The Spectrum of Dermatitis and Eczema

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1		Radoslaw Spiewak	--	5571	2023-07-26 00:35:45	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	5571	2023-07-26 07:42:33	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms241310468

Dermatitis (eczema) is a noninfectious inflammation of the epidermis and dermis that manifests itself through an array of efflorescences, including erythema, edema, inflammatory infiltrate, papules, vesicles, scales, serous crusts and lichenification. Depending on the stage and intensity of the disease, these skin changes may emerge in various constellations simultaneously or may evolve from one another. They are typically accompanied by the subjective sensation of itch (pruritus), pain or stinging or burning sensations of various intensities. The histological picture of dermatitis/eczema includes spongiosis, acanthosis, parakeratosis or hyperkeratosis in the epidermis, in addition to lymphocytic and granulocytic infiltration of the upper dermis and epidermis. The term “dermatitis” means literally “inflammation of the skin”; however, its use in dermatology is restricted to a subgroup of non-infectious inflammatory skin diseases with similar clinical appearances, creating the spectrum of dermatitis and eczema (SoDE). Therefore, tinea (a fungal infection of the skin), psoriasis or inflammatory acne will not be referred to as “dermatitis” even though inflammation of the skin is their inherent feature. Depending on the country and dermatology school, the term “eczema” could refer to acute dermatitis (e.g., in the USA) or chronic dermatitis (e.g., in Germany). Moreover, some scholars maintain that “eczema” means dermatitis with a known cause, while “dermatitis” would suggest that there is no definite diagnosis yet. Finally, the term “eczema” is used by some scholars as a synonym of “atopic dermatitis” (AD), which should be strongly discouraged as misleading and confusing. In light of these contradictions, it seems most reasonable to consider the terms “dermatitis” and “eczema” synonyms.

dermatitis eczema systematics clinical criteria molecular diagnostics

1. Atopic Dermatitis (AD)

AD (synonym: atopic eczema) seems to be a most popular diagnosis within the spectrum of dermatitis and eczema (SoDE). It is certainly one of most studied skin diseases, with a striking underrepresentation of other diseases from the SoDE which collectively exceed the rates of atopic dermatitis by far. Owing to its strong presence in social consciousness and on social media, the frequent use of the term in cosmetic marketing and its popularity with both patients and doctors, AD is arguably also one of the skin diseases most prone to overdiagnosis nowadays. The classical diagnostic criteria of AD proposed by Hanifin and Rajka ^[1], which are still the most frequently cited and used to date, are a collation of clinical features that can each be found in other diseases. This leaves a considerable space for a clinician’s subjective judgement and may partly explain the striking differences in the reported prevalence rates of AD in various countries, which range from 0.18 to 38.33% (median 4.91%) ^[2]. The creators of the above-mentioned criteria seem to have been aware of these limitations. As Jon Hanifin put it, “until there is a precise laboratory marker, we are dependent on obviously imprecise clinical criteria. We must constantly remember that these criteria are imprecise; no amount of mathematical, statistical manipulation or validation will make them precise” ^[3]. The name of the disease “atopic dermatitis” implies a causative role of atopy in the disease, which has long been disputed. Georg Rajka rated the name “atopic dermatitis” as “an unfortunate choice of term”, further explaining that “the flaw lies in the conclusion from recent experience that the disease can no longer be considered a typical atopic disease” ^[4]. In an attempt at reconciling fire with water, the European Academy of Allergy and Clinical Immunology (EAACI) proposed the term “Atopic Eczema/Dermatitis Syndrome (AEDS)” as a replacement for the term “atopic dermatitis”. According to the proposal, AEDS was divided into “nonallergic AEDS” and “allergic AEDS”, with the latter further subdivided into “IgE-associated allergic AEDS” and “non-IgE-associated allergic AEDS”. In the same paper, atopy was defined as a “personal or familial tendency to produce IgE” ^[5]; thus, the term proposed in the classification, “non-IgE-associated allergic AEDS”, would literally expand to “non-IgE-associated, i.e., non-atopic, allergic atopic, i.e., characterized by tendency to produce IgE, dermatitis/eczema syndrome”, a term implicating the absence and at the same time the presence of an association with IgE. This somewhat bizarre story illustrates the deep confusion around the disease currently known as “atopic dermatitis”, a confusion that may undermine progress in both clinical and molecular research. In an attempt at solving this conundrum, Bos et al. have proposed that only AD cases with allergen-specific IgE as a hallmark of atopy (corresponding with extrinsic AD, see below) should be referred to as “atopic dermatitis”, while the variant without atopy (intrinsic AD) should be called “atopiform dermatitis”, hinting at the possibility that these entities may in fact constitute two separate diseases ^[6]. This pertinent proposal did not gain any wider recognition. Perhaps substituting the name “Hanifin Rajka Syndrome” for AD could offer a less confusing and more acceptable interim solution until we know better. The proposed term builds on the widely recognized Hanifin and Rajka criteria and comprises all cases fulfilling these criteria without speculating on the underlying causes and mechanisms. The term “syndrome” also implies that one deals with a group of symptoms rather than a disease with defined causes and a pathophysiology ^[7].

Recent molecular research demonstrated different mechanisms involved in individual patients bearing a diagnosis of AD. Based on a serum biomarker analysis, Thijs et al. divided adult AD patients into four distinct clusters: the patients in cluster 1 were characterized by symptoms with high levels of severity, the involvement of large body surfaces and the highest levels of the pulmonary and activation-regulated chemokine (PARC/CCL18), tissue MP1 inhibitor and soluble CD14 antigen. Cluster 2 was characterized by a low level of clinical severity and the lowest levels of IFN-alpha, tissue MP1 inhibitor and vascular endothelial growth factor (VEGF). The patients grouped into cluster 3 demonstrated high levels of severity and the lowest levels of IFN-beta, IL-1, epithelial cytokines IL-25 and IL-33 and thymic stromal lymphopoietin (TSLP). Patients in cluster 4 shared low levels of disease severity and the highest levels of IL-1, IL-4, IL-13 and TSLP ^[8]. In a more recent study of another population with AD, the same research group developed a new division that only partly overlapped with the previous results: in the newer division, cluster A comprised patients with higher levels of skin-homing C-C chemokines (CTACK/CCL27, TARC/CCL17, MDC/CCL22 and RANTES/CCL5) and IL-1R1; this “skin-homing chemokines/IL-1R1–dominant” cluster did not correspond to any cluster from the earlier division. Cluster B represented patients with the highest levels of TH2-related (IL-4, IL-5 and IL-13), TH1-related (IFN-gamma, TNF-alpha and TNF-beta), TH17-related (IL-17 and IL-21) and epithelial cytokines (IL-25, IL-33 and TSLP). This “TH1/TH2/TH17-dominant” cluster B was comparable to cluster 4 in the earlier division. Cluster C comprised patients with high levels of TH2-related cytokines (PARC, IL-13, IL-5, eotaxin and eotaxin-3), IL-22 and IL-33. The constellation of molecular markers in the “TH2/TH22/PARC-dominant” cluster C corresponded with cluster 1 from the previous work. Cluster D represented patients with AD characterized by a relatively low inflammatory state which made them distinctive from other clusters due to low serum levels of TH2/severity-related (MDC, PARC and TARC) and eosinophil-related markers (RANTES, eotaxin and eotaxin-3). The secretory profile of this “TH2/eosinophil-inferior” cluster D resembled the previously identified cluster 2 ^[9]. A similar approach applied by the same group in a pediatric AD population revealed four pediatric clusters: children stratified in cluster 1 (“TH2 cell/retinol–dominant”) were characterized by the highest levels of retinol-binding protein 4 (RBP4) and with elevated levels of IL-4, IL-5, IL-13 and TSLP. Cluster 2 (“skin-homing–dominant cluster”) consisted of children with the highest levels of apelin and markers related to skin homing (PARC/CCL18, TARC/CCL17 and CTACK/CCL27) and the lowest levels of markers related to tissue remodeling and angiogenesis (adiponectin, MMP-8 and TIMP1). This cluster also had the highest incidences of food allergies. Cluster 3 (“TH1 cell/TH2 cell/TH17 cell/IL-1–dominant”) was defined by the highest levels of biomarkers related to the TH1 cell pathway (IL-2, IL-12, IFN-alpha, IFN-gamma, TNF-alpha, TNF-beta, MIG/CXCL9 and ITAC/CXCL11), the TH2 cell pathway (IL-4, IL-5, IL-13, eotaxin-3/CCL26, TSLP and MCP-4/CCL13), the TH17 cell pathway (IL-23, IL-26, MIP3a/CCL20 and GM-CSF), the IL-1 family pathway (IL-1a, IL-1Ra, IL-1R1, IL-18BPa and IL-37), the TNF superfamily pathway (TNFR1, TNFR2, TWEAK/TNFSF12 and LIGHT/TNFSF14) and T-cell activation (sIL2Ra). Cluster 4 (“TH1 cell/IL-1/eosinophil–inferior cluster”) comprised children with the highest levels of the chemokines RANTES/CCL5 and PF4/CXCL4 and the monocyte activation marker soluble CD14, as well as the lowest levels of biomarkers related to the TH1 cell pathway (MIG/CXCL9, ITAC/CXCL11 and MIP1b/CCL2), eosinophil trafficking (eotaxin-1/CCL11 and eotaxin-3/CCL26), the IL-1 family pathway (IL1R1 and IL-18BPa), the TNF superfamily pathway (TNFR1, TNFR2 and TWEAK/TNFSF12), neutrophil activation and trafficking (elastase and GCP2) and T-cell activation and skin homing (sIL2Ra and CTACK). The incidences of food allergies were lowest in this cluster. Of all the pediatric clusters, only cluster 3 (TH1 cell/TH2 cell/TH17 cell/IL-1–dominant) corresponded with a cluster previously defined in adults, i.e., cluster B (cluster 4 in the study of 2017) ^[10]. The above-mentioned studies are exemplary with respect to application of an “omics” methodology in future research in this field. At the same time, they raise a question as to what extent the heterogeneity of the results was due to imprecise clinical criteria and the resultant heterogeneity of the populations studied. Nevertheless, these studies illustrate the change in AD research thanks to “omics” studies, though the real meaning of these discoveries can be only assessed in the broader context of other diseases from the SoDE and preferably other skin diseases.

Studies on AD demonstrate a considerable variability in genetics, epidemiology, clinical phenotypes and treatment responses [39]. Racial differences in the mechanisms involved have led to calls for dividing AD into Asian AD, African AD and European AD [40,41]. A widely accepted division of AD is its division into extrinsic AD and intrinsic AD. Extrinsic AD (exogenous eczema) is characterized by skin barrier impairment, mainly due to filaggrin mutations, and the development of IgE specifically in response to common environmental allergens, e.g., house dust mites, fungal spores, airborne pollen or foods [41]. There is growing evidence that the specific production of IgE and the development of a type I allergy toward environmental allergens is a phenomenon secondary to skin barrier impairment and inflammation [42]. The intrinsic subtype of AD (endogenous eczema) is characterized by a predominance of the female gender, normal skin barrier function and no excess of type I allergies.

2. Irritant Contact Dermatitis (ICD)

ICD is an acquired inflammatory disease of the skin provoked by irritants, i.e., exogenous physical or chemical agents causing damage to keratinocytes. Examples of irritants are detergents, solvents, degreasers, dry air, low temperature, acids and alkalis, repetitive microtrauma, pressure and friction ^[11]. Even factors essential to life like water or foods may cause ICD under prolonged exposure. The potency of a chemical irritant and its ability to penetrate the skin are determined by its properties, including its molecular weight, ionization state and fat solubility. Different irritants target different structures in the epidermis depending on their physicochemical properties ^[12]. In acute ICD, strong irritants may cause visible skin symptoms within minutes or hours. There is a quantitative rather than qualitative difference between acute ICD and a chemical burn. In a chemical burn, the destruction of the epidermis and dermis with erosions, ulceration and necrosis may develop in areas of maximal exposure to the irritant, while the surrounding skin may manifest signs of acute ICD, including edema, dark-red or livid-red erythema, a glazed, parched or scalded appearance and serous exudate in case of a deeper-reaching destruction of epidermis. These symptoms are accompanied by pain or a burning or stinging sensation (typically, there is no urge to scratch) ^[13]. A typical clinical picture of chronic ICD consists of hyperkeratosis with large, thick scales and a tendency toward the fissuring (breaking) of the thickened skin because of its dryness and stiffness. ICD does not involve specific hypersensitivity reactions, meaning that all people exposed to the irritants will develop similar skin reactions, though some people will succumb to a lower dose or intensity, while others (“thick skinned” individuals) will react to a higher intensity of the damaging factor. Chronic ICD may result from repeated subthreshold damages, i.e., insults by various irritants that individually go unnoticed, but when the interval between the insults is too short to allow for complete recovery, these combined effects may lead to noticeable skin disease ^[12]. This cumulative effect may be due to various irritants damaging the skin sequentially or in parallel. Therefore, unlike allergic contact dermatitis (ACD - see below), clinical improvement in ICD may be expected only if all irritants in the patient’s surroundings (work, home, hobby, climate, etc.) are reduced.

3. Phototoxic Dermatitis

Similar to ICD, the damage to the epidermis in phototoxic dermatitis depends on the physicochemical properties of the phototoxic agents, bearing similarities with ICD. This damage is caused by radicals generated during photochemical reactions, meaning that the development of phototoxic dermatitis is always preceded by exposure to light (typically UVA) in the presence of a photosensitizer, i.e., a chemical that absorbs the energy of light. Photons caught by a photosensitizer’s molecule increase its internal energy by pushing its electrons into higher orbitals. This excess chemical energy may facilitate the creation of free radicals (type 1 phototoxic reactions) or oxygen radicals (type 2) that damage cell structures, e.g., lipid membranes or proteins. In an excited state, some photosensitizers (e.g., psoralens) are capable of creating stable covalent bonds with DNA strains ^[14]. These structural damages lead to a release of inflammatory mediators, complement activation, granulocyte migration and keratinocyte apoptosis, which manifest clinically as dermatitis. No specific (adaptive) immune response is involved in phototoxicity, differentiating it from photoallergic reactions, though there are chemicals that may act as both phototoxic and photoallergic agents ^[15]. Phototoxic agents may enter the skin from outside, e.g., ingredients in cosmetics or topical drugs or from plants (phototoxic contact dermatitis) or from inside, e.g., drugs or dietary supplements (systemic phototoxic dermatitis) ^[16].

4. Radiodermatitis (RD)

RD (synonym: radiation dermatitis) is another form of inflammatory skin disease caused by an external factor: ionizing radiation. Individual susceptibility seems to play no role or a limited role because all exposed people will develop RD depending on the dose of energy absorbed. Acute RD develops within 90 days of irradiation and initially presents as primary transient erythema, followed by generalized erythema, pruritus, xerosis, hyperpigmentation, dry scaling and peeling of the skin. Moist scaling hints at deeper damage to the skin with the exudation of tissue fluids. These changes may be accompanied by hair loss (anagen effluvium) in the irradiated area. Dermatitis that emerges (or persists) more than 90 days since the last bout of irradiation, which is referred to as chronic RD, may manifest as skin thinning due to the atrophy of the dermis and epidermis or skin thickening of the dermis due to fibrosis and may be accompanied by edema, dyspigmentations, telangiectasias or dermal necrosis ^[17]. Ionizing radiation causes extensive and irreversible genetic damage to nuclear and mitochondrial DNA that inhibits cells’ ability to replicate. It is especially detrimental to keratinocytes in the Malpighian layer where all the mitotic activity of the epidermis takes place. This DNA damage, combined with the generation of reactive oxygen species (ROS) that damage structural proteins, enzymes and lipid membranes, initiates epidermal and dermal inflammatory responses and skin cell necrosis, which collectively manifest as RD. ROS damage β-catenin and E-cadherin, which are pivotal proteins in adherens junctions—the cell-to-cell connections that ensure the integrity of the epidermis. Damage to adherens junctions leads to a loss of contact between keratinocytes and spongiosis, which correlates with the severity of the disease. In humans, spongiosis was observed after a 4-week course of radiotherapy with a cumulative dose of 46 Gy, in addition to the upregulation of the Hippo signaling pathway, which seems to be involved in cell proliferation and repair ^[18]. The role of Hippo pathway activation in dermatitides seems to have not been studied much thus far. Damage to β-catenin and E-cadherin is probably not restricted to RD but a more common occurrence among diseases from the SoDE, all of which include spongiosis ^[19].

5. Seborrheic Dermatitis (SD)

SD (synonym: seborrheic eczema) is an inflammatory skin disease confined to regions with high densities of sebaceous glands: the scalp, face, central upper back and sternum ^[20]. The maturation of the sebaceous glands seems to be a prerequisite for the development of SD; therefore, this disease typically develops after puberty except for infantile SD, when the glands are upregulated by maternal sex hormones. Although the disease’s name suggests an association with the overproduction of sebum (seborrhea), SD may also develop in people with normal sebum outputs ^[21]. It seems that changes in the sebum composition may also be a contributing factor ^[22]. Changes in the amount or composition of sebum, in addition to a defective epidermal barrier, amount to the primary events in the pathology of SD that provide favorable conditions for a secondary overgrowth of lipophilic yeasts from the genus Malassezia, which provokes an inflammatory response in the skin ^[23]. Malassezia spp. are commensal lipophilic yeasts belonging to normal skin microbiota which may turn into opportunistic pathogens under favorable conditions. The hydrolysis of sebum by Malassezia yeasts liberates oleic acid, which possesses irritant properties and activates the innate immune system via pattern recognition receptors, inflammasome, IL-1β and NF-κB, resulting in the secretion of proinflammatory cytokines IL-8, IL-17 and IL-4 ^[23]. In this way, SD fits into the spectrum of ICD rather than fungal infections, regardless the role of live fungus in its pathology. Malassezia in SD is a source of irritants rather than an invader. Nevertheless, antifungal treatment is a relevant therapeutic option as Malassezia loads correlate with the severity of SD, and a reduction in the Malassezia load leads to a remission of the disease ^[24]. Ketoconazole—one of the preferred antifungals used in the therapy of SD—also modifies the lipid profile of sebum and suppresses inflammation; therefore, the therapeutic effect of the drug may be not entirely due to its antifungal activity ^[25].

Infantile SD is a common, self-limiting and benign condition. Its prevalence is the highest in the first 3 months of life and rapidly decreases thereafter ^[26]. Meanwhile, infantile SD can easily be misdiagnosed as AD. The presence of pruritus, a positive family history of atopy and the age of onset are altogether of limited value in the differential diagnosis between AD and infantile SD. The most distinctive features are the presence of lesions on the forearms and shins in AD, while the localization of skin lesions solely to the napkin area or the axillae favors a diagnosis of SD; however, the significance of these features decreases with the spread of lesions to multiple body sites ^[27]. Once again, this illustrates the need for reliable diagnostic criteria beyond clinical features. A transcriptomic analysis of scales from lesional skin (dandruff) in SD revealed a strong upregulation of the genes coding interleukin-1 receptor antagonist gene (IL-1Ra) and IL-8, as well as the genes S100A8, S100A9 and S100A11 ^[28]. The study singled out genes whose expression clearly differentiated between involved and uninvolved skin, as well as between SD patients and healthy controls; however, it is not known which of those would differentiate SD from other diseases in the SoDE. The proinflammatory cytokine IL-8 is probably upregulated in every dermatitis, limiting its value in the differential diagnosis. On the other hand, the suppression of genes related to lipid metabolism observed in the aforementioned study may correspond with the assumption that changes in the lipid composition of sebum play a role in the development of SD, making these genes an interesting target for further research. An increased risk of developing SD may also be connected with the human leucocyte antigen (HLA) alleles A*32, DQB1*05 and DRB1*01, mutations in the LCE3 gene cluster and mutations impairing the ability of the immune system to restrict Malassezia growth ^[23].

6. Allergic Contact Dermatitis (ACD)

ACD (synonym: allergic contact eczema) is an inflammatory skin disease initiated by specific immune reaction to a hapten. Haptens are low-molecular-weight chemicals that are not immunogenic per se. Instead, these reactive chemicals can bind to the body’s own proteins in a process referred to as haptenization. As a result of haptenization, the spatial conformation of endogenous proteins becomes distorted by the covalent bonds with haptens to such extent that they no longer are recognized as self-antigens and can provoke an immune response like any non-self-antigen ^[29]. The sensitizing potential of a hapten is determined by its physicochemical properties ^[30]^[31]. The most frequent causes of ACD are metals and cosmetic ingredients, mainly fragrances and preservatives. Not all environmental substances responsible for ACD are actual haptens—some of them are hapten precursors that convert into haptens in one of two possible ways: prehaptens turn into reactive haptens due to spontaneous oxidation via contact with air, while prohaptens undergo enzymatic activation in the host’s organism ^[32]. For example, the fragrance linalool is a prehapten that spontaneously degrades into hydroperoxides, which are the actual sensitizing haptens ^[33].

Only a minority of people exposed to a particular hapten will develop ACD, meaning that individual predisposition is prerequisite for developing a specific immune hypersensitivity: a contact allergy (a delayed-type reaction). The term “contact allergy” (CA) is not synonymous with ACD. Confusing CA with ACD appears to be a quite frequent mistake in clinical practice that sometimes also contaminates published research and may interfere with scientific progress in the field. The term “contact allergy” refers to a state of altered immune response to a specific hapten, which is not synonymous with the disease.

The natural course of a CA and ACD is divided into an initial sensitization phase and a subsequent elicitation phase ^[34]. The sensitization phase (synonyms: afferent or induction phase) is facilitated by cells of the innate immune system, beginning with the detection of haptenated proteins by Langerhans cells (LC). Depending on the nature of the hapten, e.g., its irritant potential and the presence of cofactors, e.g., inflammatory cytokines or reactive oxygen species (ROS) at the site of encounter, LCs may ignore the hapten or become activated and carry epitopes (antigenic fragments) of the haptenated proteins to local lymph nodes. Within the lymph node, LCs present the epitopes in the context of major histocompatibility complexes to scores of naïve CD4+ and CD8+ cells, including T helper (Th) type 1 cells. When T cells with TCR receptors fitting to the LC complex are found, they undergo clonal expansion into a population of effector T cells that migrate back to the entry point of the hapten, where they orchestrate an inflammatory reaction, engaging eosinophils, neutrophils, macrophages or cytotoxic lymphocytes. The cell composition of the inflammatory infiltrate determines the clinical appearance of skin lesions. The inflammatory activities of these effector cells results in the death of keratinocytes, which manifests as spongiosis. The types of spongiosis observed in ACD include eosinophilic spongiosis (eosinophils within the foci of spongiosis), spongiosis with subepidermal edema (dermal type ACD), pityriasiform spongiosis (small vesicles with lymphocytes, histiocytes and LC) or haphazard spongiosis (no particular pattern) ^[35].

The word “contact” present in both terms—CA and ACD—implies that the skin is exposed to haptens via contact, i.e., from the outside. This is true in most cases, with one special exception being the systemic reactivation of ACD (SRACD) in which haptens enter the body not through the skin but via ingestion, inhalation, oral absorption, injection or implantation and are subsequently redistributed via circulation within the body, including the skin. Hematogenous ACD is a hybrid of “classical entrance” with SRACD.

Throughout the medical literature, SRACD is commonly referred to as “systemic contact dermatitis”—a term that is easy to remember and pronounce but unfortunately misleading: The adjective “contact” implies that the triggering factor enters the skin from outside, while “systemic” implies a route from inside. Therefore, the term “systemic contact dermatitis” would literally mean “dermatitis caused by factors that enter the skin from inside yet at the same time from outside”, which is neither true in the induction phase (penetration from outside) nor in the elicitation phase (penetration from inside). The longer and more accurate term “systemic reactivation of allergic contact dermatitis” also stresses the fact that this type of reaction occurs in people previously sensitized via a typical route, i.e., skin contact. In the case of SRACD caused by systemic drugs, the synonym “symmetrical drug-related intertriginous and flexural exanthema” (SDRIFE) seems popular among authors ^[36]^[37]^[38].

People are constantly exposed to environmental chemicals, and chemical processes of hapten activation and the haptenization of autologous proteins into non-self-antigens are constantly ongoing in everyone’s bodies. Significant effort has been invested into the early identification of emerging haptens (e.g., new cosmetic ingredients, drugs and industrial chemicals) which have considerable potential to cause a CA and ACD ^[31]^[39]^[40]. However, the fact that only a minority of people will ultimately develop a CA to one or a few of the hundreds of haptens they are constantly exposed to makes it clear that the prerequisites for the development of a CA are individual predispositions in combination with other co-factors, e.g., inflammation on the site of hapten penetration ^[41]^[42]^[43]. The recognition of markers connected with the risk of developing a CA and specific molecular markers of ACD would benefit many people, either by facilitating prevention or improving the clinical diagnosis of ACD. Until the present, the few “omics” studies performed on ACD have focused on the haptenation of endogenous proteins, with an overall conclusion that different haptens target different proteins ^[44].

7. Photoallergic Dermatitis

Photoallergic dermatitis is a variant of the above-discussed ACD, with the only difference being that the haptens initiating allergic reactions bind to endogenous proteins in a photochemical reaction. The external energy delivered by the photons is needed to activate photohaptens and enable them to bond covalently to endogenous proteins and change their spatial conformation from the tolerated “self” to the immunogenic “non-self” conformation. UVA is the typical energy carrier for most photohaptens, followed by UBV and visible light ^[45]^[46]. Photohaptens may enter the skin from outside, e.g., sunscreens and other cosmetic ingredients or topical drugs (photoallergic contact dermatitis) or from inside, e.g., systemic drugs and food additives or dietary supplements (systemic photoallergic dermatitis) ^[16]^[47]. Systemic photoallergic dermatitis may be viewed as a variant of SRACD as the photohaptens enter the skin from inside via circulation, with subsequent photohaptenization to form the actual antigens in the irradiated skin.

8. Protein Contact Dermatitis (PCD)

PCD is an acquired inflammatory skin disease due to specific allergic reactions to foreign allergens—proteins with molecular weights exceeding 10,000 daltons which are usually of animal or plant origin ^[48]. Due to their size, the allergens cannot penetrate healthy skin because they cannot cross an undamaged epidermis. Therefore, an inherent element of PCD is the disruption of the skin barrier manifesting as irregularities in the corneocytes—cells of the outermost layer of the epidermis, which contributes to its barrier function, as well as increased transepidermal water loss (TEWL) and decreased skin capacitance. After the resolution of visible dermatitis, the function of skin barrier remains impaired and recovers over several months, similar to AD ^[49]. Immune mechanisms overlapping type I and type IV allergic reactions have been postulated in PCD ^[48]. Proteins causing PCD are full antigens capable of inducing a type I reaction, which is in contrary to ACD in which haptens must bind to endogenous proteins to initiate an allergic reaction. On the other hand, the allergen-specific IgEs in PCD are bound as receptors on the surface of the LCs, whose participation resembles ACD, rather than a type I allergy. PCD is typically diagnosed as an occupational disease of farmers, veterinarians, butchers or food handlers—workers massively exposed to protein allergens in combination with wet work and repeated damages that disrupt the epidermal barrier and enable the penetration of large allergenic molecules into the skin ^[50].

9. Autoimmune Dermatitis

The concept of autoimmune dermatitis, initially referred to as “auto-sensitization” or “autoeczematization”, was first presented a century ago ^[51]. In the following decades, it remained a rather “niche” topic limited to clinical observations that a considerable group of children and adults with eczema react on patch or scratch tests with extracts from human dander, i.e., antigens from their own or donor keratinocytes, and develop skin reactions consistent with their disease (summarized in ^[52]^[53]). These early clinical observations were later supported by epidemiological data showing that patients with diagnosed AD are at a significantly higher risk of developing autoimmune diseases, with the highest odds ratio for alopecia areata (an 8–10-fold increased risk in AD patients), followed by vitiligo, celiac disease, inflammatory bowel disease, systemic lupus erythematosus, systemic sclerosis, thrombocytopenia and autoimmune thyroiditis ^[54]^[55].

The existence of autoimmune dermatitis as a separate disease seems to be supported by the recognized existence of a disease referred to as autoimmune progesterone dermatitis (AIPD). Compared with other dermatitides, AIPD becomes clinically distinct mainly through exacerbations synchronized with the menstrual cycle (catamenial pattern). The confirmed sensitizer here is progesterone—an endogenous steroid sex hormone whose molecular weight of 314 daltons places it among haptens. To date, more than a hundred cases diagnosed as AIPD have been reported throughout the medical literature; however, this number also includes cases of non-eczematous dermatoses, e.g., progesterone-triggered urticaria, which appears to comprise one-third of the reported cases ^[56]. The knowledge of AIPD pathomechanisms is limited. The combined evidence available thus far includes mentions of delayed-type reactions to progesterone on patch tests and intracutaneous tests (hinting at a type IV allergy) in patients with non-urticarial lesions, in addition to histopathologic picture featuring perivascular eosinophilic infiltrates with interface changes ^[57].

Autoimmune estrogen dermatitis (AIED) is a less well-known catamenial dermatitis with a handful of cases published so far; again, some of these studies seem affected by a too-liberal use of the term “dermatitis”. In a small group of patients with AIED, the formation of Langerhans cell nests in the epidermis and hair follicles, in addition to perivascular infiltrates of CD4+ and CD8+ lymphocytes in the dermis, was confirmed in skin lesions described as “prurigo, acneiform and annular erythema” but not in “urticaria-type AIED” ^[58] The characteristic feature of both AIPD and AEPD is the exacerbation of eczema in the luteal phase, especially on the days preceding menses, with remissions in the follicular phase ^[59].

10. Stasis Dermatitis

The main cause of stasis dermatitis is venous hypertension, which typically occurs in chronic venous insufficiency. Venous hypertension and the resulting blood congestion in the vessels (stasis) alone seem sufficient to cause stasis dermatitis. In a study of 10 patients with stasis dermatitis, all fully recuperated following a surgical intervention that resulted in the normalization of venous pressure ^[60]. Compression stockings were devised to prevent the ill effects of intravenous hypertension by applying counter-pressure from the outside. Among patients with stasis dermatitis who used compression stockings on an everyday basis, only 5% complained of frequent exacerbations of the disease compared with 64% of those who did not use the stockings ^[61].

Increased pressure in the veins and capillaries leads to an accumulation of leukocytes which attach to the endothelium (“leukocyte trapping”) and initiate processes leading to the apoptosis or necrosis of endothelial cells, fibroblasts, myocytes and parenchymal cells of the venous wall. The disruption in the vessels results in the extravasation of erythrocytes into surrounding tissues. Hemoglobin from these erythrocytes subsequently decomposes into hemosiderin, an insoluble complex of iron which induces an influx of macrophages attracted via hemoglobin scavenger receptor CD163. The accumulating macrophages secrete proteolytic enzymes and proinflammatory cytokines that induce skin damage which manifests as spongiosis in the epidermis, in addition to the fibrosis and neogenesis of capillary vessels in the dermis ^[62]^[63].

11. Deficiency Dermatitis

The term “deficiency dermatitis” refers to a situation in which insufficient supplies of essential nutrients (vitamins, amino acids or microelements) lead to pathologic manifestations in the skin consistent with the clinical picture of eczema or dermatitis. Some cases may be due to a faulty processing of nutrients (e.g., genetic defects) rather than an insufficient supply. Clinical cases of deficiency dermatitis may pose significant challenges to doctors and researchers because patients may suffer from combined nutrient deficiencies, or deficiencies may aggravate the course of preexisting diseases from the SoDE.

Zinc deficiency dermatitis is arguably the most studied form of deficiency dermatitis. Zinc is a microelement substantial for the differentiation of keratinocytes, as well as for anti-inflammatory and wound healing processes. Its deficiency leads to ATP-mediated inflammation and impairs the maturation and functioning of T, B and NK lymphocytes ^[64]. Zinc deficiency may develop in the course of acrodermatitis enteropathica, which is an autosomal recessive genetic disease. An acquired zinc deficiency may be due to an insufficient supply, malabsorption or excessive loss of zinc, e.g., in disorders of the gastrointestinal or urinary tract, or increased zinc requirement (e.g., pregnancy or breastfeeding) ^[65]. A full-blown zinc deficiency manifests clinically with the classical triad of dermatitis, alopecia and diarrhea.

The role of vitamin D deficiency in initiating and aggravating the course of inflammatory dermatoses is well documented; the same is true for the beneficial effects of its supplementation ^[66]^[67]^[68]. However, low vitamin D levels could hardly be viewed as a nutritional deficiency because “vitamin D” is in fact a group of nuclear hormones with pleiotropic actions, including immunomodulation ^[69]^[70]^[71]. Under favorable circumstances, all active forms of vitamin D are synthesized entirely in the body; therefore, low levels of vitamin D should be viewed as a hormonal disorder rather than nutrient deficiency ^[72]. Hints as to other deficiencies that might induce or aggravate dermatitis seem mainly based on accidental clinical observations, uncontrolled studies or animal experiments.

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