2018).
如前所述,TRPA1 是参与急性(组胺能)和慢性(组胺依赖性)瘙痒的各种 GPCR 信号级联的下游介质。TRPA1的已知调节剂包括TSLP受体,胆汁酸受体TGR5和MRGPR(Xie和胡,2018)。

In atopic dermatitis, TRPA1 was shown to be coupled with the thymic stromal lymphopoietin (TSLP) receptor. Thymic stromal lymphopoietin overexpression in keratinocytes invokes vigorous scratching and an AD-like skin phenotype in murine models (note that TSLP overexpression can be induced by PAR2; Li et al., 2005). When TSLP was injected into murine skin, subsequent itch was attenuated with functional ablation of TRPA1 (Wilson et al., 2013).
在特应性皮炎中,TRPA1 被证明与胸腺基质淋巴细胞生成素 (TSLP) 受体偶联。胸腺基质淋巴细胞在角质形成细胞中的过表达在小鼠模型中引起剧烈的抓挠和 AD 样皮肤表型(请注意,TSLP 过表达可由 PAR2 诱导;Li 等人,2005 年)。当将TSLP注射到小鼠皮肤中时,随后的瘙痒通过TRPA1的功能性消融减轻(Wilson等人,2013)。

Another study of both TRPV1 and TRPA1 antagonists showed that inhibiting TRPA1 reduced H4R- but not H1R-induced itch (Wilzopolski et al., 2021). Additionally, TRPA1 on sensory neurons can be stimulated by miRNA-711, inducing itch in mice (Han et al., 2018). A blocking peptide that disrupts TRPA1/miRNA-711 interaction decreased lymphoma-associated itch (Han et al., 2018). TRPA1 inhibitors have not yet investigated for their effects in human pruritus.
另一项对 TRPV1 和 TRPA1 拮抗剂的研究表明,抑制 TRPA1 可减少 H4R- 但不能减少 H1R 引起的瘙痒(Wilzopolski 等人,2021 年)。此外,感觉神经元上的TRPA1可以被miRNA-711刺激,诱导小鼠瘙痒(Han等人,2018)。破坏TRPA1 / miRNA-711相互作用的阻断肽可减少淋巴瘤相关瘙痒(Han等人,2018)。TRPA1抑制剂尚未研究其对人类瘙痒症的影响。

5.5. TRPV4

Detected in skin cells and sensory neurons of dorsal root ganglion and trigeminal ganglion, TRPV4 has emerged as a contributor to dry skin-, histamine-, and 5-hydroxtryptamine-mediated (non-histaminergic) itch in mouse models (Zhang et al., 2022). Human skin biopsies have indicated that TRPV4 is upregulated in chronic idiopathic pruritus (Luo et al., 2018). Studies of TRPV4 antagonists in humans have been limited to congestive heart failure (Goyal et al., 2019) and chronic cough (NCT03372603).
在背根神经节和三叉神经节的皮肤细胞和感觉神经元中检测到,TRPV4 已成为小鼠模型中皮肤干燥、组胺和 5-羟色胺介导(非组胺能)瘙痒的原因(Zhang 等人,2022 年)。人体皮肤活检表明,TRPV4在慢性特发性瘙痒中上调(Luo等人,2018)。对人类TRPV4拮抗剂的研究仅限于充血性心力衰竭(Goyal等人,2019)和慢性咳嗽(NCT03372603)。

5.6. Mas-related G protein coupled receptors
5.6. Mas相关G蛋白偶联受体

Mas-related G protein coupled receptors (MRGPR) include a family of four receptors (MRGPRX1–4). MRGPRX2 and MRGPRX4 are more recently discovered mediators implicated in itch (Cao et al., 2021; Green, Limjunyawong, Gour, Pundir, & Dong, 2019; McNeil et al., 2015; Meixiong, Vasavda, Snyder, & Dong, 2019; Yu et al., 2019).
Mas 相关 G 蛋白偶联受体 (MRGPR) 包括一个由 4 个受体组成的家族 (MRGPRX1–4)。MRGPRX2 和 MRGPRX4 是最近发现的与瘙痒有关的介质(Cao 等人,2021 年;Green,Limjunyawong,Gour,Pundir和Dong,2019;McNeil 等人,2015 年;Meixiong,Vasavda,Snyder和Dong,2019;Yu 等人,2019 年)。

MRGPRX2 is expressed predominantly on mast cells, leading to degranulation independent of IgE (Kashem et al., 2011; Lansu et al., 2017). Studies have shown that the substances released by the mast cells through this IgE-independent pathway are unique compared to the IgE-FcεRI pathway (Meixiong et al., 2019). MRGPRX2-mediated mast cell degranulation consists of more tryptase, less histamine, and less serotonin and excitation of a distinct itch-sensory neuron population. Since its discovery, many medications (fluoroquinolones, neuromuscular blocking drugs, antidepressants, antiallergic drugs, antipsychotics) and endogenous substances (substance P, proadrenomedullin peptide, hemokinin-1) have been shown to activate this receptor (Green et al., 2019; Manorak et al., 2018; McNeil et al., 2015; Wolf et al., 2021).
MRGPRX2主要在肥大细胞上表达,导致独立于IgE的脱颗粒(Kashem等人,2011;Lansu 等人,2017 年)。研究表明,与IgE-FcεRI途径相比,肥大细胞通过这种IgE非依赖性途径释放的物质是独一无二的(Meixiong等人,2019)。MRGPRX2介导的肥大细胞脱颗粒包括更多的类胰蛋白酶、更少的组胺和更少的血清素,以及独特的瘙痒感觉神经元群的激发。自发现以来,许多药物(氟喹诺酮类药物、神经肌肉阻滞药物、抗抑郁药、抗过敏药、抗精神病药)和内源性物质(P物质、肾上腺髓质素肽、血激肽-1)已被证明可以激活这种受体(Green等人,2019;Manorak 等人,2018 年;McNeil 等人,2015 年;Wolf 等人,2021 年)。

MRGPRX2 (and its mouse homolog, MRGPRB2) has been implicated in a variety of pathogenic conditions include allergic contact dermatitis, chronic spontaneous urticaria, atopic dermatitis, and asthma (Meixiong, Anderson, Limjunyawong, et al., 2019; Nattkemper et al., 2018; Serhan et al., 2019; Thapaliya, Chompunud Na Ayudhya, Amponnawarat, Roy, & Ali, 2021). In murine models of allergic contact dermatitis, itch was reduced in the Mrgprb2- deficient condition (Meixiong, Anderson, Limjunyawong, et al., 2019). A.
MRGPRX2(及其小鼠同源物 MRGPRB2)与多种致病性疾病有关,包括过敏性接触性皮炎、慢性自发性荨麻疹、特应性皮炎和哮喘(Meixiong、Anderson、Limjunyawong 等人,2019 年;Nattkemper 等人,2018 年;Serhan 等人,2019 年;Thapaliya、Chompunud Na Ayudhya、Amponnawarat、Roy 和 Ali,2021 年)。在过敏性接触性皮炎的小鼠模型中,在 Mrgprb2 缺乏的情况下瘙痒减轻(Meixiong、Anderson、Limjunyawong 等人,2019 年)。一个。

MRGPRX4 mediates cholestatic itch through binding its known agonists, bile acids (Cao et al., 2021; Yu et al., 2019) and bilirubin (Meixiong et al., 2019). When bile flow is interrupted in cholestatic disease, these two constituents diffuse into the serum and can accumulate in the skin. Yu et al. showed that these elevated levels of bile acids activate the MRGPRX4 receptor expressed in human dorsal root ganglion neurons (Yu et al., 2019). MRGPRX4 co-expresses with histamine itch receptor HRH1, leading to neuronal activation and transmission of pruritus signaling.
MRGPRX4通过结合其已知的激动剂胆汁酸介导胆汁淤积性瘙痒(Cao等人,2021;Yu等人,2019)和胆红素(Meixiong等人,2019)。当胆汁淤积性疾病中的胆汁流动中断时,这两种成分会扩散到血清中并积聚在皮肤中。Yu等人表明,这些升高的胆汁酸水平激活了在人类背根神经节神经元中表达的MRGPRX4受体(Yu等人,2019)。MRGPRX4 与组胺瘙痒受体 HRH1 共表达,导致神经元激活和瘙痒信号的传递。

Research supports that a high-affinity MRGPRX2 antagonist may be useful for nonhistaminergic itch, type 2 inflammatory conditions, and neurogenic inflammation (Ogasawara & Noguchi, 2021). The first in human clinical trial of EP547, a MRGPRX4 receptor antagonist, was designed for patients with cholestatic and uremic pruritus, though it is currently on hold (NCT04510090).
研究支持高亲和力MRGPRX2拮抗剂可能对非组胺能性瘙痒、2型炎症和神经源性炎症有用(Ogasawara&Noguchi,2021)。EP547(一种MRGPRX4受体拮抗剂)的人体临床试验首次设计用于胆汁淤积和尿毒症瘙痒症患者,但目前处于搁置状态(NCT04510090)。

6. Important new clinical targets: Drugs targeting neural sensitization
6、重要的新临床靶点:靶向神经致敏的药物

6.1. Neurokinin 1/Substance P
6.1. 神经激肽 1/P 物质

Substance P (SP) is a neuropeptide that acts in the central and peripheral nervous system and with its receptor, neurokinin-1 (NK-1), has been shown to be highly expressed in many chronic itch conditions (Ständer & Yosipovitch, 2019). Within the skin, SP is produced and secreted by nerve fibers, creating local neurogenic inflammation (Perner et al., 2020). SP release can be stimulated by proteases including tryptase, kallikreins, and trypsins (Steinhoff et al., 2000). SP binds to neurokinin receptors (NKRs), which are GPCRs (Azimi et al., 2017; Gherardini et al., 2020; McNeil & Dong, 2014; Steinhoff, Buddenkotte, & Lerner, 2018; Suvas, 2017). NK1R is expressed in several cells found in the skin including keratinocytes, endothelial cells, mast cells, and fibroblasts, as well as the sensory nerve endings themselves (Liu, Hu, Zhu, Li, & Sun, 2006; Scholzen et al., 1998; Scholzen et al., 2001; Ständer & Yosipovitch, 2019; Suvas, 2017). When SP binds to NK1R, downstream signaling leads to mast cell degranulation and release of proinflammatory pruritogens including histamine, leukotriene B4, interferon-γ, vascular endothelial growth factor, interleukins, tumor necrosis factor alpha, and nerve growth factor (Burbach et al., 2001; Columbo, Horowitz, Kagey-Sobotka, & Lichtenstein, 1996; Dallos et al., 2006; Shi, Wang, Clark, & Kingery, 2013).
P物质(SP)是一种作用于中枢和周围神经系统的神经肽,其受体神经激肽-1(NK-1)已被证明在许多慢性瘙痒疾病中高度表达(Ständer&Yosipovitch,2019)。在皮肤内,SP 由神经纤维产生和分泌,产生局部神经源性炎症(Perner 等人,2020 年)。SP的释放可以由蛋白酶刺激,包括类胰蛋白酶,激肽释放酶和胰蛋白酶(Steinhoff等人,2000)。SP与神经激肽受体(NKR)结合,神经激肽受体是GPCR(Azimi等人,2017;Gherardini 等人,2020 年;McNeil & Dong,2014 年;Steinhoff,Buddenkotte和Lerner,2018;苏瓦斯,2017 年)。NK1R在皮肤中发现的几种细胞中表达,包括角质形成细胞,内皮细胞,肥大细胞和成纤维细胞,以及感觉神经末梢本身(Liu,胡,Zhu,Li和Sun,2006;Scholzen 等人,1998 年;Scholzen 等人,2001 年;Ständer & Yosipovitch,2019 年;苏瓦斯,2017 年)。当SP与NK1R结合时,下游信号转导导致肥大细胞脱颗粒和促炎性瘙痒原的释放,包括组胺,白三烯B4,干扰素-γ,血管内皮生长因子,白细胞素,肿瘤坏死因子α和神经生长因子(Burbach等人,2001;Columbo,Horowitz,Kagey-Sobotka和Lichtenstein,1996;Dallos 等人,2006 年;Shi,Wang,Clark和Kingery,2013)。

NK1R is upregulated in chronic prurigo/prurigo nodularis (Ohanyan et al., 2018; Zeidler & Ständer, 2016), plaque psoriasis (Amatya, El-Nour, Holst, Theodorsson, & Nordlind, 2011; Nattkemper et al., 2018), atopic dermatitis (Zhang et al., 2017), bullous pemphigoid itch (Hashimoto et al., 2020b), and chronic itch of unknown origin in primates (Nattkemper et al., 2018; Nattkemper, Fourzali, & Yosipovitch, 2021). In both plaque psoriasis and bullous pemphigoid, the degree of NK1R expression is correlated with pruritus intensity (Amatya et al., 2011; Nattkemper et al., 2021). Additionally, the levels of serum SP are increased in chronic spontaneous urticaria (Metz et al., 2014).
NK1R在慢性瘙痒症/结节性痒疹中上调(Ohanyan等人,2018;Zeidler&Ständer,2016),斑块状银屑病(Amatya,El-Nour,Holst,Theodorsson和Nordlind,2011;Nattkemper 等人,2018 年)、特应性皮炎(Zhang 等人,2017 年)、大疱性类天疱疮性疱疮(Hashimoto 等人,2020b)和灵长类动物不明原因的慢性瘙痒(Nattkemper 等人,2018 年;Nattkemper、Fourzali 和 Yosipovitch,2021 年)。在斑块状银屑病和大疱性类天疱疮中,NK1R的表达程度与瘙痒强度相关(Amatya等人,2011;Nattkemper 等人,2021 年)。此外,慢性自发性荨麻疹的血清SP水平升高(Metz等人,2014)。

The neurokinin 1 antagonists include aprepitant, tradipitant, and serlopitant. In a randomized, placebo-controlled, split-sided, double-blind trial of aprepitant in chronic prurigo, aprepitant was no better than placebo at reducing the severity of pruritus (Ohanyan et al., 2018).
神经激肽 1 拮抗剂包括阿瑞匹坦、曲替匹坦和锯氨酸。在一项随机、安慰剂对照、分侧、双盲试验中,阿瑞匹坦在降低瘙痒严重程度方面并不优于安慰剂(Ohanyan 等人,2018 年)。

In a phase 2 randomized, double-blind, placebo-controlled study of 168 patients with refractory chronic pruritus associated with atopic dermatitis, the proportion of patients reporting at least a 50% improvement in worst itch and Visual Analog Scale were greater in patients receiving tradipitant (Worst Itch-Visual Analog Scale: tradipitant = 52.6%, placebo = 34.7%)(Welsh et al., 2019). In a phase 3, randomized, placebo-controlled, double-blind clinical trial in 375 patients with atopic dermatitis, tradipitant showed numerical benefit in the tradipitant group over placebo, but did not meet its primary endpoint of reduction in pruritus [Least Squares (LS) Mean difference (95% CI), −0.2 (−0.8 to 0.4)] (Welsh et al., 2021). However, it did show significant improvement in patient-reported worst itch and sleep disturbance in those with mild atopic dermatitis [validated Investigator Global Assessment for Atopic Dermatitis at baseline −1.6 (−2.9 to −0.3)].
在一项针对 168 名与特应性皮炎相关的难治性慢性瘙痒患者的 2 期随机、双盲、安慰剂对照研究中,在接受 tradipitant 的患者中,报告最严重瘙痒和视觉模拟量表至少改善 50% 的患者比例更高(最严重瘙痒-视觉模拟量表:tradipitant = 52.6%,安慰剂 = 34.7%)(Welsh 等人,2019 年)。在一项针对 375 名特应性皮炎患者的 3 期随机、安慰剂对照、双盲临床试验中,tradipitant 组显示出优于安慰剂的数值优势,但未达到其减少瘙痒的主要终点 [最小二乘 (LS) 平均差 (95% CI),-0.2(-0.8 至 0.4)](Welsh 等人,2021 年)。然而,它确实显示轻度特应性皮炎患者报告的最严重的瘙痒和睡眠障碍有显着改善 [基线 -1.6(-2.9 至 -0.3)时经验证的特应性皮炎研究者整体评估]。

As for serlopitant, clinical phase 2 trials have explored treatment in chronic pruritus (Yosipovitch et al., 2018), psoriatic pruritus (Pariser et al., 2020), prurigo nodularis (Ständer et al., 2019), and epidermolysis bullosa (Chiou et al., 2020). A phase 2 randomized, double-blind, 6-week, placebo-controlled trial of serlopitant in 257 patients with chronic pruritus showed statistically significant reductions in visual analog scale pruritus scores from baseline with 1- and 5-mg doses of serlopitant than with placebo at Week 6 (Yosipovitch, Ständer, et al., 2018). The largest difference was seen for the serlopitant 5-mg dose, in which 53% of patients reported a 4-cm decrease in average Visual Analog Scale pruritus score versus 26% of placebo-treated patients. In these trials, serlopitant was well tolerated. However, phase 3 trials in prurigo nodularis (NCT03546816, NCT03677401; Menlo Therapeutics, 2020a) and a phase 2 trial in chronic itch of unknown origin (NCT03841331; Menlo Therapeutics, 2020b) failed to meet end points.
至于舍洛匹坦,临床 2 期试验探索了慢性瘙痒症(Yosipovitch 等人,2018 年)、银屑病性瘙痒症(Pariser 等人,2020 年)、结节性痒疹(Ständer 等人,2019 年)和大疱性表皮松解症(Chiou 等人,2020 年)的治疗。一项针对 257 名慢性瘙痒患者的 2 期随机、双盲、6 周、安慰剂对照试验显示,在第 6 周时,与安慰剂相比,使用 1 毫克和 5 mg 剂量的锯氨酸剂的视觉模拟量表瘙痒评分较基线显着降低(Yosipovitch、Ständer 等人,2018 年)。5mg 剂量的 serlopitant 差异最大,其中 53% 的患者报告平均视觉模拟量表瘙痒评分降低 4 厘米,而安慰剂治疗的患者为 26%。在这些试验中,serlopitant耐受性良好。然而,结节性痒疹 (NCT03546816, NCT03677401;Menlo Therapeutics,2020a)和不明原因慢性瘙痒的2期试验(NCT03841331;Menlo Therapeutics,2020b)未能达到终点。

6.2. Opioid imbalance 6.2. 阿片类药物失衡

Opioid-induced itch is hypothesized to be due to an imbalance of pro-itch μ-opioid receptor activity (MOR) and anti-itch κ-opioid receptor (KOR) activity (Kim et al., 2022; Melo et al., 2018). Thus, opioids that induce KOR activity or inhibit MOR activity can be utilized in non-histaminergic itch.
阿片类药物引起的瘙痒被认为是由于促痒μ-阿片受体活性 (MOR) 和抗痒 κ-阿片受体 (KOR) 活性的不平衡(Kim 等人,2022 年;Melo等人,2018)。因此,诱导KOR活性或抑制MOR活性的阿片类药物可用于非组胺能性瘙痒。

Difelikefalin is a peripherally selective KOR agonist. It has received FDA-approval for chronic kidney disease itch in patients on dialysis. Results from three clinical trials reported significant reduction of itch intensity in patients with chronic kidney disease receiving intravenous difelikefalin when compared to a placebo (Fishbane, Jamal, Munera, Wen, Menzaghi, and KALM-1 Trial Investigators, 2020; Fishbane et al., 2020; Narita et al., 2022).
Difelikefalin 是一种外周选择性 KOR 激动剂。它已获得 FDA 批准用于透析患者的慢性肾病瘙痒。三项临床试验的结果显示,与安慰剂相比,接受静脉注射地非利福林的慢性肾病患者的瘙痒强度显着降低(Fishbane、Jamal、Munera、温、Menzaghi 和 KALM-1 试验研究者,2020 年;Fishbane 等人,2020 年;Narita 等人,2022 年)。

Nalbuphine is an oral KOR agonist with antagonist activity on MOR. Several clinical trials have demonstrated its efficacy as a prophylactic measure against opioid-induced itch in obstetric settings (Davies & From, 1988; Ibrahim, Aly, Thabet, & Abdelaziz, 2019). One clinical trial found significantly reduced itch intensity in chronic kidney disease patients treated with extended release (ER) nalbuphine (Mathur et al., 2017). Nabulphine ER was also found to be efficacious in treating prurigo nodularis. A phase 2 study demonstrated itch reduction among 8/12 (67%) subjects completing Week 10 versus 8/20 (40%) subjects taking placebo; Weisshaar et al., 2022). As for the magnitude of response, 33% treated with 162 mg twice daily achieved ≥50% reduction in worst itch at Week 10. Nalbuphine solution given for pain has a black box warning against concomitant use with benzodiazepines and other central nervous system depressants. The overall safety profile of nalbuphine in itch studies is good with few side effects of drowsiness and dizziness.
Nalbuphine 是一种口服 KOR 激动剂,对 MOR 具有拮抗剂活性。一些临床试验已经证明,在产科环境中,它作为预防阿片类药物引起的瘙痒的措施是有效的(Davies&From,1988;易卜拉欣,Aly,Thabet和Abdelaziz,2019)。一项临床试验发现,接受缓释 (ER) 纳布啡治疗的慢性肾病患者的瘙痒强度显着降低(Mathur 等人,2017 年)。还发现 Nabulphine ER 可有效治疗结节性痒疹。一项 2 期研究表明,8/12 (67%) 受试者完成第 10 周与 8/20 (40%) 受试者服用安慰剂相比,瘙痒减轻;Weisshaar 等人,2022 年)。至于反应的程度,33%的人每天两次接受162毫克治疗,在第10周时最严重的瘙痒减少了≥50%。用于疼痛的纳布啡溶液有一个黑框警告,不要同时使用苯二氮卓类药物和其他中枢神经系统抑制剂。纳布啡在瘙痒研究中的总体安全性良好,嗜睡和头晕的副作用很少。

6.3. Gamma-aminobutyric acid (GABA)
6.3. γ-氨基丁酸(GABA)

GABA agonists have long been used to alleviate itch due to their ability to increase inhibitory signaling, but they have a significant sedative effect sometimes limiting their usefulness. A study of muscimol (a GABA-A receptor agonist) and baclofen (a GABA-B receptor agonist) was conducted in IL-31 overexpressing transgenic mice, simulating atopic dermatitis refractory to antihistamines (Cevikbas et al., 2017). A variety of doses were used to first establish non-sedative doses, followed by determining the therapeutic window for the anti-pruritic effects. Alone, each drug demonstrated a narrow therapeutic window. When combined in subthreshold doses, muscimol and baclofen produced a significant synergistic antipruritic effect in both acute and chronic itch models, without concomitant sedation. Clinical studies are needed to extrapolate these results to human pruritus.
GABA激动剂长期以来一直被用于缓解瘙痒,因为它们能够增加抑制信号传导,但它们具有显着的镇静作用,有时会限制其有用性。在过表达转基因的IL-31小鼠中进行了muscimol(GABA-A受体激动剂)和巴氯芬(GABA-B受体激动剂)的研究,模拟抗组胺药难治性特应性皮炎(Cevikbas等人,2017)。首先使用各种剂量确定非镇静剂量,然后确定抗瘙痒作用的治疗窗口。单独而言,每种药物都显示出狭窄的治疗窗口。当以亚阈值剂量联合使用时,麝香酚和巴氯芬在急性和慢性瘙痒模型中均产生显着的协同止痒作用,而没有伴随镇静作用。需要临床研究将这些结果外推到人类瘙痒症。

6.4. Cannabinoid system 6.4. 大麻素系统

Cannabinoids are a class of active compounds which physiologically mimic the psychotropic extract from the Cannabis sativa plant, thus modulating the endogenous endocannabinoid system (Avila, Massick, Kaffenberger, Kwatra, & Bechtel, 2020). This modulation occurs both in peripheral itch fibers and centrally (Bilir, Anli, Ozkan, Gunduz, & Ulugol, 2018; Clayton, Marshall, Bountra, & O'Shaughnessy, 2002). The various bioactive lipid mediators stimulate G-protein coupled cannabinoid receptors (CB1 and CB2) as well as TRPV1 (Bilir et al., 2018; Garbutcheon-Singh & Smith, 2021; Kim et al., 2015; Odan et al., 2012). Within the skin, these receptors are also expressed on keratinocytes, sebocytes, and hair follicle epithelial cells in addition to nerve fibers (Caterina, 2014).
大麻素是一类活性化合物,在生理上模仿大麻植物的精神药物提取物,从而调节内源性内源性大麻素系统(Avila、Massick、Kaffenberger、Kwatra和Bechtel,2020)。这种调节发生在外周瘙痒纤维和中央(Bilir,Anli,Ozkan,Gunduz和Ulugol,2018;Clayton,Marshall,Bountra和O'Shaughnessy,2002)。各种生物活性脂质介质刺激G蛋白偶联大麻素受体(CB1和CB2)以及TRPV1(Bilir等人,2018;Garbutcheon-Singh & Smith,2021 年;Kim 等人,2015 年;Odan等人,2012)。在皮肤内,除了神经纤维外,这些受体还在角质形成细胞,皮脂细胞和毛囊上皮细胞上表达(Caterina,2014)。

In mouse and rat models, the itch induced by the pruritogens histamine, serotonin, and substance P was attenuated with introduction of CB2 agonists (Haruna et al., 2015). Another mouse model of dry skin-induced chronic itching showed induced expression of IL-13 and IL-31, which were subsequently decreased with application of a cannabinoid agonist (Todurga Seven, Çakır Gündoğdu, Ozyurt, & Özyazgan, 2022). A model of canine atopic dermatitis utilizing a nutraceutical mixture containing flavonoids, stilbene, and cannabinoids showed decreased expression of canine AD Th1/Th2 inflammatory genes (Massimini et al., 2021).
在小鼠和大鼠模型中,由瘙痒原组胺,血清素和P物质引起的瘙痒随着CB2激动剂的引入而减弱(Haruna等人,2015)。另一种干燥皮肤诱发的慢性瘙痒小鼠模型显示IL-13和IL-31的诱导表达,随后随着大麻素激动剂的应用而降低(Todurga Seven,ÇakırGündoğdu,Ozyurt和Özyazgan,2022)。使用含有类黄酮、二苯乙烯和大麻素的营养混合物的犬特应性皮炎模型显示犬 AD Th1/Th2 炎症基因的表达降低(Massimini 等人,2021 年)。

Clinical open label studies have showed promise in the treatment of pruritus induced by dry skin (Visse, Blome, Phan, Augustin, & Ständer, 2017); atopic dermatitis (Maghfour et al., 2021; Pulvirenti, Nasca, & Micali, 2007); asteatotic eczema (Yuan et al., 2014); prurigo, lichen simplex, and pruritus (Ständer, Reinhardt, & Luger, 2006); and uremic pruritus (Szepietowski, Reich, & Szepietowski, 2005). Further controlled studies are needed.
临床开放标签研究显示,在治疗皮肤干燥引起的瘙痒方面很有希望(Visse,Blome,Phan,Augustin和Ständer,2017);特应性皮炎(Maghfour 等人,2021 年;Pulvirenti,Nasca和Micali,2007);脂肪性湿疹(Yuan et al., 2014);瘙痒,单纯苔藓和瘙痒(Ständer,Reinhardt和Luger,2006);和尿毒症性瘙痒(Szepietowski,Reich和Szepietowski,2005)。需要进一步的对照研究。

6.5. P2X3

P2X3 are a subtype of ATP-gated cation channels which have been discovered within cervical dorsal root ganglion neurons and nerve endings in the skin (Shiratori-Hayashi et al., 2019). These channels are stimulated by ATP, which may be released from keratinocytes after mechanical stimulation or from damaged skin tissues (Moehring et al., 2018). Murine studies showed that intradermal injection of ATP or α,β-meATP induced scratching behavior, which was decreased after administration of a P2X3 antagonist (Shiratori-Hayashi et al., 2019). Additionally, a mouse model of atopic dermatitis demonstrated that P2X3R mRNA was increased in the dorsal root ganglion, but not skin and that scratching was attenuated with intradermal P2X3 antagonist without affecting skin inflammation (Shiratori-Hayashi et al., 2019). A phase 2 clinical trial for a P2X3 antagonist in pruritus associated with atopic dermatitis did not show statistical significance in itch reduction (NCT04693195).
P2X3 是 ATP 门控阳离子通道的一种亚型,已在颈椎背根神经节神经元和皮肤神经末梢内发现(Shiratori-Hayashi 等人,2019 年)。这些通道受到ATP的刺激,ATP可能在机械刺激后从角质形成细胞或受损的皮肤组织中释放(Moehring等人,2018)。小鼠研究表明,皮内注射ATP或α,β-meATP诱导抓挠行为,在给予P2X3拮抗剂后减少(Shiratori-Hayashi等人,2019)。此外,特应性皮炎小鼠模型表明,P2X3R mRNA在背根神经节中增加,但皮肤没有增加,并且皮内P2X3拮抗剂减轻了抓挠,而不影响皮肤炎症(Shiratori-Hayashi等人,2019)。一项针对 P2X3 拮抗剂治疗特应性皮炎相关瘙痒的 2 期临床试验在减少瘙痒方面未显示出统计学意义 (NCT04693195)。

6.6. Inhibition via neurotoxin
6.6. 通过神经毒素抑制

Botulinum toxin type A is emerging as a therapy for neuropathic pruritus. It is believed to act through inhibition of the pruritogens substance P, acetylcholine, and glutamate. In a randomized, single-blinded study of 35 healthy subjects, botulinum toxin type A was injected intradermally into the forearm of each subject with contralateral injection of saline for a placebo control (Nattkemper et al., 2017). After application of cowhage–an inducer of nonhistaminergic itch–the itch intensity was significantly lower in the forearm treated with the botulinum toxin compared to the saline control at one week, 1 month, and 3 months, with a lower overall perceived itch (percent change from baseline). A similar study of 14 patients pricked with histamine showed reductions in itch intensity, flare size, and vasomotor reactions compared to a saline control (Gazerani, Pedersen, Drewes, & Arendt-Nielsen, 2009). Based on these two trials, it can be inferred that botulinum toxin A is effective in both histaminergic and nonhistaminergic itch. Additional small clinical studies have shown benefit in the off-label treatment of various localized pruritic conditions including brachioradial pruritus, post herpetic itch, post burn itch (Akhtar & Brooks, 2012), dyshidrotic eczema (Wollina & Karamfilov, 2002) and lichen simplex chronicus. No benefit has been reported for notalgia paresthetica. Mixed results have been reported for vulvodynia. No large-scale clinical trials have been conducted and there is no consensus on optimal dosage and delivery route (Gazerani, 2018).
A 型肉毒杆菌毒素正在成为神经性瘙痒症的治疗方法。它被认为通过抑制瘙痒原物质 P、乙酰胆碱和谷氨酸起作用。在一项针对 35 名健康受试者的随机单盲研究中,将 A 型肉毒杆菌毒素皮内注射到每个受试者的前臂中,并对侧注射生理盐水作为安慰剂对照(Nattkemper 等人,2017 年)。在施用非组胺能瘙痒诱导剂 cowhage 后,与生理盐水对照组相比,用肉毒杆菌毒素治疗的前臂在 1 周、1 个月和 3 个月时瘙痒强度显着降低,总体感知瘙痒较低(相对于基线的百分比变化)。一项针对14名组胺刺破患者的类似研究表明,与生理盐水对照组相比,瘙痒强度,耀斑大小和血管舒缩反应有所降低(Gazerani,Pedersen,Drewes和Arendt-Nielsen,2009)。根据这两项试验,可以推断肉毒杆菌毒素A对组胺能性和非组胺能性瘙痒均有效。其他小型临床研究表明,在各种局部瘙痒症的标签外治疗中有益,包括肱桡瘙痒,带状疱疹后瘙痒,烧伤后瘙痒(Akhtar&Brooks,2012),汗疱疹性湿疹(Wollina&Karamfilov,2002)和慢性单纯性苔藓。没有关于感觉异常的益处的报道。外阴痛的结果好坏参半。尚未进行大规模临床试验,也没有就最佳剂量和给药途径达成共识(Gazerani,2018)。

7. Important new clinical targets: Other drug targets
7、重要的新临床靶点:其他药物靶点

7.1. Oxidative stress 7.1. 氧化应激

Oxidative stress can induce itch primarily via induction of TRPA1 (Liu & Ji, 2012). N-acetylcysteine (NAC) is an antioxidant that can be used to prevent itch-inducing oxidative stress in sensory neurons (Zhou et al., 2017). Mouse models demonstrated improvement of acute- and dry skin-induced chronic itch with NAC administration (Zhou et al., 2017). However, there are no current clinical trials using NAC for chronic itch.
氧化应激主要通过TRPA1的诱导诱发瘙痒(Liu&Ji,2012)。N-乙酰半胱氨酸(NAC)是一种抗氧化剂,可用于预防感觉神经元中引起瘙痒的氧化应激(周等人,2017)。小鼠模型显示,NAC给药可改善急性和干燥性皮肤引起的慢性瘙痒(周等人,2017)。然而,目前还没有使用 NAC 治疗慢性瘙痒的临床试验。

8. Conclusion 8. 结论

Millions of people suffer from chronic itch. As our understanding of skin, neuro-immune interactions, and peripheral and central nervous system itch has expanded, so too has the number of available therapeutics to alleviate this symptom. However, the complexity of itch and numerous receptors involved will require more drugs to be developed based on pathophysiology. The development of small molecules and monoclonal antibodies have ushered in targeted therapy, and personalized medicine within the itch arena will allow integration of genomic data to predict individualized response to different therapies. All of these advances aim to improve quality of life for those afflicted with various pruritic conditions.
数以百万计的人患有慢性瘙痒。随着我们对皮肤、神经免疫相互作用以及外周和中枢神经系统瘙痒的理解不断扩大,缓解这种症状的可用疗法的数量也在增加。然而,瘙痒的复杂性和涉及的众多受体将需要根据病理生理学开发更多的药物。小分子和单克隆抗体的发展迎来了靶向治疗,瘙痒领域的个性化医疗将允许整合基因组数据,以预测对不同疗法的个体化反应。所有这些进步都旨在改善患有各种瘙痒症的人的生活质量。

Declaration of Competing Interest
利益争夺声明

G Yosipovitch conducted clinical trials or received honoraria for serving as a member of the Scientific Advisory Board and consultant of Pfizer, TREVI, Regeneron, Sanofi, Galderma, Novartis, Bellus, Kiniksa, and Eli Lilly and received research funds from Pfizer, Leo, Sanofi, Regeneron, Eli Lilly, and Novartis. The remaining authors declare no financial conflict of interest regarding the content of this report.
G Yosipovitch 因担任辉瑞、TREVI、Regeneron、Sanofi、Galderma、Novartis、Bellus、Kiniksa 和 Eli Lilly 的科学顾问委员会成员和顾问而进行临床试验或获得酬金,并获得辉瑞、Leo、赛诺菲、Regeneron、Eli Lilly 和诺华的研究资金。其余作者声明与本报告内容没有财务利益冲突。

Acknowledgments 确认

None. 没有。

References 引用