Rev Environ Health 2014; 29(3): 195–206
Iris S. Ale* and Howard I. Maibach
Irritant contact dermatitis Abstract: Irritant contact dermatitis (ICD) is the most common form of contact dermatitis. It represents the cutaneous response to the toxic/physical effects of a wide variety of environmental agents. Nowadays, it is recognized that irritancy does not represent a single monomorphous entity but rather a complex biologic syndrome with diverse pathophysiology and clinical manifestations. The clinical presentation is highly variable depending on several factors, including properties and strength of the irritant, dose, duration and frequency of exposure, environmental factors, and skin susceptibility. The pathophysiological mechanism depends on activation of the innate immune system and involves skin barrier disruption, cellular changes, and release of proinflammatory mediators that directly recruit and activate T lymphocytes. The diagnosis of irritant contact dermatitis is often clinical, and involves a comprehensive history and examination, as well as the exclusion of allergic contact dermatitis with patch testing. Recent advances in understanding the pathogenesis as well as better awareness of the clinical significance of ICD will lead to a improved care for our patients. Keywords: contact dermatitis; cutaneous toxicity; irritancy; irritant contact dermatitis; irritants. DOI 10.1515/reveh-2014-0060 Received August 11, 2014; accepted August 13, 2014
dermatitis (OCD) tends to become chronic, resulting in impaired quality of life and loss of work ability (1). According to the pathophysiological mechanisms involved, two main types of CD may be recognized, namely, irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD). Other additional forms of CD are photocontact (photoallergic and phototoxic) dermatitis and protein CD. ICD has traditionally been defined as a local inflammatory non-specific reaction of the skin following a single or repeated exposure to an irritant. Likewise, an irritant has been defined as any agent, physical or chemical, that is capable of producing cellular perturbation if applied for sufficient time and in sufficient concentration (2). Nowadays, it is recognized that irritancy represents a clinical and pathological spectrum of diseases and more than just a single entity, entailing a combination of both exogenous and endogenous factors (3). The spectrum of the clinical presentations and etiological factors of ICD is extremely broad. It is widely accepted that several mechanisms are involved in the development of ICD, including skin barrier disruption, keratinocyte damage, and release of proinflammatory mediators that directly recruit and activate T lymphocytes (4–6). Current insights regarding the genetic and immunological factors involved in the susceptibility to ICD allow for identification of subgroups of patients in need of specific preventive and educational interventions. This review will summarize recent advances in the understanding of ICD.
Introduction Contact dermatitis (CD) is an inflammatory skin condition that is primarily induced by exposure to an environmental agent. It represents one of the most frequent types of human immunotoxicity, which represents more than 90% of occupational skin disorders, giving good reason for its significant socioeconomic impact. Occupational contact
*Corresponding author: Iris S. Ale, Department of Allergology and Department of Dermatology, University Hospital, Republic University of Uruguay, Arazati 1194 11300, Montevideo, Uruguay, Phone: +(598) 98786141, E-mail: [email protected] Howard I. Maibach: Department of Dermatology, School of Medicine, University of California in San Francisco, San Francisco, CA, USA
Pathophysiology ICD is due to inflammatory and cytotoxic effects caused by exposure to various irritant stimuli acting as adjuvants, which activate the innate immune system. Irritants generate innate immune responses by similar pathways than those used by pathogens (7, 8). Microbes activate the innate immune system by generating danger signals in the form of so-called pathogen-associated molecular patterns (PAMPs). These molecules are highly conserved determinants typical of whole classes of pathogens, and can be bacterial or fungal cell wall components, microbial nucleic acids, proteins, or sugars. Most normal hemato poietic and nonhematopoietic cells express pattern
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196 Ale et al.: Irritant contact dermatitis recognition receptors (PRRs) like the membrane-associated Toll-like receptors (TLR) and the cytotosolic NOD-like receptors (NLR), which detect such danger signals and activate inflammatory signaling pathways (9–13). Irritants can induce ligands for the TLR, as well as activate the NLRP3 inflammasome and the production of reactive oxygen species. This activation of the innate immune and stress responses triggers a multitude of intracellular signaling pathways, including adaptor molecules, kinases (e.g., mitogen-activated protein kinases or MAPK) and transcription factors, which produce proinflammatory mediators and induce the maturation of dendritic cells (DCs); in turn, this facilitates the activation of the adaptive immune system. It now appears that innate and adaptive immune responses are much more closely linked than previously believed, and that the innate inflammatory immune response is a prerequisite for the activation and shaping of the adaptive immune response (14–16). In this sense, recent advances in the pathophysiology of chemical-induced skin inflammation (xenoinflammation) have shown that ICD and ACD are intimately associated, and that irritancy may predispose the development of allergic contact sensitization (17–20). Hence, an efficient way to prevent ACD is to develop strategies to avoid ICD. Irritants induce skin barrier disruption and direct cellular damage. Keratinocytes play a central role in the inflammatory response releasing cytokines, upregulating their major histocompatibility complex (MHC) class II antigens, and expressing cell adhesion molecules. Interleukin (IL)-1α, IL-1β and tumor necrosis factor (TNF)-α are key cytokines in this response. Preformed IL-1α, which is stored in the SC and the keratinocytes, probably starts the cytokine cascade (21–23). Additionally, TNF-α increases MHC class II and intracellular adhesion molecule (ICAM)-1 expression on the epidermis and dermis, playing a key role in perpetuating the inflammatory process (24–26). Some irritant reactions can be blocked by the injection of
anti-TNF-α antibodies or recombinant soluble receptors (26). Therefore, polymorphisms in TNF-α genes may represent a risk factor for ICD (27). T lymphocytes entering the skin in the contact area express a surface molecule, the cutaneous lymphocyteassociated antigen (CLA), which is crucial for the skin homing of T lymphocites participating in their transendothelial migration (28). The ligand for CLA is E- selectin, which is upregulated in various skin diseases, including CD. Other cell adhesion molecules like ICAM-1 and Lymphocyte function-associated antigen (LFA) (1), facilitate the extravasation of inflammatory T lymphocytes to the inflammatory site. This process may be enforced by the release of the chemoattractant IL-8 by the keratinocytes. Additional pro-inflammatory released molecules are IL-6, IL-8, CCL20, CCL27, IL12 and IL18, among others. The chemokine CCL21, produced by dermal lymphatic endothelial cells, is also upregulated in ICD (29). It facilitates the migration of T-lymphocytes, resulting in a skin inflammatory response.
Clinical aspects The clinical spectrum of ICD is broad and ranges from slight scaling, erythema, edema, and erosions, to an eczematous condition indistinguishable from ACD and other types of eczema. The characteristics and severity of the lesions are influenced by several factors, including the nature, concentration and duration of contact with the irritant chemical; the pre-existing skin condition and other constitutional factors; as well as concomitant exposure factors like mechanical, thermal, or climatic effects (Table 1). This diversity in clinical presentation has generated a classification scheme that is mainly based on the morphology and time course of the clinical lesions has been described along with various “genotypes" of ICD (30) (Table 2).
Table 1 Factors influencing the irritancy potential. Agent
Molecular structure Inherent toxicity pH pK Hydrophobicity (log P) Solubility Physical form: liquid, gas solid Vehicle Multiple chemical contact (additive or sinergic effect)
Exposure Concentration/dose Frequency of contact Duration of contact Type of contact Mode of application
Concomitant (modifying) exposure factors: Mechanical Thermal Climatic
Endogenous factors Region of the skin Age Race/skin color/phototype Dry skin Sweating Hormonal influences Active or previously active skin diseases Sensitive skin Atopy, atopic dermatitis
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Ale et al.: Irritant contact dermatitis 197 Table 2 Types of irritant contact dermatitis. Type of ICD
Agent
Clinical course
Acute ICD
Delayed acute ICD
Strong irritant (usually single agent)
Irritant reaction
Acute onset after exposure Usually (not always) quick recovery Onset delayed- 12–24 h or longer after exposure Usually acute onset, multiple exposures Usually (not always) recovery with withdrawal Symptoms occur quickly following exposure Early stage of skin irritation
Erythema, edema, vesicles, bullae, exudation Usually sharp demarcation Burning, pain, stinging, pruritus Similar to acute ICD except for delayed onset Usually monomorphic appearance: redness, scaling, chapping, pustules, or erosions
Slowly developing (weeks to years) Slowly developing after preceding trauma Slowly developing
Mild erythema, xerosis, hyperkeratosis, fissuring. Pruritus, soreness and pain Similar to chronic ICD
Subjective (sensory) irritation
Non-erythematous (suberythematous) irritation Chronic (cumulative) ICD
Distinctive delayed/acute irritants Mild irritants like water, soap, and detergents
Distinctive agents inducing sensory irritation
Traumatic ICD
Frictional dermatitis
Mild irritants like water, soap, and detergents Several weak irritants (chemical and physical agents) Traumatic factors (physical or chemical) Low-grade frictional force
Asteatotic irritant eczema
Low humidity, low temperatures
Slowly developing
Acneiform ICD
Slowly developing (weeks to months)
Airborne ICD
Metal, tars, oils, greases, metalworking fluids and chlorinated agents Irritants released into the air (dusts, fibers, fumes, vapors)
Variable, usually acute onset
Acute ICD Acute ICD is caused by exposure to a strong irritant. Classical signs of acute ICD are erythema, edema, oozing/exudation, bullae and erosions, starting soon after exposure to the irritant. Symptoms are burning, pain, stinging, pruritus, and soreness of the skin. The lesions frequently have a sharp demarcation and are mostly limited to the contact area, because the concentration of the substance spreading outside this area almost immediately declines below the critical threshold necessary to elicit a reaction. The diagnosis of acute ICD is usually straightforward because the rapid onset of skin lesions after exposure points to the causative agent. Acute ICD usually regresses soon after exposure, providing that there is no re-exposure. However, depending on the severity and susceptibility factors, it may persist for weeks and even months after exposure.
Clinical signs and symptoms
No clinical signs. Stinging, tingling, burning or itching No clinical signs
Erythema, scaling hyperkeratosis, and fissuring in areas of friction Xerosis, ichthyosiform scaling, and superficial fissuring, especially on the lower legs Open and closed comedones, cysts, pustules, nodules Dermatitis predominates in exposed areas, although it may affect protected skin due to contaminated clothing
The intensity of the acute irritancy lesions may vary from a mild erythema, to a “chemical burn" with necrosis, depending on factors like the characteristics of the irritant (e.g., strong acids or alkalis), the exposure time, and concomitant exposure factors. In fact, differentiation between acute ICD and a primary chemical burn is not always possible. Strong acids and alkalis are the major causes of chemical burns, but other chemicals like oxidants or reducing agents, as well as certain elemental metals may also produce similar lesions (31). The halogenated acids are especially dangerous because they may lead to continuous tissue destruction and necrosis even after short exposures. In most cases, chemical burns arise as a result of an occupational accident, but they may also occur outside of work. Sometimes, caustic chemicals are trapped by gloves, or other protective pieces of clothing, resulting in deeper injuries via the occlusion effect and deferred
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198 Ale et al.: Irritant contact dermatitis removal. Usually, the symptoms start immediately after the exposure, but with some chemicals, the damage is not always obvious and the onset may be delayed.
Delayed acute ICD In simple acute ICD, the reaction occurs within minutes to hours after exposure; by contrast, in delayed acute ICD, the onset of symptoms may be delayed for 8–24 h or more. Except for the delayed onset, the clinical expressions and courses are similar to those of acute ICD. Due to this delayed onset, this type of ICD may be misdiagnosed as ACD. A careful history and properly performed and interpreted patch test can lead to accurate diagnosis. Delayed acute ICD is characteristic of certain irritants, including dithranol, calcipotriol, benzalkonium chloride, nonanoic acid, sodium lauryl sulfate, propylene glycol, tazarotene and diacrylates, among others (32, 33).
Irritant reaction Irritants may induce cutaneous reactions that do not fulfill the clinical picture of dermatitis. These reactions are monomorphic, rather than the usual polymorphic appearance of ICD, and are characterized by one or more of the following signs: redness, scaling, chapping, pustules, or erosions. Irritant reactions are mostly seen in individuals significantly exposed to mild irritants like water, soap and detergents. High-risk occupations are those of hairdressers, cleaners, caterers, metal workers, and so on, especially in the early stage of occupational training. Frequently, this condition heals spontaneously with hardening of the skin. However, repeated episodes may lead to a chronic irritant contact dermatitis (Figure 1).
Figure 1 Chronic hand dermatitis.
Subjective or sensorial irritation Subjective irritation is characterized by a sensory discomfort, usually manifesting as a stinging, tingling, burning or itchy sensation, in the absence of clinical and histological evidence of skin lesions. Typically, symptoms occur rapidly following exposure (i.e., within seconds to minutes). The threshold for this reaction varies between subjects, and is independent of the susceptibility to other types of irritation (34). It is sometimes difficult to distinguish subjective irritation from subclinical contact urticaria. Among women, symptoms of subjective skin irritation (burning, stinging, etc.) occur more frequently in those who consider that they have sensitive skin (53%) than in those who do not (17%) (35, 36). Therefore, “sensitive skin” might be considered a marker of a form of skin irritancy. Hydroxy acids and propylene glycol are common subjective irritants. Interestingly, surfactant sodium lauryl sulphate (SLS), a potent objective irritant, does not generally induce stinging. Subjective irritation has both neural and vascular components that contribute to the clinical symptoms. The outcome is generally good.
Nonerythematous or suberythematous irritation More than a special type of irritancy, this represents an early stage of skin irritation, where there is no obvious clinical inflammation, but the incipient epidermal and skin barrier damage may be evidenced by bioengineering techniques (37, 38).
Chronic (cumulative) ICD Cumulative ICD, also known as “wear and tear dermatitis” and “traumiterative dermatitis”, ICD is the clinical consequence of a series of repeated events of subthreshold irritant injury to the skin, with brief intervals between events that prevent the complete restoration of the skin barrier function. Cumulative ICD typically occurs with exposure to weak irritants rather than strong ones, including both chemical agents and various harmful physical factors like friction, microtrauma, low humidity, the desiccant effects of dust or soil, and temperature. Clinical dermatitis often arises when the defense or repair capacity of the skin is exhausted and the irritant load exceeds the individual’s elicitation threshold.
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Ale et al.: Irritant contact dermatitis 199
Figure 4 Traumatic irritant contact dermatitis. Figure 2 Cumulative irritant contact dermatitis in an atopic patient.
Once the stratum corneum barrier has been breached, many normally innocuous agents may act as perpetuating factors. Patients with sensitive skin (i.e., atopic individuals) have a diminished irritant threshold or a prolonged skin restoration time, making them more susceptible to develop irritant contact dermatitis. Clinical signs of cumulative ICD are mild erythema, xerosis, and hyperkeratosis with frequent fissur ing (Figure 2). The lesions are usually localized at the contact area, although these are less defined than in acute ICD. The patients report both pruritus and pain, caused by fissuring of the hyperkeratotic skin. Symptoms do not occur immediately after the exposure, so differential diagnosis with ACD may be tricky. Chronic ICD often presents as hand eczema elicited by exposure to weak irritants (occupational or domestic), which adds to the difficulty of identifying causative factors (Figure 3).
Figure 3 Subacute irritant contact dermatitis of the dorsal hands.
Traumatic irritant contact dermatitis This uncommon form of ICD appears after an acute cutaneous trauma (e.g., a sudden exposure to a strong irritant). It is characterized by incomplete healing of the original insult followed by a nummular eczema-like lesion (Figure 4). It frequently has a chronic course and may persist or recur for long periods of time, sometimes being resistant to therapy (39).
Frictional dermatitis Frictional dermatitis is the cutaneous irritant response to a low-grade frictional force, that is, a shearing force acting horizontally to the surface. It is confined to the locations of frictional trauma, affecting mostly the hands, especially the palms and fingers on the dominant hand (Figure 5). Clinically, it is characterized by erythema, scaling hyperkeratosis, and fissuring. Occupations associated with frictional dermatitis include driving and repetitive handling of paper, plastic, cardboard, fabric or metal components, among others. Wet work, contact allergy, atopy, and psoriasis have been described as concurrent factors in some patients (40). Prognosis is usually good. However, in an
Figure 5 Frictional dermatitis.
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200 Ale et al.: Irritant contact dermatitis occupational setting, modification of the job to decrease frictional forces cannot always be achieved.
Asteatotic eczema The asteatotic eczema (syn. exsiccation eczematide, eczema cracquelé) is seen mainly in the lower legs of elderly individuals during the winter months. The condition is mostly due to environmental insults like low humidity and low temperatures, although other factors (e.g., wet work, chemical insults, and friction) may play a contributory role. Clinically, the skin is xerotic, with ichthyosiform scaling and fissuring due to the cracking of the superficial epidermal layers often associated with eczematous changes. The condition is due to a decrease in skin surface lipid and reduced water content in the stratum corneum, causing the corneocytes to be shed in large polygonal scales (41). In severe cases, a reduction of skin content of amino acid due to low profilaggrin biosynthesis can be found (42).
Pustular and acneiform dermatitis Exposure to metals, tars, mineral oils and greases, asphalt, metalworking fluids, and chlorinated agents can result in a pustular and acneiform dermatitis, especially in atopic patients. Not all individuals exposed to these agents will develop the dermatitis; hence, this type of ICD seems to be dependent on both chemical and constitutional factors. Acne cosmetica represents an acneiform ICD caused by the irritant effect of certain cosmetic agents in the pilosebaceous follicles. (e.g., pomade acne). Other etiologic factors are repeated mechanical irritation through friction, rubbing or pressure (e.g., acne mechanica). Occupational oil acne is mostly due to petroleum by-products, cutting oils, and metalworking oils. It is mostly seen in machinetool operators, mechanics, and workers exposed to petroleum and its derivatives. The clinical lesions are open and closed comedones, pustules, and nodules predominating in the arms, forearms, and dorsal hands. In addition, oil contaminated clothing produces lesions in protected skin areas (43–45). Chloracne is due to occupational or environmental exposure to chlorinated hydrocarbons (chlornaphthalenes, chlordiphenyls, and chlordiphenyloxides). Skin lesions are comedones and yellowish cysts that are predominantly in the face, although they may involve other areas. Systemic toxicity may be present (46–49). Pustular/acneiform ICD should always be considered in the differential diagnosis of acneiform lesions in adults.
Airborne ICD Airborne ICD is a clinical diagnosis that includes different types of dermatitis (e.g., acute, chronic, subjective dermatitis), which are caused by substances released into the air and settling down on the skin. Most of the airborne irritants identified are found in occupational settings (50–52) and can be present under various physical forms: i.e., fibers, dust particles, sprays, mists, vapors, and gases. The most common sites of airborne dermatitis are the skin areas that are directly exposed to the air: the face, neck, décolleté, hands, and forearms. In the face, the upper eyelids are particularly susceptible to airborne substances as a result of the higher penetration of chemicals through the thin skin. Sometimes, the dermatitis may involve the covered areas, especially the body folds because the substances may be trapped under clothing. The clinical lesions and severity of the dermatitis will depend on the agents and degree of exposure. They consists of small papules or papulovesicles, linear erosions caused by scratching or a maculopapular rash. Acute edematous lesions may be seen following accidental exposure to irritants vapors or gases. Itching, stinging, and burning sensations are the major symptoms.
Modulation of irritant contact dermatitis The development of occupational ICD is complex, and determined by a multiplicity of intrinsic and extrinsic factors. Extrinsic factors like the physicochemical properties of the irritant, the circumstances, duration and intensity of exposure, and effect of concurrent exposure to other substances have to be considered together with the intrinsic factors (individual susceptibility), including age, atopic constitution, skin condition, or a history of dermatitis. The individual susceptibility for the development of ICD shows a high degree of variability, which may be attributed to both genetic and environmental factors. Recently, several studies have investigated the link between individual susceptibility to CD and variations in the genes that are involved in the skin barrier function, the inflammatory response, and biotransformation (53–58). Genetic variations related to the skin barrier, which contribute to increased susceptibility to ICD, include loss of function mutations in the gene encoding the epidermal differentiation protein filaggrin (FLG). These mutations represent a relevant individual risk factor for AD and also
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Ale et al.: Irritant contact dermatitis 201
for ICD and nickel ACD. Individuals with AD and FLG mutations have an increased risk of acquiring occupational ICD. Visser et al. (53) investigated the relative contribution and interaction of FLG mutations and AD in German patients with occupational ICD and controls. They observed that FLG mutations were present in 15.9% and 8.3% of the ICD patients and controls, respectively; the crude odds ratio (OR) was 2.09 [95% confidence interval (CI) 1.33–3.28] for the combined genotype. The adjusted OR for FLG mutations, corrected for AD, was 1.62 (95% CI 1.01–2.58). Their results indicate that both FLG mutations and AD increase the risk of ICD; therefore, individuals with concurrent FLG mutations and AD are at the highest risk of developing ICD. Landeck et al. (54) genotyped 459 patients for four FLG mutations (the patients had occupational ICD of the hands); of these, 327 (71.2%) were atopic and 132 were nonatopic. Atopy status made subjects more resistant to therapy, resulting in lower rates of recovery and higher use of topical corticosteroids. In addition, Landeck et al. found that carriage of FLG loss-of-function mutations in combination with atopy further aggravated the clinical course. Among the genes coding for cytokines involved in skin inflammation, a TNF-308 G/A polymorphism has been shown to associate with susceptibility to both ICD and ACD. Carriers of the allele TNF-308 A (TNF 2 allele) have increased production of TNFα, and, apart from a lower irritation threshold to model irritants like SLS, have also been shown to develop ICD at lower irritant exposure levels compared with carriers of TNF 308 G (TNF 1 allele) (55). In a case-control study, Landeck et al. (56) genotyped 478 patients with occupational ICD of the hands for TNFα238 and TNFα-308 polymorphisms, and analyzed both allelic forms of the TNF α enhancer/promoter region, namely, TNF α -308G and TNF α -3O8A. The results were compared with those for 393 apprentices from the same high-risk occupations (controls). They observed that carriers of the variant TNFA-308A allele were more prone to develop ICD of the hands. By contrast, individuals with a TNFA-238 polymorphism were less prone to ICD suggesting a protective effect. Upon skin contact to irritants, IL-1α is released in the stratum corneum as a primary step of skin inflammation. Variations in the gene encoding IL-1α (e.g., the presence of an IL1A 889 T allele) have been shown to exert protective effects toward the development of manifest dermatitis that are attributed to reduced IL-1α levels in the stratum corneum (57).
Diagnosis of irritant contact dermatitis The diagnosis of ICD is based on history, clinical examination and patch testing, where no clinically relevant allergens are revealed. Therefore, the diagnosis is made through the intuitive judgment of the clinician and is based on the existence of irritant exposure, which can be linked to the expression of the dermatitis process, as well as on the exclusion of other types of dermatitis, especially ACD. Undoubtedly, this is suboptimal, but at present, there is no other method of diagnosis. A thorough history that covers the clinical evolution of the dermatitis and all possible etiological factors is essential for the diagnosis. It should assess the occupational exposure, including the description of the job, performed tasks, substances encountered, physical environmental factors, protective measures, and cleansing practices. The existence of irritant exposure during domestic or leisuretime activities like gardening, woodwork, or painting should also be disclosed (59). The assessment of exposure includes the determination of the intrinsic irritant potential of the suspected agent(s) together with quantitative data, including the dose, frequency and duration of exposure, and the extent of the exposed skin surface area. The most common skin irritant is wet work, which is defined as the exposure of the skin to liquid for longer than 2 h per day, the use of occlusive gloves for longer than 2 h per day, or frequent hand cleaning. Combined exposure to water and watersoluble irritants like soap and detergents is significant in high-risk occupations like hairdressing, cleaning, catering, or health care. We also have to consider the simultaneous exposure to several irritants and concomitant exposure factors like occlusion, friction, trauma and heat, among others, which might enhance the percutaneous penetration. The type and characteristics of the clinical lesions and distribution patterns of the dermatitis may provide clues that point out to the causative agent. However, ICD typically has no pathognomonic features. Although a preliminary working diagnosis of ICD can be made after a thorough clinical assessment, deciding whether the dermatitis primarily depends on irritancy or on allergy is not always straightforward (60) (Table 3). To further complicate the matter, most allergens also have irritant properties, and dermatitis is often the result of both irritancy and allergy. Sometimes, clinical examination may reveal a special “mark”, which points out to a specific exposure. For instance, eczematous lesions affecting the exposed areas of the face, eyelids, and
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202 Ale et al.: Irritant contact dermatitis Table 3 Clinical differences between ICD and ACD.
Morphology
ICD
Acute ICD includes erythema and edema and sometimes vesicles or bullae, oozing and pustules; necrosis and ulceration may also be seen with corrosive materials. ICD is mostly characterized by dryness, roughness, glazed, or scalded appearance of the skin. Chronic ICD may have hyperkeratosis, desquamation, lichenification, and fissuring. Lesions are characteristically sharply circumscribed to the contact area. Usually there is absence of distant lesions, but dermatitis may sometimes be generalized depending on the nature of the exposure. Symptoms of acute ICD are burning, stinging, prickling, pain, and soreness of the skin (pruritus may be present). Acute ICD may appear after first exposure (at least with strong irritants).
Symptoms
Clinical course
In acute ICD, lesions appear rapidly, usually minutes to few hours after exposure, but delayed reactions can be seen. Irritant reactions are characterized by the "decrescendo phenomenon". The reaction reaches its peak quickly, and then starts to heal.
skin folds are commonly observed in airborne ICD from fumes, dusts, or other airborne particles. Compromise of the dorsal aspects of the hand and fingers, and especially, the finger webs is frequently observed in ICD that is mainly due to wet work. However, both ACD and endogenous eczema frequently involve the dorsal aspects of the hands and fingers, and may also affect the finger webs. There is a tendency for vesicular eczema of the palms and sides of the fingers to be endogenous. Yet, certain irritants and allergens may induce vesicular eczema of the palmar aspects of the hands and fingers. In fact, hand dermatitis is frequently the joint outcome of endogenous, irritant and allergic factors, and may be due to occupational and/or non occupational causes. In addition, the original pattern of the dermatitis is often modified by secondary infection, treatment, and so on, which require a sensitive diagnostic approach.
Management of irritant contact dermatitis ICD is a multifarious disease; hence, its management is not clearly defined. In a systematic review on CD
ACD Pustules, necrosis, or ulceration are rarely seen.
ACD is mostly characterized by edema, vesicles and oozing; however, these features are usually not present in subacute or chronic ACDChronic ACD may display hyperkeratosis, desquamation, lichenification, and fissuring. Clinical lesions are stronger in the contact area, but their limits are usually ill defined. Dissemination of the dermatitis with distant lesions may occur. Pruritus is the main symptom of ACD.
Sensitizing exposure(s) is required. Clinical lesions appear after subsequent challenges with re-presentation of the antigent to already primed (memory) T-cells. Lesions usually appear 24–72 h after the last exposure to the causative agent, but they may develop as early as 5 h or as late as seven days after exposure. Allergic reactions are characterized by the "crescendo phenomenon", and the kinetics of resolution may be slower
treatment, only a limited number of interventions have been demonstrated to be effective (61). For these reasons, well controlled studies that involve a sufficient number of individuals and use real-world setting evaluations are clearly needed. The principles of management of ICD involve avoidance, protection, and substitution; they also concern both the treatment of the present dermatitis and the prevention of new flare-ups. Preventive measures are crucial and should be instituted in all cases. Causative(s) agents should be avoided and exposure to all other common potential irritants like soaps and detergents should be limited. It is important to remember that almost any material may be considered a cutaneous irritant if the skin is exposed to sufficiently high concentrations for a long enough period of time. The irritated skin becomes hyper reactive and even minor contact with the irritant agents may trigger a dermatitis flare. Furthermore, it has been demonstrated that after an irritant insult, the barrier function may take several weeks to normalize, even when the skin appears normal. To measure the recovery time of the skin barrier, chronic ICD was induced on the forearms of 10 volunteers by occluded application of the model surfactant 1% SLS for 30 min on 5 consecutive days each week for 3 weeks.
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Ale et al.: Irritant contact dermatitis 203
At variable times after induction, a provocation was made using 7.5% SLS both at treated and untreated areas. Their results showed that skin reactivity of previous chronic ICD sites assessed by visual scale scores, transepidermal water loss, skin color reflectance, and electrical capacitance increased even after 10 weeks post-induction (62). Similarly, another work demonstrated that, after inducing an acute ICD by a 24-h SLS application, the bioengineering parameters did not normalize until 2 weeks after the induction. In addition, hyper-irritability vis-à-vis a new SLS challenge persisted for up to 4 weeks (63). ICD is often induced by workplace exposure; therefore, successful prevention involves generating a safe work environment as well as adequate working practices. Collective (or general) measures are usually more effective than individual measures. These are directed to eliminate, as much as possible, any possible skin contact with potentially harmful environmental exposures, either by substitution or by process engineering, including enclosure and automation of the work procedures, appropriate exhaust and ventilation systems, good housekeeping, and convenient washing and changing facilities (64). Individual protection measures involve protective clothing and gloves. Gloves are the most common protection for ICD of the hands. For general purposes and household tasks, vinyl or rubber household gloves are usually suitable. In the occupational setting, the type of glove preferred depends on the nature of the chemicals to which the worker is exposed. However, the use of certain gloves may also contribute to an increased risk of dermatitis. Non-specific irritation can occur from sweat entrapment and friction of the gloves against the skin; accidental occlusion of harmful agents beneath the glove may occur, thus enhancing cutaneous absorption of the substances. Furthermore, contact allergy from vulcanizing agents in rubber gloves may occur. It is important to remove gloves on a regular basis to reduce perspiration and sweating. The use of a cotton glove liner for latex, nitrile, and vinyl gloves is recommended, and care must always be taken to ensure that irritants do not come into contact with the skin through punctured or damaged gloves. In addition to gloves and protective clothing, barrier creams and skin conditioning products should be readily available in the workplace. Mild soap-free skin cleansers should be used in place of soap, and harsh abrasives and solvents should be avoided. Many times, a careful rinsing with water or soap-free cleanser will be enough to remove irritants and allergens from the skin. Waterless hand cleansers and abrasive soaps should be used sparingly and only when necessary (65, 66).
Cool compresses of Burrow’s solution (aluminum acetate in water), saline, or plain tap water can help control the vesiculation and exudation in acute irritant dermatitis. Burrow’s solution also has an antiseptic effect. Bland emollients should be used after washing hands, after bathing or showering, and at bedtime. A number of agents commonly found in therapeutic and cosmetic products for the skin (e.g., propylene glycol, lactic acid, urea, salicylic acid) may produce further skin inflammation and may need to be avoided in these patients. Educational measures to increase the understanding of workers about workplace hazards and to motivate them to use skin protection measures appropriately are just as important as the careful selection of skin protection materials. A comprehensive review of randomized clinical trials, which studied the effectiveness of barrier creams, moisturizers, gloves, complex educational interventions, and other interventions for the primary prevention of occupational irritant hand dermatitis, concluded that, there was insufficient evidence for the effectiveness of most of these interventions, even if the findings were generally positive (67). Topical corticosteroids play a limited role in the treatment of irritant contact dermatitis (68–70). Avoiding the irritant exposure is the most important measure, and corticosteroids may be helpful for diminishing the inflammatory process, although there are some reports suggesting that they may compromise barrier function. Topical immunomodulators have also been evaluated. In a randomized, double-blind, controlled trial, healthy volunteers were exposed to 5% SLS and 50% and nonanoic acid (NON) in a cumulative wash test. Different treatments were evaluated (triamcinolone acetonide, clobetasol propionate, tacrolimus and glycerol ointment), wherein vehicle and no treatment served as the control. No treatments were significantly better than the other treatments and controls. There was a trend toward worsened irritancy by tacrolimus on SLS-irritated skin (71). Fuchs et al. (72) evaluated the effects of tacrolimus in a 4-day repetitive irritation test with twice daily application of SLS, and in a shortwave ultraviolet light (UVB) erythema model. The effect was evaluated visually and then quantified by non-invasive bioengineering methods, namely, chromametry and tewametry (TEWL). On the one hand, when tacrolimus was applied 30 min after SLS irritation, a trend toward increased inflammation compared with controls was observed in all three methods. On the other hand, pimecrolimus was suggested as effective in the treatment of skin disorders with an impaired function of the epidermal barrier (73). In a randomized, placebo-controlled study, SLS (3% v/v) was applied under occlusion on the
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204 Ale et al.: Irritant contact dermatitis back of 36 healthy volunteers for 24 h. Subsequently, the test areas were treated for 24 h with pimecrolimus cream, 1% hydrocortisone in a hydrophilic ointment, and the vehicle alone over 3 consecutive days. Pimecrolimus and 1% hydrocortisone cream significantly reduced the SLSinduced erythema, supporting the notion that pimecrolimus may be useful in the treatment of acute ICD (73). Phototherapy has been reserved generally for patients with refractory dermatitis deemed unresponsive to conventional therapy. Oral psoralen photochemotherapy (PUVA) and UVB were applied in the treatment of chronic allergic and ICD of the hands. Rosen et al. (74) studied 35 volunteers with eczematous hand dermatitis, 22 of whom had ACD, and 6 had ICD. The treated hand cleared in all PUVA-treated volunteers who completed the study. However, although UVBtreated volunteers had clinical improvement, there were no cases of resolution of the hand dermatitis. Recurrences appeared in 9 of 14 patients after a mean period of 3 months, indicating the necessity of maintenance therapy. It has been reported that sensory irritation may be treated by applying strontium salts, which selectively block the activation of cutaneous type C fibers involved in the universal transmission of itch, burn, and sting sensations regardless of the irritation stimulus (68, 75).
Conclusion ICD is the most common form of CD. Nowadays, it is recognized that irritancy does not represent a single monomorphous entity, but rather a complex biologic syndrome with diverse pathophysiology and clinical manifestations. The clinical presentation is highly variable depending on several factors, including properties and strength of the irritant; dose, duration and frequency of exposure; environmental factors; and skin susceptibility. The pathophysiological mechanism depends on the activation of the innate immune system, and involves skin barrier disruption, cellular changes, as well as the release of proinflammatory mediators that directly recruit and activate T lymphocytes. There have been a number of advances in the understanding of ICD, and some interesting new areas of research include the role of the loss-of-function mutations in the gene encoding filaggrin and the TNF-α gene polymorphisms. The diagnosis of ICD may present difficulties to the clinician, especially since it rests on the exclusion of other types of dermatitis, especially ACD. Despite the differences in the clinical subtypes of ICD, the treatment should include avoidance of irritants, use of appropriate protective gloves where there is hand involvement, and suitable measures of skin care products
like non irritating cleansers and moisturizers. There have been some recent concerns raised about the use of topical corticosteroids in the treatment of ICD as they may impair barrier function. Overall, recent advances in understanding the pathogenesis as well as better awareness of the clinical significance of ICD can lead to improved quality care for our patients.
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Iris S. Ale* and Howard I. Maibach
Irritant contact dermatitis Abstract: Irritant contact dermatitis (ICD) is the most common form of contact dermatitis. It represents the cutaneous response to the toxic/physical effects of a wide variety of environmental agents. Nowadays, it is recognized that irritancy does not represent a single monomorphous entity but rather a complex biologic syndrome with diverse pathophysiology and clinical manifestations. The clinical presentation is highly variable depending on several factors, including properties and strength of the irritant, dose, duration and frequency of exposure, environmental factors, and skin susceptibility. The pathophysiological mechanism depends on activation of the innate immune system and involves skin barrier disruption, cellular changes, and release of proinflammatory mediators that directly recruit and activate T lymphocytes. The diagnosis of irritant contact dermatitis is often clinical, and involves a comprehensive history and examination, as well as the exclusion of allergic contact dermatitis with patch testing. Recent advances in understanding the pathogenesis as well as better awareness of the clinical significance of ICD will lead to a improved care for our patients. Keywords: contact dermatitis; cutaneous toxicity; irritancy; irritant contact dermatitis; irritants. DOI 10.1515/reveh-2014-0060 Received August 11, 2014; accepted August 13, 2014
dermatitis (OCD) tends to become chronic, resulting in impaired quality of life and loss of work ability (1). According to the pathophysiological mechanisms involved, two main types of CD may be recognized, namely, irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD). Other additional forms of CD are photocontact (photoallergic and phototoxic) dermatitis and protein CD. ICD has traditionally been defined as a local inflammatory non-specific reaction of the skin following a single or repeated exposure to an irritant. Likewise, an irritant has been defined as any agent, physical or chemical, that is capable of producing cellular perturbation if applied for sufficient time and in sufficient concentration (2). Nowadays, it is recognized that irritancy represents a clinical and pathological spectrum of diseases and more than just a single entity, entailing a combination of both exogenous and endogenous factors (3). The spectrum of the clinical presentations and etiological factors of ICD is extremely broad. It is widely accepted that several mechanisms are involved in the development of ICD, including skin barrier disruption, keratinocyte damage, and release of proinflammatory mediators that directly recruit and activate T lymphocytes (4–6). Current insights regarding the genetic and immunological factors involved in the susceptibility to ICD allow for identification of subgroups of patients in need of specific preventive and educational interventions. This review will summarize recent advances in the understanding of ICD.
Introduction Contact dermatitis (CD) is an inflammatory skin condition that is primarily induced by exposure to an environmental agent. It represents one of the most frequent types of human immunotoxicity, which represents more than 90% of occupational skin disorders, giving good reason for its significant socioeconomic impact. Occupational contact
*Corresponding author: Iris S. Ale, Department of Allergology and Department of Dermatology, University Hospital, Republic University of Uruguay, Arazati 1194 11300, Montevideo, Uruguay, Phone: +(598) 98786141, E-mail: [email protected] Howard I. Maibach: Department of Dermatology, School of Medicine, University of California in San Francisco, San Francisco, CA, USA
Pathophysiology ICD is due to inflammatory and cytotoxic effects caused by exposure to various irritant stimuli acting as adjuvants, which activate the innate immune system. Irritants generate innate immune responses by similar pathways than those used by pathogens (7, 8). Microbes activate the innate immune system by generating danger signals in the form of so-called pathogen-associated molecular patterns (PAMPs). These molecules are highly conserved determinants typical of whole classes of pathogens, and can be bacterial or fungal cell wall components, microbial nucleic acids, proteins, or sugars. Most normal hemato poietic and nonhematopoietic cells express pattern
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196 Ale et al.: Irritant contact dermatitis recognition receptors (PRRs) like the membrane-associated Toll-like receptors (TLR) and the cytotosolic NOD-like receptors (NLR), which detect such danger signals and activate inflammatory signaling pathways (9–13). Irritants can induce ligands for the TLR, as well as activate the NLRP3 inflammasome and the production of reactive oxygen species. This activation of the innate immune and stress responses triggers a multitude of intracellular signaling pathways, including adaptor molecules, kinases (e.g., mitogen-activated protein kinases or MAPK) and transcription factors, which produce proinflammatory mediators and induce the maturation of dendritic cells (DCs); in turn, this facilitates the activation of the adaptive immune system. It now appears that innate and adaptive immune responses are much more closely linked than previously believed, and that the innate inflammatory immune response is a prerequisite for the activation and shaping of the adaptive immune response (14–16). In this sense, recent advances in the pathophysiology of chemical-induced skin inflammation (xenoinflammation) have shown that ICD and ACD are intimately associated, and that irritancy may predispose the development of allergic contact sensitization (17–20). Hence, an efficient way to prevent ACD is to develop strategies to avoid ICD. Irritants induce skin barrier disruption and direct cellular damage. Keratinocytes play a central role in the inflammatory response releasing cytokines, upregulating their major histocompatibility complex (MHC) class II antigens, and expressing cell adhesion molecules. Interleukin (IL)-1α, IL-1β and tumor necrosis factor (TNF)-α are key cytokines in this response. Preformed IL-1α, which is stored in the SC and the keratinocytes, probably starts the cytokine cascade (21–23). Additionally, TNF-α increases MHC class II and intracellular adhesion molecule (ICAM)-1 expression on the epidermis and dermis, playing a key role in perpetuating the inflammatory process (24–26). Some irritant reactions can be blocked by the injection of
anti-TNF-α antibodies or recombinant soluble receptors (26). Therefore, polymorphisms in TNF-α genes may represent a risk factor for ICD (27). T lymphocytes entering the skin in the contact area express a surface molecule, the cutaneous lymphocyteassociated antigen (CLA), which is crucial for the skin homing of T lymphocites participating in their transendothelial migration (28). The ligand for CLA is E- selectin, which is upregulated in various skin diseases, including CD. Other cell adhesion molecules like ICAM-1 and Lymphocyte function-associated antigen (LFA) (1), facilitate the extravasation of inflammatory T lymphocytes to the inflammatory site. This process may be enforced by the release of the chemoattractant IL-8 by the keratinocytes. Additional pro-inflammatory released molecules are IL-6, IL-8, CCL20, CCL27, IL12 and IL18, among others. The chemokine CCL21, produced by dermal lymphatic endothelial cells, is also upregulated in ICD (29). It facilitates the migration of T-lymphocytes, resulting in a skin inflammatory response.
Clinical aspects The clinical spectrum of ICD is broad and ranges from slight scaling, erythema, edema, and erosions, to an eczematous condition indistinguishable from ACD and other types of eczema. The characteristics and severity of the lesions are influenced by several factors, including the nature, concentration and duration of contact with the irritant chemical; the pre-existing skin condition and other constitutional factors; as well as concomitant exposure factors like mechanical, thermal, or climatic effects (Table 1). This diversity in clinical presentation has generated a classification scheme that is mainly based on the morphology and time course of the clinical lesions has been described along with various “genotypes" of ICD (30) (Table 2).
Table 1 Factors influencing the irritancy potential. Agent
Molecular structure Inherent toxicity pH pK Hydrophobicity (log P) Solubility Physical form: liquid, gas solid Vehicle Multiple chemical contact (additive or sinergic effect)
Exposure Concentration/dose Frequency of contact Duration of contact Type of contact Mode of application
Concomitant (modifying) exposure factors: Mechanical Thermal Climatic
Endogenous factors Region of the skin Age Race/skin color/phototype Dry skin Sweating Hormonal influences Active or previously active skin diseases Sensitive skin Atopy, atopic dermatitis
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Ale et al.: Irritant contact dermatitis 197 Table 2 Types of irritant contact dermatitis. Type of ICD
Agent
Clinical course
Acute ICD
Delayed acute ICD
Strong irritant (usually single agent)
Irritant reaction
Acute onset after exposure Usually (not always) quick recovery Onset delayed- 12–24 h or longer after exposure Usually acute onset, multiple exposures Usually (not always) recovery with withdrawal Symptoms occur quickly following exposure Early stage of skin irritation
Erythema, edema, vesicles, bullae, exudation Usually sharp demarcation Burning, pain, stinging, pruritus Similar to acute ICD except for delayed onset Usually monomorphic appearance: redness, scaling, chapping, pustules, or erosions
Slowly developing (weeks to years) Slowly developing after preceding trauma Slowly developing
Mild erythema, xerosis, hyperkeratosis, fissuring. Pruritus, soreness and pain Similar to chronic ICD
Subjective (sensory) irritation
Non-erythematous (suberythematous) irritation Chronic (cumulative) ICD
Distinctive delayed/acute irritants Mild irritants like water, soap, and detergents
Distinctive agents inducing sensory irritation
Traumatic ICD
Frictional dermatitis
Mild irritants like water, soap, and detergents Several weak irritants (chemical and physical agents) Traumatic factors (physical or chemical) Low-grade frictional force
Asteatotic irritant eczema
Low humidity, low temperatures
Slowly developing
Acneiform ICD
Slowly developing (weeks to months)
Airborne ICD
Metal, tars, oils, greases, metalworking fluids and chlorinated agents Irritants released into the air (dusts, fibers, fumes, vapors)
Variable, usually acute onset
Acute ICD Acute ICD is caused by exposure to a strong irritant. Classical signs of acute ICD are erythema, edema, oozing/exudation, bullae and erosions, starting soon after exposure to the irritant. Symptoms are burning, pain, stinging, pruritus, and soreness of the skin. The lesions frequently have a sharp demarcation and are mostly limited to the contact area, because the concentration of the substance spreading outside this area almost immediately declines below the critical threshold necessary to elicit a reaction. The diagnosis of acute ICD is usually straightforward because the rapid onset of skin lesions after exposure points to the causative agent. Acute ICD usually regresses soon after exposure, providing that there is no re-exposure. However, depending on the severity and susceptibility factors, it may persist for weeks and even months after exposure.
Clinical signs and symptoms
No clinical signs. Stinging, tingling, burning or itching No clinical signs
Erythema, scaling hyperkeratosis, and fissuring in areas of friction Xerosis, ichthyosiform scaling, and superficial fissuring, especially on the lower legs Open and closed comedones, cysts, pustules, nodules Dermatitis predominates in exposed areas, although it may affect protected skin due to contaminated clothing
The intensity of the acute irritancy lesions may vary from a mild erythema, to a “chemical burn" with necrosis, depending on factors like the characteristics of the irritant (e.g., strong acids or alkalis), the exposure time, and concomitant exposure factors. In fact, differentiation between acute ICD and a primary chemical burn is not always possible. Strong acids and alkalis are the major causes of chemical burns, but other chemicals like oxidants or reducing agents, as well as certain elemental metals may also produce similar lesions (31). The halogenated acids are especially dangerous because they may lead to continuous tissue destruction and necrosis even after short exposures. In most cases, chemical burns arise as a result of an occupational accident, but they may also occur outside of work. Sometimes, caustic chemicals are trapped by gloves, or other protective pieces of clothing, resulting in deeper injuries via the occlusion effect and deferred
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198 Ale et al.: Irritant contact dermatitis removal. Usually, the symptoms start immediately after the exposure, but with some chemicals, the damage is not always obvious and the onset may be delayed.
Delayed acute ICD In simple acute ICD, the reaction occurs within minutes to hours after exposure; by contrast, in delayed acute ICD, the onset of symptoms may be delayed for 8–24 h or more. Except for the delayed onset, the clinical expressions and courses are similar to those of acute ICD. Due to this delayed onset, this type of ICD may be misdiagnosed as ACD. A careful history and properly performed and interpreted patch test can lead to accurate diagnosis. Delayed acute ICD is characteristic of certain irritants, including dithranol, calcipotriol, benzalkonium chloride, nonanoic acid, sodium lauryl sulfate, propylene glycol, tazarotene and diacrylates, among others (32, 33).
Irritant reaction Irritants may induce cutaneous reactions that do not fulfill the clinical picture of dermatitis. These reactions are monomorphic, rather than the usual polymorphic appearance of ICD, and are characterized by one or more of the following signs: redness, scaling, chapping, pustules, or erosions. Irritant reactions are mostly seen in individuals significantly exposed to mild irritants like water, soap and detergents. High-risk occupations are those of hairdressers, cleaners, caterers, metal workers, and so on, especially in the early stage of occupational training. Frequently, this condition heals spontaneously with hardening of the skin. However, repeated episodes may lead to a chronic irritant contact dermatitis (Figure 1).
Figure 1 Chronic hand dermatitis.
Subjective or sensorial irritation Subjective irritation is characterized by a sensory discomfort, usually manifesting as a stinging, tingling, burning or itchy sensation, in the absence of clinical and histological evidence of skin lesions. Typically, symptoms occur rapidly following exposure (i.e., within seconds to minutes). The threshold for this reaction varies between subjects, and is independent of the susceptibility to other types of irritation (34). It is sometimes difficult to distinguish subjective irritation from subclinical contact urticaria. Among women, symptoms of subjective skin irritation (burning, stinging, etc.) occur more frequently in those who consider that they have sensitive skin (53%) than in those who do not (17%) (35, 36). Therefore, “sensitive skin” might be considered a marker of a form of skin irritancy. Hydroxy acids and propylene glycol are common subjective irritants. Interestingly, surfactant sodium lauryl sulphate (SLS), a potent objective irritant, does not generally induce stinging. Subjective irritation has both neural and vascular components that contribute to the clinical symptoms. The outcome is generally good.
Nonerythematous or suberythematous irritation More than a special type of irritancy, this represents an early stage of skin irritation, where there is no obvious clinical inflammation, but the incipient epidermal and skin barrier damage may be evidenced by bioengineering techniques (37, 38).
Chronic (cumulative) ICD Cumulative ICD, also known as “wear and tear dermatitis” and “traumiterative dermatitis”, ICD is the clinical consequence of a series of repeated events of subthreshold irritant injury to the skin, with brief intervals between events that prevent the complete restoration of the skin barrier function. Cumulative ICD typically occurs with exposure to weak irritants rather than strong ones, including both chemical agents and various harmful physical factors like friction, microtrauma, low humidity, the desiccant effects of dust or soil, and temperature. Clinical dermatitis often arises when the defense or repair capacity of the skin is exhausted and the irritant load exceeds the individual’s elicitation threshold.
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Ale et al.: Irritant contact dermatitis 199
Figure 4 Traumatic irritant contact dermatitis. Figure 2 Cumulative irritant contact dermatitis in an atopic patient.
Once the stratum corneum barrier has been breached, many normally innocuous agents may act as perpetuating factors. Patients with sensitive skin (i.e., atopic individuals) have a diminished irritant threshold or a prolonged skin restoration time, making them more susceptible to develop irritant contact dermatitis. Clinical signs of cumulative ICD are mild erythema, xerosis, and hyperkeratosis with frequent fissur ing (Figure 2). The lesions are usually localized at the contact area, although these are less defined than in acute ICD. The patients report both pruritus and pain, caused by fissuring of the hyperkeratotic skin. Symptoms do not occur immediately after the exposure, so differential diagnosis with ACD may be tricky. Chronic ICD often presents as hand eczema elicited by exposure to weak irritants (occupational or domestic), which adds to the difficulty of identifying causative factors (Figure 3).
Figure 3 Subacute irritant contact dermatitis of the dorsal hands.
Traumatic irritant contact dermatitis This uncommon form of ICD appears after an acute cutaneous trauma (e.g., a sudden exposure to a strong irritant). It is characterized by incomplete healing of the original insult followed by a nummular eczema-like lesion (Figure 4). It frequently has a chronic course and may persist or recur for long periods of time, sometimes being resistant to therapy (39).
Frictional dermatitis Frictional dermatitis is the cutaneous irritant response to a low-grade frictional force, that is, a shearing force acting horizontally to the surface. It is confined to the locations of frictional trauma, affecting mostly the hands, especially the palms and fingers on the dominant hand (Figure 5). Clinically, it is characterized by erythema, scaling hyperkeratosis, and fissuring. Occupations associated with frictional dermatitis include driving and repetitive handling of paper, plastic, cardboard, fabric or metal components, among others. Wet work, contact allergy, atopy, and psoriasis have been described as concurrent factors in some patients (40). Prognosis is usually good. However, in an
Figure 5 Frictional dermatitis.
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200 Ale et al.: Irritant contact dermatitis occupational setting, modification of the job to decrease frictional forces cannot always be achieved.
Asteatotic eczema The asteatotic eczema (syn. exsiccation eczematide, eczema cracquelé) is seen mainly in the lower legs of elderly individuals during the winter months. The condition is mostly due to environmental insults like low humidity and low temperatures, although other factors (e.g., wet work, chemical insults, and friction) may play a contributory role. Clinically, the skin is xerotic, with ichthyosiform scaling and fissuring due to the cracking of the superficial epidermal layers often associated with eczematous changes. The condition is due to a decrease in skin surface lipid and reduced water content in the stratum corneum, causing the corneocytes to be shed in large polygonal scales (41). In severe cases, a reduction of skin content of amino acid due to low profilaggrin biosynthesis can be found (42).
Pustular and acneiform dermatitis Exposure to metals, tars, mineral oils and greases, asphalt, metalworking fluids, and chlorinated agents can result in a pustular and acneiform dermatitis, especially in atopic patients. Not all individuals exposed to these agents will develop the dermatitis; hence, this type of ICD seems to be dependent on both chemical and constitutional factors. Acne cosmetica represents an acneiform ICD caused by the irritant effect of certain cosmetic agents in the pilosebaceous follicles. (e.g., pomade acne). Other etiologic factors are repeated mechanical irritation through friction, rubbing or pressure (e.g., acne mechanica). Occupational oil acne is mostly due to petroleum by-products, cutting oils, and metalworking oils. It is mostly seen in machinetool operators, mechanics, and workers exposed to petroleum and its derivatives. The clinical lesions are open and closed comedones, pustules, and nodules predominating in the arms, forearms, and dorsal hands. In addition, oil contaminated clothing produces lesions in protected skin areas (43–45). Chloracne is due to occupational or environmental exposure to chlorinated hydrocarbons (chlornaphthalenes, chlordiphenyls, and chlordiphenyloxides). Skin lesions are comedones and yellowish cysts that are predominantly in the face, although they may involve other areas. Systemic toxicity may be present (46–49). Pustular/acneiform ICD should always be considered in the differential diagnosis of acneiform lesions in adults.
Airborne ICD Airborne ICD is a clinical diagnosis that includes different types of dermatitis (e.g., acute, chronic, subjective dermatitis), which are caused by substances released into the air and settling down on the skin. Most of the airborne irritants identified are found in occupational settings (50–52) and can be present under various physical forms: i.e., fibers, dust particles, sprays, mists, vapors, and gases. The most common sites of airborne dermatitis are the skin areas that are directly exposed to the air: the face, neck, décolleté, hands, and forearms. In the face, the upper eyelids are particularly susceptible to airborne substances as a result of the higher penetration of chemicals through the thin skin. Sometimes, the dermatitis may involve the covered areas, especially the body folds because the substances may be trapped under clothing. The clinical lesions and severity of the dermatitis will depend on the agents and degree of exposure. They consists of small papules or papulovesicles, linear erosions caused by scratching or a maculopapular rash. Acute edematous lesions may be seen following accidental exposure to irritants vapors or gases. Itching, stinging, and burning sensations are the major symptoms.
Modulation of irritant contact dermatitis The development of occupational ICD is complex, and determined by a multiplicity of intrinsic and extrinsic factors. Extrinsic factors like the physicochemical properties of the irritant, the circumstances, duration and intensity of exposure, and effect of concurrent exposure to other substances have to be considered together with the intrinsic factors (individual susceptibility), including age, atopic constitution, skin condition, or a history of dermatitis. The individual susceptibility for the development of ICD shows a high degree of variability, which may be attributed to both genetic and environmental factors. Recently, several studies have investigated the link between individual susceptibility to CD and variations in the genes that are involved in the skin barrier function, the inflammatory response, and biotransformation (53–58). Genetic variations related to the skin barrier, which contribute to increased susceptibility to ICD, include loss of function mutations in the gene encoding the epidermal differentiation protein filaggrin (FLG). These mutations represent a relevant individual risk factor for AD and also
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for ICD and nickel ACD. Individuals with AD and FLG mutations have an increased risk of acquiring occupational ICD. Visser et al. (53) investigated the relative contribution and interaction of FLG mutations and AD in German patients with occupational ICD and controls. They observed that FLG mutations were present in 15.9% and 8.3% of the ICD patients and controls, respectively; the crude odds ratio (OR) was 2.09 [95% confidence interval (CI) 1.33–3.28] for the combined genotype. The adjusted OR for FLG mutations, corrected for AD, was 1.62 (95% CI 1.01–2.58). Their results indicate that both FLG mutations and AD increase the risk of ICD; therefore, individuals with concurrent FLG mutations and AD are at the highest risk of developing ICD. Landeck et al. (54) genotyped 459 patients for four FLG mutations (the patients had occupational ICD of the hands); of these, 327 (71.2%) were atopic and 132 were nonatopic. Atopy status made subjects more resistant to therapy, resulting in lower rates of recovery and higher use of topical corticosteroids. In addition, Landeck et al. found that carriage of FLG loss-of-function mutations in combination with atopy further aggravated the clinical course. Among the genes coding for cytokines involved in skin inflammation, a TNF-308 G/A polymorphism has been shown to associate with susceptibility to both ICD and ACD. Carriers of the allele TNF-308 A (TNF 2 allele) have increased production of TNFα, and, apart from a lower irritation threshold to model irritants like SLS, have also been shown to develop ICD at lower irritant exposure levels compared with carriers of TNF 308 G (TNF 1 allele) (55). In a case-control study, Landeck et al. (56) genotyped 478 patients with occupational ICD of the hands for TNFα238 and TNFα-308 polymorphisms, and analyzed both allelic forms of the TNF α enhancer/promoter region, namely, TNF α -308G and TNF α -3O8A. The results were compared with those for 393 apprentices from the same high-risk occupations (controls). They observed that carriers of the variant TNFA-308A allele were more prone to develop ICD of the hands. By contrast, individuals with a TNFA-238 polymorphism were less prone to ICD suggesting a protective effect. Upon skin contact to irritants, IL-1α is released in the stratum corneum as a primary step of skin inflammation. Variations in the gene encoding IL-1α (e.g., the presence of an IL1A 889 T allele) have been shown to exert protective effects toward the development of manifest dermatitis that are attributed to reduced IL-1α levels in the stratum corneum (57).
Diagnosis of irritant contact dermatitis The diagnosis of ICD is based on history, clinical examination and patch testing, where no clinically relevant allergens are revealed. Therefore, the diagnosis is made through the intuitive judgment of the clinician and is based on the existence of irritant exposure, which can be linked to the expression of the dermatitis process, as well as on the exclusion of other types of dermatitis, especially ACD. Undoubtedly, this is suboptimal, but at present, there is no other method of diagnosis. A thorough history that covers the clinical evolution of the dermatitis and all possible etiological factors is essential for the diagnosis. It should assess the occupational exposure, including the description of the job, performed tasks, substances encountered, physical environmental factors, protective measures, and cleansing practices. The existence of irritant exposure during domestic or leisuretime activities like gardening, woodwork, or painting should also be disclosed (59). The assessment of exposure includes the determination of the intrinsic irritant potential of the suspected agent(s) together with quantitative data, including the dose, frequency and duration of exposure, and the extent of the exposed skin surface area. The most common skin irritant is wet work, which is defined as the exposure of the skin to liquid for longer than 2 h per day, the use of occlusive gloves for longer than 2 h per day, or frequent hand cleaning. Combined exposure to water and watersoluble irritants like soap and detergents is significant in high-risk occupations like hairdressing, cleaning, catering, or health care. We also have to consider the simultaneous exposure to several irritants and concomitant exposure factors like occlusion, friction, trauma and heat, among others, which might enhance the percutaneous penetration. The type and characteristics of the clinical lesions and distribution patterns of the dermatitis may provide clues that point out to the causative agent. However, ICD typically has no pathognomonic features. Although a preliminary working diagnosis of ICD can be made after a thorough clinical assessment, deciding whether the dermatitis primarily depends on irritancy or on allergy is not always straightforward (60) (Table 3). To further complicate the matter, most allergens also have irritant properties, and dermatitis is often the result of both irritancy and allergy. Sometimes, clinical examination may reveal a special “mark”, which points out to a specific exposure. For instance, eczematous lesions affecting the exposed areas of the face, eyelids, and
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202 Ale et al.: Irritant contact dermatitis Table 3 Clinical differences between ICD and ACD.
Morphology
ICD
Acute ICD includes erythema and edema and sometimes vesicles or bullae, oozing and pustules; necrosis and ulceration may also be seen with corrosive materials. ICD is mostly characterized by dryness, roughness, glazed, or scalded appearance of the skin. Chronic ICD may have hyperkeratosis, desquamation, lichenification, and fissuring. Lesions are characteristically sharply circumscribed to the contact area. Usually there is absence of distant lesions, but dermatitis may sometimes be generalized depending on the nature of the exposure. Symptoms of acute ICD are burning, stinging, prickling, pain, and soreness of the skin (pruritus may be present). Acute ICD may appear after first exposure (at least with strong irritants).
Symptoms
Clinical course
In acute ICD, lesions appear rapidly, usually minutes to few hours after exposure, but delayed reactions can be seen. Irritant reactions are characterized by the "decrescendo phenomenon". The reaction reaches its peak quickly, and then starts to heal.
skin folds are commonly observed in airborne ICD from fumes, dusts, or other airborne particles. Compromise of the dorsal aspects of the hand and fingers, and especially, the finger webs is frequently observed in ICD that is mainly due to wet work. However, both ACD and endogenous eczema frequently involve the dorsal aspects of the hands and fingers, and may also affect the finger webs. There is a tendency for vesicular eczema of the palms and sides of the fingers to be endogenous. Yet, certain irritants and allergens may induce vesicular eczema of the palmar aspects of the hands and fingers. In fact, hand dermatitis is frequently the joint outcome of endogenous, irritant and allergic factors, and may be due to occupational and/or non occupational causes. In addition, the original pattern of the dermatitis is often modified by secondary infection, treatment, and so on, which require a sensitive diagnostic approach.
Management of irritant contact dermatitis ICD is a multifarious disease; hence, its management is not clearly defined. In a systematic review on CD
ACD Pustules, necrosis, or ulceration are rarely seen.
ACD is mostly characterized by edema, vesicles and oozing; however, these features are usually not present in subacute or chronic ACDChronic ACD may display hyperkeratosis, desquamation, lichenification, and fissuring. Clinical lesions are stronger in the contact area, but their limits are usually ill defined. Dissemination of the dermatitis with distant lesions may occur. Pruritus is the main symptom of ACD.
Sensitizing exposure(s) is required. Clinical lesions appear after subsequent challenges with re-presentation of the antigent to already primed (memory) T-cells. Lesions usually appear 24–72 h after the last exposure to the causative agent, but they may develop as early as 5 h or as late as seven days after exposure. Allergic reactions are characterized by the "crescendo phenomenon", and the kinetics of resolution may be slower
treatment, only a limited number of interventions have been demonstrated to be effective (61). For these reasons, well controlled studies that involve a sufficient number of individuals and use real-world setting evaluations are clearly needed. The principles of management of ICD involve avoidance, protection, and substitution; they also concern both the treatment of the present dermatitis and the prevention of new flare-ups. Preventive measures are crucial and should be instituted in all cases. Causative(s) agents should be avoided and exposure to all other common potential irritants like soaps and detergents should be limited. It is important to remember that almost any material may be considered a cutaneous irritant if the skin is exposed to sufficiently high concentrations for a long enough period of time. The irritated skin becomes hyper reactive and even minor contact with the irritant agents may trigger a dermatitis flare. Furthermore, it has been demonstrated that after an irritant insult, the barrier function may take several weeks to normalize, even when the skin appears normal. To measure the recovery time of the skin barrier, chronic ICD was induced on the forearms of 10 volunteers by occluded application of the model surfactant 1% SLS for 30 min on 5 consecutive days each week for 3 weeks.
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At variable times after induction, a provocation was made using 7.5% SLS both at treated and untreated areas. Their results showed that skin reactivity of previous chronic ICD sites assessed by visual scale scores, transepidermal water loss, skin color reflectance, and electrical capacitance increased even after 10 weeks post-induction (62). Similarly, another work demonstrated that, after inducing an acute ICD by a 24-h SLS application, the bioengineering parameters did not normalize until 2 weeks after the induction. In addition, hyper-irritability vis-à-vis a new SLS challenge persisted for up to 4 weeks (63). ICD is often induced by workplace exposure; therefore, successful prevention involves generating a safe work environment as well as adequate working practices. Collective (or general) measures are usually more effective than individual measures. These are directed to eliminate, as much as possible, any possible skin contact with potentially harmful environmental exposures, either by substitution or by process engineering, including enclosure and automation of the work procedures, appropriate exhaust and ventilation systems, good housekeeping, and convenient washing and changing facilities (64). Individual protection measures involve protective clothing and gloves. Gloves are the most common protection for ICD of the hands. For general purposes and household tasks, vinyl or rubber household gloves are usually suitable. In the occupational setting, the type of glove preferred depends on the nature of the chemicals to which the worker is exposed. However, the use of certain gloves may also contribute to an increased risk of dermatitis. Non-specific irritation can occur from sweat entrapment and friction of the gloves against the skin; accidental occlusion of harmful agents beneath the glove may occur, thus enhancing cutaneous absorption of the substances. Furthermore, contact allergy from vulcanizing agents in rubber gloves may occur. It is important to remove gloves on a regular basis to reduce perspiration and sweating. The use of a cotton glove liner for latex, nitrile, and vinyl gloves is recommended, and care must always be taken to ensure that irritants do not come into contact with the skin through punctured or damaged gloves. In addition to gloves and protective clothing, barrier creams and skin conditioning products should be readily available in the workplace. Mild soap-free skin cleansers should be used in place of soap, and harsh abrasives and solvents should be avoided. Many times, a careful rinsing with water or soap-free cleanser will be enough to remove irritants and allergens from the skin. Waterless hand cleansers and abrasive soaps should be used sparingly and only when necessary (65, 66).
Cool compresses of Burrow’s solution (aluminum acetate in water), saline, or plain tap water can help control the vesiculation and exudation in acute irritant dermatitis. Burrow’s solution also has an antiseptic effect. Bland emollients should be used after washing hands, after bathing or showering, and at bedtime. A number of agents commonly found in therapeutic and cosmetic products for the skin (e.g., propylene glycol, lactic acid, urea, salicylic acid) may produce further skin inflammation and may need to be avoided in these patients. Educational measures to increase the understanding of workers about workplace hazards and to motivate them to use skin protection measures appropriately are just as important as the careful selection of skin protection materials. A comprehensive review of randomized clinical trials, which studied the effectiveness of barrier creams, moisturizers, gloves, complex educational interventions, and other interventions for the primary prevention of occupational irritant hand dermatitis, concluded that, there was insufficient evidence for the effectiveness of most of these interventions, even if the findings were generally positive (67). Topical corticosteroids play a limited role in the treatment of irritant contact dermatitis (68–70). Avoiding the irritant exposure is the most important measure, and corticosteroids may be helpful for diminishing the inflammatory process, although there are some reports suggesting that they may compromise barrier function. Topical immunomodulators have also been evaluated. In a randomized, double-blind, controlled trial, healthy volunteers were exposed to 5% SLS and 50% and nonanoic acid (NON) in a cumulative wash test. Different treatments were evaluated (triamcinolone acetonide, clobetasol propionate, tacrolimus and glycerol ointment), wherein vehicle and no treatment served as the control. No treatments were significantly better than the other treatments and controls. There was a trend toward worsened irritancy by tacrolimus on SLS-irritated skin (71). Fuchs et al. (72) evaluated the effects of tacrolimus in a 4-day repetitive irritation test with twice daily application of SLS, and in a shortwave ultraviolet light (UVB) erythema model. The effect was evaluated visually and then quantified by non-invasive bioengineering methods, namely, chromametry and tewametry (TEWL). On the one hand, when tacrolimus was applied 30 min after SLS irritation, a trend toward increased inflammation compared with controls was observed in all three methods. On the other hand, pimecrolimus was suggested as effective in the treatment of skin disorders with an impaired function of the epidermal barrier (73). In a randomized, placebo-controlled study, SLS (3% v/v) was applied under occlusion on the
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204 Ale et al.: Irritant contact dermatitis back of 36 healthy volunteers for 24 h. Subsequently, the test areas were treated for 24 h with pimecrolimus cream, 1% hydrocortisone in a hydrophilic ointment, and the vehicle alone over 3 consecutive days. Pimecrolimus and 1% hydrocortisone cream significantly reduced the SLSinduced erythema, supporting the notion that pimecrolimus may be useful in the treatment of acute ICD (73). Phototherapy has been reserved generally for patients with refractory dermatitis deemed unresponsive to conventional therapy. Oral psoralen photochemotherapy (PUVA) and UVB were applied in the treatment of chronic allergic and ICD of the hands. Rosen et al. (74) studied 35 volunteers with eczematous hand dermatitis, 22 of whom had ACD, and 6 had ICD. The treated hand cleared in all PUVA-treated volunteers who completed the study. However, although UVBtreated volunteers had clinical improvement, there were no cases of resolution of the hand dermatitis. Recurrences appeared in 9 of 14 patients after a mean period of 3 months, indicating the necessity of maintenance therapy. It has been reported that sensory irritation may be treated by applying strontium salts, which selectively block the activation of cutaneous type C fibers involved in the universal transmission of itch, burn, and sting sensations regardless of the irritation stimulus (68, 75).
Conclusion ICD is the most common form of CD. Nowadays, it is recognized that irritancy does not represent a single monomorphous entity, but rather a complex biologic syndrome with diverse pathophysiology and clinical manifestations. The clinical presentation is highly variable depending on several factors, including properties and strength of the irritant; dose, duration and frequency of exposure; environmental factors; and skin susceptibility. The pathophysiological mechanism depends on the activation of the innate immune system, and involves skin barrier disruption, cellular changes, as well as the release of proinflammatory mediators that directly recruit and activate T lymphocytes. There have been a number of advances in the understanding of ICD, and some interesting new areas of research include the role of the loss-of-function mutations in the gene encoding filaggrin and the TNF-α gene polymorphisms. The diagnosis of ICD may present difficulties to the clinician, especially since it rests on the exclusion of other types of dermatitis, especially ACD. Despite the differences in the clinical subtypes of ICD, the treatment should include avoidance of irritants, use of appropriate protective gloves where there is hand involvement, and suitable measures of skin care products
like non irritating cleansers and moisturizers. There have been some recent concerns raised about the use of topical corticosteroids in the treatment of ICD as they may impair barrier function. Overall, recent advances in understanding the pathogenesis as well as better awareness of the clinical significance of ICD can lead to improved quality care for our patients.
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