4.1. INTRODUCTION

Psoriasis is a chronic, inflammatory skin disease affecting about 1% to 3% of the Caucasian population and slightly less frequently occurring also in other races. The most common variant of psoriasis, namely, plaque-type psoriasis, is clinically characterized by the presence of well-demarcated papules and plaques covered by silvery scales, which classically demonstrate symmetric distribution involving most commonly scalp, sacral area, and extensor surfaces of elbows and knees (Figure 4.1). Less often skin lesions may occur within the flexures and on the face. Other clinical subtypes include guttate, erythrodermic, and generalized or localized pustular psoriasis. Many patients (up to 80%) have nail abnormalities, and some of them (about 5%–30%) develop psoriatic arthritis. The disease may occur at any age, but two peaks of morbidity can be observed: the first one between 20 and 30 years of age, and the second one between 50 and 60 years of age (van de Kerkhof 2003). The pathogenesis of psoriasis is still not completely understood. The genetic background seems to be the most important factor, and many genes have been identified to predispose to this skin disease so far (van de Kerkhof 2003; Reich and Szepietowski 2007). However, environmental factors like infections, stress, some drugs, smoking, or alcohol also play a role. Altogether, genetic and extrinsic factors lead to abnormal keratinocyte proliferation, cutaneous inflammation, and skin vessel disturbances finally resulting in clinical features of psoriasis (Reich and Szepietowski 2007).

FIGURE 4.1

Clinical presentation of psoriasis.

To date, a number of treatment options of psoriasis have been developed, but none is a curative one. Patients with psoriasis frequently experience relapses of skin lesions, causing a need of a lifelong therapy. This may also lead to discouragement and abandonment of treatment. Because of its chronicity and visibility, psoriasis is responsible for significant distress, suffering, decrease of quality of life level, and stigmatization (Böhm et al. 2013; Hrehorów et al. 2012; Raho et al. 2012). Several studies documented that patients with psoriasis often suffer from chronic pruritus, which further contributes to lowering of psoriatic patients’ well-being (Yosipovitch et al. 2000; Reich et al. 2010a).

4.2. PREVALENCE, SEVERITY, AND CLINICAL PRESENTATION OF ITCH IN PSORIASIS

For years, psoriasis was handled as a skin disease, which only occasionally was accompanied by pruritus. However, studies being performed over the last 30 years have clearly documented that pruritus in psoriasis must be considered as a frequent phenomenon (Weisshaar 2012). In 1977, Newbold noted pruritus in 92% of 200 consecutive hospitalized patients with psoriasis. Other authors confirmed high frequency of itching among psoriatic subjects, which has ranged from 64% to 97% of studied individuals (Gupta et al. 1988; Yosipovitch et al. 2000; Szepietowski et al. 2002; Reich et al. 2003, 2007a; Sampogna et al. 2004; Chang et al. 2007; Amatya et al. 2008; Bilac et al. 2009; Prignano et al. 2009) (Figure 4.2). Importantly, itch was the most common subjective symptom reported by psoriatic patients (Sampogna et al. 2004; Bilac et al. 2009). Usually, pruritus was limited to lesional skin, but in some patients (in about 20%–30%) itch was also present within the uninvolved skin (Yosipovitch et al. 2000; Szepietowski et al. 2002; Prignano et al. 2009). In addition, women with psoriasis often reported vulvar pruritus that did not necessarily correlate with the presence of vulvar psoriatic plaques (Zamirska et al. 2008). Itch may involve all areas of the body, most commonly occurring on the extremities, trunk, and scalp, while the face and neck being only occasionally pruritic. However, a subgroup of patients was shown to suffer from generalized pruritus (Yosipovitch et al. 2000; Szepietowski et al. 2002; Amatya et al. 2008). In one study the mean pruritus-affected body surface area was estimated to be 18.1% ± 16.3% (Amatya et al. 2008). The itch location was unrelated to handedness (Yosipovitch et al. 2000).

FIGURE 4.2

Prevalence of pruritus in psoriasis (the horizontal line indicates the mean prevalence from all studies).

The mean severity of pruritus assessed according to visual analog scale (VAS) ranged from 4.2 to 6.4 points (Yosipovitch et al. 2000; Reich et al. 2003, 2010a; Amatya et al. 2008; Wiśnicka et al. 2004; Remröd et al. 2007). Despite VAS not being the only way of itch assessment, it correlated well with other methods of itching measurement (Szepietowski et al. 2002; Amatya et al. 2008). On the basis of the recent grouping of VAS scores (Reich et al. 2012) it can be assumed that, in general, pruritus in psoriasis is of moderate severity; however, individual variance may of course occur. Although not all, some studies demonstrated a significant correlation between pruritus intensity and psoriasis severity (Szepietowski et al. 2002; Sampogna et al. 2004; Chang et al. 2007; Kou et al. 2012). However, the correlation was rather weak, indicating that other factors also must play an important role in evoking this symptom in psoriasis. In most studies the frequency and intensity of itching was independent of age, marital status, family history of psoriasis or atopy, alcohol or smoking habits, education level, and duration of psoriasis (Yosipovitch et al. 2000; Szepietowski et al. 2002; Sampogna et al. 2004; Amatya et al. 2008; Bilac et al. 2009; Prignano et al. 2009). Some authors observed that pruritus was more frequent and more intense in women compared to men (Sampogna et al. 2004; Amatya et al. 2008). Interestingly, Prignano et al. (2009) found that presence of pruritus correlated with BMI scoring: 40% of patients with pruritus were overweight (BMI between 25 and 30) and 10% obese (BMI > 30). Itch severity was rated as greater at night and during the winter time (O’Neill et al. 2011). Itch in psoriasis was most commonly described by the patients as related to stinging, tickling, and crawling sensations (Amatya et al. 2008). Some patients reported pain and heat sensation during itch episodes (Amatya et al. 2008). Many patients described it also as bothersome, annoying, or unbearable (Amatya et al. 2008). In about three quarters of patients with psoriasis, pruritus appeared on the daily basis and had prolonged duration (Yosipovitch et al. 2000; Amatya et al. 2008). According to patient’s evaluation, the most intensive itching was observed during the skin lesions appearance or the extension of psoriatic lesions, while significant relief of itching was usually associated with complete resolving of psoriatic lesions (Szepietowski et al. 2002). Most important factors exacerbating itch in psoriasis were ambient heat, skin dryness, sweating, and emotional stress, while sleep and cold showers were often mentioned as itch alleviating measures (Yosipovitch et al. 2000).

4.3. MECHANISM OF ITCH IN PSORIASIS

The pathomechanism of pruritus in psoriasis is still not fully elucidated. Nevertheless, it seems to be rather a complex phenomenon, at least partially related to neurogenic inflammation ongoing in the skin. A relationship between pruritus and emotional stress might support this hypothesis (Reich et al. 2003; Verhoeven et al. 2009a,b; Reich et al. 2010b). Neuropeptides, i.e., peptides and small proteins released from dermal nerve endings, which possess various immunomodulatory properties, might be one of possible mediators of pruritus in psoriasis. They may degranulate mast cells, activate dendritic cells, lymphocytes, macrophages and neutrophils, exert hyperproliferative effect on keratinocytes, induce angiogenesis, expression of vascular adhesion molecules, and dilatation of vessels as well as stimulate synthesis of nitric oxide (Saraceno et al. 2006; Reich et al. 2007b, 2010b). Several studies demonstrated abnormal expression and/or distribution within the psoriatic skin of various neuropeptides and their receptors including substance P, calcitonin gene-related peptide (CGRP), somatostatin, beta-endorphin, vasoactive intestinal peptide (VIP), or pituitary adenylate cyclase activating polypeptide (PACAP) (Eedy et al. 1991; Naukkarinen et al. 1993; Glinski et al. 1994; Al’Abadie et al. 1995; Chan et al. 1997; Jiang et al. 1998; Raychaudhuri et al. 1998; Staniek et al. 1999; Steinhoff et al. 1999; He et al. 2000; Saraceno et al. 2006; Reich et al. 2007b).

Regarding pruritus in psoriasis, Nakamura et al. (2003) found a significantly increased number of substance P-positive nerves in the perivascular area as well as decreased expression of neutral endopeptidase (i.e., enzyme responsible for neuropeptide degradation) in the epidermal basal layer and in endothelial cells of cutaneous blood vessels in psoriatics with pruritus. These findings were accompanied in pruritic skin by significantly increased number of nerve growth factor (NGF) immunoreactive keratinocytes, elevated NGF content in lesional skin, higher expression of high-affinity receptor for NGF (Trk-A) in the epidermis and dermal nerve fibers, and more numerous protein gene product 9.5 (PGP-9.5) immunoreactive nerve fibers in the epidermis and in the upper dermal areas, indicating that abnormal cutaneous innervation may be, at least in part, connected with pruritus in psoriasis. The pruritus intensity in psoriatic patients significantly correlated with the number of PGP-9.5-immunoreactive intraepidermal nerve fibers, number of NGF-immunoreactive keratinocytes, and expression level of Trk-A in the epidermis (Nakamura et al. 2003). Recently, it was also shown that expression of semaphorin-3A, an axon-guidance molecule that inhibits neurite outgrowth of sensory C-fibers, was decreased in psoriasis with pruritus, and the level of semaphorin-3A expression negatively correlated with itch intensity assed by VAS (Taneda et al. 2011; Kou et al. 2012). As suggested by authors, downregulation of semaphorin-3A and upregulation of NGF in psoriatic skin may trigger hyperinnervation of C-fibers in the epidermis, leading to increased itch (Kou et al. 2012). Furthermore, Nakamura et al. (2003) found an increased number of activated mast cells in the papillary dermis with the presence of free mast cell granules in the close connection to unmyelinated nerve fibers, a phenomenon never observed in the skin from patients without pruritus. However, no differences between pruritic and nonpruritic psoriatics were found regarding the skin expression of brain derived neurotrophic factor, neurotrophin 3, VIP, neuropeptide Y, somatostatin, low-affinity receptor for NGF, and angiotensin converting enzyme (Nakamura et al. 2003). Similarly, Chang et al. (2007) analyzing 154 patients with psoriasis, observed that lesional keratinocytes of subjects with pruritus not only demonstrated increased expression of Trk-A but also showed higher expression of receptors for substance P and CGRP, while the immunoreactivity for substance P, CGRP, VIP, and PACAP did not significantly differ between pruritic and nonpruritic individuals. Amatya et al. (2011) also found a significant correlation between the pruritus intensity and the number of substance P-positive nerve fibers and number of neurokinin-2 receptor immunoreactive cells in the lesional skin. Despite in one other study the authors did not find any relevant correlation between pruritus severity and the number of substance P-positive nerve fibers nor cells, these results cannot be taken as of great relevance because of the limited number of analyzed patients (n = 13) (Remröd et al. 2007). Our group observed decreased neuropeptide Y plasma level in patients with pruritus compared to those without pruritus, while CGRP plasma level was elevated, and, in addition, CGRP plasma levels correlated with itching intensity in selected subgroups of patients with psoriasis (Wiśnicka et al. 2004; Reich et al. 2007a). The important role of altered innervation and neuropeptide imbalance in pruritus accompanying psoriasis may also be supported by the observation that topically applied capsaicin, a potent substance P depletory, effectively relieved pruritus in psoriatics (Bernstein et al. 1986; Ellis et al. 1993) (Table 4.1).

TABLE 4.1

Possible Mechanisms Involved in the Pathomechanism of Pruritus in Psoriasis

Regarding other possible mechanisms of pruritus in psoriasis it seems that histamine, a well-known and potent pruritogen, does not play a significant role, as no differences in histamine plasma level between patients suffering from psoriasis with and without pruritus were noted, as well as the plasma level of histamine was not correlated with pruritus intensity (Wiśnicka et al. 2004). Furthermore, antihistamines are rather of limited value. Although some patients may sometimes benefit from these drugs, it is rather due to their sedative properties and not due to histamine blockade (Szepietowski et al. 2002; Dawn and Yosipovitch 2006).

Recently, two other interesting mechanisms of pruritus origin have been postulated. Taneda et al. (2011) observed that lesional epidermis of psoriatic patients suffering from pruritus showed decreased expression of κ-opioid receptors, while the expression of µ-opioid receptors remained unaltered. Reduced expression of κ-opioid receptor was accompanied by the decreased expression of its agonist, dynorphin A (Taneda et al. 2011). These observations have recently been confirmed by our study showing a reduced expression of κ-opioid receptors in the skin of subjects with pruritus, while patients without pruritus had expression levels similar to healthy controls (Kupczyk et al. 2012). Furthermore, pruritus intensity inversely correlated with the expression of κ-opioid receptors (Kupczyk et al. 2012). As it is believed that activation of µ-opioid receptors may evoke itching, while activation of κ-opioid receptors exerts antipruritic effect, it seems highly probable that misbalance of the cutaneous opioid system in psoriasis may partake in pruritus origin (Bigliardi et al. 2009). However, the exact mechanism why the κ-opioid pathway is depressed in psoriasis remains unclear and requires further investigations.

Another interesting observation was reported by Nigam et al. (2010), who demonstrated that lesional psoriatic skin showed increased number of inflammatory cells with immunoreactivity for gamma-aminobutyric acid (GABA) and its receptor GABA_A. Interestingly, the number of GABA-positive and GABA_A receptor positive inflammatory cells significantly correlated with pruritus intensity (Nigam et al. 2010). GABA is an important neurotransmitter that regulates neuronal activation in the nervous system and primarily GABAergic neurons inhibit neuronal transmission. GABA is responsible, e.g., for controlling hypothalamic–pituitary–adrenocortical axis in rats (Cullinan et al. 2008; Mikkelsen et al. 2008). However, GABA may also modulate activity of various immune cells (Tian et al. 1999; Rane et al. 2005). Thus, the pruritogenic activity of GABA may be explained by controlling the neuroendocrine functions or by stimulating synthesis of some mediators by immune cells. Future studies should demonstrate whether any of these hypotheses is valid. A possible pruritogenic molecule could be e.g., interleukin 2 as Nakamura et al. (2003) found an increased number of IL-2 immunoreactive cells in pruritic in comparison to nonpruritic lesions of psoriasis. Another interesting option would be interleukin 31, which was shown to be unregulated in psoriasis (Narbutt et al. 2012). Interleukin 31 is believed to be the most important cytokine engaged in pruritus pathogenesis (Sonkoly et al. 2006). Other cytokines, like interferon γ, tumor necrosis factor α, and interleukins 1α, 1β, 4, 5, 6, 8, 10, or 12 seem to be unrelated to pruritus in psoriasis (Nakamura et al. 2003) (Table 4.1).

Some data indicate that pruritus is also partially driven by vascular abnormalities. Nakamura et al. (2003) observed significant increase of the density of endothelial leukocyte adhesion molecule 1 (ELAM-1) positive venules in patients with pruritus and the itching intensity significantly correlated with the density of E-selectin immunoreactive vessels. Our group found that psoriatic patients with pruritus showed an elevated serum level of soluble vascular adhesion protein 1 (VAP-1) (Madej et al. 2007). The cutaneous expression of other adhesion molecules (intercellular cell adhesion molecule 1, ICAM-1; vascular cell adhesion molecule 1, VCAM-1; or platelet endothelial cell adhesion molecule 1, PECAM-1) does not seem to be important for itch perception in psoriasis (Nakamura et al. 2003) (Table 4.1).

4.4. BURDEN OF ITCH IN PSORIASIS

Many patients consider pruritus as the most bothersome symptom of psoriasis, even though the severity of itch in psoriasis seems to be lower than in other pruritic skin conditions (Gupta et al. 1988; Welz-Kubiak et al. 2012). Patients with pruritus showed more reduced health-related quality of life (on average a large decrease is noted), compared to those without pruritus, who usually had moderately decreased quality of life and the pruritus intensity correlated with the degree of quality of life impairment (Reich et al. 2011). Psoriatic subjects with pruritus also demonstrated more depressive symptoms. The pruritus intensity significantly influenced the severity of depressive symptoms, as well as the level of stigmatization (Reich et al. 2011). In addition, many patients with pruritus demonstrated problems in falling asleep and more frequent awakenings (Yosipovitch et al. 2000; Gowda et al. 2010). Because of pruritus, 35% of patients became more agitated, 24% depressed, 30% showed concentration difficulties, 23% changed their eating habits, and 35% reported their sexual function to be decreased or nonexistent (Yosipovitch et al. 2000). Amatya et al. (2008) also documented that a majority of patients with psoriasis consider pruritus as a symptom negatively affecting their quality of life, with mood, concentration, sleep, sexual desire, and appetite being the most impaired daily life aspects. Psoriasis patients also reported more embarrassment associated with itch than did patients with atopic dermatitis (O’Neill et al. 2011). Pruritus significantly altered the work ability in psoriasis patients: it was mentioned by 48% of subjects as the most important symptom of psoriasis interfering with the work activity, and only scaling was more frequently reported. Furthermore, significant inverse correlation was found between itch intensity and work ability (R = –0.31, p < 0.01) (Zimoląg et al. 2009).

4.5. TREATMENT OF ITCH IN PSORIASIS

Treatment of pruritus in psoriasis is challenging. To date, no antipruritic therapy has been properly tested in a randomized way in psoriasis. Furthermore, causative treatment is difficult to be rationally developed, as the pathogenesis of this symptom is still not completely understood.

Usually, some relief is provided by proper skin moisturizing with emollients and moisturizers; however, only a minority of psoriatic patients (less than 20%) considered them as highly effective (Szepietowski et al. 2002; Dawn and Yosipovitch 2006). Usually, patients claimed that the disappearance of pruritus is related to the complete resolution of skin lesions (Szepietowski et al. 2002; Reich et al. 2011). It is in contrast to, e.g., lichen planus, in which pruritus reliefs within a couple of days after treatment initiation (Reich et al. 2011). Thus, the most effective antipsoriatic therapies should lead to the improvement of pruritus, if this symptom is really of psoriasis origin. However, a number of patients cannot achieve complete long-lasting remission of skin plaques, and therefore many of them may suffer from a chronic itch. In the review by Dawn and Yosipovitch (2006), several types of antipsoriatic treatment modalities were described as possibly helpful in treating patients with psoriasis who simultaneously suffered from itch, such as tar products, topical corticosteroids, topical salicylates, vitamin D analogs, topical immunomodulators, phototherapy, methotrexate, and biologics. One study documented efficacy of narrowband ultraviolet B (UVB) therapy in treating psoriatic itch (Gupta et al. 1999). Recently, Narbutt et al. (2012) have shown that treatment with narrowband UVB decreased the level of interleukin 31 in the sera of psoriatic patients, a finding that might explain the antipruritic effect of phototherapy. However, it must be underlined that in some patients at the beginning of the treatment, narrowband UVB may even aggravate itch owing to increasing of skin dryness, and therefore concomitant use of moisturizers or emollients throughout phototherapy is highly recommended (Dawn and Yosipovitch 2006).

As mentioned in the pathogenesis section, histamine seems not to be involved in transmission of itch stimuli in psoriasis; thus, antihistamines seem to be ineffective unless they cause sedation. On the basis of our own practice, hydroxyzine (10–25 mg two to three times a day) or clemastine (1–2 mg twice daily) are very useful for pruritus diminishment, but this suggestion has not confirmed in any controlled study so far. In more severe cases, oral antidepressants like mirtazapine (15 mg at night), doxepin (10–20 mg three times daily) or paroxetine (20 mg/d) can be tried. Mirtazapine was shown to relieve itch even in severe pruritus associated with erythrodermic psoriasis (Dawn and Yosipovitch 2006). Mirtazapine exert a sedative effect due to its H₁-antihistamine properties, but it also acts as an antagonist on noradrenergenic α2-receptors and 5-HT₂ and 5-HT₃ serotonin receptors (Dawn and Yosipovitch 2006). Furthermore, support given by the family and/or health professionals may increase the ability of patients to cope with itching (van Os-Medendorp et al. 2008).

It seems that in patients unresponsive to any kind of the above mentioned modalities, one may try therapeutic strategies used in recalcitrant chronic itch patients of different origin. On the basis of recent studies on pathogenesis of itch in psoriasis, drugs acting on peripheral opioid system (e.g., nalfurafine, a kappa receptor agonist) (Kumagai et al. 2012; Reich and Szepietowski 2012) or activating GABA receptors (e.g., pregabalin and gabapentin) seems to be the most promising ones (Solak et al. 2012; Ahuja and Gupta 2013); however, no studies confirming their efficacy in psoriasis exist. In addition, it would be of interest to prove whether endocannabinoids could be effective as well (Kupczyk et al. 2009; Tóth et al. 2011).

Summarizing, the therapy of psoriatic itch remains a real and urgent challenge. No single therapy exists that is effective in all psoriasis patients with itch. In seems that some patients may benefit from a combination of different methods of pruritus treatment. Complete clearance of psoriatic lesions usually is accompanied by itch resolution, but the majority of patients require antipruritic therapy prior to clearance of visible skin lesions (Dawn and Yosipovitch 2006).

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