Mediators of Pruritus in Psoriasis

1. INTRODUCTION

Local inflammatory mechanisms may induce pruritus in many dermatoses. Mild-to-severepruritus accompanies numerous inflammatory skin disorders including atopicdermatitis, eczema, psoriasis, or lichen planus. Psoriasis is one of the most common chronic inflammatory skin diseases with a complex, multifactorial, andstill not fully understood etiopathogenesis. The main factors contributing to the development of psoriatic lesions are genetic predispositions and immunologicaldisturbances [1, 2]. However, the exacerbation of psoriasis can also be provoked by numerous exogenous factors including stress, smoking, infections, and somedrugs [2]. Pruritus is observed in about70 to 90% of patients with psoriasis [3–9], and many of them (at least 30%) hadgeneralized itching [5, 6]. The mean intensity of this symptom assessedaccording to 10 point Visual Analogue Scale ranged between 3.7–6.4 points[5,7, 10–12]. This is less than the intensity of pruritus observed in atopic dermatitis or uremic pruritus [13, 14]. However, despite less intensive,pruritus was mentioned by many psoriatic patients as the most bothersomesymptom of psoriasis [5] and it was clearly documented that pruritus intensitysignificantly correlated in psoriatics with degree of quality of lifeimpairment, level of stigmatization, as well as the presence and severity of depressive symptoms [12]. It seems that patients with pruritus suffer from moresevere psoriasis [4, 6, 8] although some authors did not find a significant relationshipbetween pruritus intensity and psoriasis severity [5]. The presence andintensity of itching were independent on age,gender, marital status, family history of psoriasis or atopy, type ofpsoriasis, alcohol or smoking habits, duration of the disease, as well asduration of the last outbreak of psoriasis [5, 6, 8]. Despite the high frequencyof this symptom, the pathogenesis of pruritus in psoriasis remains unclear. Here, we reviewed the available literature data on this symptom in order tosummarize our current knowledge of the origin of pruritus in psoriasis.

2. HISTAMINE

Histamine, one of the major mediators ofpruritus, does not seem to be involved in its development in psoriasis. Therewas no correlation between pruritus intensity and histamine plasma level in psoriasis, as well as no difference was observed in histamine plasma levels between pruritics and nonpruritics patients with psoriasis [10]. In addition, less than 20% of psoriatic subjectsclaimed that oral antihistaminics were effective in reducing pruritus [6]. Itseems that only sedating antihistaminics should be tried in pruritic psoriaticsas they sometimes could be effective due to evoked sedation [15]. It isgenerally accepted that the histamine blockade does not prevent pruritus inpsoriasis [15].

3. NEUROPEPTIDES AND ALTERED CUTANEOUS INNERVATIONS

The most often discussed theory on pruritus inpsoriasis mentioned the importance of impaired innervation and neuropeptidesimbalance in psoriatic skin. Interactions between nerves, neuropeptides, andmast cells, leading to neurogenic inflammation, have also been implicated inanother chronic itchy immunodermatosis: atopic dermatitis [16, 17]. Severalstudies demonstrated altered expression and/or distribution of severalneuropeptides and their receptors within various layers of psoriatic skin,including substance P (SP), calcitonin gene-related peptide (CGRP), vasoactiveintestinal peptide (VIP), somatostatin, β-endorphin, or pituitary adenylatecyclase activating polypeptide (PACAP) [17–26]. Neuropeptides degranulatemastocytes, activate dendritic cells, lymphocytes, macrophages, andneutrophils, and produce vascular changes in the skin by inducing angiogenesis,dilatation of vessels, and stimulation of synthesis of nitric oxide [26]. Theyalso stimulate synthesis and release of many proinflammatory cytokines from mastcells, lymphocytes, dendritic cells, fibroblasts, and keratinocytes, induceexpression of vascular adhesion molecules on endothelium, and exert hyperproliferativeeffect on keratinocytes [26]. Neuropeptides in the skin may be released fromdermal nerve endings, but they can also be directly produced by several celltypes, for example, mastocytes [17].

Nakamura et al. [27] observed that pruritic psoriatic skindemonstrated significantly increased number of nerve growth factor- (NGF-) immunoreactivekeratinocytes, elevated NGF content in the lesional skin, and enhancedexpression of high-affinity receptor for NGF (Trk-A) in the epidermis anddermal nerve fibres. Moreover, pruritic skin showed increased number of proteingene product (PGP) 9.5-immunoreactive nerve fibers in the epidermis and in theupper dermal areas, increased number of SP-containing nerves in theperivascular areas, as well as decreased expression of neutral endopeptidase(NEP) in the epidermal basal layer and in the endothelia of blood vessels [27].The pruritus intensity correlated with the number of PGP 9.5-immunoreactiveintraepidermal nerve fibers, the number of NGF-immunoreactive keratinocytes andthe expression level of TrkA in the epidermis [27]. Nakamura et al. [27] also found an increased number of mast cells in the papillarydermis of pruritic psoriatic skin among the various cellular componentsexamined, including resident cells and infiltrating cells in the skin lesions.Ultrastructural examination showed that these mast cells possesseddegranulating specific granules indicating that mast cells in pruriticpsoriatic skin are activated. The particularly characteristic finding of mastcells in lesional skin from patients with pruritus was the presence of freemast cell granules in close apposition to the perineurium surroundingunmyelinated nerve fibers. This phenomenon was never observed in the skin frompatients without pruritus [27]. In contrast, Nakamura et al. [27]did not find any differences between pruritic and nonpruritic psoriaticsregarding the skin expression of brain-derived neurotrophic factor,neurotrophin-3, VIP, neuropeptides Y (NPY), somatostatin, low-affinity receptorfor NGF, and angiotensin-converting enzyme. In another study [8], ahyperproliferation of small cutaneous nerves was found in the lesional skin ofpruritic psoriatic subjects compared to nonpruritic ones. Keratinocytes in thepsoriatic plaques of patients with pruritus also showed consistently increasedexpression of SP receptor, TrkA and CGRP receptor, but the immunoreactivity forSP, CGRP, VIP, and PACAPwas independent on the occurrence of pruritus. The expression of NGF,neurotrophin-4, low-affinity receptor for NGF, PACAP receptor expression, aswell as NEP activity did not differ between pruritus and nonpruritus group [8].Interestingly, Remröd et al. [11] did not find any relationship between SP-positivefibers nor cells and the degree of pruritus, but the analyzed group of patientsin this study was very small. In addition, the NPY plasma level wassignificantly decreased in patients with pruritus compared to patients withoutpruritus [9]. Plasma levels of SP, CGRP, and VIP did not differ significantlybetween pruritics and nonpruritics, however, a tendency to lower SP and VIPplasma levels in patients with pruritus was noted [9]. Moreover, significant, negativecorrelations between pruritus severity and SP as well as VIP plasma levels werefound [9]. It seems probable, that increased expression of neuropeptides in thepruritic skin might activate the neuropeptides degrading enzymes like NEP or angiotensin-convertingenzyme in a regulatory mechanism. This phenomenon could lead to the decreasedplasma level of selected neuropeptides. This hypothesis could be supported bythe observations that the proportion between chymase- and tryptase-positivemast cells was shown to be disturbed in lesional psoriatic skin [28] as well as patients with psoriasiswere characterized by higher serum activity of angiotensin-converting enzymewhich was normalized after effective antipsoriatic treatment [29]. In the study by our group [10] it was noted thatCGRP plasma level was significantly elevated in pruritic psoriatic patientscompared to healthy subjects, a difference that was not found between nonpruriticpsoriatics and healthy volunteers, and that CGRP plasma level correlated withitching intensity in some subgroups of psoriatics. The important role ofaltered innervations and neuropeptide imbalance in pruritus accompanyingpsoriasis may also be supported by the observations that topically applied capsaicin, apotent SP depletory, effectively treated pruritus in psoriatics [30, 31].Finally, it was documented that stress-exacerbated pruritus in psoriasis [7] and neuropeptidesseem to be good candidates for linking nervous system and skin [17]. It couldbe hypothesized that increased innervations in the skin of psoriatic patientswith pruritus may lead to a lower threshold for pruritic stimuli compared topatients without pruritus. Additionally,pruritus might be evoked by the release of selected neuropeptides from dermalnerve endings and cells during stress, but this hypothesis still requiresfurther investigations (Table 1).

4. CYTOKINES

Concerning therole of cytokines in pruritus in psoriasis, Nakamura et al. [27] found anincreased number of interleukin (IL)-2 immunoreactive cells in pruritic versusnonpruritic lesions of psoriasis (Table 1). There were no significantdifferences in the expression of other cytokines (interferon (INF)-γ, tumornecrosis factor (TNF)-α, IL-1α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-12)[27]. Recently, a novel cytokine, IL-31, was suggested to play an importantrole in pruritus in atopic dermatitis, as IL-31 caused the itch-associatedscratching behavior in conventional NC/Nga mice, an experimental animal modelfor atopic dermatitis [32].Whether this cytokine also participates in pruritus in psoriasis needs to bedetermined.

5. VESSELS AND ADHESION MOLECULES

Vascular abnormalities are frequently observedin psoriatic lesions [33]. It seems that changes of dermal vasculature may beimportant in the pathogenesis of pruritus in psoriasis (Table 1). A markedincrease of the density of E-selectin-positivevenules was found in psoriatic patients with pruritus compared to nonpruriticsubjects [27]. However, there was no statistical difference in the number ofvessels immunoreactive for intercellular cell adhesion molecule (ICAM)-1,vascular cell adhesion molecule (VCAM)-1, or platelet endothelial cell adhesionmolecule (PECAM)-1 in the upper dermis or in the expression of ICAM-1 in theepidermis [27]. However, significant correlation was observed between theitching intensity and the density of E-selectin-immunoreactive vessels [27]. In addition, Madej etal. [33] found an increased serum concentration of soluble vascular adhesionprotein (VAP)-1 in psoriatic subjects with pruritus compared to patient free ofthis symptom.

6. OTHER POSSIBLE MEDIATORS

Despite the lack of solid laboratory data,other mediators may also play a role in the pathogenesis of pruritus inpsoriasis (Table 1). They were found to be important in several pruriticconditions, but have not been investigated in psoriasis yet.

It could be speculated that neuropeptides in psoriatic skin may induce expression and/or activity of dermal proteases, and these enzymes acting via protease-activated receptors (PAR) might be responsible for prurtius [43].Recent findings suggested that proteases are not only degrading enzymes,but rather represent a group of mediators communicating with nerves, andthereby modulating inflammation, pain, and pruritus [43, 44]. A massive itchbehavior was noted in mice overexpressing epidermal kallikrein-7 [43]. Tryptaseand microbial proteases induced itch by the PAR-2-mediated neurogenic mechanism[43, 45]. Activation of PAR-2 evoked itching both in mice and in human [43–46].Because PAR-2 is irreversibly activated by proteases, it might be a goodcandidate for the explanation of chronic itch.

Pruritus maybe elucidated by the opioid system as well. It is believed that activation ofμ-opioid receptors induces while activation of κ-opioid receptors alleviatespruritus. A significantly altered μ- and κ-opioid receptor expression wasobserved in the epidermis of patients with atopic dermatitis, showing mainlydownregulation of κ-opioid system [35, 36]. PUVA treatment, a frequently appliedand effective therapy of atopic dermatitis, was shown to reconstitute thealtered opioid receptor distribution in epidermis of these patients [36].Opioids may also induce pruritus acting in central nervous system. It was shownthat intrathecal administration of morphine elicits pruritus and both naloxoneand naltrexone, the potent μ-opioid receptor antagonists, reduces histamine-inducedpruritus in atopic dermatitis subjects to greater extend than antihistaminicdrugs [37, 38]. On the other hand, nalfurafine, a κ-opioid receptor agonist, ledto significant reduction of itching in patients with uremic or cholestaticpruritus [39, 40].

Prostanoids,mainly prostaglandin D₂ [41, 42] and tromboxane A₂ [47] orserotonin [48], could be further candidates as mediators of pruritus inpsoriasis. The importance of the latter one might besupported by the observations that mirtazapine, anantihistaminic drug acting also via noradrenergenic α2-receptors and 5HT₂ and 5HT₃ serotonin receptors,relieved psoriatic itch even in cases of severe pruritus associated witherythrodermic psoriasis [34].

7. THE ROLE OF CENTRAL NERVOUS SYSTEM

Pruritus causes thedesire to scratch the skin and is experienced as a sensation arising in theskin [49]. However, like all other skin sensations, itch is a product ofcentral nervous system activities [49]. The itch-selective spinal neurons forma distinct pathway projecting from lamina I of the spinal cord to theventrocaudal part of the nucleus medialis, which projects to the anteriorcingulated and dorsal insular cortex [49]. Recent studies characterized thesupraspinal processing of itch in humans by different imaging techniques. Intradermalinjection of histamine in healthy volunteers led to activation of anteriorcingulate cortex, supplementary motor area, premotor area, and inferiorparietal lobe [50, 51]. Prolonged itch stimuli activated a superior frontalgyrus and the gyrus rectus in both hemispheres as well as in a small area ofthe left anterior cingulated gyrus [52]. Further activation was located in theleft temporal pole and some parts of the left cerebellum [52]. Repetitive scratchinginduced bilateral activation of the secondary somatosensory cortex, insularcortex, inferior parietal lobe, and cerebellum while anterior and posteriorcingulated cortices were deactivated [53]. The main limitation of these studiesis the observations of healthy subjects. As it was demonstrated by Ishiuji etal. [54], the brain processing of itch in chronic skin conditions like inatopic dermatitis is significantly different than in healthy individuals.Therefore, further data are needed to identify the brain areas responsible forpruritus in patients with chronic itch, including those having psoriasis.

8. CONCLUSIONS

Summarizing, pruritus is an important symptomof psoriasis. Despite the fact that several studies have been undertaken toinvestigate the pathogenesis of pruritus in psoriasis, many aspects have notbeen studied yet (Table 1). Therefore, the pathogenesis of this symptoms is farto be well understood and, as a consequence, the therapy of pruritic psoriaticpatients still remains a big challange for clinicians. We hope that in the nearfuture new studies will be conducted to better characterize and understand thissymptom in psoriasis. We do believe that this progress may facilitate thedevelopment of new effective antipruritic treatment modalities.