38 The Phenomenon of Irritable Skin in Atopic Eczema

38 The Phenomenon of Irritable Skin

in Atopic Eczema

J. Huss-Marp, B. Eberlein-König, J. Ring

38.1

Introduction

The skin, as the outer boundary of the body, plays the major role of protecting the organism against harmful exogenous influences. It is the interface between the organism and the environment and serves as a barrier ensuring the maintenance of the body functions. In irritable skin, this function is impaired and environ- mental factors that are normally not harmful to the skin can lead to a disturbance of the skin’s integrity.

Due to a lack of objective parameters and a clear-cut definition of irritable skin, the condition of sensitive or irritable skin is difficult to assess with clinical or exper- imental methods. For the most part, the diagnosis is based on the patient’s history, which typically includes skin reactions following nonspecific stimulation of the skin with external triggering factors.

In atopic eczema (AE), irritable skin is frequently found to be partly responsible for its dependence on environmental conditions and its exacerbation follow- ing exposure to certain nonallergenic external stimuli.

Before discussing the impact of irritable skin on atopic eczema, it is therefore necessary to define the phenom- enon of irritable skin in itself and objective methods of measurement.

38.2

Definition of Irritable Skin

Irritable skin can be defined as a decreased resistance towards external nonallergic stimuli, which are not able to provoke a reaction in normal skin [27]. Irritable skin is not a rare condition and can be found in indi- viduals without skin diseases as well as a symptom of common skin disorders such as atopic eczema, where it

tends to be more pronounced as it is often the cause of serious exacerbations after exposure to irritants. Also, in other skin disorders such as seborrhoeic eczema or polymorphous light eruption, irritable skin plays an important role [18, 27]. The spectrum of stimuli caus- ing reactions in irritable skin is very wide and can include physical (sunlight, abrasive clothing) and chemical factors (use of detergents for cleaning the skin). There are also multiple individual factors modu- lating the intensity of the skin reaction: sex [55, 70], ethnic background [45, 55], age [19, 55], season [5], body region [19], menstrual cycle [7], previous expo- sure to sun light [44], pressure [29], etc.

As diverse as the factors causing skin irritation are, the skin reactions themselves range from eczematous reactions such as redness, scaling, and edema to pap- ules or urticaria, leading to sensations such as burning and pruritus, which can cause substantial discomfort for the patient. Typical of these reactions is a wide inter- and intraindividual variability concerning their intensity [6, 20, 66]. In the following, irritable skin is referred to as the tendency to develop an eczematous reaction after exposure to irritating, nonallergic sub- stances.

38.3

Quantification of Irritable Skin

To quantify skin irritability, irritant contact dermatitis

is induced experimentally and the reaction of the skin

is measured. For this purpose, a number of tests were

developed using, for example, sodium lauryl sulfate

(SLS), sodium dodecyl sulfate (SDS), dimethylsulfox-

ide (DMSO) or a modification of the alkali resistance

test. However, the substance used most frequently as

model irritant in skin testing is SLS; guidelines for

exposure testing with this substance were published by the Standardization Group of the European Society of Contact Dermatitis in 1997 [61]. The guidelines pro- pose testing protocols allowing the evaluation of an individual’s irritant susceptibility and individual and environmental factors determining this susceptibility.

The evaluation of skin reactions after irritancy test- ing was initially based on visual scoring only, and even though visual assessment of human skin irritation has been shown as sensitive and reproducible tool [11], bioengineering methods are far more precise and reli- able, especially in detecting barely visible changes in the skin after the exposure to irritants generating reproducible, investigator-independent results [8, 47].

Noninvasive methods to evaluate the irritability of the skin include transepidermal water loss (TEWL), laser Doppler flowmetry, ultrasound measurement, electri- cal capacitancy measurement, and colorimetry.

Since skin irritation often leads to an impairment of the epidermal barrier, a suitable method for its assess- ment is the measurement of TEWL. According to the guidelines for TEWL measurement of the Standardiza- tion Group of the European Society of Contact Derma- titis [51], TEWL should be assessed on the skin of a resting individual under stable environmental condi- tions concerning temperature and relative humidity and the use of a draught screen.

Skin redness, a typical symptom of irritated skin, can be evaluated in an objective fashion using the laser Doppler imaging technique (LDI), which is a suitable method for monitoring the dermal blood flow [48].

The device consists of a low-power laser beam, which is directed via a moving mirror to produce a raster pat- tern across the skin’s surface. The Doppler-shifted light from moving blood and the nonshifted light from the tissue are then directed on detectors. According to the detected light signal, the parameter of flux (propor- tional to the dermal blood flow) can be calculated. The LDI measurement was shown to be a suitable method to evaluate the skin blood flow in patients with AE [36].

Skin hydration depends on the water-holding capacity of the stratum corneum. Irritants can damage the cutaneous barrier and lead to a reduced water con- tent. To evaluate the degree of skin dryness, the hydra- tion of the stratum corneum can be assessed using a method that is based on the measurement of the elec- trical capacitance or conductance of the uppermost layer of the skin, which is in turn highly dependent on the actual water content [13, 43, 62].

Ultrasound measurement allows a noninvasive assessment of the skin’s thickness, which can be increased in a skin reaction following an irritant patch testing. The distance between the acoustic echo from the stratum corneum and the interface of the dermis and subcutis is measured and the thickness of the epi- dermis and dermis together is calculated [58].

To detect the formation of an erythema of the skin, color measurement can be performed with the help of a colorimeter. The skin surface color is quantified using the standard tristimulus system defined by the Commission Internationale de l’Eclairage [65].

For TEWL, the skin blood flow and the stratum cor- neum hydration circadian variations can be shown, a fact which should be taken into consideration when comparing the results of different noninvasive mea- surements of the skin [69, 71].

Of the above-mentioned methods, the TEWL mea- surement is considered to be the most important in assessing irritable skin reactions, whereas the colorim- etry showed the least reliable results [4]. However, even though less precise than the bioengineering methods, the ultimate endpoint should always be the clinical scoring of the irritant reaction as a sign of clinical rele- vance [61].

38.4

Definition of Irritable Skin in Atopic Eczema

Diagnostic criteria for atopic eczema were first pub- lished by Hanifin and Rajka [33] and include four major features and many associated findings. The major features are (a) pruritus, (b) facial and extensor eczema in infants and children or flexural eczema in adults, (c) chronic or relapsing dermatitis, (d) a per- sonal or family history of atopic diseases. Other diag- nostic criteria for atopic eczema are the “UK Refined

Table 38.1. Diagnostic criteria for atopic eczema published in 1982 (see [56])

) Eczematous skin lesions ) Pruritus

) Typical localization (according to age) ) Stigmata of atopic constitution

) Personal or family history of atopic diseases

) IgE-mediated allergic sensitization

374 38 The Phenomenon of Irritable Skin in Atopic Eczema

Table 38.2. Stigmata of atopic constitution or features of atopy ) Xerosis: pathologic dryness of the skin, conjunctiva, or

mucous membranes

) Hyperlinearity of palms and soles (ichthyosis palms) ) Linear grooves on fingertips

) Dennie-Morgan infraorbital folds: a line below both lower eyelids caused by edema

) Thinning of lateral eyebrows (Hertoghe’s sign) ) Low hairline (fur hat-like)

) Facial pallor and orbital darkening ) Delayed blanch responses to acetylcholine

) White dermatographism: a white whealing in the skin in the site and configuration of applied stroking by pres- sure or friction

Criteria,” the “Millennium Criteria,” and the criteria established by Ring in 1982 (Table 38.1) [56].

Even though a lowered resistance toward skin irri- tants is a common clinical observation in patients with AE, the term “irritable skin” itself is not mentioned in the diagnostic criteria for the disease. Nevertheless, paraphrases of irritable skin are included in the description of stigmata of atopic constitution, which belong to the diagnostic criteria for AE.

In order to establish the presence of an atopic dispo- sition or an atopic disease, a number of characteristic features have been recognized (Table 38.2) [53]. Some of these so-called stigmata can be associated with the presence of irritable skin. These are in particular (a) itch when sweating, (b) light sensitivity, (c) irritation from textiles, (d) solvent intolerance, and (e) the dependence on environmental factors.

38.4.1

Itch when Sweating

Patients with AE often complain about increased itch when sweating, even though there is no clear data con- cerning the difference in sweating between patients with AE and controls [54]. Excessive sweating might exert an irritant effect on the skin.

38.4.2

Light Sensitivity

Concerning the skin’s sensitivity to light, a higher vas- cular response after UVB irradiation was found in

patients with AE compared to controls [29, 30]. This was assessed by measuring the cutaneous blood flow slope of the irradiated skin area after 24 h using the laser Doppler imaging technique described above.

These experimental findings are in concordance with anamnestic data of atopic individuals, which indicated an increased light sensitivity and identified UVB as an important skin irritant.

38.4.3

Irritation from Textiles

When speaking of the irritation from textiles, one has to distinguish between wool intolerance on the one hand and the intolerance to occlusive clothing on the other. Wool intolerance in atopics may be due to the surface structure of wool with sharp and pointy fiber endings that are especially harmful in patients with AE with an already disturbed epidermal barrier even in healthy-looking skin areas [12, 32, 64].

The detrimental influence of occlusive clothing is related to the above-mentioned lowered itch threshold when sweating and can be associated with an impaired thermoregulation in occluded skin [35]. Furthermore, increased temperature can enhance the skin’s suscepti- bility to irritants [49].

38.4.4

Solvent Intolerance

Excessive use of lipid solvents is known to impair the integrity of the epidermal barrier in healthy and atopic skin, and can be particularly harmful if the barrier is already disturbed, as is the case in patients with AE [6].

Gehring et al. [28] investigated the effect of repeated washing with 0.1 % SLS, a slightly acid soap-free wash- ing emulsion and tap water for 2 weeks on the eczema risk of individuals with different atopy scores and found the subjects with the highest atopy score to have the highest risk of developing an eczema after repeti- tive washing with SLS.

According to the “brick and mortar” model [25],

lipids represent an essential component in the stratum

corneum and their removal by lipid solvents can dam-

age the epidermal barrier substantially.

38.4.5

Dependence on Environmental Factors

The dependence of the skin condition on nonallergic environmental factors can be attributed to an in- creased irritability of the skin. Eberlein-König et al.

[24] investigated the effect of the environmental pollut- ant formaldehyde at domestic concentrations and found an impairment of the skin barrier function in patients with atopic eczema, which did not appear in controls. Furthermore, our group showed in human exposure experiments that volatile organic compounds (VOC) – at concentrations commonly found in indoor environments – can damage the epidermal barrier and enhance the adverse effect of house dust mite allergens in allergic subjects with AE (Huss-Marp et al., in prepa- ration). These effects were of clinical relevance and led to an increased susceptibility of the exposed subjects to developing stronger eczematous skin reactions in the atopy patch test, which was applied after the exposure experiments with VOC compared to control experi- ments with filtered ambient air [37].

38.5

Clinical Evidence of Irritable Skin in Atopic Eczema

In atopic eczema, the skin is dry and rough with reduced levels of surface lipids and ceramides. Cerami- de-synthesizing enzymes are differently expressed in atopic skin compared to healthy individuals [14, 38].

Transepidermal water loss increases as the barrier function in eczema patients is increasingly impaired in noninvolved [2] and even more in eczematous skin.

These changes are likely to increase the permeability of the skin to exogenous substances such as allergens, leading to elevated cutaneous sensitization rates and subsequently to an enhanced TH2 response.

The interaction between dryness of the skin and pruritus, which in turn leads to scratching and further skin lesions, is complex. The disturbed barrier func- tion also renders the skin more vulnerable to irritants, which can cause inflammation and enhance pruritus.

Investigations into the quality of pruritus using a com- ponent analysis of atopic itch in the Eppendorf Itch Questionnaire identified specific patterns of a compul- sive character to atopic pruritus [21].

38.6

Experimental Evidence of Irritable Skin in Atopic Eczema

A number of experimental studies investigating the phe- nomena of irritable skin in atopic eczema have been car- ried out in the last few years. The individuals investigat- ed in these studies can be divided into five main groups:

(a) patients with acute atopic eczema, (b) patients with chronic atopic eczema, (c) patients with a history of the disease but no active skin lesions at the time of examina- tion, (d) atopics with no sign of skin disease, and (e) healthy nonatopic volunteers as controls.

For the first three groups of atopic eczema patients, most of the studies published showed increased irrita- bility of the skin: patients with acute atopic eczema were found to have an enhanced skin reactivity to SLS compared to controls [1, 3, 63]. Also, patients with chronic atopic eczema showed an increased irritability to DMSO compared to controls [26]. Furthermore, enhanced irritability was detected in patients with a history of atopic eczema but no active skin lesions [18, 60]. Even though there have been contradictory studies showing similar results for skin irritability in patients with a past or present history of atopic skin symptoms and controls, the phenomenon of an enhanced irrita- bility in atopic eczema is generally accepted [60].

For atopics with no sign of skin symptoms, the situ-

ation is somehow more complex and the results of the

studies conducted by several groups differed consider-

ably. In 1994, Nassif et al. reported significantly greater

irritant responses to different concentrations of SLS,

not only for subjects with acute atopic eczema and

patients with inactive atopic eczema (only slight ery-

thema, scaling, or papules in very restricted areas), but

also in atopics with allergic respiratory disease but no

skin disease compared to controls [46]. The authors

hypothesize that these findings stem from an abnormal

systemic intrinsic hyperreactivity in inflammatory

cells in patients with AE and atopics without dermati-

tis, rather than a phenomenon confined to skin cells

alone. These results are supported by Basketter et al.,

who found 30 atopics (defined by specific and total IgE)

to show enhanced irritant reactions to SDS compared

to nonatopics [10]. However, contradictory results

were published by Seidenari et al. [57], who reported

patients with respiratory atopy without dermatitis to

have no increased skin reactivity to SLS. The interpre-

tation of the results is made difficult by differences in

376 38 The Phenomenon of Irritable Skin in Atopic Eczema

the study design (e.g., testing the irritant at different concentrations) and evaluation methods (visual scor- ing vs bioengineering methods) [34]. Another study demonstrating no association between skin atopy and increased irritability assessed by irritant testing with NaOH, DMSO, and SLS was conducted by Stolz et al.

[59] in 205 Swiss metal workers who where character- ized according to an atopy score proposed by Diepgen and Fartasch [23]. Also in the study investigating a pre- dictive washing test for the evaluation of the eczema risk by Gehring [28], the value of the atopy score for predictively judging the individual eczema risk was found to be limited.

In spite of these reports, it cannot be overlooked that increased irritant reactions were found in atopics without skin disease [11, 46], indicating irritable skin not only being a phenomenon of atopic eczema but also of atopy. In this context, it is important to note that irritable skin itself is not included in the diagnostic cri- teria of AE, but is paraphrased in the stigmata of atopic constitution as signs of atopy and not exclusively of AE, as shown above.

38.7

Pathophysiology of Irritable Skin in Atopic Eczema

In a recent review article on the variability in respon- siveness to irritants, Willis [66] discusses possible underlying pathophysiological mechanisms of this phenomenon with regard to patients with atopy as well as the healthy, nonatopic population. A multitude of endogenous factors are involved in the generation of an inflammatory response to an irritant giving rise to the clinical picture of an irritant contact dermatitis. In the early phase of this inflammation, the most important mediators are the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF- [ ), which have the potency to independently trigger an inflammatory skin reaction by activating sufficient effector mechanisms leading to the migration of leukocytes into the involved skin areas [17, 41]. Furthermore, oxidative stress was shown to be a significant component in acute and chronic skin reactions to irritants [40, 66, 67] and mechanisms that might play a protective role against cell damage induced by oxidative stress (heat shock protein, HSP) were found to be upregulated in the epi- dermis after exposure to irritants (HSP27) [9].

38.7.1

IL-1 in Irritant Contact Dermatitis

In a number of experimental studies, IL-1 was identi- fied as a major pro-inflammatory cytokine in irritant contact dermatitis. IL-1 [ and IL-1 q stimulate the pro- duction of other cytokines (IL-6, IL-8), induce adhe- sion molecule expression, and costimulate the prolifer- ation of T cells [42]. In patients with AE, the phenome- non of increased skin irritability could be explained by an enhanced IL-1 production: in epidermal scrapings from clinical uninvolved skin of patients with AE, sig- nificantly higher baseline IL-1 q levels, compared to controls, were found using the PCR technique [39].

Also, keratinocytes from patients with AE released more IL-1 [ in cell culture after stimulation with INF- * compared to healthy controls [50].

38.7.2

TNF- ␣ in Irritant Contact Dermatitis

TNF- [ is considered a critical mediator in irritant reac- tions [52], since it can upregulate MHC class I and II expression and induce the production of other cyto- kines and the expression of adhesion molecules. Exper- imental findings that could contribute to explaining the enhanced irritability of atopic skin are an increased background level of TNF- [ in the epidermis of patients with AE as well as higher numbers of TNF- [ -positive mast cells in lesional and nonlesional skin [22]. Also, cell culture studies of keratinocytes from patients with AE revealed an increased release of TNF- [ after expo- sure to a pro-inflammatory stimulus (INF- * ) [50]. Fur- thermore, there is a high degree of polymorphism in the gene region that encodes for TNF- [ , resulting in different degrees of transcriptional activity. Interest- ingly, the rarer allele, which is associated with high TNF- [ activity, was found to be more frequent in a population of patients with AE in a Spanish study, pos- sibly contributing to the increased irritability of the skin [15].

This data is in accordance with the findings pub-

lished by Nassif et al. [46], who suggested increased

amounts of cytokines and other mediators in peripher-

al blood, mucosal tissues, and skin that enhance the

response to irritants, with reference to earlier studies

on an altered regulation of the cytokine production by

prostaglandin E

[16]. Even though many studies

showed enhanced basal TEWL values, indicating a dis-

turbed epidermal barrier, to be significantly correlated with an increased susceptibility to developing skin reactions after exposure to irritants [4], this seems to be a secondary phenomenon in regard to skin irritabil- ity. Naturally, a defective barrier predisposes to greater irritant effects, but the data currently available indicate an underlying inflammation mediated by the cytokines mentioned above to be mainly responsible for lowering the irritant threshold.

38.8 Conclusion

The phenomenon of irritable skin is a frequent feature of AE but also of atopy alone, other skin diseases, and even of healthy individuals, shown in numerous exper- imental and clinical studies cited above. The patho- physiological basis of this phenomenon is not fully understood yet and individual differences in skin irri- tability – though widely recognized – cannot accurate- ly be predicted and explained.

Since the hyperirritability of the skin is of great clin- ical relevance, leading not only to skin lesions at the site of exposure but, due to a phenomenon called “con- ditioned hyperirritability” or “status eczematicus,”

also to eczematous reactions in distant areas or even generalized over the entire body. This must be taken into consideration when treating patients with AE as well as instructing them concerning skin care and the exposure to irritants.

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