Abstract
Primary cutaneous T-cell lymphomas (CTCL), which include mycosis fungoides (MF) and Sézary syndrome (SS), are a group of lymphoproliferative disorders characterized by clonal accumulation of neoplastic T-lymphocytes in the skin. Severe pruritus, one of the most common and distressing symptoms in primary CTCL, can significantly impair emotional well-being, physical functioning, and interpersonal relationships, thus greatly reducing quality of life. Unfortunately, effectively managing pruritus remains challenging in CTCL patients as the underlying mechanisms are, as of yet, not fully understood. Previous studies investigating the mechanisms of itch in CTCL have identified several mediators and their corresponding antagonists used for treatment. However, a comprehensive overview of the mediators and receptors contributing to pruritus in primary CTCL is lacking in the current literature. Here, we summarize and review the mediators and receptors that may contribute to pruritus in primary CTCL to explore the mechanisms of CTCL pruritus and identify effective therapeutic targets using the PubMed and Web of Science databases. Studies were included if they described itch mediators and receptors in MF and SS. Overall, the available data suggest that proteases (mainly tryptase), and neuropeptides (particularly Substance P) may be of greatest interest. At the receptor level, cytokine receptors, MRGPRs, and TRP channels are most likely important. Future drug development efforts should concentrate on targeting these mediators and receptors for the treatment of CTCL pruritus.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Per definition, primary cutaneous lymphomas are non-Hodgkin lymphomas in the skin without evidence of extracutaneous disease at the time of diagnosis [1]. The group of cutaneous lymphomas consists of primary cutaneous T cell lymphoma (CTCL) and primary cutaneous B cell lymphoma (CBCL) subtypes, with CTCL accounting for about 75–80% of all cutaneous lymphomas worldwide [1]. Among all CTCL, mycosis fungoides (MF) is the most common variant, representing approximately 60% of all cases [1]. Variants of MF include folliculotropic MF, pagetoid reticulosis, and granulomatous slack skin [2, 3]. The other classic type of CTCL, Sézary syndrome (SS), accounts for less than 3% of all CTCL [1], and is a rare, aggressive leukemic subtype of CTCL of slow onset [4, 5]. CBCL, constituting ∼20% to 25% of all primary cutaneous lymphomas, is subdivided into three main subtypes, marginal zone B-cell lymphoma, follicle center lymphoma and diffuse large B-cell lymphoma [6]. Even though about 40% of CBCL patients report localized pruritus [7], the clinical significance of itch seems to be of less importance in CBCL patients than in CTCL patients.
Pruritus is among the most severe and challenging clinical symptoms in CTCL patients [8,9,10,11]. It affects up to 88% of all CTCL patients, 61% of MF patients, and 94% of patients with SS [9, 12]. The average pruritus intensity, as assessed by a visual analogue scale ranging from 0 (no itch) to 10 (unbearable itch) is reported to increase in MF with progression of the disease from 3.4 in early stage disease (Ia-IIa) to 6.6 in late stage (IIb-IVb), and 7.7 in SS patients [9]. Pruritus in CTCL is usually long lasting and refractory to standard treatment with topical steroids or oral antihistamines [6, 13,14,15]. Overall, it has been shown that pruritus is one of the main factors affecting the health-related quality of life and mental health of patients with CTCL [16,17,18].
While the mechanisms underlying pruritus in CTCL are still poorly understood, the increasing information on pruritus-associated mediators and receptors allows to speculate on their possible roles on pruritus in CTCL. In this review, we aim to summarize published evidence on mediators and receptors that are potentially involved in CTCL-associated pruritus and could serve as antipruritic targets.
Methods
PubMed and Web of Science were searched using the terms ‘itch’, ‘pruritus’, ‘cutaneous T-cell lymphomas’, ‘Mycosis Fungoides’ and ‘Sézary syndrome’. All relevant published papers available from 1950 to May 2023 were included. Figure 1 represents the flowchart of inclusion and exclusion criteria considered to select the relevant references.
Cytokines and chemokines
Interleukin-4 and interleukin-13
Interleukin (IL)-4 and IL-13 are cytokines that have overlapping secondary structural features and share 25% sequence homology [19, 20]. They can be produced and released by various cells, including CD4 + T cells, basophils, eosinophils, mast cells, natural killer T cells, and group 2 innate lymphoid cells [21, 22]. IL-4 signals via type I or type II receptors, consisting either of IL-4Rα paired with common γ-chain (type I; IL-4Rα/ γc) or IL-4Rα paired with IL-13Rα1 (type II; IL-4Rα/IL-13Rα1). While the IL-4Rα/ γc receptor complex only binds IL-4, IL-4Rα/IL-13Rα1 can also interact with IL-13, which also binds and signals through IL-13Rα2 [22,23,24] (Fig. 2).
It has been shown that transgenic mice overexpressing IL-4 in the epidermis spontaneously develop a pruritic inflammatory skin disease [25]. Importantly, IL-4 as well as IL-13 have also been found to directly activate a subset of sensory neurons, thereby sensitizing them for subsequent stimulation with pruritogenic mediators such as IL-31, histamine, thymic stromal lymphopoietin (TSLP) or chloroquine [26]. Consistent with these findings, clinical trials in patients with moderate to severe atopic dermatitis (AD) have shown that the monoclonal antibody to IL-4Rα, dupilumab, effectively reduces pruritus [27,28,29], and the anti-IL-13 antibodies lebrikizumab and tralokinumab lead to an improvement of pruritus in moderate to severe AD [30,31,32] (Table 1). In chronic prurigo and chronic pruritus of unknown origin, dupilumab has also been proven to be efficacious in a large number of case reports and case series [33]. Furthermore, patients suffering from chronic pruritus of unknown origin or AD benefit from inhibition of JAK1, which is the major signaling component in type I and type II IL-4R signaling [26]. All together, these findings suggest that IL-4 and IL-13 can contribute to and promote chronic pruritus.
In CTCL, studies have shown that IL-4 may be an early indicator of disease progression. The levels of IL-4 in peripheral blood mononuclear cells (PBMC) of patients with SS and erythrodermic MF were significantly higher than those in control groups [34, 35]. The expression level of IL-13 mRNA in the lymph nodes of SS patients was significantly higher than that in other lymphomas, including diffuse large cell lymphomas, follicular lymphomas, peripheral T-cell lymphomas, anaplastic large cell lymphomas, and tumor-free reactive lymph nodes [36]. Recent reports on patients with CTCL indicate that dupilumab treatment can improve pruritus in CTCL [37, 38]. It has to be noted, however, that several studies reported about the development or exacerbation of CTCL after dupilumab treatment [39,40,41,42,43,44,45,46,47,48,49]. One suggested mechanism for the potential acceleration of CTCL progression by dupilumab involves an increase in the availability of IL-13 for binding at the IL-13 receptor (IL-13R) α2 site due to the indirect blockade of the IL-13Rα1 site by dupilumab [42]. CTCL cells have been observed to produce higher levels of IL-13 and IL-13Rα2 compared to normal skin, resulting in self-sustaining growth signals for tumors [42]. The blocking of the α subunit of the IL-4R by dupilumab effectively enhances the pool of available IL-13, which can then contribute to the promotion of tumorigenic pathways [42, 50]. Another hypothesis suggests that the worsening of CTCL might be linked to the direct advancement of malignant T-cell clones, which correlates with the depletion of tumor-suppressive, tumor-infiltrating lymphocytes [41]. Moreover, tumor cells may develop resistance to the effects of dupilumab, leading to the emergence of a clone that is no longer responsive to treatment [41]. Therefore, in CTCL patients, the potential symptomatic benefit of dupilumab must be weighed against the risk of disease progression [50, 51].
Interleukin-5
Interleukin-5 belongs to the common β chain (βc) signaling cytokine family including IL-3 and GM-CSF, which share the βc for signaling, while the IL-5R specifically interacts with IL-5 [52,53,54]. The major cellular sources of IL-5 are Th2 cells, Tc2 cells, mast cells, eosinophils, and γδT cells [55]. In addition, group 2 innate lymphoid cells can produce high levels of IL-5 when properly stimulated [56]. While the IL-5R subunit is strongly expressed by eosinophils and basophils, mast cells exhibit a rather low expression [52, 57]. (Fig. 2).
IL-5 plays a key role in the production and function of eosinophils. Monoclonal antibodies against IL-5 (mepolizumab, reslizumab) and IL-5R (benralizumab) have been reported to dramatically decrease blood eosinophil counts in asthma patients [58,59,60] and in patients with hypereosinophilic syndrome (HES) [61]. HES patients with skin involvement usually present with severe pruritus. Treatment of HES patients with mepolizumab and reslizumab has been shown to lead to a reduction of itch intensity along with decreased eosinophil counts [62, 63]. Similar effects were observed in a patient with Wells syndrome, another eosinophilic skin disease [64]. (Table 1).
Currently, there is only little data available for a potential role of eosinophil-mediated pruritus in CTCL. Nevertheless, eosinophil infiltration was detected in the skin of MF patients who presented with pruritus, but not in those without pruritus [65]. Furthermore, the group of patients with intense pruritus exhibited a significantly higher number of eosinophils that infiltrated the MF skin [65]. In addition, a positive correlation was observed between the presence of eosinophils in MF lesions and the disease stage [66]. Eosinophil presence is rare in the early stages of MF, but becomes a common characteristic in advanced stages [66]. The efficacy of biologics targeting IL-5 or IL-5R has not yet been explored in the treatment of CTCL-associated pruritus.
Interleukin-25
Interleukin-25, also known as IL-17E, belongs to the family of IL-17 cytokines along with IL-17A-F [67, 68]. It is produced by activated Th2 cells, eosinophils, basophils, mast cells, and macrophages [69]. IL-25 signals through a heterodimer complex consisting of IL-17 receptor A (IL-17RA) and IL-17 receptor B (IL-17RB) [70, 71]. The IL-17RB mRNA expression seen in naïve T cells, Th2 and Th9 cells indicates that these cells may be IL-25 targets [70, 72]. In addition, skin macrophages, in particular of the M2 phenotype, and keratinocytes are also targets of IL-25 [73]. (Fig. 2).
IL-25 has been suggested to be involved in pruritus in AD by mutual upregulation with endothelin-1 [74], a potent pruritogen in human and mice [75,76,77,78]. In line with this, plasma endothelin-1 and serum IL-25 levels have been found to strongly positively correlate with itch intensity in AD and to be significantly elevated as compared to healthy control subjects [79, 80].
There is not much known about the connection of IL-25 and itch in CTCL. In patients with advanced disease, expression of IL-25 in keratinocytes and serum levels of IL-25 were significantly higher than in healthy control subjects [81], which also correlated with serum lactic acid dehydrogenase levels, a disease severity marker of MF and SS [81, 82]. However, the relationship between IL-25 levels in the lesions or serum of CTCL patients and the severity of pruritus is, as of yet, unknown.
Interleukin-31
Interleukin-31 is a member of the IL-6 cytokine family and is thought to be mainly produced by activated Th2 cells, but also by other cells such as mast cells, macrophages, and dendritic cells [83, 84]. IL-31 signals via a heterodimeric receptor complex, which is composed of IL-31RA and the oncostatin M receptor β (OSMRβ) [85]. The IL-31R complex is expressed by many cell types, including T cells, keratinocytes, dendritic cells, eosinophils, macrophages, and dorsal root ganglia [86]. (Fig. 2).
IL-31 is thought to be importantly involved in the pathophysiology of chronic pruritus associated with various dermatological diseases. For example, in both stasis dermatitis and scabies, increased numbers of IL-31-producing M2 macrophages in the lesion have been linked to the severe pruritus in these patients [87, 88]. Furthermore, in patients with allergic contact dermatitis, serum levels of IL-31 are significantly higher as compared to healthy controls and correlate with the severity of pruritus [89]. A monoclonal antibody targeting the IL-31RA, nemolizumab, has been studied in AD and prurigo nodularis and was very effective in reducing pruritus in these patients [90,91,92,93,94]. (Table 1).
The information on the pruritogenic role of IL-31 in CTCL is conflicting. Some studies found serum levels of IL-31 to be significantly elevated compared to healthy controls [95,96,97], whereas another study showed that translational and transcriptional expression levels of IL-31 were very low or undetectable in CTCL patients [98]. One of the studies reporting increased serum IL-31 in CTCL did not observe a correlation with itch intensity [96], whereas the other two did [97, 99]. For example, Abreu et al. reported that, in CTCL patients with itch, IL-31 levels are higher than in those without and that the highest levels of IL-31 are found in those patients with severe itch (visual analogue scale of 6 or higher) [97]. Also, the level of IL-31 mRNA in peripheral blood mononuclear cells of CTCL patients have been found to be significantly increased and to correlate with the intensity of itch [99]. Additionally, the expression levels of IL-31, IL-31RA and OSMRβ in skin lesions of CTCL patients have been found to be increased, and the expression levels of IL-31 correlate with pruritus intensity [100]. The efficacy of nemolizumab has not yet been explored in the treatment of CTCL pruritus.
CCL-1 and CCL-26
Chemokine CC motif ligand (CCL)-1 (also known as thymus-derived chemotactic agent 3) is a small glycoprotein and a typical chemokine, belonging to CC-type chemokines. CCL-26 (eotaxin-3) belongs to the eotaxin family, a CC chemokine subfamily that also includes CCL-11 (eotaxin-1) and CCL-24 (eotaxin-2) [101, 102]. CCL-1 is secreted by monocytes, activated macrophages and T lymphocytes. It is also expressed by dermal microvessels and epidermal antigen-presenting cells [103, 104]. CCL-26 is mainly produced by resident skin cells, including fibroblasts and smooth muscle cells, and is generally expressed only in non-hematopoietic cells [105]. CC chemokine receptor (CCR) 8 is the specific receptor of CCL-1, which most T cells in normal human skin express. It is also expressed by nerve cells and glial cells [103, 106]. CCR3, the receptor of CCL-26 [107], is highly expressed by eosinophils, with noted expression in basophils, Th2 cells, mast cells, and airway epithelial cells [108]. (Fig. 2).
Compared with healthy controls, serum CCL-1 and CCL-26 levels were significantly higher in patients with AD and bullous pemphigoid, both pruritic diseases [109,110,111].
In CTCL patients, serum CCL-1 and CCL-26 levels were significantly increased, especially in advanced cases [111, 112]. There is, furthermore, a significant correlation between serum levels of CCL1 and CCL26 with itch intensity in CTCL patients [113]. In addition, the expression of CCL26 mRNA in fibroblasts from skin lesions of CTCL patients is higher than in normal skin [112]. Currently, there are no therapeutic options available for testing the effects of CCL-1 and -26 targeted treatment of pruritus in CTCL.
Thymic stromal lymphopoietin
Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family [114] and is mainly expressed by cells forming barrier surfaces, i.e. epithelial cells and keratinocytes [115]. The TSLP receptor is a heterodimeric receptor consisting of an IL-7 receptor α-chain and a common receptor-γ chain [116]. TSLP receptor mRNA has been found on many immune cell types, including dendritic cells, T cells, B cells, mast cells, natural killer T cells, and monocytes [117] (Fig. 2).
TSLP is held to be involved in the pathogenesis of pruritus in various dermatological diseases. For example, in dermatitis herpetiformis, skin-derived TSLP was shown to correlate with the intensity of pruritus [118]. A human monoclonal antibody specific for TSLP, tezepelumab, demonstrated significant but minor improvement in pruritus in moderate to severe AD patients as compared to placebo [119] (Table 1).
Compared with healthy controls, the expression level of TSLP in serum and lesions were significantly increased in CTCL patients, especially in the early-stage of the disease [120, 121]. However, the relationship between TSLP expression levels and CTCL pruritus are, as of yet, unclear and need further exploration. The efficacy of tezepelumab has not yet been explored in the treatment of CTCL pruritus.
Neuropeptides and neurotrophins
Nerve growth factor
Nerve growth factor (NGF), together with brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5, belongs to the family of neurotrophins [122, 123]. The production and maturation of NGF are accredited to a variety of cell types, such as keratinocytes, neurons and mast cells [124]. NGF binds to tropomyosin receptor kinase A (TrkA) with high affinity and to the p75 neurotrophin receptor (p75NTR) with low affinity [125]. In addition to nerve cells, many immune cells such as macrophages and mast cells also express NGF receptors and respond to NGF stimulation to induce a variety of effects that can be pro- or anti-inflammatory [126] (Fig. 3).
In patients with pruritic skin diseases including AD, prurigo nodularis and psoriasis, the levels of NGF in the plasma and expression of its receptors TrkA and p75NTR in lesional skin were significantly higher and associated with strong pruritus [127,128,129]. In line with this, significantly higher expression levels of NGF and TrkA were found in psoriasis patients with pruritus as compared to patients without pruritus, and the expression levels of NGF and TrkA were associated with pruritus severity [130, 131]. Furthermore, treatment of patients with psoriasis with the topical TrkA inhibitor CT327 was associated with a significant reduction of pruritus [132] (Table 1).
As for CTCL, patients with SS were reported to exhibit higher serum NGF levels as compared to healthy controls [113]. In addition, NGF-positive dermal nerve fibers were increased in the skin of these patients, while they were rarely detected in MF patients as well as healthy controls [113]. The efficacy of topical CT327 or of other NGF-targeting therapies has not yet been explored in the treatment of CTCL pruritus.
Substance P
Substance P (SP) is a highly conserved peptide neurotransmitter that belongs to the tachykinin family [133]. Although mainly expressed by neurons, it is also expressed by non-neuronal cell types, such as microglia and immune cells [134]. The specific receptor of SP is neurokinin-1 receptor (NK-1R), a G protein-coupled receptor (GPCR). NK-1R is expressed by a variety of cells, including neurons, smooth muscle cells, fibroblasts, mast cells, T cells, B cells, and NK cells [135]. In addition, SP strongly activates Mas-related G-protein coupled receptor member X2 (MRGPRX2), a member of the Mas-related gene family, which is expressed in sensory neurons, mast cells, and keratinocytes [136,137,138] (Fig. 3).
SP and its receptors are thought to be involved in various dermatological and non-dermatological pruritic conditions. For example, plasma concentrations of SP were found to be elevated in AD patients as compared to healthy controls, and to correlate with pruritus intensity in these patients [139]. In patients with psoriasis, SP levels have also been shown to be elevated, and the number of SP-positive nerve fibers in lesional skin correlated with the severity of pruritus in these patients [131, 139, 140]. Compared to healthy skin and non-lesional skin, the number of SP-positive nerve fibers and expression of NK-1R were also significantly increased in other itchy diseases, such as chronic prurigo and chronic pruritus associated with internal diseases, drug-induced pruritus, brachioradial pruritus, and chronic pruritus of unknown origin. Levels of SP are also significantly increased in the blood of patients with chronic spontaneous urticaria [140,141,142,143,144].
Aprepitant, an NK-1R antagonist, has been reported to be an effective anti-pruritic drug in many case reports and case-series. Aprepitants’ antipruritic effects have been shown in patients with chronic pruritus, prurigo nodularis, brachioradial pruritus, drug-induced pruritus, paraneoplastic pruritus, and pruritus associated with systemic diseases such as chronic kidney disease, hyperuricemia and iron deficiency [145,146,147,148,149,150,151,152,153]. In randomized controlled trials in patients with chronic prurigo, microbial eczema, AD, pruritus and eczema craquelé, aprepitant, however, failed to significantly improve pruritus [154, 155]. Another NK-1R antagonist, serlopitant, was tested for the treatment of pruritus associated with prurigo nodularis (phase 2 trial positive, phase 3 negative), pruritus associated with psoriasis (phase 2 trial positive), CPUO (phase 2 trial positive), and pruritus associated with epidermolysis bullosa (phase 2 trial negative) [156,157,158,159,160]. Other NK-1R antagonists in clinical investigations as antipruritic drugs are tradipitant, which has shown some antipruritic effects in patients with mild AD [161], and orvepitant [162, 163] (Table 1).
In CTCL, serum levels of SP expression are significantly increased in patients as compared to healthy controls, and positively correlate with disease severity in MF patients [164]. The correlation of itch intensity and SP levels has, as of yet, not been assessed. Nevertheless, the efficacy of the NK-1R antagonist aprepitant has been explored in the treatment of CTCL pruritus and has shown a significant antipruritic effect in many case reports and case series [165,166,167,168,169,170] (Table 1). In SS, the results of a small randomized, double-blind, placebo-controlled crossover study did not support the antipruritic efficacy of aprepitant [171]. The authors acknowledged, however, that this study had several limitations, with one notable limitation being the recruitment of only 5 patients [171]. Furthermore, they attributed the differences in clinical response compared to previous studies to changes in disease activity and external factors, such as ambient temperature and humidity, which have the potential to influence the scoring of pruritus using the visual analog scale in patients with SS [171].
Vascular endothelial growth factor
Vascular endothelial growth factors (VEGFs), also known as vascular permeability factors, are a family of growth factors, which consists of seven members, VEGF-A, -B, -C, -D, -E, and -F, and PlGF [172]. There are three types of VEGF receptors: VEGFR-1, 2, and 3, and different VEGFs have different affinities to different receptors [173].
Especially for VEGF-A, several observations support a role in pruritus in different conditions. For example, in psoriasis patients, expression of VEGF-A in lesional skin of patients with severe pruritus was higher than in those without pruritus [174]. In patients with AD, expression of VEGF-A in the epidermal stratum corneum was increased, and levels of VEGF were significantly higher in the serum and correlated with pruritus [175,176,177]. In chronic prurigo, VEGF-A immunoreactivity was markedly increased in the epidermis, dermis, and subcutis, which was associated with a marked increase in the number of blood vessels and epidermal thickness of prurigo lesions [178].
Bevacizumab, a VEGF-A inhibitor, was found to be effective in a patient with chronic prurigo, where it reduced pruritus [179] (Table 1). In addition, axitinib, an inhibitor of VEGFR-1-3, inhibits the scratching behavior seen in imiquimod-induced psoriasis mouse models [174].
In erythrodermic MF and SS, serum VEGF-A levels were significantly higher than those in healthy controls, and the levels significantly decreased after treatment, including topical and oral corticosteroids, ultraviolet phototherapy, oral etretinate, oral vorinostat and/or systemic chemotherapy. Furthermore, serum VEGF-A levels were significantly associated with the severity of pruritus in MF/SS patients [180]. However, the efficacy of bevacizumab has not yet been explored in the treatment of CTCL pruritus.
Proteases
Kallikreins
Kallikreins (KLKs) are a group of secreted serine proteases [181, 182]. In the skin, KLKs are mainly expressed in the upper stratum granulosum and stratum corneum [183, 184] (Fig. 3). There are at least 11 KLKs expressed in the epidermis, of which KLK5 is most abundant in the skin and may play an important role in itch [185, 186]. KLK5 can activate protease-activated receptor (PAR)-2, a GPCR expressed in a variety of skin cells, including sensory nerves, keratinocytes, and mast cells, which are thought to be involved in the elicitation of pruritus [187,188,189].
KLK5 activity was found to be increased in the skin of AD patients, and protein expression levels were significantly higher than those in healthy controls [190, 191]. In an animal experiment, mice injected with KLK5 exhibited significantly increased scratching behavior relative to vehicle controls [192].
KLK5 may also be involved in MF-associated pruritus. A study with 37 MF patients showed that the protein expression levels of KLK5 increased with the severity of pruritus [65].
Tryptase
Tryptase is one of the major serine-proteinases and is secreted mainly by tissue mast cells and, to a lesser extent, also basophils [193, 194] (Fig. 3). Two main types of mast cell tryptase have been described, α- and β-tryptase. While α-tryptase is constitutively released by mast cells as an inactive pro-enzyme, β-tryptase is stored in mast cell granules and is released upon their activation [195]. β-tryptase cleaves several extracellular substrates including extracellular matrix proteins, activates PARs, in particular PAR-2, and it is a useful serum marker for mast cell activation in anaphylaxis and anaphylactoid reactions [195, 196].
Tryptase is thought to be involved in pruritus associated with various diseases. For example, serum tryptase levels were increased in renal disease with pruritus, and the intensity of pruritus correlated significantly with tryptase levels [197]. Tryptase level were also increased in AD patients with moderate to severe pruritus [198]. The connection of tryptase and pruritus is further supported by the correlation of blood tryptase reduction in AD patients treated with fexofenadine, an antihistamine, with pruritus improvement [199] (Fig. 3) Enhanced levels of tryptase release and tryptase activity are related to itch in chronic dermatitis, P-phenylenediamine-induced itch, and ovalbumin allergy-induced itch in mice [200,201,202]. Nafamostat mesilate, an oral serin protease inhibitor, inhibits itch-associated responses in mice mainly through the inhibition of mast cell tryptase [203].
However, although there is strong evidence in support of a direct connection between tryptase and itch from various diseases, there is currently only one study that involved a small group of patients with MF. This study observed numerically higher serum levels of tryptase in MF patients with pruritus compared to those without pruritus [204]. Furthermore, since tryptase is a marker of mast cell activation, any association between pruritus and tryptase may reflect the role of mast cell activation and the consecutive release of other pruritus associated mediators. Studies on the role of tryptase and mast cells are needed and should be performed.
Itch associated receptors and ion channels
Mas-related G protein coupled receptors
MRGPRs, including MRGPRA to -H and MRGPRX, comprise a large family of seven transmembrane-domain receptors mainly expressed in sensory neurons of the dorsal root and, importantly, on mast cells [205,206,207]. Of these, the MRGPRX receptors (MRGPRX1-4) are primarily expressed in humans and held to induce pruritus [208] (Fig. 3).
MRGPRs can be activated by a large variety of substances and mediators, including numerous synthetic drugs and a number of neuropeptides. For example, chloroquine, a widely used anti-malarial drug, activates MRGPRX1 and induces itch [209]. IPDef1, a tick salivary peptide, can evoke itch by activating MRGPRX1 on dorsal root ganglion neurons, and the concentration of PAMP1-20, an MRGPRX2 agonists, was found to be elevated in the skin in allergic contact dermatitis [210]. Levels of MRGPRX2 mRNA were increased in pruritic skin of patients with AD and psoriasis [141]. MRGPRX4 is thought to be implicated in the transmission of cholestatic itch where bilirubin excites peripheral sensory neurons and elicits pruritus through binding to and activation of MRGPRX4 [211]. Transgenic mice expressing human MRGPRX4 scratched more upon injection of bile acids, which are increased in the blood of cholestatic patients [205].
The role and relevance of MRGPRs in CTCL pruritus is, as of yet, entirely unclear and needs to be investigated.
Opioids
The endogenous opioid system is one of the human innate pain-relief systems and uses specialized opioid receptors [212]: µ-type opioid receptors (MOR) for endorphins, k-type opioid receptors (KOR) for dynorphins, and δ–type opioid receptors for enkephalins [213]. Interestingly, opioid receptors have been found to differently connect with itch. For example, KOR signaling suppresses itch, whereas MOR signaling can stimulate itch [214, 215] (Fig. 3). These findings are derived from experiments with selective agonists and antagonists for the individual receptors. For instance, MOR antagonists, such as naltrexone, nalmefene, and naloxone, can significantly relieve severe itching caused by several different diseases, including AD, uremia, psoriasis, chronic prurigo, cholestatic itch and lichen simplex chronicus [216,217,218,219,220,221,222,223,224]. Intrathecal injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching and pruritus in mice and humans [225,226,227]. KOR agonists, such as difelikefalin and nalfurafine, can markedly improve pruritus in chronic kidney disease patients undergoing dialysis and pruritus in chronic liver disease [228,229,230,231,232,233,234,235,236]. Nalbuphine, a KOR agonist and MOR antagonist, can prevent intrathecal morphine-induced pruritus and be effective against pruritus in prurigo nodularis and uremia [237,238,239,240,241]. Butorphanol, another KOR agonist and MOR antagonist, has been reported to reduce chronic pruritus associated with various dermatological, internal, and neurological diseases [242,243,244,245,246,247] (Table 1).
In almost all lymph nodes of patients with SS, in contrast to all other lymphoma patients, MORs were found to be highly expressed [36]. Naltrexone, an orally semisynthetic MOR antagonist, was demonstrated to be effective in suppressing pruritus in patients with CTCL [216, 248,249,250], and another MOR antagonist, naloxone, improved pruritus in a patient with MF [251]. In the same patient, however, exacerbation of pruritus occurred after treatment with naltrexone, which may reflect the complexity of the opioid system [251].
Protease-activated receptor-2
PAR-2, a G-protein coupled receptor (GPCR), is activated by serine proteases such as trypsin and tryptase [252, 253]. It belongs to the group of PARs which also includes PAR-1, -3, and -4 [254]. PAR-2 is expressed by epithelial, endothelial, and smooth muscle cells, as well as by cells of the immune and nervous systems [255, 256] (Fig. 3).
PAR-2 is involved in the pathophysiology of many inflammatory diseases, including AD. In the skin of patients with AD, the number of PAR-2 positive nerve fibers is significantly increased, and intracutaneous injection of endogenous PAR-2 agonists causes enhanced and prolonged itch [198]. Interestingly, skin of patients with AD has been found to be presensitized for protease-induced itch [257]. In mice, PAR-2 agonists can also induce scratching behavior [200, 258]. Mice with epidermal overexpression of PAR-2 develop an enhanced spontaneous scratching [259, 260], whereas inhibition of PAR-2 activation by PAR2 inhibitors such as SAM-11 and PZ-252 suppresses scratching behaviour [200, 202, 261].
Immunohistochemistry demonstrated that the expression of PAR-2 in the skin of MF patients is higher than in healthy controls. However, there was no difference of PAR-2 expression in MF patients with different degrees of pruritus [65].
Transient receptor potential channels
Transient receptor potential channels (TRP channels) are non-selective calcium-permeable cation channels that compose the TRP ion channel superfamily located on the cell membrane [262,263,264,265]. TRP channels are divided into seven subgroups based on protein homology: TRPC, TRPV, TRPM, TRPA, TRPN, TRPP, and TRPML. Among them, five have been proposed to play a role in itch: TRPA1, TRPV1, TRPV3, TRPV4, and TRPM8 [266, 267]. They are expressed in different cell types in the skin and nervous system, such as keratinocytes and dorsal root ganglion neurons [268] (Fig. 3).
TRPA1 is considered to be an important mediator for itch signaling in mice and humans [262, 264, 269,270,271,272]. Burn patients with pruritus had increased TRPA1 mRNA compared to burn patients without pruritus, and TRPA1 mRNA expression showed a positive correlation with the intensity of post-burn pruritus [273]. Overexpression of TRPV 1 in pruritic skin was found to be positively correlated with itch intensity ratings in both AD and psoriasis patients [141]. Numerous clinical trials have confirmed that topical application of capsaicin – a TRPV1 agonist – is effective in reducing chronic pruritus of unknown origin [274, 275], and PAC-14028, a TRPV1 antagonist, showed a trend towards improvement of pruritus in AD patients in a phase 2b clinical trial [276, 277] (Table 1).
TRPV3 is implicated in itch in many skin diseases, including Olmsted syndrome and AD [278,279,280]. TRPV3 mRNA expression is higher in AD patients with pruritus than AD patients without pruritus and healthy controls [281, 282]. In burn patients, TPRV3 was significantly elevated in the epidermis of burn scars with pruritus when compared with burn scars without pruritus and was positively correlated with the intensity of pruritus [273]. A TRPV3 activator, carvacrol, has been reported to cause pruritus in humans [283, 284].
TRPV4 is also involved in a variety of pruritic conditions [285,286,287]. Like TRPV3, TRPV4 mRNA expression was increased in burn patients with pruritus compared to burn patients without pruritus and normal skin, and is positively correlated with the intensity of pruritus [273]. In numerous mouse disease models (psoriasis, allergic contact dermatitis and dry skin) and models using pruritus-inducing substances and TRPV4 agonists, a role for TRPV4 in itch induction has been confirmed [268, 285, 288,289,290,291,292,293].
Activation of TRPM8 induces a long-lasting cooling effect in the skin, and the application of cold is a well-known remedy for pruritus in many conditions [294]. TRPM8 agonists such as cryosim-1, menthoxypropanediol, and icilin can significantly improve recalcitrant pruritus associated with many diseases, including eczema, urticaria, AD, lichen sclerosus et atrophicus, and scalp itch [295,296,297,298,299].
TRP channels may also be involved in CTCL-asociated pruritus. The use of a CTCL mouse model demonstrated that one of the itch mediators in CTCL, miR-711, induced itching through direct activation of TRPA1 on sensory neurons, and this pruritus was decreased in TRPA1-knockout mice [300]. The efficacy of PAC-14028 or other TRP antagonists has not yet been explored in the treatment of CTCL pruritus.
Conclusion
Chronic pruritus is complex, involves different pathways, and is likely to be different between diseases [301,302,303]. Although remarkable progress is being made in exploring the pathogenesis of pruritus, the underlying pathophysiology in CTCL-associated itch remains largely elusive. Here, we summarized and discussed the published evidence for a variety of mediators and receptors held be involved in itch associated with CTCL. In some instances, the evidence is rather circumstantial and requires investigations in CTCL patients or mouse models. In others, a relevant role in CTCL is supported by correlations of itch intensity and mediator levels. Although it is too early to say which mediators and receptors that drive pruritus in CTCL, the significant involvement of proteases (primarily tryptase), and neuropeptides (mainly SP) in the development and severity of pruritus in various dermatological diseases, including CTCL, suggests their potential as key players in this context. At the receptor level, cytokine receptors, MRGPRs and TRP channels are most likely important, and future drug development should target these receptors for the treatment of CTCL pruritus.
Currently, CTCL-associated itch is difficult to treat and has substantial impact on quality of life in these patients [8, 10, 304, 305]. Therefore, novel, effective and safe treatment options for pruritus in CTCL are desperately needed. The publication of further case reports and series is encouraged, but what we really need are controlled clinical trials.
Data availability
Data sharing not applicable to this article as no datasets were generated or analysed during the current Review.
Abbreviations
- AD:
-
Atopic dermatitis
- CBCL:
-
Cutaneous B-cell lymphomas
- CCL:
-
Chemokine C–C motif ligand
- CCR:
-
CC chemokine receptor
- CTCL:
-
Cutaneous T-cell lymphomas
- GPCR:
-
G protein-coupled receptor
- HES:
-
Hypereosinophilic syndrome
- IL:
-
Interleukin
- KLKs:
-
Kallikrein-related peptidas
- KOR:
-
K-type opioid receptor
- MF:
-
Mycosis fungoides
- MOR:
-
µ -Type opioid receptor
- MRGPRs:
-
Mas-related G protein-coupled receptors
- MRGPRX2:
-
Mas-related G-protein coupled receptor member X2
- NGF:
-
Nerve growth factor
- NK-1R:
-
Neurokinin-1 receptor
- OSMRβ:
-
Oncostatin M receptor β
- PAR:
-
Protease-activated receptor
- SS:
-
Sézary syndrome
- SP:
-
Substance P
- TrkA:
-
Tropomyosin receptor kinase A
- TRP channels:
-
Transient receptor potential channels
- TSLP:
-
Thymic stromal lymphopoietin
- VEGF:
-
Vascular endothelial growth factor
References
Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;134:1112. https://doi.org/10.1182/blood.2019002852.
Kempf W, Zimmermann AK, Mitteldorf C. Cutaneous lymphomas-an update 2019. Hematol Oncol. 2019;37(Suppl 1):43–7. https://doi.org/10.1002/hon.2584.
Dummer R, Vermeer MH, Scarisbrick JJ, et al. Cutaneous T cell lymphoma. Nat Rev Dis Primers. 2021;7:61. https://doi.org/10.1038/s41572-021-00296-9.
Saunes M, Nilsen TI, Johannesen TB. Incidence of primary cutaneous T-cell lymphoma in Norway. Br J Dermatol. 2009;160:376–9. https://doi.org/10.1111/j.1365-2133.2008.08852.x.
Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768–85. https://doi.org/10.1182/blood-2004-09-3502.
Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. Blood. 2009;113:5064–73. https://doi.org/10.1182/blood-2008-10-184168.
Olszewska-Szopa M, Sobas M, Laribi K, et al. Primary cutaneous indolent B-cell lymphomas - a retrospective multicenter analysis and a review of literature. Acta Oncol. 2021;60:1361–8. https://doi.org/10.1080/0284186x.2021.1956689.
Wright A, Wijeratne A, Hung T, et al. Prevalence and severity of pruritus and quality of life in patients with cutaneous T-cell lymphoma. J Pain Symptom Manage. 2013;45:114–9. https://doi.org/10.1016/j.jpainsymman.2012.01.012.
Vij A, Duvic M. Prevalence and severity of pruritus in cutaneous T cell lymphoma. Int J Dermatol. 2012;51:930–4. https://doi.org/10.1111/j.1365-4632.2011.05188.x.
Ottevanger R, van Beugen S, Evers AWM, et al. Quality of life in patients with mycosis fungoides and sézary syndrome: a systematic review of the literature. J Eur Acad Dermatol Venereol. 2021;35:2377–87. https://doi.org/10.1111/jdv.17570.
Lewis DJ, Huang S, Duvic M. Inflammatory cytokines and peripheral mediators in the pathophysiology of pruritus in cutaneous T-cell lymphoma. J Eur Acad Dermatol Venereol. 2018;32:1652–6. https://doi.org/10.1111/jdv.15075.
Demierre MF, Gan S, Jones J, Miller DR. Significant impact of cutaneous T-cell lymphoma on patients’ quality of life: results of a 2005 national cutaneous lymphoma foundation survey. Cancer. 2006;107:2504–11. https://doi.org/10.1002/cncr.22252.
Meyer N, Paul C, Misery L. Pruritus in cutaneous T-cell lymphomas: frequent, often severe and difficult to treat. Acta Derm Venereol. 2010;90:12–7. https://doi.org/10.2340/00015555-0789.
Moses S. Pruritus. Am Fam Physician. 2003;68:1135–42.
Lansigan F. Navigating the treatment choices for mycosis fungoides. Oncology. 2010;24:508.
Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): part II. Prognosis, management, and future directions. J Am Acad Dermatol. 2014;70:223. https://doi.org/10.1016/j.jaad.2013.08.033.
Sampogna F, Frontani M, Baliva G, et al. Quality of life and psychological distress in patients with cutaneous lymphoma. Br J Dermatol. 2009;160:815–22. https://doi.org/10.1111/j.1365-2133.2008.08992.x.
Holahan HM, Farah RS, Fitz S, et al. Health-related quality of life in patients with cutaneous T-cell lymphoma? Int J Dermatol. 2018;57:1314–9. https://doi.org/10.1111/ijd.14132.
Rael EL, Lockey RF. Interleukin-13 signaling and its role in asthma. World Allergy Organ J. 2011;4:54–64. https://doi.org/10.1097/WOX.0b013e31821188e0.
Carr C, Aykent S, Kimack NM, Levine AD. Disulfide assignments in recombinant mouse and human interleukin 4. Biochemistry. 1991;30:1515–23. https://doi.org/10.1021/bi00220a011.
Kelly-Welch A, Hanson EM, Keegan AD. Interleukin-4 (IL-4) pathway. Sci STKE. 2005. https://doi.org/10.1126/stke.2932005cm9.
Junttila IS. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol. 2018;9:888. https://doi.org/10.3389/fimmu.2018.00888.
Amo-Aparicio J, Garcia-Garcia J, Francos-Quijorna I, et al. Interleukin-4 and interleukin-13 induce different metabolic profiles in microglia and macrophages that relate with divergent outcomes after spinal cord injury. Theranostics. 2021;11:9805–20. https://doi.org/10.7150/thno.65203.
Popovic B, Breed J, Rees DG, et al. Structural characterisation reveals mechanism of IL-13-neutralising monoclonal antibody tralokinumab as inhibition of binding to IL-13Rα1 and IL-13Rα2. J Mol Biol. 2017;429:208–19. https://doi.org/10.1016/j.jmb.2016.12.005.
Chan LS, Robinson N, Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol. 2001;117:977–83. https://doi.org/10.1046/j.0022-202x.2001.01484.x.
Oetjen LK, Mack MR, Feng J, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017;171:217–28. https://doi.org/10.1016/j.cell.2017.08.006.
Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130–9. https://doi.org/10.1056/NEJMoa1314768.
Bonnekoh H, Butze M, Metz M. Characterization of the effects on pruritus by novel treatments for atopic dermatitis. J Dtsch Dermatol Ges. 2022;20:150–6. https://doi.org/10.1111/ddg.14678.
Silverberg JI, Yosipovitch G, Simpson EL, et al. Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS. J Am Acad Dermatol. 2020;82:1328–36. https://doi.org/10.1016/j.jaad.2020.02.060.
Guttman-Yassky E, Blauvelt A, Eichenfield LF, et al. Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: a phase 2b randomized clinical trial. JAMA Dermatol. 2020;156:411–20. https://doi.org/10.1001/jamadermatol.2020.0079.
Wollenberg A, Blauvelt A, Guttman-Yassky E, et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br J Dermatol. 2021;184:437–49. https://doi.org/10.1111/bjd.19574.
Silverberg JI, Toth D, Bieber T, et al. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol. 2021;184:450–63. https://doi.org/10.1111/bjd.19573.
Gael M, Adam T, Mariano-Bourin M, Bursztejn AC. Efficacy of dupilumab in chronic prurigo and chronic idiopathic pruritus: a systematic review of current evidence and analysis of response predictors. J Eur Acad Dermatol Venereol. 2022. https://doi.org/10.1111/jdv.18221.
Vowels BR, Cassin M, Vonderheid EC, Rook AH. Aberrant cytokine production by Sezary syndrome patients: cytokine secretion pattern resembles murine Th2 cells. J Invest Dermatol. 1992;99:90–4. https://doi.org/10.1111/1523-1747.ep12611877.
Papadavid E, Economidou J, Psarra A, et al. The relevance of peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation of patients with mycosis fungoides and Sézary syndrome. Br J Dermatol. 2003;148:709–18. https://doi.org/10.1046/j.1365-2133.2003.05224.x.
Bénard A, Cavaillès P, Boué J, et al. mu-opioid receptor is induced by IL-13 within lymph nodes from patients with Sézary syndrome. J Invest Dermatol. 2010;130:1337–44. https://doi.org/10.1038/jid.2009.433.
Mollanazar NK, Savage KT, Pousti BT, et al. Cutaneous T-cell lymphoma and concomitant atopic dermatitis responding to dupilumab. Cutis. 2020;106:131–2. https://doi.org/10.12788/cutis.0066.
Steck O, Bertschi NL, Luther F, et al. Rapid and sustained control of itch and reduction in Th2 bias by dupilumab in a patient with Sézary syndrome. J Eur Acad Dermatol Venereol. 2021;35:1331–7. https://doi.org/10.1111/jdv.17001.
Ayasse M, Nelson K, Glass F, Silverberg JI. Mycosis fungoides unmasked by dupilumab treatment in a patient with a history of atopic dermatitis. Dermatitis. 2021;32:e88–9. https://doi.org/10.1097/der.0000000000000679.
Chiba T, Nagai T, Osada SI, Manabe M. Diagnosis of Mycosis fungoides following administration of dupilumab for misdiagnosed atopic dermatitis. Acta Derm Venereol. 2019;99:818–9. https://doi.org/10.2340/00015555-3208.
Espinosa ML, Nguyen MT, Aguirre AS, et al. Progression of cutaneous T-cell lymphoma after dupilumab: case review of 7 patients. J Am Acad Dermatol. 2020;83:197–9. https://doi.org/10.1016/j.jaad.2020.03.050.
Claire Hollins L, Wirth P, Fulchiero Jr GJ, Foulke GT. Long-standing dermatitis treated with dupilumab with subsequent progression to cutaneous T-cell lymphoma. Cutis. 2020. https://doi.org/10.12788/cutis.0074.
Newsom M, Hrin ML, Hamid RN, et al. Two cases of mycosis fungoides diagnosed after treatment non-response to dupilumab. Dermatol Online J. 2021;27.
Sokumbi O, Shamim H, Davis MDP, et al. Evolution of dupilumab-associated cutaneous atypical lymphoid infiltrates. Am J Dermatopathol. 2021;43:714–20. https://doi.org/10.1097/dad.0000000000001875.
Miyashiro D, Vivarelli AG, Gonçalves F, Cury-Martins J, Sanches JA. Progression of mycosis fungoides after treatment with dupilumab: a case report. Dermatol Ther. 2020;33:e13880. https://doi.org/10.1111/dth.13880.
Russomanno K, Carver DeKlotz CM. Acceleration of cutaneous T-cell lymphoma following dupilumab administration. JAAD Case Rep. 2021;8:83–5. https://doi.org/10.1016/j.jdcr.2020.12.010.
Lazaridou I, Ram-Wolff C, Bouaziz JD, et al. Dupilumab treatment in two patients with cutaneous T-cell lymphomas. Acta Derm Venereol. 2020;100:adv00271. https://doi.org/10.2340/00015555-3576.
Tran J, Morris L, Vu A, Duvic M. Development of Sézary syndrome following the administration of dupilumab. Dermatol Online J. 2020;26.
Umemoto N, Demitsu T, Otaki K, et al. Dupilumab therapy in Sézary syndrome misdiagnosed as atopic dermatitis: a case report. J Dermatol. 2020;47:e356–7. https://doi.org/10.1111/1346-8138.15501.
Park A, Wong L, Lang A, et al. Cutaneous T-cell lymphoma following dupilumab use: a systematic review. Int J Dermatol. 2023;62:862–76. https://doi.org/10.1111/ijd.16388.
Hamp A, Hanson J, Schwartz RA, Lambert WC, Alhatem A. Dupilumab-associated mycosis fungoides: a cross-sectional study. Arch Dermatol Res. 2023. https://doi.org/10.1007/s00403-023-02652-z.
Dougan M, Dranoff G, Dougan SK. GM-CSF, IL-3, and IL-5 Family of cytokines: regulators of inflammation. Immunity. 2019;50:796–811. https://doi.org/10.1016/j.immuni.2019.03.022.
Varricchi G, Poto R, Marone G, Schroeder JT. IL-3 in the development and function of basophils. Semin Immunol. 2021;54:101510. https://doi.org/10.1016/j.smim.2021.101510.
Broughton SE, Dhagat U, Hercus TR, et al. The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol Rev. 2012;250:277–302. https://doi.org/10.1111/j.1600-065X.2012.01164.x.
Takatsu K, Nakajima H. IL-5 and eosinophilia. Curr Opin Immunol. 2008;20:288–94. https://doi.org/10.1016/j.coi.2008.04.001.
Doherty TA. At the bench: understanding group 2 innate lymphoid cells in disease. J Leukoc Biol. 2015;97:455–67. https://doi.org/10.1189/jlb.5BT0814-374R.
Kouro T, Takatsu K. IL-5- and eosinophil-mediated inflammation: from discovery to therapy. Int Immunol. 2009;21:1303–9. https://doi.org/10.1093/intimm/dxp102.
Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985–93. https://doi.org/10.1056/NEJMoa0805435.
Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3:355–66. https://doi.org/10.1016/s2213-2600(15)00042-9.
Laviolette M, Gossage DL, Gauvreau G, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132:1086–96. https://doi.org/10.1016/j.jaci.2013.05.020.
Harish A, Schwartz SA. Targeted anti-IL-5 therapies and future therapeutics for hypereosinophilic syndrome and rare eosinophilic conditions. Clin Rev Allergy Immunol. 2020;59:231–47. https://doi.org/10.1007/s12016-019-08775-4.
Buttgereit T, Bonnekoh H, Church MK, et al. Effective treatment of a lymphocytic variant of hypereosinophilic syndrome with reslizumab. J Dtsch Dermatol Ges. 2019;17:1171–2. https://doi.org/10.1111/ddg.13926.
Plötz SG, Simon HU, Darsow U, et al. Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med. 2003;349:2334–9. https://doi.org/10.1056/NEJMoa031261.
Terhorst-Molawi D, Altrichter S, Röwert J, et al. Effective treatment with mepolizumab in a patient with refractory wells syndrome. J Dtsch Dermatol Ges. 2020;18:737–9. https://doi.org/10.1111/ddg.14151.
Shimizu K, Andoh T, Makino T, et al. Mechanisms of itching in mycosis fungoides: grade of itching correlates with eosinophil infiltration and kallikrein 5 expression. Eur J Dermatol. 2019;29:268–73. https://doi.org/10.1684/ejd.2019.3560.
Fredholm S, Gjerdrum LM, Willerslev-Olsen A, et al. STAT3 activation and infiltration of eosinophil granulocytes in mycosis fungoides. Anticancer Res. 2014;34:5277–86.
Tamachi T, Maezawa Y, Ikeda K, Iwamoto I, Nakajima H. Interleukin 25 in allergic airway inflammation. Int Arch Allergy Immunol. 2006;140(Suppl 1):59–62. https://doi.org/10.1159/000092713.
Kostareva OS, Gabdulkhakov AG, Kolyadenko IA, Garber MB, Tishchenko SV. Interleukin-17: functional and structural features, application as a therapeutic target. Biochemistry (Mosc). 2019;84:S193–205. https://doi.org/10.1134/s0006297919140116.
Valizadeh A, Khosravi A, Zadeh LJ, Parizad EG. Role of IL-25 in immunity. J Clin Diagn Res. 2015;9:Oe10. https://doi.org/10.7860/jcdr/2015/12235.5814.
Reynolds JM, Lee YH, Shi Y, et al. Interleukin-17B antagonizes interleukin-25-mediated mucosal inflammation. Immunity. 2015;42:692–703. https://doi.org/10.1016/j.immuni.2015.03.008.
Liu Y, Shao Z, Shangguan G, Bie Q, Zhang B. Biological properties and the role of IL-25 in disease pathogenesis. J Immunol Res. 2018;2018:6519465. https://doi.org/10.1155/2018/6519465.
Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C. Regulation of IL-9 expression by IL-25 signaling. Nat Immunol. 2010;11:250–6. https://doi.org/10.1038/ni.1846.
Senra L, Mylonas A, Kavanagh RD, et al. IL-17E (IL-25) enhances innate immune responses during skin inflammation. J Invest Dermatol. 2019;139:1732–42. https://doi.org/10.1016/j.jid.2019.01.021.
Aktar MK, Kido-Nakahara M, Furue M, Nakahara T. Mutual upregulation of endothelin-1 and IL-25 in atopic dermatitis. Allergy. 2015;70:846–54. https://doi.org/10.1111/all.12633.
Kido-Nakahara M, Buddenkotte J, Kempkes C, et al. Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. J Clin Invest. 2014;124:2683–95. https://doi.org/10.1172/jci67323.
Akiyama T, Carstens E. Neural processing of itch. Neuroscience. 2013;250:697–714. https://doi.org/10.1016/j.neuroscience.2013.07.035.
Ferreira SH, Romitelli M, de Nucci G. Endothelin-1 participation in overt and inflammatory pain. J Cardiovasc Pharmacol. 1989;13(Suppl 5):S220–2. https://doi.org/10.1097/00005344-198900135-00065.
McQueen DS, Noble MA, Bond SM. Endothelin-1 activates ETA receptors to cause reflex scratching in BALB/c mice. Br J Pharmacol. 2007;151:278–84. https://doi.org/10.1038/sj.bjp.0707216.
Tsybikov NN, Petrisheva IV, Kuznik BI, Magen E. Plasma endothelin-1 levels during exacerbation of atopic dermatitis. Allergy Asthma Proc. 2015;36:320–4. https://doi.org/10.2500/aap.2015.36.3846.
Jaworek AK, Szafraniec K, Zuber Z, Wojas-Pelc A, Jaworek J. Interleukin 25, thymic stromal lymphopoietin and house dust mites in pathogenesis of atopic dermatitis. J Physiol Pharmacol. 2020. https://doi.org/10.26402/jpp.2020.2.14.
Nakajima R, Miyagaki T, Hirakawa M, et al. Interleukin-25 is involved in cutaneous T-cell lymphoma progression by establishing a T helper 2-dominant microenvironment. Br J Dermatol. 2018;178:1373–82. https://doi.org/10.1111/bjd.16237.
Miyagaki T, Sugaya M. Erythrodermic cutaneous T-cell lymphoma: how to differentiate this rare disease from atopic dermatitis. J Dermatol Sci. 2011;64:1–6. https://doi.org/10.1016/j.jdermsci.2011.07.007.
Hermanns HM. Oncostatin M and interleukin-31: cytokines, receptors, signal transduction and physiology. Cytokine Growth Factor Rev. 2015;26:545–58. https://doi.org/10.1016/j.cytogfr.2015.07.006.
Takamori A, Nambu A, Sato K, et al. IL-31 is crucial for induction of pruritus, but not inflammation, in contact hypersensitivity. Sci Rep. 2018;8:6639. https://doi.org/10.1038/s41598-018-25094-4.
Andoh T, Harada A, Kuraishi Y. Involvement of leukotriene B4 released from keratinocytes in itch-associated response to intradermal interleukin-31 in mice. Acta Derm Venereol. 2017;97:922–7. https://doi.org/10.2340/00015555-2697.
Raap U, Gehring M, Kleiner S, et al. Human basophils are a source of - and are differentially activated by - IL-31. Clin Exp Allergy. 2017;47:499–508. https://doi.org/10.1111/cea.12875.
Hashimoto T, Kursewicz CD, Fayne RA, et al. Mechanisms of itch in stasis dermatitis: significant role of IL-31 from macrophages. J Invest Dermatol. 2020;140:850–9. https://doi.org/10.1016/j.jid.2019.09.012.
Hashimoto T, Satoh T, Yokozeki H. Pruritus in ordinary scabies: IL-31 from macrophages induced by overexpression of thymic stromal lymphopoietin and periostin. Allergy. 2019;74:1727–37. https://doi.org/10.1111/all.13870.
Guarneri F, Minciullo PL, Mannucci C, et al. IL-31 and IL-33 circulating levels in allergic contact dermatitis. Eur Ann Allergy Clin Immunol. 2015;47:156–8.
Ruzicka T, Hanifin JM, Furue M, et al. Anti-Interleukin-31 receptor a antibody for atopic dermatitis. N Engl J Med. 2017;376:826–35. https://doi.org/10.1056/NEJMoa1606490.
Kabashima K, Furue M, Hanifin JM, et al. Nemolizumab in patients with moderate-to-severe atopic dermatitis: randomized, phase II, long-term extension study. J Allergy Clin Immunol. 2018;142:1121-1130.e1127. https://doi.org/10.1016/j.jaci.2018.03.018.
Silverberg JI, Pinter A, Pulka G, et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus. J Allergy Clin Immunol. 2020;145:173–82. https://doi.org/10.1016/j.jaci.2019.08.013.
Ständer S, Yosipovitch G, Legat FJ, et al. Trial of nemolizumab in moderate-to-severe prurigo nodularis. N Engl J Med. 2020;382:706–16. https://doi.org/10.1056/NEJMoa1908316.
Tsoi LC, Hacini-Rachinel F, Fogel P, et al. Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab. J Allergy Clin Immunol. 2021. https://doi.org/10.1016/j.jaci.2021.10.004.
Ohmatsu H, Sugaya M, Suga H, et al. Serum IL-31 levels are increased in patients with cutaneous T-cell lymphoma. Acta Derm Venereol. 2012;92:282–3. https://doi.org/10.2340/00015555-1345.
Malek M, Gleń J, Rębała K, et al. Il-31 does not correlate to pruritus related to early stage cutaneous T-cell lymphomas but is involved in pathogenesis of the disease. Acta Derm Venereol. 2015;95:283–8. https://doi.org/10.2340/00015555-1958.
Abreu M, Miranda M, Castro M, et al. IL-31 and IL-8 in cutaneous T-cell lymphoma: looking for their role in itch. Adv Hematol. 2021;2021:5582–2581. https://doi.org/10.1155/2021/5582581.
van Santen S, Out JJ, Zoutman WH, et al. Serum and cutaneous transcriptional expression levels of IL31 are minimal in cutaneous T cell lymphoma variants. Biochem Biophys Rep. 2021;26:101007. https://doi.org/10.1016/j.bbrep.2021.101007.
Singer EM, Shin DB, Nattkemper LA, et al. IL-31 is produced by the malignant T-cell population in cutaneous T-Cell lymphoma and correlates with CTCL pruritus. J Invest Dermatol. 2013;133:2783–5. https://doi.org/10.1038/jid.2013.227.
Nattkemper LA, Martinez-Escala ME, Gelman AB, et al. Cutaneous T-cell lymphoma and pruritus: the expression of IL-31 and its receptors in the skin. Acta Derm Venereol. 2016;96:894–8. https://doi.org/10.2340/00015555-2417.
Sokol CL, Luster AD. The chemokine system in innate immunity. Cold Spring Harb Perspect Biol. 2015. https://doi.org/10.1101/cshperspect.a016303.
Huber AK, Giles DA, Segal BM, Irani DN. An emerging role for eotaxins in neurodegenerative disease. Clin Immunol. 2018;189:29–33. https://doi.org/10.1016/j.clim.2016.09.010.
Schaerli P, Ebert L, Willimann K, et al. A skin-selective homing mechanism for human immune surveillance T cells. J Exp Med. 2004;199:1265–75. https://doi.org/10.1084/jem.20032177.
Saito M, Sejima H, Naito T, et al. The CC chemokine ligand (CCL) 1, upregulated by the viral transactivator Tax, can be downregulated by minocycline: possible implications for long-term treatment of HTLV-1-associated myelopathy/tropical spastic paraparesis. Virol J. 2017;14:234. https://doi.org/10.1186/s12985-017-0902-6.
Miyagawa Y, Murakami A, Ebihara N. The proteolytic effect of mast cell tryptase to eotaxin-1/CCL11·eotaxin-2/CCL24 and eotaxin-3/CCL26 produced by conjunctival fibroblasts. Jpn J Ophthalmol. 2019;63:215–20. https://doi.org/10.1007/s10384-019-00655-w.
Akimoto N, Honda K, Uta D, et al. CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury. Cell Death Dis. 2013;4:e679. https://doi.org/10.1038/cddis.2013.198.
Fujimoto T, Imaeda H, Takahashi K, et al. Eotaxin-3 (CCL26) expression in human pancreatic myofibroblasts. Pancreas. 2016;45:420–4. https://doi.org/10.1097/mpa.0000000000000480.
Grozdanovic M, Laffey KG, Abdelkarim H, et al. Novel peptide nanoparticle-biased antagonist of CCR3 blocks eosinophil recruitment and airway hyperresponsiveness. J Allergy Clin Immunol. 2019;143:669–80. https://doi.org/10.1016/j.jaci.2018.05.003.
Gombert M, Dieu-Nosjean MC, Winterberg F, et al. CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and Langerhans-type dendritic cells to sites of atopic skin inflammation. J Immunol. 2005;174:5082–91. https://doi.org/10.4049/jimmunol.174.8.5082.
Kowalski EH, Kneibner D, Kridin K, Amber KT. Serum and blister fluid levels of cytokines and chemokines in pemphigus and bullous pemphigoid. Autoimmun Rev. 2019;18:526–34. https://doi.org/10.1016/j.autrev.2019.03.009.
Miyagaki T, Sugaya M, Kagami S, et al. Increased CCL1 levels in the sera and blister fluid of patients with bullous pemphigoid. J Dermatol Sci. 2009;54:45–7. https://doi.org/10.1016/j.jdermsci.2008.10.012.
Miyagaki T, Sugaya M, Fujita H, et al. Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma. J Invest Dermatol. 2010;130:2304–11. https://doi.org/10.1038/jid.2010.128.
Suga H, Sugaya M, Miyagaki T, et al. Association of nerve growth factor, chemokine (C-C motif) ligands and immunoglobulin E with pruritus in cutaneous T-cell lymphoma. Acta Derm Venereol. 2013;93:144–9. https://doi.org/10.2340/00015555-1428.
Ziegler SF, Roan F, Bell BD, et al. The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol. 2013;66:129–55. https://doi.org/10.1016/b978-0-12-404717-4.00004-4.
Corren J, Ziegler SF. TSLP: from allergy to cancer. Nat Immunol. 2019;20:1603–9. https://doi.org/10.1038/s41590-019-0524-9.
Li S, Yi Z, Deng M, et al. TSLP protects against liver I/R injury via activation of the PI3K/Akt pathway. JCI Insight. 2019. https://doi.org/10.1172/jci.insight.129013.
He R, Geha RS. Thymic stromal lymphopoietin. Ann N Y Acad Sci. 2010;1183:13–24. https://doi.org/10.1111/j.1749-6632.2009.05128.x.
Xia Q, Liu T, Wang J, et al. Mast cells and thymic stromal lymphopoietin (TSLP) expression positively correlates with pruritus intensity in dermatitis herpetiformis. Eur J Dermatol. 2020;30:499–504. https://doi.org/10.1684/ejd.2020.3881.
Simpson EL, Parnes JR, She D, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80:1013–21. https://doi.org/10.1016/j.jaad.2018.11.059.
Miyagaki T, Sugaya M, Fujita H, Saeki H, Tamaki K. Increased serum thymic stromal lymphopoietin levels in patients with cutaneous T cell lymphoma. Clin Exp Dermatol. 2009;34:539–40. https://doi.org/10.1111/j.1365-2230.2008.02990.x.
Tuzova M, Richmond J, Wolpowitz D, et al. CCR4+T cell recruitment to the skin in mycosis fungoides: potential contributions by thymic stromal lymphopoietin and interleukin-16. Leuk Lymphoma. 2015;56:440–9. https://doi.org/10.3109/10428194.2014.919634.
Rocco ML, Soligo M, Manni L, Aloe L. Nerve growth factor: early studies and recent clinical trials. Curr Neuropharmacol. 2018;16:1455–65. https://doi.org/10.2174/1570159x16666180412092859.
Ebendal T. Function and evolution in the NGF family and its receptors. J Neurosci Res. 1992;32:461–70. https://doi.org/10.1002/jnr.490320402.
Aarão TLS, de Sousa JR, Falcão ASC, Falcão LFM, Quaresma JAS. Nerve growth factor and pathogenesis of leprosy: review and update. Front Immunol. 2018;9:939. https://doi.org/10.3389/fimmu.2018.00939.
Skoff AM, Adler JE. Nerve growth factor regulates substance P in adult sensory neurons through both TrkA and p75 receptors. Exp Neurol. 2006;197:430–6. https://doi.org/10.1016/j.expneurol.2005.10.006.
Pincelli C. p75 Neurotrophin receptor in the skin: beyond its neurotrophic function. Front Med (Lausanne). 2017;4:22. https://doi.org/10.3389/fmed.2017.00022.
Toyoda M, Nakamura M, Makino T, et al. Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol. 2002;147:71–9. https://doi.org/10.1046/j.1365-2133.2002.04803.x.
Dou YC, Hagströmer L, Emtestam L, Johansson O. Increased nerve growth factor and its receptors in atopic dermatitis: an immunohistochemical study. Arch Dermatol Res. 2006;298:31–7. https://doi.org/10.1007/s00403-006-0657-1.
Johansson O, Liang Y, Emtestam L. Increased nerve growth factor- and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin: an exploration of the cause of neurohyperplasia. Arch Dermatol Res. 2002;293:614–9. https://doi.org/10.1007/s00403-001-0285-8.
Chang SE, Han SS, Jung HJ, Choi JH. Neuropeptides and their receptors in psoriatic skin in relation to pruritus. Br J Dermatol. 2007;156:1272–7. https://doi.org/10.1111/j.1365-2133.2007.07935.x.
Nakamura M, Toyoda M, Morohashi M. Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors. Br J Dermatol. 2003;149:718–30. https://doi.org/10.1046/j.1365-2133.2003.05586.x.
Roblin D, Yosipovitch G, Boyce B, et al. Topical TrkA kinase inhibitor CT327 is an effective, novel therapy for the treatment of pruritus due to psoriasis: results from experimental studies, and efficacy and safety of CT327 in a phase 2b clinical trial in patients with psoriasis. Acta Derm Venereol. 2015;95:542–8. https://doi.org/10.2340/00015555-2047.
Mistrova E, Kruzliak P, Chottova Dvorakova M. Role of substance P in the cardiovascular system. Neuropeptides. 2016;58:41–51. https://doi.org/10.1016/j.npep.2015.12.005.
Zieglgänsberger W. Substance P and pain chronicity. Cell Tissue Res. 2019;375:227–41. https://doi.org/10.1007/s00441-018-2922-y.
Mashaghi A, Marmalidou A, Tehrani M, et al. Neuropeptide substance P and the immune response. Cell Mol Life Sci. 2016;73:4249–64. https://doi.org/10.1007/s00018-016-2293-z.
McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519:237–41. https://doi.org/10.1038/nature14022.
Azimi E, Reddy VB, Pereira PJS, et al. Substance P activates mas-related G protein-coupled receptors to induce itch. J Allergy Clin Immunol. 2017;140:447–53. https://doi.org/10.1016/j.jaci.2016.12.980.
Porebski G, Kwiecien K, Pawica M, Kwitniewski M. Mas-Related G protein-coupled receptor-X2 (MRGPRX2) in drug hypersensitivity reactions. Front Immunol. 2018;9:3027. https://doi.org/10.3389/fimmu.2018.03027.
Teresiak-Mikołajczak E, Czarnecka-Operacz M, Jenerowicz D, Silny W. Neurogenic markers of the inflammatory process in atopic dermatitis: relation to the severity and pruritus. Postepy Dermatol Alergol. 2013;30:286–92. https://doi.org/10.5114/pdia.2013.38357.
Amatya B, El-Nour H, Holst M, Theodorsson E, Nordlind K. Expression of tachykinins and their receptors in plaque psoriasis with pruritus. Br J Dermatol. 2011;164:1023–9. https://doi.org/10.1111/j.1365-2133.2011.10241.x.
Nattkemper LA, Tey HL, Valdes-Rodriguez R, et al. The genetics of chronic itch: gene expression in the skin of patients with atopic dermatitis and psoriasis with severe itch. J Invest Dermatol. 2018;138:1311–7. https://doi.org/10.1016/j.jid.2017.12.029.
Haas S, Capellino S, Phan NQ, et al. Low density of sympathetic nerve fibers relative to substance P-positive nerve fibers in lesional skin of chronic pruritus and prurigo nodularis. J Dermatol Sci. 2010;58:193–7. https://doi.org/10.1016/j.jdermsci.2010.03.020.
Pincelli C, Fantini F, Massimi P, et al. Neuropeptides in skin from patients with atopic dermatitis: an immunohistochemical study. Br J Dermatol. 1990;122:745–50. https://doi.org/10.1111/j.1365-2133.1990.tb06261.x.
Metz M, Krull C, Hawro T, et al. Substance P is upregulated in the serum of patients with chronic spontaneous urticaria. J Invest Dermatol. 2014;134:2833–6. https://doi.org/10.1038/jid.2014.226.
Agelopoulos K, Rülander F, Dangelmaier J, et al. Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation. J Eur Acad Dermatol Venereol. 2019;33:2371–9. https://doi.org/10.1111/jdv.15905.
Ally MS, Gamba CS, Peng DH, Tang JY. The use of aprepitant in brachioradial pruritus. JAMA Dermatol. 2013;149:627–8. https://doi.org/10.1001/jamadermatol.2013.170.
Santini D, Vincenzi B, Guida FM, et al. Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol. 2012;13:1020–4. https://doi.org/10.1016/s1470-2045(12)70373-x.
Ito J, Fujimoto D, Nakamura A, et al. Aprepitant for refractory nivolumab-induced pruritus. Lung Cancer. 2017;109:58–61. https://doi.org/10.1016/j.lungcan.2017.04.020.
Vincenzi B, Tonini G, Santini D. Aprepitant for erlotinib-induced pruritus. N Engl J Med. 2010;363:397–8. https://doi.org/10.1056/NEJMc1003937.
Villafranca JJ, Siles MG, Casanova M, Goitia BT, Domínguez AR. Paraneoplastic pruritus presenting with Hodgkin’s lymphoma: a case report. J Med Case Rep. 2014;8:300. https://doi.org/10.1186/1752-1947-8-300.
Damiani G, Kridin K, Pacifico A, et al. Antihistamines-refractory chronic pruritus in psoriatic patients undergoing biologics: aprepitant versus antihistamine double dosage, a real-world data. J Dermatol Treat. 2020. https://doi.org/10.1080/09546634.2020.1840502.
He A, Alhariri JM, Sweren RJ, Kwatra MM, Kwatra SG. Aprepitant for the treatment of chronic refractory pruritus. Biomed Res Int. 2017;2017:4790810. https://doi.org/10.1155/2017/4790810.
Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 2010;5:e10968. https://doi.org/10.1371/journal.pone.0010968.
Tsianakas A, Zeidler C, Riepe C, et al. Aprepitant in anti-histamine-refractory chronic nodular prurigo: a multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II trial (APREPRU). Acta Derm Venereol. 2019;99:379–85. https://doi.org/10.2340/00015555-3120.
Wallengren J. Topical aprepitant in clinical and experimental pruritus. Arch Dermatol. 2012;148:957–9. https://doi.org/10.1001/archdermatol.2012.1018.
Ständer S, Kwon P, Hirman J, et al. Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial. J Am Acad Dermatol. 2019;80:1395–402. https://doi.org/10.1016/j.jaad.2019.01.052.
Pariser DM, Bagel J, Lebwohl M, et al. Serlopitant for psoriatic pruritus: a phase 2 randomized, double-blind, placebo-controlled clinical trial. J Am Acad Dermatol. 2020;82:1314–20. https://doi.org/10.1016/j.jaad.2020.01.056.
Yosipovitch G, Ständer S, Kerby MB, et al. Serlopitant for the treatment of chronic pruritus: results of a randomized, multicenter, placebo-controlled phase 2 clinical trial. J Am Acad Dermatol. 2018;78:882–91. https://doi.org/10.1016/j.jaad.2018.02.030.
Chiou AS, Choi S, Barriga M, et al. Phase 2 trial of a neurokinin-1 receptor antagonist for the treatment of chronic itch in patients with epidermolysis bullosa: a randomized clinical trial. J Am Acad Dermatol. 2020;82:1415–21. https://doi.org/10.1016/j.jaad.2019.09.014.
Ständer S, Spellman MC, Kwon P, Yosipovitch G. The NK1 receptor antagonist serlopitant for treatment of chronic pruritus. Expert Opin Investig Drugs. 2019;28:659–66. https://doi.org/10.1080/13543784.2019.1638910.
Welsh SE, Xiao C, Kaden AR, et al. Neurokinin-1 receptor antagonist tradipitant has mixed effects on itch in atopic dermatitis: results from EPIONE, a randomized clinical trial. J Eur Acad Dermatol Venereol. 2021;35:e338–40. https://doi.org/10.1111/jdv.17090.
Trower MK, Fisher A, Upton N, Ratti E. Neurokinin-1 receptor antagonist orvepitant is an effective inhibitor of itch-associated response in a mongolian gerbil model of scratching behaviour. Exp Dermatol. 2014;23:858–60. https://doi.org/10.1111/exd.12528.
Pojawa-Gołąb M, Jaworecka K, Reich A. NK-1 receptor antagonists and pruritus: review of current literature. Dermatol Ther (Heidelb). 2019;9:391–405. https://doi.org/10.1007/s13555-019-0305-2.
Tuzova M, Conniff T, Curiel-Lewandrowski C, et al. Absence of full-length neurokinin-1 receptor protein expression by cutaneous T cells: implications for substance P-mediated signaling in mycosis fungoides. Acta Derm Venereol. 2015;95:852–4. https://doi.org/10.2340/00015555-2097.
Maroñas-Jiménez L, Estrach T, Gallardo F, et al. Aprepitant improves refractory pruritus in primary cutaneous T-cell lymphomas: experience of the spanish working group on cutaneous lymphomas. Br J Dermatol. 2018;178:e273–4. https://doi.org/10.1111/bjd.16128.
Song JS, Tawa M, Chau NG, Kupper TS, LeBoeuf NR. Aprepitant for refractory cutaneous T-cell lymphoma-associated pruritus: 4 cases and a review of the literature. BMC Cancer. 2017;17:200. https://doi.org/10.1186/s12885-017-3194-8.
Duval A, Dubertret L. Aprepitant as an antipruritic agent? N Engl J Med. 2009;361:1415–6. https://doi.org/10.1056/NEJMc0906670.
Torres T, Fernandes I, Selores M, Alves R, Lima M. Aprepitant: evidence of its effectiveness in patients with refractory pruritus continues. J Am Acad Dermatol. 2012;66:e14–5. https://doi.org/10.1016/j.jaad.2011.01.016.
Ladizinski B, Bazakas A, Olsen EA. Aprepitant: a novel neurokinin-1 receptor/substance P antagonist as antipruritic therapy in cutaneous T-cell lymphoma. J Am Acad Dermatol. 2012;67:e198–9. https://doi.org/10.1016/j.jaad.2012.02.008.
Booken N, Heck M, Nicolay JP, et al. Oral aprepitant in the therapy of refractory pruritus in erythrodermic cutaneous T-cell lymphoma. Br J Dermatol. 2011;164:665–7. https://doi.org/10.1111/j.1365-2133.2010.10108.x.
Zic JA, Straka BT, McGirt LY, et al. Aprepitant for the treatment of pruritus in sézary syndrome: a randomized crossover clinical trial. JAMA Dermatol. 2018;154:1221–2. https://doi.org/10.1001/jamadermatol.2018.2510.
Hoeben A, Landuyt B, Highley MS, et al. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56:549–80. https://doi.org/10.1124/pr.56.4.3.
de Ruiz Almodovar C, Lambrechts D, Mazzone M, Carmeliet P. Role and therapeutic potential of VEGF in the nervous system. Physiol Rev. 2009;89:607–48. https://doi.org/10.1152/physrev.00031.2008.
Wong LS, Otsuka A, Yamamoto Y, et al. Vascular endothelial growth factor partially induces pruritus via epidermal hyperinnervation in imiquimod-induced psoriasiform dermatitis in mice. J Dermatol Sci. 2016;83:148–51. https://doi.org/10.1016/j.jdermsci.2016.04.008.
Amarbayasgalan T, Takahashi H, Dekio I, Morita E. Content of vascular endothelial growth factor in stratum corneum well correlates to local severity of acute inflammation in patients with atopic dermatitis. Int Arch Allergy Immunol. 2012;157:251–8. https://doi.org/10.1159/000327556.
Zhang Y, Matsuo H, Morita E. Increased production of vascular endothelial growth factor in the lesions of atopic dermatitis. Arch Dermatol Res. 2006;297:425–9. https://doi.org/10.1007/s00403-006-0641-9.
Samochocki Z, Bogaczewicz J, Sysa-Jędrzejowska A, et al. Expression of vascular endothelial growth factor and other cytokines in atopic dermatitis, and correlation with clinical features. Int J Dermatol. 2016;55:e141-146. https://doi.org/10.1111/ijd.13132.
Krull C, Schoepke N, Ohanyan T, et al. Increased angiogenesis and VEGF expression correlates with disease severity in prurigo patients. J Eur Acad Dermatol Venereol. 2016;30:1357–61. https://doi.org/10.1111/jdv.13406.
Krause K, Krull C, Kessler B, et al. Effective control of recalcitrant pruritus by bevacizumab: A possible role for vascular endothelial growth factor in chronic itch? Acta Derm Venereol. 2013;93:175–9. https://doi.org/10.2340/00015555-1445.
Sakamoto M, Miyagaki T, Kamijo H, et al. Serum vascular endothelial growth factor A levels reflect itch severity in mycosis fungoides and sézary syndrome. J Dermatol. 2018;45:95–9. https://doi.org/10.1111/1346-8138.14033.
Masurier N, Arama DP, El Amri C, Lisowski V. Inhibitors of kallikrein-related peptidases: an overview. Med Res Rev. 2018;38:655–83. https://doi.org/10.1002/med.21451.
Nielsen VG, Frank N. The kallikrein-like activity of Heloderma venom is inhibited by carbon monoxide. J Thromb Thrombolysis. 2019;47:533–9. https://doi.org/10.1007/s11239-019-01853-6.
Debela M, Beaufort N, Magdolen V, et al. Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7. Biol Chem. 2008;389:623–32. https://doi.org/10.1515/bc.2008.075.
Kishibe M. Physiological and pathological roles of kallikrein-related peptidases in the epidermis. J Dermatol Sci. 2019;95:50–5. https://doi.org/10.1016/j.jdermsci.2019.06.007.
Shaw JL, Diamandis EP. Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem. 2007;53:1423–32. https://doi.org/10.1373/clinchem.2007.088104.
Furio L, de Veer S, Jaillet M, et al. Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of netherton syndrome. J Exp Med. 2014;211:499–513. https://doi.org/10.1084/jem.20131797.
Stefansson K, Brattsand M, Roosterman D, et al. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J Invest Dermatol. 2008;128:18–25. https://doi.org/10.1038/sj.jid.5700965.
Lee MS, Lerner EA. Targeting PAR2 with pepducins. J Invest Dermatol. 2019;139:282–4. https://doi.org/10.1016/j.jid.2018.09.008.
Ruppenstein A, Limberg MM, Loser K, et al. Involvement of neuro-immune interactions in pruritus with special focus on receptor expressions. Front Med (Lausanne). 2021;8:627985. https://doi.org/10.3389/fmed.2021.627985.
Komatsu N, Saijoh K, Kuk C, et al. Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients. Exp Dermatol. 2007;16:513–9. https://doi.org/10.1111/j.1600-0625.2007.00562.x.
Zhu Y, Underwood J, Macmillan D, et al. Persistent kallikrein 5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity. J Allergy Clin Immunol. 2017;140:1310-1322.e1315. https://doi.org/10.1016/j.jaci.2017.01.025.
Andoh T, Tsujii K, Kuraishi Y. Increase in pruritogenic kallikrein 5 in the skin of NC mice with chronic dermatitis. Exp Dermatol. 2015;24:978–80. https://doi.org/10.1111/exd.12828.
Caughey GH. Tryptase genetics and anaphylaxis. J Allergy Clin Immunol. 2006;117:1411–4. https://doi.org/10.1016/j.jaci.2006.02.026.
Ni WW, Cao MD, Huang W, Meng L, Wei JF. Tryptase inhibitors: a patent review. Expert Opin Ther Pat. 2017;27:919–28. https://doi.org/10.1080/13543776.2017.1322064.
Payne V, Kam PC. Mast cell tryptase: a review of its physiology and clinical significance. Anaesthesia. 2004;59:695–703. https://doi.org/10.1111/j.1365-2044.2004.03757.x.
Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316:1622–6. https://doi.org/10.1056/nejm198706253162603.
Dugas-Breit S, Schöpf P, Dugas M, et al. Baseline serum levels of mast cell tryptase are raised in hemodialysis patients and associated with severity of pruritus. J Dtsch Dermatol Ges. 2005;3:343–7. https://doi.org/10.1111/j.1610-0387.2005.05706.x.
Steinhoff M, Neisius U, Ikoma A, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci. 2003;23:6176–80. https://doi.org/10.1523/jneurosci.23-15-06176.2003.
Kawakami T, Kaminishi K, Soma Y, Kushimoto T, Mizoguchi M. Oral antihistamine therapy influences plasma tryptase levels in adult atopic dermatitis. J Dermatol Sci. 2006;43:127–34. https://doi.org/10.1016/j.jdermsci.2006.04.002.
Tsujii K, Andoh T, Ui H, Lee JB, Kuraishi Y. Involvement of tryptase and proteinase-activated receptor-2 in spontaneous itch-associated response in mice with atopy-like dermatitis. J Pharmacol Sci. 2009;109:388–95. https://doi.org/10.1254/jphs.08332fp.
Che D, Gao J, Du X, et al. p-Phenylenediamine induces immediate contact allergy and non-histaminergic itch via MRGPRX2. Chem Biol Interact. 2022;351:109751. https://doi.org/10.1016/j.cbi.2021.109751.
Zhu Y, Pan WH, Wang XR, et al. Tryptase and protease-activated receptor-2 stimulate scratching behavior in a murine model of ovalbumin-induced atopic-like dermatitis. Int Immunopharmacol. 2015;28:507–12. https://doi.org/10.1016/j.intimp.2015.04.047.
Ui H, Andoh T, Lee JB, Nojima H, Kuraishi Y. Potent pruritogenic action of tryptase mediated by PAR-2 receptor and its involvement in anti-pruritic effect of nafamostat mesilate in mice. Eur J Pharmacol. 2006;530:172–8. https://doi.org/10.1016/j.ejphar.2005.11.021.
Terhorst-Molawi D, Lohse K, Ginter K, et al. Mast cells and tryptase are linked to itch and disease severity in mycosis fungoides: results of a pilot study. Front Immunol. 2022;13:930979. https://doi.org/10.3389/fimmu.2022.930979.
Meixiong J, Vasavda C, Snyder SH, Dong X. MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus. Proc Natl Acad Sci U S A. 2019;116:10525–30. https://doi.org/10.1073/pnas.1903316116.
Cao C, Kang HJ, Singh I, et al. Structure, function and pharmacology of human itch GPCRs. Nature. 2021;600:170–5. https://doi.org/10.1038/s41586-021-04126-6.
Bader M, Alenina N, Andrade-Navarro MA, Santos RA. MAS and its related G protein-coupled receptors. Mrgprs Pharmacol Rev. 2014;66:1080–105. https://doi.org/10.1124/pr.113.008136.
Lembo PM, Grazzini E, Groblewski T, et al. Proenkephalin A gene products activate a new family of sensory neuron–specific GPCRs. Nat Neurosci. 2002;5:201–9. https://doi.org/10.1038/nn815.
Liu Q, Tang Z, Surdenikova L, et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell. 2009;139:1353–65. https://doi.org/10.1016/j.cell.2009.11.034.
Meixiong J, Anderson M, Limjunyawong N, et al. Activation of mast-cell-expressed mas-related G-protein-coupled receptors drives non-histaminergic itch. Immunity. 2019;50:1163-1171.e1165. https://doi.org/10.1016/j.immuni.2019.03.013.
Yu H, Zhao T, Liu S, et al. MRGPRX4 is a bile acid receptor for human cholestatic itch. Elife. 2019;8:e48431. https://doi.org/10.7554/eLife.48431.
Holden JE, Jeong Y, Forrest JM. The endogenous opioid system and clinical pain management. AACN Clin Issues. 2005;16:291–301. https://doi.org/10.1097/00044067-200507000-00003.
Satoh M, Minami M. Molecular pharmacology of the opioid receptors. Pharmacol Ther. 1995;68:343–64. https://doi.org/10.1016/0163-7258(95)02011-x.
Kupczyk P, Reich A, Hołysz M, et al. Opioid receptors in psoriatic skin: relationship with itch. Acta Derm Venereol. 2017;97:564–70. https://doi.org/10.2340/00015555-2595.
Melo H, Basso L, Iftinca M, et al. Itch induced by peripheral mu opioid receptors is dependent on TRPV1-expressing neurons and alleviated by channel activation. Sci Rep. 2018;8:15551. https://doi.org/10.1038/s41598-018-33620-7.
Lee J, Shin JU, Noh S, Park CO, Lee KH. Clinical efficacy and safety of naltrexone combination therapy in older patients with severe pruritus. Ann Dermatol. 2016;28:159–63. https://doi.org/10.5021/ad.2016.28.2.159.
Monroe EW. Efficacy and safety of nalmefene in patients with severe pruritus caused by chronic urticaria and atopic dermatitis. J Am Acad Dermatol. 1989;21:135–6. https://doi.org/10.1016/s0190-9622(89)80353-6.
Phan NQ, Bernhard JD, Luger TA, Ständer S. Antipruritic treatment with systemic μ-opioid receptor antagonists: a review. J Am Acad Dermatol. 2010;63:680–8. https://doi.org/10.1016/j.jaad.2009.08.052.
Murray-Brown FL. Naltrexone for cholestatic itch: a systematic review. BMJ Support Palliat Care. 2021;11:217–25. https://doi.org/10.1136/bmjspcare-2020-002801.
Bigliardi PL, Stammer H, Jost G, et al. Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol. 2007;56:979–88. https://doi.org/10.1016/j.jaad.2007.01.007.
Lee B, Elston DM. The uses of naltrexone in dermatologic conditions. J Am Acad Dermatol. 2019;80:1746–52. https://doi.org/10.1016/j.jaad.2018.12.031.
Joshi GG, Thakur BS, Sircar S, Namdeo A, Jain AK. Role of intravenous naloxone in severe pruritus of acute cholestasis. Indian J Gastroenterol. 2009;28:180–2. https://doi.org/10.1007/s12664-009-0070-8.
Kremer AE, Beuers U, Oude-Elferink RP, Pusl T. Pathogenesis and treatment of pruritus in cholestasis. Drugs. 2008;68:2163–82. https://doi.org/10.2165/00003495-200868150-00006.
Bergasa NV, Alling DW, Talbot TL, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med. 1995;123:161–7. https://doi.org/10.7326/0003-4819-123-3-199508010-00001.
Wang Z, Jiang C, Yao H, et al. Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition. Brain. 2021;144:665–81. https://doi.org/10.1093/brain/awaa430.
Pirie K, Doane MA, Riedel B, Myles PS. Analgesia for major laparoscopic abdominal surgery: a randomised feasibility trial using intrathecal morphine. Anaesthesia. 2022. https://doi.org/10.1111/anae.15651.
Weigl W, Bieryło A, Wielgus M, et al. Perioperative analgesia after intrathecal fentanyl and morphine or morphine alone for cesarean section: a randomized controlled study. Medicine (Baltimore). 2017;96:e8892. https://doi.org/10.1097/md.0000000000008892.
Fishbane S, Jamal A, Munera C, Wen W, Menzaghi F. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N Engl J Med. 2020;382:222–32. https://doi.org/10.1056/NEJMoa1912770.
Fishbane S, Mathur V, Germain MJ, et al. Randomized controlled trial of difelikefalin for chronic pruritus in hemodialysis patients. Kidney Int Rep. 2020;5:600–10. https://doi.org/10.1016/j.ekir.2020.01.006.
Deeks ED. Difelikefalin: first approval. Drugs. 2021;81:1937–44. https://doi.org/10.1007/s40265-021-01619-6.
Wikström B, Gellert R, Ladefoged SD, et al. Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol. 2005;16:3742–7. https://doi.org/10.1681/asn.2005020152.
Yoshikawa S, Asano T, Morino M, et al. Pruritus is common in patients with chronic liver disease and is improved by nalfurafine hydrochloride. Sci Rep. 2021;11:3015. https://doi.org/10.1038/s41598-021-82566-w.
Kumagai H, Ebata T, Takamori K, et al. Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant. 2010;25:1251–7. https://doi.org/10.1093/ndt/gfp588.
Kozono H, Yoshitani H, Nakano R. Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch(®) capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus. Int J Nephrol Renovasc Dis. 2018;11:9–24. https://doi.org/10.2147/ijnrd.S145720.
Miyamoto Y, Oh T, Aihara E, Ando A. Clinical profiles of nalfurafine hydrochloride for the treatment of pruritus patients. Handb Exp Pharmacol. 2022;271:455–72. https://doi.org/10.1007/164_2020_400.
Kumada H, Miyakawa H, Muramatsu T, et al. Efficacy of nalfurafine hydrochloride in patients with chronic liver disease with refractory pruritus: a randomized, double-blind trial. Hepatol Res. 2017;47:972–82. https://doi.org/10.1111/hepr.12830.
Charuluxananan S, Kyokong O, Somboonviboon W, Narasethakamol A, Promlok P. Nalbuphine versus ondansetron for prevention of intrathecal morphine-induced pruritus after cesarean delivery. Anesth Analg. 2003;96:1789–93. https://doi.org/10.1213/01.Ane.0000066015.21364.7d.
Alhashemi JA, Crosby ET, Grodecki W, et al. Treatment of intrathecal morphine-induced pruritus following caesarean section. Can J Anaesth. 1997;44:1060–5. https://doi.org/10.1007/bf03019227.
Weisshaar E, Szepietowski JC, Bernhard JD, et al. Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase. J Eur Acad Dermatol Venereol. 2021. https://doi.org/10.1111/jdv.17816.
Mathur VS, Kumar J, Crawford PW, Hait H, Sciascia T. A multicenter, randomized, double-blind, placebo-controlled trial of nalbuphine ER tablets for uremic pruritus. Am J Nephrol. 2017;46:450–8. https://doi.org/10.1159/000484573.
Hawi A, Alcorn H Jr, Berg J, et al. Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus. BMC Nephrol. 2015;16:47. https://doi.org/10.1186/s12882-015-0043-3.
Wu Z, Kong M, Chen J, et al. Continous epidural butorphanol decreases the incidence of intrathecal morphine-related pruritus after cesarean section: a randomized, double-blinded, placebo-controlled trial: epidural butorphanol decreases the incidence of intrathecal morphine-related pruritus. Cell Biochem Biophys. 2014;70:209–13. https://doi.org/10.1007/s12013-014-9884-9.
Wu Z, Kong M, Wang N, Finlayson RJ, Tran QH. Intravenous butorphanol administration reduces intrathecal morphine-induced pruritus after cesarean delivery: a randomized, double-blind, placebo-controlled study. J Anesth. 2012;26:752–7. https://doi.org/10.1007/s00540-012-1421-7.
Golpanian RS, Yosipovitch G, Levy C. Use of butorphanol as treatment for cholestatic itch. Dig Dis Sci. 2021;66:1693–9. https://doi.org/10.1007/s10620-020-06392-2.
Ingrasci G, Arbrouk M, Haitz K, Kirsner R, Yosipovitch G. A protracted, postherpetic neuralgic ulcer treated with risperidone and intranasal butorphanol. JAAD Case Rep. 2021;15:7–10. https://doi.org/10.1016/j.jdcr.2021.06.026.
Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol. 2006;54:527–31. https://doi.org/10.1016/j.jaad.2005.12.010.
Khanna R, Kwon CD, Patel SP, et al. Intranasal butorphanol rescue therapy for the treatment of intractable pruritus: a case series from the Johns Hopkins itch clinic. J Am Acad Dermatol. 2020;83:1529–33. https://doi.org/10.1016/j.jaad.2020.07.017.
Brune A, Metze D, Luger TA, Ständer S. Antipruritic therapy with the oral opioid receptor antagonist naltrexone. Open, non-placebo controlled administration in 133 patients. Hautarzt. 2004;55:1130–6. https://doi.org/10.1007/s00105-004-0802-8.
Metze D, Reimann S, Beissert S, Luger T. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases. J Am Acad Dermatol. 1999;41:533–9.
Ekelem C, Juhasz M, Khera P, Mesinkovska NA. Utility of naltrexone treatment for chronic inflammatory dermatologic conditions: a systematic review. JAMA Dermatol. 2019;155:229–36. https://doi.org/10.1001/jamadermatol.2018.4093.
Sullivan JR, Watson A. Naltrexone: a case report of pruritus from an antipruritic. Australas J Dermatol. 1997;38:196–8. https://doi.org/10.1111/j.1440-0960.1997.tb01696.x.
Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev. 2004;84:579–621. https://doi.org/10.1152/physrev.00028.2003.
Kong W, McConalogue K, Khitin LM, et al. Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc Natl Acad Sci U S A. 1997;94:8884–9. https://doi.org/10.1073/pnas.94.16.8884.
Hollenberg MD, Mihara K, Polley D, et al. Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease. Br J Pharmacol. 2014;171:1180–94. https://doi.org/10.1111/bph.12544.
Lieu T, Savage E, Zhao P, et al. Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2. Br J Pharmacol. 2016;173:2752–65. https://doi.org/10.1111/bph.13554.
Steinhoff M, Corvera CU, Thoma MS, et al. Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp Dermatol. 1999;8:282–94. https://doi.org/10.1111/j.1600-0625.1999.tb00383.x.
Hawro T, Lehmann S, Altrichter S, et al. Skin provocation tests may help to diagnose atopic dermatitis. Allergy. 2016;71:1745–52. https://doi.org/10.1111/all.12995.
Chung K, Pitcher T, Grant AD, et al. Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour. Neurobiol Pain. 2019;6:100032. https://doi.org/10.1016/j.ynpai.2019.100032.
Frateschi S, Camerer E, Crisante G, et al. PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. Nat Commun. 2011;2:161. https://doi.org/10.1038/ncomms1162.
Buhl T, Ikoma A, Kempkes C, et al. Protease-activated receptor-2 regulates neuro-epidermal communication in atopic dermatitis. Front Immunol. 2020;11:1740. https://doi.org/10.3389/fimmu.2020.01740.
Barr TP, Garzia C, Guha S, et al. PAR2 pepducin-based suppression of inflammation and itch in atopic dermatitis models. J Invest Dermatol. 2019;139:412–21. https://doi.org/10.1016/j.jid.2018.08.019.
Feng J, Yang P, Mack MR, et al. Sensory TRP channels contribute differentially to skin inflammation and persistent itch. Nat Commun. 2017;8:980. https://doi.org/10.1038/s41467-017-01056-8.
Shirolkar P, Mishra SK. Role of TRP ion channels in pruritus. Neurosci Lett. 2022;768:136379. https://doi.org/10.1016/j.neulet.2021.136379.
Kittaka H, Tominaga M. The molecular and cellular mechanisms of itch and the involvement of TRP channels in the peripheral sensory nervous system and skin. Allergol Int. 2017;66:22–30. https://doi.org/10.1016/j.alit.2016.10.003.
Moore C, Gupta R, Jordt SE, Chen Y, Liedtke WB. Regulation of Pain and Itch by TRP Channels. Neurosci Bull. 2018;34:120–42. https://doi.org/10.1007/s12264-017-0200-8.
Venkatachalam K, Montell C. TRP channels. Annu Rev Biochem. 2007;76:387–417. https://doi.org/10.1146/annurev.biochem.75.103004.142819.
Montell C. The TRP superfamily of cation channels. Sci STKE. 2005;2005:re3. https://doi.org/10.1126/stke.2722005re3.
Yan J, Ye F, Ju Y, et al. Cimifugin relieves pruritus in psoriasis by inhibiting TRPV4. Cell Calcium. 2021;97:102429. https://doi.org/10.1016/j.ceca.2021.102429.
Ross SE. Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr Opin Neurobiol. 2011;21:880–7. https://doi.org/10.1016/j.conb.2011.10.012.
Liu B, Escalera J, Balakrishna S, et al. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. Faseb J. 2013;27:3549–63. https://doi.org/10.1096/fj.13-229948.
Fernandes ES, Vong CT, Quek S, et al. Superoxide generation and leukocyte accumulation: key elements in the mediation of leukotriene B4-induced itch by transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1. Faseb J. 2013;27:1664–73. https://doi.org/10.1096/fj.12-221218.
Wilzopolski J, Kietzmann M, Mishra SK, et al. TRPV1 and TRPA1 channels are both involved downstream of histamine-induced itch. Biomolecules. 2021;11:1166. https://doi.org/10.3390/biom11081166.
Yang YS, Cho SI, Choi MG, et al. Increased expression of three types of transient receptor potential channels (TRPA1, TRPV4 and TRPV3) in burn scars with post-burn pruritus. Acta Derm Venereol. 2015;95:20–4. https://doi.org/10.2340/00015555-1858.
Ellis CN, Berberian B, Sulica VI, et al. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol. 1993;29:438–42. https://doi.org/10.1016/0190-9622(93)70208-b.
Lysy J, Sistiery-Ittah M, Israelit Y, et al. Topical capsaicin–a novel and effective treatment for idiopathic intractable pruritus ani: a randomised, placebo controlled, crossover study. Gut. 2003;52:1323–6. https://doi.org/10.1136/gut.52.9.1323.
Lee YW, Won CH, Jung K, et al. Efficacy and safety of PAC-14028 cream - a novel, topical, nonsteroidal, selective TRPV1 antagonist in patients with mild-to-moderate atopic dermatitis: a phase IIb randomized trial. Br J Dermatol. 2019;180:1030–8. https://doi.org/10.1111/bjd.17455.
Lim KM, Park YH. Development of PAC-14028, a novel transient receptor potential vanilloid type 1 (TRPV1) channel antagonist as a new drug for refractory skin diseases. Arch Pharm Res. 2012;35:393–6. https://doi.org/10.1007/s12272-012-0321-6.
Singh AK, McGoldrick LL, Sobolevsky AI. Structure and gating mechanism of the transient receptor potential channel TRPV3. Nat Struct Mol Biol. 2018;25:805–13. https://doi.org/10.1038/s41594-018-0108-7.
Yoshioka T, Imura K, Asakawa M, et al. Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice. J Invest Dermatol. 2009;129:714–22. https://doi.org/10.1038/jid.2008.245.
Lin Z, Chen Q, Lee M, et al. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet. 2012;90:558–64. https://doi.org/10.1016/j.ajhg.2012.02.006.
Yamamoto-Kasai E, Imura K, Yasui K, et al. TRPV3 as a therapeutic target for itch. J Invest Dermatol. 2012;132:2109–12. https://doi.org/10.1038/jid.2012.97.
Zhao J, Munanairi A, Liu XY, et al. PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes. J Invest Dermatol. 2020;140:1524–32. https://doi.org/10.1016/j.jid.2020.01.012.
Kim HO, Jin Cheol K, Yu Gyeong K, In Suk K. Itching caused by TRPV3 (transient receptor potential vanilloid-3) activator application to skin of burn patients. Medicina (Kaunas). 2020;56:560. https://doi.org/10.3390/medicina56110560.
Kim JC, Kim HB, Shim WS, et al. Activation of transient receptor potential vanilloid-3 channels in keratinocytes induces pruritus in humans. Acta Derm Venereol. 2021;101:adv00517. https://doi.org/10.2340/00015555-3855.
Chen Y, Fang Q, Wang Z, et al. Transient receptor potential vanilloid 4 ion channel functions as a pruriceptor in epidermal keratinocytes to evoke histaminergic itch. J Biol Chem. 2016;291:10252–62. https://doi.org/10.1074/jbc.M116.716464.
Chen Y, Wang ZL, Yeo M, et al. Epithelia-sensory neuron cross talk underlies cholestatic itch induced by lysophosphatidylcholine. Gastroenterology. 2021;161:301–17. https://doi.org/10.1053/j.gastro.2021.03.049.
Zhang Q, Henry G, Chen Y. Emerging role of transient receptor potential vanilloid 4 (TRPV4) ion channel in acute and chronic itch. Int J Mol Sci. 2021;22:7591. https://doi.org/10.3390/ijms22147591.
Luo J, Feng J, Yu G, et al. Transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch. J Allergy Clin Immunol. 2018;141:608–19. https://doi.org/10.1016/j.jaci.2017.05.051.
Lee WJ, Shim WS. Cutaneous neuroimmune interactions of TSLP and TRPV4 play pivotal roles in dry skin-induced pruritus. Front Immunol. 2021;12:772941. https://doi.org/10.3389/fimmu.2021.772941.
Akiyama T, Ivanov M, Nagamine M, et al. Involvement of TRPV4 in serotonin-evoked scratching. J Invest Dermatol. 2016;136:154–60. https://doi.org/10.1038/jid.2015.388.
Sanjel B, Kim BH, Song MH, Carstens E, Shim WS. Glucosylsphingosine evokes pruritus via activation of 5-HT(2A) receptor and TRPV4 in sensory neurons. Br J Pharmacol. 2021. https://doi.org/10.1111/bph.15733.
Kim S, Barry DM, Liu XY, et al. Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations. Sci Signal. 2016;9:437. https://doi.org/10.1126/scisignal.aaf1047.
Sanders KM, Hashimoto T, Sakai K, Akiyama T. Modulation of itch by localized skin warming and cooling. Acta Derm Venereol. 2018;98:855–61. https://doi.org/10.2340/00015555-2990.
Palkar R, Ongun S, Catich E, et al. Cooling relief of acute and chronic itch requires TRPM8 channels and neurons. J Invest Dermatol. 2018;138:1391–9. https://doi.org/10.1016/j.jid.2017.12.025.
Jung MJ, Kim JC, Wei ET, et al. A randomized, vehicle-controlled clinical trial of a synthetic TRPM8 agonist (Cryosim-1) gel for itch. J Am Acad Dermatol. 2021;84:869–71. https://doi.org/10.1016/j.jaad.2020.10.065.
Misery L, Santerre A, Batardière A, et al. Real-life study of anti-itching effects of a cream containing menthoxypropanediol, a TRPM8 agonist, in atopic dermatitis patients. J Eur Acad Dermatol Venereol. 2019;33:e67–9. https://doi.org/10.1111/jdv.15199.
Ständer S, Augustin M, Roggenkamp D, et al. Novel TRPM8 agonist cooling compound against chronic itch: results from a randomized, double-blind, controlled, pilot study in dry skin. J Eur Acad Dermatol Venereol. 2017;31:1064–8. https://doi.org/10.1111/jdv.14041.
Han JH, Choi HK, Kim SJ. Topical TRPM8 agonist (icilin) relieved vulva pruritus originating from lichen sclerosus et atrophicus. Acta Derm Venereol. 2012;92:561–2. https://doi.org/10.2340/00015555-1244.
Kang SY, Choi MG, Wei ET, et al. TRPM8 agonist (cryosim-1) gel for scalp itch: a randomised, vehicle-controlled clinical trial. J Eur Acad Dermatol Venereol. 2022. https://doi.org/10.1111/jdv.18080.
Han Q, Liu D, Convertino M, et al. miRNA-711 binds and activates TRPA1 extracellularly to evoke acute and chronic pruritus. Neuron. 2018;99:449–63. https://doi.org/10.1016/j.neuron.2018.06.039.
Dong X, Dong X. Peripheral and central mechanisms of itch. Neuron. 2018;98:482–94. https://doi.org/10.1016/j.neuron.2018.03.023.
Ji RR, Donnelly CR, Nedergaard M. Astrocytes in chronic pain and itch. Nat Rev Neurosci. 2019;20:667–85. https://doi.org/10.1038/s41583-019-0218-1.
Wang F, Trier AM, Li F, et al. A basophil-neuronal axis promotes itch. Cell. 2021;184:422–40. https://doi.org/10.1016/j.cell.2020.12.033.
Welborn M, Duvic M. Antibody-based therapies for cutaneous T-cell lymphoma. Am J Clin Dermatol. 2019;20:115–22. https://doi.org/10.1007/s40257-018-0402-5.
Dummer R, Duvic M, Scarisbrick J, et al. Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous T-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome). Ann Oncol. 2014;25:1807–12. https://doi.org/10.1093/annonc/mdu231.
Acknowledgements
The figures were designed and generated using CorelDraw (2021), Photoshop (Release 22.0.0), and Blender (3.3).
Funding
Open Access funding enabled and organized by Projekt DEAL. No funds, grants, or other support was received.
Author information
Authors and Affiliations
Contributions
The first draft of the manuscript was written by MH and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no competing interests to declare.
Ethical approval
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Hu, M., Scheffel, J., Elieh-Ali-Komi, D. et al. An update on mechanisms of pruritus and their potential treatment in primary cutaneous T-cell lymphoma. Clin Exp Med 23, 4177–4197 (2023). https://doi.org/10.1007/s10238-023-01141-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10238-023-01141-x