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Carstens E, Akiyama T, editors. Itch: Mechanisms and Treatment. Boca Raton (FL): CRC Press/Taylor & Francis; 2014.

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Itch: Mechanisms and Treatment.

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Chapter 3Atopic Dermatitis

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3.1. ATOPIC ECZEMA

Atopic dermatitis (AD; atopic eczema, eczema) is an inflammatory, chronically relapsing, and intensely pruritic skin disease occurring often in families with atopic diseases (atopic dermatitis, bronchial asthma, and/or allergic rhino-conjunctivitis). AD is a noncontagious inflammation of the epidermis and dermis with characteristic clinical (itch, erythema, papule, seropapule, vesicle, squames, crusts, lichenification, in synchronous, or metachronous polymorphy) and dermatopathological (spongiosis, acanthosis, hyper- and parakeratosis, lymphocytic infiltrates, and exocytosis, eosinophils) signs. With a prevalence of 2% to 5% (in children and young adults around 15%), AD is one of the most common skin diseases. The varying etiologic concepts of this disease are mirrored by the different names that are or have been used: “neurodermatitis,” “neurodermitis,” and “endogenous eczema” are just a few examples of current terms. Atopy is a strikingly common finding in these patients (Hanifin and Rajka 1980). It can be defined as familial hypersensitivity of the skin and the mucosa to environmental substances, associated with increased production of immunoglobulin E (IgE) and/or altered pharmacologic reactivity (Ring et al. 2006; Ring 2004). More recently, a new definition for atopy, restricted to IgE production, has been proposed: “a personal or familial tendency to produce IgE antibodies in response to low doses of allergens, usually proteins, and to develop typical symptoms such as asthma, rhinoconjunctivitis, or eczema/dermatitis” (Johansson et al. 2004, pp. 832–836).

The atopic diseases are genetically linked, and the concordance in monozygotic twins is 80% versus 30% in dizygotic twins (Schultz-Larsen 1985). A multifactorial trait involving numerous gene loci on different chromosomes has been proposed (Cookson and Moffatt 2002). Described genetic polymorphisms in AD involve mediators of atopic inflammation on different chromosomes, and some of these may also play a role in respiratory atopy. To date, the highest associations were shown with mutations in the filaggrin gene also associated with ichthyosis vulgaris, highlighting the predisposing barrier defect in AD patients (review in Weidinger et al. 2008).

In the first months of life, a yellowish desquamation on the scalp, known as “cradle cap,” may be a presentation of AD. The disease may then spread to the face and extensor surfaces of the arms and legs of toddlers, sometimes showing extensive oozing and crusting. Later on, the typical preferential pattern develops with eczematous involvement of flexures, neck, and hands, accompanied by dry skin and skin barrier dysfunction reflected by an increased transepidermal water loss. Lichenification is a result of scratching and rubbing, and most frequently in adults, this may result in the prurigo type of AD with predominant excoriated nodular lesions. Exacerbations often start as increased itch without visible skin lesions. This is followed by erythema, papules, and infiltration.

The histopathology of acute AD lesions is characterized by epidermal hyperplasia, spongiosis occasionally leading to vesicle formation, by a marked inflammatory infiltrate composed of lymphocytes and histiocytes, variable number of eosinophils and mast cells in the upper dermis, and exocytosis of lymphocytes into the epidermis. Chronic, lichenified lesions show hyper- and parakeratosis, irregular epidermal hyperplasia, a moderate superficial dermal infiltrate of lymphocytes, histiocytes and some eosinophils, and increased numbers of mast cells. Moreover, thickening of the papillary dermis and venular changes including endothelial hyperplasia and basement membrane thickening are observed (Mihm et al. 1976).

As these features are not specific for AD, routine histology is not a useful tool for diagnosing AD. In the absence of a specific diagnostic laboratory marker, mostly cutaneous stigmata of atopy have been used as diagnostic signs (Hanifin and Rajka 1980; Ring et al. 2006), the diagnosis of AD is made clinically. Hanifin and Rajka stated three of four main criteria to be necessary: pruritus, typical morphology and distribution, chronic or chronically relapsing course, and atopic personal or family history, in addition to three minor criteria among a list of 21 (Hanifin and Rajka 1980). According to the UK working party (Williams et al. 1996) who developed criteria especially suitable for epidemiological purposes, but not in small children, itchy skin changes have to be diagnosed in the last 12 months, in addition to at least three of the following criteria: onset of the disease under the age of 2 years, history of involvement of skin folds, generalized dry skin, other atopic diseases, and visible flexural eczema.

Management of exacerbated AD is a therapeutic challenge, as it requires efficient short-term control of acute symptoms, without compromising the overall management plan that is aimed at long-term stabilization, flare prevention, and avoidance of side effects (Darsow et al. 2010; Ring et al. 2012).

3.2. ATOPIC ITCH

Itch is one of the most important symptoms in inflammatory skin diseases and allergic disorders. It is defined as “unpleasant sensation, eliciting the urge to scratch” (Hafenreffer 1660, pp. 98–102). This very old definition still holds true after the last 50 years of neurophysiological research (which was, however, mainly focused on pain perception). AD is one of the most pruritic skin diseases. Often, pruritus is the first symptom of eczema relapse. In severe cases, patients scratch the involved skin areas until bleeding excoriations result. Nocturnal prolonged scratching with sleep loss is a common problem in these patients. In fact, itch is an essential diagnostic feature of AD (in association with other clinical criteria: age-related eczematous appearance and localization, history and clinical signs of atopy, and IgE-mediated sensitization [Ring 2004]).

3.3. FEATURES OF ATOPIC ITCH SHOWN WITH SCALES AND QUESTIONNAIRES

In experimental itch in healthy volunteers, interindividual differences of itch sensation in response to histamine were high (Bromm et al. 1995; Darsow et al. 1996). The clinical features of itch in different pruritic skin diseases reveal a range of diversity in the perception of this symptom. In many clinical trials, a quantification of subjective itch intensity by visual analog scale (VAS) (Hägermark and Wahlgren 1992) is the only measure or itch is even omitted in symptom scores. Murray and Rees (2011) recently demonstrated that VAS ratings and nocturnal actigraphy as covariate of itch in patients with AE were not correlated. The only use of VAS may lead to an incomplete registration of the sensation, because the influence of qualitative factors on quantitative scales is already known in pain research. This has led to the development of several questionnaire instruments for pain psychophysiology and for the measurement of quality of life outcomes.

In cooperation of Dermatology and Neurophysiology Departments, a multidimensional questionnaire was developed, the Eppendorf Itch Questionnaire (EIQ) (Darsow et al. 1997). It is available in English (Darsow et al. 2001) and can be used for clinical and study purposes. The EIQ is designed in analogy to the established McGill Pain Questionnaire (Melzack 1975) in pain research. The EIQ was used in therapy assessment and evaluated in an atopy patch test model for AD (Weissenbacher et al. 2005). The German version of this questionnaire was used in 108 patients with acute AD in comparison to the SCORAD (scoring atopic dermatitis, severity instrument) (Darsow et al. 2001). Atopic itch was described as increased warmth, localizable, tingling, hot, and burning with many adversive affective descriptors. A principal component analysis with varimax rotation identified main factors of clinical itch. It was shown that atopic itch is a multidimensional sensation with 12 clusters of descriptors, but on a more general level, descriptors could be integrated in three main components (explaining 58% of total variance) that describe the atopic itch (Table 3.1). Component A, “suffering,” described the decrease in quality of life, which is caused by pruritus. Main component B contained the quality of the sensation itself (wave formed and prickling, some further descriptors were chosen here). The third component was a compulsive component describing loss of control and warm feelings. Surprisingly, it comprised also positive emotional descriptors which were chosen by the patients, and it was the only main component that was not significantly related to the eczema severity (SCORAD). We suggested that this component may represent an important factor of the so-called “itch-scratch-cycle” in AD.

TABLE 3.1

TABLE 3.1

Eppendorf Itch Questionnaire and SCORAD

We compared the itch sensation of acute inpatients with chronic urticaria and AD with VAS and the EIQ. Table 3.2 shows that the difference between these pruritic diseases is not a function of pure itch intensity itself (VAS) but of the differentiated perception of the symptom: the mean total EIQ score in patients with AD was markedly higher. This was partially due to higher loads in affective items chosen by patients with atopic eczema. It may be speculated that this phenomenon is a feature of chronification of the itch sensation. Features of AE itch in different questionnaire studies are summarized in Table 3.3.

TABLE 3.2

TABLE 3.2

Itch in Atopic Eczema and Chronic Urticaria

TABLE 3.3

TABLE 3.3

Features of Atopic Itch

Recently, the relationship between itch and psychological status of patients with AE was investigated in Poland (Chrostowska-Plak et al. 2009, 2012). Intensity of pruritus was significantly related to the stress experienced by the patients prior to disease exacerbation. A significant correlation between pruritus and a validated quality of life index was also found. Patients with symptoms suggesting depression had more intense pruritus compared with the rest of patients.

All recent questionnaire studies consistently showed a high emotional burden and chronicity as features of atopic itch (e.g., Table 3.3). Such studies and clinical observations also point to a marked central nervous processing and modulation of the itch sensation in AE patients, which is now also investigated in neuroimaging studies (Pfab et al. 2010, 2012).

3.4. MECHANISM OF ATOPIC ITCH

Itch is a common problem that can severely impair the quality of life of affected patients. In the skin and nervous system, complex cellular interaction mechanisms have a pivotal impact on the pathophysiology of itch. In the following we will describe the possible underlying mechanisms of itch in AD skin with special emphasis on peripheral nerves, eosinophils, neuropeptides, neurotrophins, and IL-31.

3.5. NERVES AND ITCH

In AD, irritants including wools can immediately lead to intense itch suggesting a hyperreactivity of the surrounding nerves (Wahlgren et al. 1991). Indeed, the distribution density of cutaneous nerve fibers was found to be much higher in AD patients than in normal control skin. Further, the diameter of these fibers was much larger, because of the large number of axons in each nerve fiber (Urashima and Mihara 1998). The number of peripheral nerves in AD skin has been described to be increased in acute lesions compared to unaffected skin of patients with AD (Sugiura et al. 1997). Also, the activity of these peripheral nerves was found to be increased in AD patients as assessed with electron microscopy revealing bulging of axons with many mitochondria and a loss of their surrounding sheath of Schwann cells (Sugiura et al. 1997). This finding suggests that the free nerve endings in skin lesions of AD are in an active state of excitation, assuming one mechanism why the skin seems to be hyperreactive with regard to unspecific activation via wools in AD patients (Sugiura et al. 1997).

In the skin, itch is mediated via free nerve endings of nonmyelinated C-type nerve fibers that are located at the dermoepidermal junction and within the epidermis. There is a subpopulation of itch-specific nonmyelinated C nerve fibers that respond only to histamine. In addition, histamine-independent itch specific nerve fibers have been described to play a role in itch regulation (Nakano et al. 2008). In this regard, specific G protein-coupled receptors that mediate chloroquine-induced itch have been identified in peripheral sensory neurons (Liu et al. 2009). These neurons also respond to other itch-inducing signals including capsaicin. Recently, it has been shown that spinal neurons express the gastrin-releasing peptide receptor (GRPR). In mice, this receptor was involved in the transmission of itch, indicating that receptor expressing neurons may be itch specific (Sun and Chen 2007). It is assumed that the GRPR-positive, itch-sensitive neurons are involved in atopic itch (Tominaga et al. 2009).

3.6. SUBSTANCE P AND ITCH

In mice, substance P (SP)-positive nerve fibers have been shown to be increased in AD models (Tominaga et al. 2009). In rats, dorsal horn neurons were demonstrated to express the SP-specific neurokinin-1 receptor, suggesting that the neurokinin/neuropeptide SP may also play a role as a spinal transmitter for itch (Carstens et al. 2010). In human skin, SP-positive nerve fibers were shown to be increased in density in dermal nerve fibers in chronic itch of patients with prurigo nodularis, underlining its role in itch regulation in humans (Haas et al. 2010). Because SP is capable of inducing the neurotrophin nerve growth factor (NGF) (Toyoda et al. 2002), SP is a very interesting neuropeptide in the neuroimmune interaction circus with regard to the mechanistic pathway of itch. Indeed, targeting the NK-1 receptor in AD pruritus has recently been shown to be effective (Ständer et al. 2010).

3.7. EOSINOPHILS AND NERVES IN ATOPIC DERMATITIS

Tissue eosinophilia is a regular finding in AD skin (Kiehl et al. 2001). An increased quantity of eosinophilic granule protein, indicating complete eosinophil activation and degranulation of eosinophils is found in acute spontaneous lesions of AD when compared to normal skin (Kiehl et al. 2001). Interestingly, eosinophils have been found in close vicinity to nerves, assuming a role in their activation (Costello et al. 1997). Recently, it was shown that eosinophils dramatically increased branching of sensory neurons isolated from the dorsal root ganglia of mice (Foster et al. 2011). Thus, it is very likely that nerves are also activated at least in part by the interplay with proinflammatory cells including eosinophils in the skin, leading to the exacerbation of pruritus in AD (Raap and Kapp 2010).

3.8. EOSINOPHILS AND NEUROTROPHINS/NEUROPEPTIDES IN THE REGULATION OF ITCH

Eosinophils constitutively express mRNA for NGF and NT-3 (Solomon et al. 1998; Kobayashi et al. 2002). This is interesting because neurotrophins are capable of inducing the cutaneous nerve sprouting and myelinization of nerves. Direct neuroimmune interactions between eosinophils and nerves have been shown in an in vitro model in which stimulated eosinophils released NGF and induced neurite outgrowth that was abolished by anti-NGF neutralizing antibodies (Kobayashi et al. 2002).

NGF and BDNF contents are higher in eosinophils of patients with AD compared with healthy controls and can be released accordingly (Toyoda et al. 2003; Raap et al. 2005). This is of interest because increased BDNF levels correlate with disease severity assessed by SCORAD score in adults (Raap et al. 2006) and in children with AD (Hon et al. 2007). Further, BDNF levels correlate with scratching activity as assessed in children with AD that had been monitored during the night with a Digi-Trac model to assess the scratching activities (Hon et al. 2007).

In mice, the neurotrophin receptor antagonist for tyrosinkinase A (trkA) led to an inhibition of scratching and skin inflammation, indicating a role of neurotrophins in the mechanism of itch (Takano et al. 2005).

BDNF, which is increased in peripheral blood and plasma of AD patients (Raap et al. 2005), was found to induce chemotaxis, but only of eosinophils derived from patients with AD and not from healthy controls, revealing a vicious circle with enhancement of the inflammatory cell infiltrate in the skin of patients with AD (Raap et al. 2005, 2008). Further, neurotrophin receptor expression is highly increased in eosinophils of AD patients, assuming a higher responsiveness of eosinophils to the per se increased neurotrophin levels in AD (Raap et al. 2008). In addition to the release of neurotrophins, eosinophils have been assessed to release the neuropeptide vascular endothelial growth factor, which has a role in pruritus induction in urticaria (Tedeschi et al. 2009).

Further, eosinophils express histamine receptors including the H4 receptor (O’Reilly et al. 2002). Thus, the capability of eosinophils to respond to various trigger factors via the production of neurotrophins, neuropeptides, and other cytokines displays a novel pathophysiological aspect of pruritus in AD skin.

3.9. IL-31 AND ITCH IN ATOPIC DERMATITIS

The T-cell cytokine named interleukin (IL)-31 was shown to have a pivotal role in severe itch and AD, as assessed in mice overexpressing IL-31 (Dillon et al. 2004). In Nc/Nga, mice IL-31 levels correlated with scratching behavior (Takaoka et al. 2005), which could be ameliorated by the use of anti-IL-31 Ab (Grimstad et al. 2009). In AD patients, IL-31 was found to be increased compared to the skin of healthy controls (Raap et al. 2008). Also, in children with AD, IL-31 serum levels correlated with disease severity and were increased compared to age matched skin of healthy children (Raap et al. 2012; Ezzat et al. 2011). In addition, to the correlation with SCORAD score, IL-31 levels correlated with TH2 cytokines including IL-4 and IL-13 (Raap et al. 2012), assuming that besides its role on the regulation of itch, IL-31 also seems to play an important role in the regulation of the inflammatory infiltrate.

In human skin, IL-31 mRNA was found to be increased in AD when compared to skin healthy controls (Sonkoly et al. 2006). In AD, staphylococcal superantigens represent a trigger factor for worsening of eczema. In this regard, superantigens were shown to induce IL-31 mRNA expression in the skin and in PBMC of atopic individuals (Sonkoly et al. 2006), indicating a role in itch sensation. The cellular source of IL-31 is represented by skin infiltrating CLA+ T-cells, CD4+ T cells, and peripheral blood CD45R0 CLA+ T-cells and mast cells (Bilsborough et al. 2006; Szegedi et al. 2012; Niyonsaba et al. 2010). Interestingly, IL-31 receptor expression has been assessed on keratinocytes and on dorsal root ganglia, indicating that regulation of itch indeed could be transmitted via IL-31 receptors (Sonkoly et al. 2006; Heise et al. 2009).

In mice, anti-IL-31 treatment lead to a significant inhibition of itch (Grimstad et al. 2009), although it displayed no impact on the remaining inflammatory infiltrate in affected skin. Thus, it still needs to be clarified as to which IL-31 contributes to itch and inflammation in humans. Trials with patients have currently been undertaken.

3.10. THERAPY OF AD ITCH

According to the complex pathophysiology of atopic itch, the treatment of AD patients is challenging. Several steps have to be considered such as the application of emollients against dry skin, disinfectants against bacterial infections, and topical steroids or calcineurininhibitors against eczema/inflammation. Despite this, itch may persist and necessitates symptomatic antipruritic therapies. Application of topicals containing urea, camphor, or menthol preparations, wet wrap dressings, wrappings with black tea, or lukewarm showers may induce short-term relief of AD (Ring et al. 2012). Also, a combination of polidocanol and 5% urea lead to the relief of AD itch and may be applied during the night or in itch attacks (Ring et al. 2012).

For long-term relief, antihistamines are usually applied, but their efficacy is limited.

Furthermore, because scratching also represents a trigger factor of AD itch contributing to the itch-scratch cycle, the control of itch as well as scratching is important in AD patients. Scratch lesions also need a specific therapy. In summary, multimodal therapy regimens are necessary in AD itch to date.

3.11. ANTI-INFLAMMATORY THERAPIES

The use of anti-inflammatory therapies often results in cessation of pruritus in those patients with acute flaring up of AD and dense skin inflammatory cell infiltrate (Ständer and Luger 2010). Systemic and topical immunomodulators such as glucocorticoids, cyclosporine A, tacrolimus, pimecrolimus, and ultraviolet light therapy continue to be consistently the most effective antipruritic agents (Ständer and Luger 2010; Wahlgren et al. 1990; Hanifin et al. 2001; Jekler and Larkö 1990; Luger et al. 2001). The topical immunomodulators tacrolimus and pimecrolimus were frequently demonstrated to reduce erythema as well as pruritus and excoriations (Hanifin et al. 2001; Luger et al. 2001). Cyclosporin A (CyA) has been reported to have an itch-relieving effect in various diseases including AD. In a randomized study, CyA was demonstrated to significantly reduce itch intensity (Ständer and Luger 2010; Wahlgren et al. 1990). A case series reported relief of itch and scratch lesions in prurigo forms of AD (Siepmann et al. 2008). Upon clinical experience, CyA is one of the most potent drugs to relief atopic itch in a short amount of time.

3.12. ANTIHISTAMINES

Although various symptomatic treatments are employed to relieve pruritus and scratching in patients with AD, no target-specific therapies for AD itch are available as of yet. Because several studies have demonstrated that different mechanisms are involved in AD, it is not surprising that conventional therapeutic modalities like antihistamines often fail to ameliorate pruritus in AD (Klein and Clark 1999). Placebo-controlled studies concerning the antipruritic effect of oral antihistamines have shown conflicting results in AD. In some studies, antihistamines demonstrated no superior effect compared to placebo, while in others, they showed a significant antipruritic effect (Ring et al. 2012; Ständer and Luger 2010; Hannuksela et al. 1993). For example, cetirizine showed some benefit (Hannuksela et al. 1993), while an evidence-based review of the efficacy of antihistamines in relieving pruritus in AD concluded that little objective evidence exists in general for the antipruritic efficacy of H1-antihistamines in AD (Klein and Clark 1999).

3.13. TARGET-SPECIFIC THERAPY

There are some therapies that may target aspects of the complex pathophysiology of AD pruritus. For example, PUVA was described to reduce the neuronal hyperplasia and increased levels of NGF in AD patients (Tominaga et al. 2009). Skin neuropeptides are targeted by topical capsaicin, tacrolimus, or systemic application of SP-antagonists (Ständer and Luger 2010; Inagaki et al. 2010). Besides this, some new targets have been identified in AD itch as for example IL-31, the histamine 4 receptor, the neurokinin 1 receptor (NK1R), mu-opioid-receptors, proteinase activated receptor 2, nerve growth factor, and prostaglandin D2. It is currently unknown which mediator or receptor is the most important one. There is already some clinical evidence that targeting the NK1R leads to clinical relevant reduction of itch (Ständer et al. 2010). However, the development of new therapies against AD itch is urgently needed (Ständer and Weisshaar 2012). Fortunately, some targets are currently evaluated in clinical trials that selected as indication AD itch. This refers, for example, to new studies addressing the antipruritic potency of topical mu-opioid-receptor antagonist, systemical interleukin 31 antagonist, systemic proteinase activated receptor 2 antagonists, or prostaglandin D2 inductor (Ständer and Weisshaar 2012).

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