Contact dermatitis II. Clinical aspects and diagnosis

ARTICLE

Contact dermatitis (CD) is an altered state of skin reactivity induced by exposure to an external agent. "Eczema" and "dermatitis" are often used synonymously to denote a polymorphic pattern of inflammation of the skin characterized, at least in its acute phase, by erythema, vesiculation and pruritus. Substances that induce CD after single or multiple exposures may be irritant or allergic in nature. The clinical presentation may vary depending on the identity of the triggering agent and the reactivity of the subject, but in all cases the lesions are primarily confined to the site of contact.

According to the mechanism of elicitation, the following types of contact reactions may be distinguished: (1) allergic contact dermatitis (ACD); (2) irritant contact dermatitis (ICD); (3) phototoxic and photoallergic contact dermatitis, and (4) immediate type contact reactions. The present review will focus on allergic contact dermatitis. ACD is the clinical presentation of contact sensitivity in humans. The pathophysiology of the contact sensitivity reaction has been reviewed in a preceding issue of this journal [1]. (Key words: contact sensitivity, contact dermatitis, haptens.)

Clinical hallmarks

In a sensitized individual, ACD appears or is exacerbated 24 to 96 hrs after contact with the causative allergen. Its initial localization is at the site of contact (Fig. 1). In its acute phase, ACD is characterized by erythema and edema, followed by the appearance of papules, closely set vesicles, oozing and crusting. In the chronic stage, the involved skin becomes lichenified, fissured and pigmented, but new episodes of oozing and crusting may supervene, often as a consequence of a new exposure to the causative allergen. Unlike ICD, in which pain and burning usually prevail, ACD is accompanied by intense pruritus. The edges of the lesions may be well demarcated, but unlike irritant contact dermatitis it may propagate in the immediate vicinity or to distant unrelated sites.

"Systemically induced eczema" or "hematogenous contact dermatitis" is induced by oral or parenteral application of certain contact allergens in previously sensitized individuals [2, 3]. The clinical morphology corresponds to classical eczematous skin lesions but the distribution is often symmetrical. The best known example is the "flare-up" phenomenon at sites of previous eczematous skin changes following an experimental challenge by oral or parenteral application. Substances most often implicated in inducing hematogenous contact eczema are metal salts (nickel, sodium, mercury) and drugs (sulphonamides, local anesthetics, phenothiazines) [3].

Histopathology and immunopathology

The histopathologic findings are different in acute and chronic ACD and are dependent on the severity of the inflammatory reaction. The most common histologic feature is spongiosis, which results from intercellular edema (Fig. 2A). It is often limited to the lower epidermis but, if the reaction is severe, it may affect the upper layers. The clinical expression of intense fluid accumulation in the acute stage is the formation of vesicles that may rupture at the epidermal surface (Fig. 2C). The papillary vessels are dilated, with perivascular lymphohistiocytic infiltrate, and the upper dermis is edematous. The infiltrate extends into the epidermis (exocytosis) and accumulates in the spongiotic vesicles. In subacute and chronic ACD the spongiotic pattern gradually fades, the epidermis becomes hyperplastic, and parakeratosis develops.

The main immunopathologic feature in ACD is the presence of a high number of CD4⁺, CD45RO⁺, TCR alpha ß T lymphocytes in the inflammatory infiltrate [4, 5] (Fig. 2B). CD8⁺ T cells are only rarely found. However, a predominantly CD4⁺, CD45RO⁺ infiltrate is common to most of the chronic inflammatory dermatosis, including atopic dermatitis, psoriasis, lichen planus, discoid lupus erythematosus [6]. The relative contribution of the various cell types in the inflammatory infiltrate of ACD does not show hapten-dependent variations [7, 8]. Hapten-specific T lymphocytes from lesional skin and peripheral blood of nickel and urushiol contact dermatitis patients have been cloned and characterized. The majority of urushiol-specific T cell clones have been found to be CD8⁺ [9], while hapten-specific T cell clones isolated from nickel-allergic patients are predominantly CD4⁺ [10].

The number of CD1a⁺ epidermal Langerhans cells may be increased [7] or decreased [11]. In the dermis, CD1a⁺ dendritic cells may be increased and represent up to 20% of infiltrating cells [7, 8, 11].

Adhesion molecules are up-regulated on keratinocytes (ICAM-1) and on the endothelial cells (ICAM-1 and E-selectin) [7, 12, 13].

Differentiation between ACD and ICD is of major interest in occupational medicine, but despite their different pathogenesis the clinical, histologic and phenotypic features are remarkably similar [11]. However spongiosis has been reported more consistently as a feature of ACD, while pyknosis and predominantly superficial vesicles containing polymorphonuclear cells have been related to ICD.

Diagnosis

Physical examination and history taking

The site and clinical appearance of the lesions frequently suggest the etiologic factor when the patient is first seen. Thus, sharply delineated geometric lesions are evocative of sensitivity to rosin in adhesive tape. Dermatitis at the site of contact with jewelry, blue jeans buttons, wrist watches, and other metallic objects are seen in nickel dermatitis. It is important to know the location of the initial skin changes and to try to establish a list of possible contactants that may have been used. Inhalents, dust exposure and ingestion have to be considered. If the dermatitis has taken a chronic course, the patient's observations about factors causing relapses may be helpful. A search for possible sources should concentrate on (1) occupation, (2) hobbies, (3) clothing and personal objects, (4) home environment, and (5) past and present treatment. A family history or a past history of atopy and psoriasis may be decisive, particularly when a diagnosis of hand eczema is discussed.

Questioning should focus on allergens that are particularly frequent causes of contact dermatitis at the site of the primary lesions [14] (Table I).

Patch testing

Purpose, indications and contra-indications to patch testing. Patch testing is the universally accepted method for the detection of causative contact allergens. The positive patch test reproduces an experimental contact dermatitis on a limited area of the skin. Atopy patch testing and photoallergy testing are beyond the scope of this paper. The method of patch testing was devised by Joseph Jadassohn in 1895. Patch testing is indicated whenever the allergen is unknown or uncertain, whenever a primary ACD or an ACD developing on a pre-existing dermatosis is suspected, or for forensic reasons. Contra-indications are acute and widespread ACD, long-term immunossuppressive therapy, UV irradiation and pregnancy.

Technique, materials and methods. Details about patch testing techniques are given in many textbooks. A good patch test indicates contact sensitization, which may be of past or present relevance, and produces no false positive reactions.

Finn chambers and several other tape methods are currently in use. Allergens, usually incorporated in petrolatum, are applied in round or square chambers of inert material (aluminium, polyethylene), which are mounted on adhesive tapes free from colophony. When application of the allergens in petrolatum is done by hand, the test material should be in an amount equal to slightly more than half of the chamber volume (i.e. 12-15 µl) [15]. A drop of volatile test material or aqueous solution on filter paper is sufficient, and it must be applied immediately before patch testing.

Patch tests are usually applied on the upper half of the back but the outer aspect of the upper arm may be used if necessary. The skin should be free from lesions and hairless. Marking of the test strips may be done with color or fluorescent ink. The optimal application time has been estimated to be 48 hrs [16] but a 24 hrs occlusion time seems to yield comparable results [17].

Most allergens used in patch testing are well-defined chemical substances. Testing with single allergens gives the most accurate information. To save place and time, mixes of chemically related compounds may be used (fragrance mix, paraben mix, lactone mix, etc.). This involves problems of concentration, interference, stability and formulation of the material as well as the risk of the generation of a "neo-antigen" [18, 19]. Some naturally occurring substances which are among the most common contact sensitizers (balsam of Peru, colophony, lanolin), contain a number of allergens, some of which are not well defined.

The most frequently encountered contact allergens have been selected by various international contact dermatitis groups and included in standard patch test series. Due to geographical variations in the natural and industrial occurrence of contact allergens, three major standard series have been elaborated and are in use: the European (Table II), the North American and the Japanese standard series [20, 21]. Despite the selection of the most wide-spread contact allergens for inclusion in these series, recent studies have shown that the yield of positive patch tests using testing with standard series alone varies from 23 to 73% [22, 23]. Therefore testing with allergens from the patient's specific environment increases to a great extent the chances of finding the causative allergen. There are additional series aimed at specific occupations and other spheres of activities. Most commercially available allergens supplied in syringes are incorporated in petrolatum. Aqueous solutions, solvents (ethanol, acetone, methyl ethyl ketone, ethyl ether), olive oil, and lanolin are recommended for others.

The concentration of the allergen in the patch test material should be sufficient to elicit an allergic reaction in all sensitized individuals but below the threshold that induces an irritant reaction. Considerable efforts have been made to standardize the concentration of the allergens to ensure comparable results worldwide. The purity of the material is of great importance for the accuracy of diagnosis.

Great care should be taken in testing with nonstandardized chemicals, usually brought by the patients. An initial concentration not exceeding 1% is recommended. The same substance should be tested on control subjects to make sure that the positive reactions are not due to irritancy. Ointments, cosmetics, and other substances that are formulated for prolonged skin application may be tested undiluted. Rinse-off cosmetics containing solvents and emulsifiers, pharmaceutical products containing antiseptics and any other household or industrial products that are potentially irritant may be tested using "semi-open" tests, provided that the pH value is between 3 and 11 [24]. A liquid substance is then applied on an area of 1 cm². After evaporation of the liquid an acrylic adhesive is applied on the skin and tests are read 2 days later. This method reduces the risks of irritant reactions when testing with nonstardardized allergens.

Patch test reading and evaluation. Patches are read at least 20 min after their removal to allow nonspecific irritation and dermographism to subside. It is recommended that a second reading 24 hrs or 48 hrs later be performed. In doing only a single reading, a large number of delayed reactions will be missed, while others due to early irritant effects will be considered allergic [25-27].

The method of recording recommended by the European and North American contact dermatitis groups is as follows [28]:

+ weak (nonvesicular] reaction: erythema, infiltration, papules

++ strong (edematous and vesicular reaction: erythema, papules, vesicles)

+++ extreme (spreading, bullous, ulcerative) reaction

? doubtful reaction (weak erythema only)

IR irritant reaction

­ negative reaction

NT not tested

Erythema, infiltration (edema), fine structure, surface distribution of the reaction, and the area involved are the parameters evaluated in a patch test [29]. Erythema cannot discriminate between an irritant and an allergic reaction. Infiltration should be present in an allergic reaction, but is not evidence of an allergy. The fine structure is the most important parameter in discriminating between an irritant and an allergic reaction. Allergic reactions may present discrete or distinct papules, papulovesicles, and coalescing vesicles. Several types of irritant responses may occur: fine wrinkling (silk paper structure) usually produced by soaps and detergents (Fig. 3A); erythema and papules in follicular distribution; petechiae, pustules, bullae and necrosis. Usually allergic reactions cover homogeneously the test area and may extend beyond the borders, while many irritant reactions are irregular, patchy, ring-shaped, or follicular in distribution. The type of positive reaction that can safely be interpreted as indicating allergic contact sensitivity exhibits erythema, edema, and small vesicles extending slightly beyond the patch border (Fig. 3B). Pruritus and reactivation of previous eczematous skin lesions at the time of testing indicate allergy. Rapid resolution of the patch test reaction after patch test removal is evocative of irritation.

Reading of patch test reactions is a subjective interpretation based on visual clues. The results can vary from one clinician to the next. Attempts have been made to find a reliable instrument for objective evaluation but further work is needed before a device could replace the visual scoring system [30].

False-positive and false-negative reactions. False-positive reactions are reactions that are evaluated as positive in the absence of sensitization. A false-negative reaction is present if a sensitized patient does not react positively to the patch test performed with the causative allergen. The most important causes of false-positive and false-negative reactions are listed in Table III.

Adverse reactions. Adverse reactions to patch testing are relatively uncommon. Anaphylactoid reactions (to latex, antibiotics) may occur within minutes of application. A flare-up of pre-existing dermatitis may be observed. Perhaps the most important side effect is the risk of sensitizing the tested individual. This phenomenon, known as active sensitization, usually occurs with potent allergens such as DNCB, SADBE, DNCP used in immunotherapy [31], but also with some allergens included in the standard patch test series (primin, para-phenylenediamine, epoxy resin, paratertiary-butylphenol-formaldehyde resin) [27]. It is recognized by a flare-up of the patch test reaction occurring later than 7 days after the patch test application [28]. In patients with psoriasis and lichen planus, the Koebner phenomenon may be provoked. Secondary infection may occur at sites with exudative changes. Hyperpigmentation, depigmentation, pseudolymphoma and keloid reactions may appear as late sequelae [28].

Accuracy and relevance of patch test reactions. Accuracy refers to the relation between the patch test reaction and the allergic sensitization of the patient [32]. While the accuracy of doubtful (?) and weak (+) reactions is low, the accuracy of strong (++) reactions exceeds 80% [33].

Relevance reflects the relationship between an accurate test reaction and the patient's disease [32]. A positive patch test may be of past or present relevance depending on its relation to past or present dermatitis. Methods for increasing the relevance of positive patch tests are (1) precise collecting of clinical history; (2) performing additional testing procedures such as sequential patch tests, repeated open application test (ROAT), and use test; (3) chemical analysis of the products brought by the patient; (4) collecting information about the chemical content of the products from the manufacturer [34].

Common causes of allergic contact dermatitis

The etiologic factors of ACD can hardly be enumerated. More than 100,000 chemical compounds are in industrial use and every year 2,000 newly synthesized molecules are brought on to the market. These new substances represent a potential new source of contact sensitization despite the tests carried out before their marketing. More than 3,700 molecules have been recognized as contact allergens [35]. The most frequently encountered contact allergens are listed below.

Metals

Nickel is the most common cause of ACD in women in almost all countries, affecting 20% of young women in some series. The greater exposure of women to high-nickel content jewelry may be a predisposing factor. In men nickel allergy is usually occupationally related. Ear piercing is considered to be a principal inducer of nickel contact dermatitis [36]. Nickel is part of stainless steel and almost all alloys. The typical clinical presentation is at the site of contact with objects containing nickel (Fig. 1A and B). Hand eczema in nickel sensitive patients may be a disabling condition. It is often of the dyshidrotic type and may be aggravated by nickel ingestion. The dimethylglyoxime spot test has been elaborated to detect nickel in alloys. Avoidance of nickel is extremely difficult because of the ubiquity of the metal. A threshold of 0.5 microgram of nickel/cm²/week has been established, where only a small number of the nickel sensitive patients will react [37]. Efforts have been undertaken by the European legislation to forbid the use of nickel in the manufacture of objects introduced in human ears and in other parts of the human body during epithelisation, in products placed in direct and prolonged skin contact with human skin: (earrings, watches) and to restrict the release of nickel from plated objects to below the threshold mentioned above [38].

Chromate is the most common contact allergen in men and sensitization to it is usually occupationally related. Contact allergy is elicited by hexavalent chromium compounds. Chromium is also ubiquitous. Occupational exposure is most frequent in construction workers who handle cement. Other common sources of chromate are chrome-tanned leather, bleaching agents, paints, printing solutions. The typical clinical presentation of chromate dermatitis is that of a chronic hand eczema (Fig. 4A).

Cosmetics and skin care products

More than 10% of patients examined for contact allergy have positive patch tests related to cosmetics in some series [39]. The face and the periorbital area are the most frequently affected areas. Cosmetics are complex products; more than 5,300 ingredients are available. The most often encountered cosmetic sensitizers are fragrances and preservatives [39, 40]. The full labeling of ingredients in cosmetics which has been gradually undertaken by the manufacturers in different countries under the pressure exerted by contact dermatitis committees will greatly contribute to the diagnosis of cosmetic dermatitis.

Fragrances. Fragrance materials are not only present in products primarily used for their scent such as perfume, eau de toilette, deodorant and aftershave, but also in cosmetics, toiletries, household products and industrial materials. It is often difficult to investigate contact dermatitis to fragrances since a single perfume may contain more than 300 ingredients [41]. Fragrance allergy affects approximately 1% of the general population [41]. Balsam of Peru and colophony, both of which are naturally occurring mixes of allergens, and the specially devised "fragrance mix", consisting of the eight most frequently encountered sensitizers in perfumes, are indicators of sensitization. The fragrance mix allows the detection of 52-81% of perfume allergies [41, 42].

Preservatives, antioxidants and antiseptics are numerous and some of them are found in cutting oils and other industrial products as well. They are added in a concentration of 0.01 to 0.1% to prevent the finished product from spoiling. Several preservatives (paraben mix, formaldehyde, quaternium 15, CL+Me-isothiazolinone) are included in the European standard series and others are found in additional series. The parabens are the most commonly used preservatives in cosmetics but the risk of sensitization to them is low despite their widespread use [43]. Formaldehyde is an important sensitizer. It is released by a number of biocides. Its greatest use in cosmetics is in shampoos. Cl+Me-isothiazolinone (Kathon CG), largely introduced in cosmetics in the mid-1970s, has elicited a great number of sensitizations in consumers. This has lead to its withdrawal from cosmetics other than rinse-off products; however it is still in use in industry and may be a cause of occupational sensitization. Its most popular substitute, Euxyl K 400, containing phenoxyethanol and dibromodicyanobutane, has proved to be at least as potent a sensitizer [44, 45].

Vehicles and emulsifiers. Of all the vehicle components of cosmetics, lanolin and propylene glycol are the most prominent causes of contact dermatitis [43]. Cocamidopropyl betaine, an amphoteric surfactant found chiefly in shampoos and other rinse-off cosmetics is an emerging contact sensitizer [46].

Hair dyes. Contact dermatitis to paraphenylene diamine and related cross-reacting dyes involves the scalp, face and neck of persons who have recently had their hair dyed. Oxidized hair dyes are not sensitizing, therefore dyed hair can be handled without danger. Paraphenylene diamine is the main cause of allergic hand eczema in hairdressers and sensitization to it usually necessitates a job change.

Nail cosmetics. Toluenesulphonamide formaldehyde resin in nail varnish is a frequent sensitizer [47]. Nail varnish dermatitis is a diagnostic problem, as periungual lesions are often absent and lesions are scattered on the eyelids, cheeks and neck. Acrylates in artificial nails have also been identified as sensitizers.

Dermatitis from clothes and shoes

Clothes dermatitis is usually located in the axillae, which is due to the release of allergens from the textile under the action of sweat and friction. Clothing dermatitis from formaldehyde is rare nowadays. Formaldehyde may be present in greater quantities in new clothes. The incidence of textile dye dermatitis varies from 1 to 15.9% in different countries and disperse dyes are the most frequently incriminated nowadays [48]. Leather articles contain several substances that may cause ACD: chrome, adhesives (paratertiary butyl phenol formaldehyde resin), and dyes (paraphenylene diamine). A number of accelerators and antioxidants used in the production of synthetic rubber may also cause contact dermatitis.

Drug dermatitis

Drug dermatitis may be elicited by the active ingredient of a topical drug, by the vehicle or by a preservative. Contact sensitization to antibiotics, antiseptics, and anesthetics is relatively frequent, especially in leg ulcer patients. ACD from topical corticosteroids and ophthalmics has been reported with increasing frequency [49]. Systemic application of a drug to which an individual has been sensitized by a previous cutaneous exposure may cause systemic contact dermatitis [50, 51].

Plant dermatitis

Plant dermatitis can manifest itself in a variety of ways, depending upon the plant and the means of exposure. Airborne contact dermatitis mimicking photodermatitis may be caused by sesquiterpene lactones found in the Compositae family. Contact dermatitis to plants from the Liliaceae and Alstroemeriaceae families may present as a dry painful dermatitis of the fingers in bulb growers, called "tulip finger" (Fig. 4B) [52]. Urushiol, present in poison ivy and poison oak is the most common cause of ACD in the United States, with 50% of the adult population clinically sensitive to it [52]. Primula dermatitis is the plant dermatitis most frequently encountered in Europe (Fig. 3C). It may also present as an airborne contact dermatitis.

Occupational contact dermatitis

Occupational contact dermatitis can be defined medically as contact dermatitis for which exposure at work can be shown to be the main cause or one of the factors contributing to its occurrence. From a legal viewpoint, some forms are excluded, and legislation varies from one country to another [53].

Contact dermatitis is the occupational disorder that causes the greatest disability and affects workers in the younger age groups [54]. 70-80% of occupational contact dermatitis involves the hands [55]. Most occupational dermatitis is irritant or of mixed origin (irritant and allergic). Job descriptions of various occupations with a list of the most common irritants and allergens in each of them are provided in many textbooks [56, 57].

The diagnosis of occupational contact dermatitis can be established on the basis of the patient's history, physical examination, and patch testing using the following criteria [58-60]: onset of the eruption after the patient began work; identification of the precise cause of the dermatitis (irritant, allergic, phototoxic, photoallergic) or contact urticaria; primary exposure to the etiologic factor at work; exposure of the site of onset to the causative agent; time between the beginning of exposure and the development of the dermatitis appropriate to the pathophysiology involved; clinical appearance and distribution of the skin lesions consistent with the type of dermatitis known to be caused by the suspected agent; exclusion of nonoccupational etiology; fluctuation of severity corresponding to exposure to the putative cause; other workers similarly affected; process change or introduction of a new material prior to the onset of the dermatitis; and positive patch test reaction(s) to a non-irritating concentration of an allergen in cases of ACD. There is no objective test to support the diagnosis of the more common ICD.

Occupational contact dermatitis has a poor prognosis in almost all studies. The prognosis is not always improved by a job change [61]. Poor prognostic factors are long duration of dermatitis, ACD caused by chromium, nickel and other ubiquitous allergens, dyshidrotic type of eczema, ICD, atopic dermatitis, insufficient healing time, care of young children, lack of family assistance with housework, poor industrial hygiene, poor worker education regarding industrial hazards [58].

Differential diagnosis

The most common skin disorders that should be differentiated from contact dermatitis are atopic dermatitis, palmo-plantar dyshidrosis, xerotic skin, photoallergic and photocontact dermatitis, protein dermatitis, psoriasis, pustular eruptions of the hands and soles, herpes simplex and herpes zoster, drug eruptions, scabies, initial erysipelas and lichen planus, mycoses. However, differential diagnosis includes in the first place irritant contact dermatitis

Once considered as a monomorphous disorder, ICD is now understood as a complex biological syndrome, evolving through diverse pathophysiological mechanisms [62]. An irritant is any agent that is capable of producing cell damage if applied for sufficient time and in sufficient concentration [14]. In general, the intensity of the reaction to irritants is proportional to the concentration and the exposure time. ICD arises without previous sensitization when the repair capacity of the skin is exhausted or when the contact with a strong primary irritant provokes an immediate inflammatory reaction on first contact. Irritants affect everyone, although individual susceptibility varies greatly [63]. The factors governing the individual response to irritants are currently under study. It is likely that the skin barrier function, mainly related to lipid composition, as well as other genetically determined factors (related to atopic background, seborrhea, psoriasis, etc.) play a key role in the susceptibility to irritation. It is often difficult to distinguish between ICD and ACD on clinical, histological or immunohistological grounds. The dorsal and lateral aspects of the hands and fingers have the greatest contact with chemical irritants and are the most frequently affected sites. The clinical appearance of ICD varies, depending on a number of external factors. Several types of ICD have been differentiated [62].

Acute irritant dermatitis (primary irritation)

Contact with a strong primary irritant, usually accidental, results in an acute onset contact dermatitis in exposed individuals, independently of constitutional factors. Erythema, edema, and in the more severe forms, vesicles and bullae may be seen at the site of contact (Fig. 5). Dermatitis heals soon after exposure and is usually followed by complete resolution.

Delayed acute irritant contact dermatitis

This is a delayed onset acute ICD, related to exposure to some chemicals (anthralin, epichlorhydrin, ethylene oxide, hydrofluoric acid, podophylin). Dermatitis appears 8-24 hrs after exposure and should therefore be distinguished from ACD by patch testing.

Irritant reaction

This is a pre-eczematous condition which has usually a good prognosis. Erythema and chapping develop in the first months in individuals exposed to mild irritants or performing wet work. It may however evolve to cumulative ICD.

Cumulative irritant contact dermatitis

This is the most common type of CD. Cumulative dermatitis develops after repeated exposures to irritants when the recovery time between exposures is not sufficient. It is closely dependent on individual factors. Acute irritant dermatitis and irritant reaction are not seen in the majority of patients but irritants elicit invisible alterations of the skin. Erythema and increasing dryness develop, followed by hyperkeratosis, lichenification and fissuring. Here again, ACD should be ruled out by appropriate testing. This form of ICD, frequently encoutered in female patients performing wet work, is also known as housewife's dermatitis (Fig. 4C).

Traumatic irritant dermatitis

It develops slowly after acute skin trauma (thermal injury, lacerations). The clinical course resembles that of nummular eczema. The healing time is generally prolonged.

Pustular and acneiform dermatitis

This type of ICD depends on both constitutional factors and the nature of the chemical substance. It may be elicited by cosmetics, metals, oils, greases, tar, asphalt, chlorinated and polyhalogenated naphthalenes.

Subjective irritation

This is an invisible skin irritation experienced by some individuals ("stingers") in contact with certain chemicals. The pathophysiological mechanism is not known and it is supposed that subjective irritation might be subclinical contact urticaria. Lactic acid, which is the model compound for this type of cutaneous irritation, induces itching, stinging or tingling in sensitive individuals. Subjective irritation might account for complaints of stinging with facial compounds by 10% of women consumers.

Hand eczema

The etiologic diagnosis of hand eczema (Fig. 4) is particularly difficult. It is important but not always possible to establish the balance between endogenous and exogenous factors. Not less than 10 entities may have an identical or similar presentation: i) ACD; ii) ICD; iii) atopic dermatitis; iv) nummular eczema; v) dyshidrotic eczema or pompholyx; vi) lichen planus; vii) psoriasis; viii) palmoplantar genodermatoses; ix) protein dermatitis; x) tinea manuum ; xi) xerotic hands and xii) cutaneous T cell lymphoma. The diagnosis is especially difficult to establish in chronic hyperkeratotic palmar dermatitis and histology is usually of no help. A positive patch test confirms the existence of a contact sensitization but does not exclude a pre-existing atopic dermatitis and cannot determine the relative importance of exogenous and endogenous factors.

Treatment

Etiologic treatment. General rules

The only available etiologic treatment of ACD is elimination of the contact allergen. The patients should be informed about the identity of the offending agent and the possible sources of the sensitizer. Cross-reacting substances should be listed. Nickel being the most common contact sensitizer, different modalities of etiologic treatment have been attempted for the treatment of ACD to nickel, namely reducing the total body load of nickel by means of a nickel-restricted diet and by treatment with disulfiram. Trials have yielded conflicting results as to the clinical effect of the treatment and the application of the metal-chelator disulfiram was limited by serious side effects [64].

Patients with CD should be instructed to avoid physical and chemical irritants (wet work, cold air, hot water, solvants and detergents).

In the case of occupational ACD, scrupulous wearing of gloves and protective clothing might be sufficient to avoid recurrences. The patient may be maintained at his workplace if an efficient allergen substitution is carried out (i.g. use of hypoallergenic rubber articles in contact sensitization to accelerators, antioxidants or latex). When the worker is unable to return to his usual occupation a job change should take place. This would be appropriate only if the new environment does not contain the causative allergen or related compounds.

Local treatment

Topical steroids represent the symptomatic treatment in both the acute and the chronic stages; they are gradually replaced by emollients, lubricants and moisturizers. Corticosteroids have anti-inflammatory and immunosuppressive effects. In murine models of contact sensitivity they inhibit both the induction and elicitation phase. ACD is a major indication for topical corticosteroid treatment. Potent (class II and even class I) steroids are used for several days at the beginning of the treatment. They are gradually replaced by weaker steroids (class III and IV) and are never discontinued abruptly (risk of a rebound phenomenon). Corticosteroids have a dramatic effect on ACD but their prolonged use is limited by multiple side effects (dermal atrophy, systemic effects, tachyphylaxis). With the regression of acute dermatitis, a process often accompanied by intense skin dryness or with its progression towards subacute and chronic dermatitis, corticosteroids are gradually substituted with emollients. Antibiotics and antiseptics may be applied in the case of eminent secondary infection.

Systemic therapy

Antihistamines

Histamine is not involved in the pathogenesis of ACD. Classical antihistamines (H1-receptor antagonists) are used mainly for their antipruritic and soporific effect and their clinical usefulness is limited except for sedation.

Corticosteroids

Systemic corticosteroids are contra-indicated in the most common forms of ACD. However they may be indicated for a short period of time if ACD is widespread and severe.

Immunosuppressive therapy

Conventional immunosuppressants (azathioprine, cyclophosphamide) with profound immunosuppressive properties are not appropriate in the management of ACD.

Several open and randomized double blind studies have been conducted to evaluate the efficacy of cyclosporine in the treatment of chronic hand eczema. Oral cyclosporine at a dose as low as 3 mg/kg/day was as effective as topical betamethasone-17,21-dipropionate [65]. Low-dose cyclosporine may be useful as an alternative treatment of severe chronic hand eczema in patients unresponsive to conventional treatment, provided monitoring of blood pressure and serum creatinine level is carried out. A topical form of cyclosporine with improved penetration would be an interesting alternative to topical corticosteroid therapy.

UV therapy

Topical and sytemic PUVA, as well as UVB radiation are currently used in chronic hand eczema, usually in combination with topical treatment [16].

Acitretin

10 days pulse therapy followed by low-dose or intermittent dose treatment is very suitable for hyperkeratotic hand and foot eczema [66].

Immunotherapy

Oral hyposensitization

Oral hyposensitization to urushiol [52, 67] and nickel [68-70] has been attempted but is not as yet performed in practice. Improvement of clinical nickel dermatitis after an initial flare-up of the lesions has been achieved by oral desensitization [68, 69] and by subcutaneous application of nickel in combination with UVB treatment [70]. Nickel-specific proliferation as assessed by lymphocyte proliferation assays was decreased after treatment in one study [68] and showed no significant trend in another [69]. While the mechanism of suppression of the disease still remains to be elucidated, oral hyposensitization and T cell vaccination using nickel-reactive T lymphocytes [71] open new areas of investigation for the treatment of contact allergy.

Perspectives in immunotherapy

Advances in the elucidation of the physiopathology of contact sensitivity have contributed to the development of new strategies in the therapy of allergic contact dermatitis. Murine experimental models have been used for exploring the possibilities of therapeutic application of new concepts and some clinical trials based on these studies are under way. New strategies are aimed at inducing allergen-specific down-regulation of ongoing immune responses. The ideal approach to the control of chronic ACD would be local immune suppression by topically applied drugs. Perspectives in pharmacological intervention in allergic contact dermatitis include new classes of immunosuppressors (topical FK 506, ascomycin), inhibitors of cellular metabolic activity, inhibitors of cell adhesion molecules, targetted skin application of regulatory cytokines, neutralization of pro-inflammatory cytokines (antisense oligonucleotides, anticytokine antibodies, soluble cytokine receptors), as well as the use of dendritic cells as tolerizing agents [72-74].

Contact dermatitis (CD) is an altered state of skin reactivity induced by exposure to an external agent.

Substances that induce CD after single or multiple exposures may be irritant or allergic in nature.

According to the mechanism of elicitation, the following types of contact reactions may be distinguished: (1) allergic contact dermatitis (ACD); (2) irritant contact dermatitis (ICD); (3) phototoxic and photoallergic contact dermatitis, and (4) immediate type contact reactions.

In a sensitized individual, ACD appears or is exacerbated 24 to 96 hrs after contact with the causative allergen. Its initial localization is at the site of contact. In its acute phase, ACD is characterized by erythema and edema, followed by the appearance of papules, closely set vesicles, oozing and crusting. In the chronic stage, the involved skin becomes lichenified, fissured and pigmented.

Unlike ICD, in which pain and burning usually prevail, ACD is accompanied by intense pruritus.

"Systemically induced eczema" or "hematogenous contact dermatitis" is induced by oral or parenteral application of contact allergens in previously sensitized individuals.

The most common histologic feature is spongiosis, which results from intercellular edema.

The main immunopathologic feature in ACD is the presence of a high number of CD4⁺, CD45RO⁺, TCR alpha ß T lymphocytes in the inflammatory infiltrate.

A good patch test indicates contact sensitization, which may be of past or present relevance, and produces no false positive reactions.

A search for possible sources should concentrate on (1) occupation, (2) hobbies, (3) clothing and personal objects, (4) home environment, and (5) past and present treatment.

Most allergens used in patch testing are well-defined chemical substances. Testing with single allergens gives the most accurate information. To save place and time, mixes of chemically related compounds may be used.

Patch testing is the universally accepted method for the detection of causative contact allergens. The positive patch test reproduces an experimental contact dermatitis on a limited area of the skin

The most frequently encountered contact allergens have been included in standard patch test series.

There are additional series aimed at specific occupations and other spheres of activities.

Patches are read at least 20 min after their removal to allow nonspecific irritation and dermographism to subside. It is recommended that a second reading 24 hrs or 48 hrs later be performed.

Erythema, infiltration (edema), fine structure, surface distribution of the reaction, and the area involved are the parameters evaluated in a patch test.

The type of positive reaction that can safely be interpreted as indicating allergic contact sensitivity exhibits erythema, edema, and small vesicles extending slightly beyond the patch border.

False-positive reactions are reactions that are evaluated as positive in the absence of sensitization. A false-negative reaction is present if a sensitized patient does not react positively to the patch test performed with the causative allergen.

More than 3,700 molecules have been recognized as contact allergens.

Nickel is the most common cause of ACD in women.

Ear piercing is considered to be a principal inducer of nickel contact dermatitis.

Chromate is the most common contact allergen in men and sensitization to it is usually occupationally related.

The most often encountered cosmetic sensitizers are fragrances and preservatives.

It is often difficult to investigate contact dermatitis to fragrances since a single perfume may contain more than 300 ingredients.

Occupational contact dermatitis can be defined medically as contact dermatitis for which exposure at work can be shown to be the main cause or one of the factors contributing to its occurrence.

Contact dermatitis is the occupational disorder that causes the greatest disability and affects workers in the younger age groups. 70-80% of occupational contact dermatitis involves the hands.

Drug dermatitis may be elicited by the active ingredient of a topical drug, by the vehicle or by a preservative.

The most common skin disorders that should be differentiated from contact dermatitis are atopic dermatitis, palmo-plantar dyshidrosis, xerotic skin, photoallergic and photocontact dermatitis, protein dermatitis, psoriasis, pustular eruptions of the hands and soles, herpes simplex and herpes zoster, drug eruptions, scabies, initial erysipelas and lichen planus, mycoses.

An irritant is any agent that is capable of producing cell damage if applied for sufficient time and in sufficient concentration. ICD arises without previous sensitization when the repair capacity of the skin is exhausted or when the contact with a strong primary irritant provokes an immediate inflammatory reaction on first contact.

It is often difficult to distinguish between ICD and ACD on clinical, histological or immunohistological grounds. The dorsal and lateral aspects of the hands and fingers have the greatest contact with chemical irritants and are the most frequently affected sites.

The etiologic diagnosis of hand eczema is particularly difficult.

Not less than 10 entities may have an identical or similar presentation: i) ACD; ii) ICD; iii) atopic dermatitis; iv) nummular eczema; v) dyshidrotic eczema or pompholyx; vi) lichen planus; vii) psoriasis; viii) palmoplantar genodermatoses; ix) protein dermatitis; x) tinea manuum ; xi) xerotic hands and xii) cutaneous T cell lymphoma.

Topical steroids represent the symptomatic treatment in both the acute and the chronic stages; they are gradually replaced by emollients, lubricants and moisturizers.

ACD is a major indication for topical corticosteroid treatment. Potent (class II and even class I) steroids are used for several days at the beginning of the treatment. They are gradually replaced by weaker steroids (class III and IV).

The only available etiologic treatment of ACD is elimination of the contact allergen.

Classical antihistamines (H1-receptor antagonists) are used mainly for their antipruritic and soporific effect.

Oral hyposensitization is not performed in practice.

Systemic corticosteroids may be indicated for a short period of time if ACD is widespread and severe.

Low-dose cyclosporine may be useful as an alternative treatment of severe chronic hand eczema in patients unresponsive to conventional treatment, provided monitoring of blood pressure and serum creatinine level is carried out.

New strategies are aimed at inducing allergen-specific down-regulation of ongoing immune responses. The ideal approach to the control of chronic ACD would be local immune suppression by topically applied drugs.

Abbreviations

ACD ­ allergic contact dermatitis.

CD ­ contact dermatitis.

ICD ­ irritant contact dermatitis.

CONCLUSION

Acknowledgements

We are indebted to BIODERMA Laboratory, 75, cours Albert-Thomas, 69447 Lyon Cedex 03, for technical assistance and financial support.

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