Atopic dermatitis (overview) L20.-

Authors: Prof. Dr. med. Peter Altmeyer, Prof. Dr. med. Martina Bacharach-Buhles

Co-Autors: Dr. med. Jeton Luzha, Hadrian Tran

All authors of this article

Last updated on: 18.11.2021

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Synonym(s)

Asthma eczema (Jadassohn); Asthmaprurigo (Sabouraud); atopic dermatitis; Atopic eczema; Bending eczema; Besnier M.; constitutional eczema (Koch); Dermatitis atopic; Dermatitis lichenoides pruriens (Neisser); Dermatosis neurogenic; Eczema atopic; Eczema constitutional; Eczema disease (Scholl); Eczema endogenous; eczema endogenum; eczema flexuarum; endogenous eczema; exudative eczema (Schreuss); exudative eczematoid; flexular mycosis (Hebra); late exudative eczema (Rost); M. Besnier; neurodermatitis atopica; neurodermatitis constitutionalis; neurodermatitis diffusa; neurodermatitis disseminata; neurodermitic eczematoid (Stümpke); neurogenic dermatosis (Epstein); neuropathic eczema (Brill); Prurigo à forme eccemato-lichénienne (Brocq); prurigo diathésique (Besnier); Prurigo eczema (Kreibich); Prurigo Veneer

History
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Willan, 1808

Definition
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A multifactorial, chronically persistent or also chronically recurrent, non-contagious, usually considerably pruritic dermatitis of varying acuity belonging to the group of atopic diseases (Greek: atopos = out of place), which develops, is maintained or is activated due to complex interactions of congenital and environmental factors.

The atopic eczema shows a topographically and morphologically different appearance in the different stages of life:

  • in infancy, rather uncharacteristic diffuse eczematous skin manifestations on the face and on the extensor sides of the extremities of varying severity and acuity (see atopic dermatitis in infancy)
  • in infancy , more localized and less diffuse eczema, with a variable and seasonal course (see atopic dermatitis in infancy)
  • inschoolchildren it occurs preferentially as flexural eczema
  • in adulthood there is a great morphological variety. Both localized minus variants of atopic dermatitis (eyelids, genitalia, hands, neck) and extensive eczema variants up to those universally affecting the entire integument (erythrodermic atopic dermatitis) characterize the extremely varied clinical picture.

Classification
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Atopic eczema shows different symptoms in different stages of life.

An alternative classification distinguishes 4 phenotypes in children (study of 1,038 children: Roduit C et al. 2017):

  1. Early transient phenotype (9.2%): HV within the first 2 LY, healing by the 4th LY. High risk of developing food allergies.
  2. Early persistent phenotype (6.5%): HV within the first 2 years, resolution by the 6th year. High risk of developing asthma. High risk of developing food allergies.
  3. Late phenotype (4.8%): HV only after the 2nd year. High risk of allergic rhinitis.
  4. Sporadic phenotype (79.5%): only isolated or absent HV.

Furthermore, a number of different variants can be assigned to atopic dermatitis, some of which have historical names (e.g. Eccema symmetricum faciale), some of which are named according to topical or seasonal aspects (e.g. atopic hand eczema, genital eczema, dermatitis hiemalis, etc.) or differ in their clinical course (e.g. prurigo form of atopic eczema). Such dermatitis may also be triggered by other factors (e.g. contact allergy).

Occurrence/Epidemiology
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  • Prevalence in industrialised countries: 10-20% of all children, 1-5% of adults (in children, atopic eczema is the most common chronic disease of all)
  • The incidence peak is in the first two LJ.
  • The prevalence has almost tripled in industrialised countries over the last 3 decades.
  • In addition, about 40-60% of patients with atopic eczema suffer from respiratory allergies (pollinosis, perennial rhinitis, allergic bronchial asthma)

Etiopathogenesis
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It is caused by a combination of genetic and environmental factors that induce skin barrier dysfunction, dysregulation of the cutaneous and systemic immune systems, dysbiosis of the skin microbiota, and a strong genetic influence (Torres T et al. 2019).

From practical clinical considerations, 2 forms with largely identical skin manifestations can be distinguished:

  • Intrinsic (non-allergic) atopic eczema (about 20-30% of patients; non-IgE mediated). At present, it is still unclear whether this clinical picture can be evaluated as a separate entity.
  • Extrinsic (allergic) atopic eczema (60-70% of patients, IgE-mediated).

Notice. Patients with intrinsic form do not have elevated IgE levels or sensitization to environmental or food allergens.

Immunopathology (see below Atopic dermatitis, Immunopathology)

Immune response in atopic skin: Clinically inconspicuous skin in patients with atopic dermatitis should not be assumed to be healthy despite being free of symptoms. There is evidence of increased skin dryness, barrier disruption with increased irritability, subtle perivascular T-cell infiltrates, increased numbers of Th2 cells with increased IL-4 and IL-13 production.

In diseased skin: due to skin barrier disruption , allergens can penetrate into the deeper layers of the epidermis (Cappello C et al. 2017). Here they are recognized and taken up by Langerhans cells. Antigen-presenting cells(Langerhans cells, inflammatory dendritic cells and macrophages with IgE molecules) are increased. Langerhans cells enter the draining lymph node with the lymph stream, reducing their dendritic extensions during this passage (so-called veiled cells - see below Langerhans cell). In the lymph node, they present the antigen to naive lymphocytes and induce a Th2 response.

There is increased expression of IL-16, C-C chemokine ligand 27, RANTES, monocyte chemotactic protein-4 and eotaxin. Activation of eosinophilic leukocytes and macrophages. The expression of IL-4 and IL-13 is decreased. Increased expression of IL-5, GM-CSF, IL-11, IL-12, IL-22 and IFN-gamma continues. Interleukin-22, in turn, is able to downregulate barrier proteins (Brüggen M-C et al. 2016).

Increased collagen deposition with lichenification is also observed. The basic mechanism here is the release of TNF-α and IL-1, which lead via activation of NF-κB to changes in the vascular endothelia with subsequent extravasation of proinflammatory cytokines.

Genetics: Genetic factors play a significant role in the predisposition of atopic eczema. The risk of a child developing atopic eczema (AE) is 50% if one parent has asthma, atopic eczema or rhinitis allergica, 75% if both parents are affected. Concordance in monozygotic twins is 72%, and 23% in dizygotic twins.

Genome studies revealed several candidate genes predisposing to atopy on chromosomes 1q21, 3q21, 5q32, 6, 11q13, 17q25 (Castro-Giner F et al 2009). Some regions correspond closely with the gene loci found for psoriasis (3q21), indicating that these genes have a general influence on "skin inflammation". Inflammatory bowel disease is found on very similar gene loci.

The genes localized on chromosome 1q21, which in their entirety as an epidermal differentiation complex are significant for the regulation of epidermal homeostasis, play a special role in the pathogenesis of atopic dermatitis (see below). Loss-of-function mutations" in the FLG gene (1q21), which codes for the protein filaggrin, show a clear association with an early occurrence and a chronic course of atopic dermatitis.

The SPINK5 gene (5q31-5q32) encodes LEKTI a serine protease. Germline mutations in the SPINK5 gene result in an enzyme defect phenotypically associated with Netherton syndrome characterized by a marked atopic diathesis. However, polymorphisms in this gene are also associated with atopic dermatitis.

Furthermore, an atopy association involves the claudin I gene, which encodes an important tight junction protein. Polymorphisms of this gene lead to disorders of the epidermal integrity, which is substantially disturbed in atopic dermatitis.

The following additional genes have been implicated as risk factors that may play a role in the initiation, maintenance, or exacerbation of atopic inflammation. Their knowledge and the encoded gene products provide information about the interplay of inflammatory components (Castro-Giner F et al. 2009):

The following genes have also been evaluated as risk factors for atopic dermatitis:

  • COL29A1 (3q21); encoded protein: collagen type XXIX, alpha1.
  • COL18A1 encoded protein: Collagen type XXIX, alpha1
  • EMSY (11q13.5); encoded protein: EMSY
  • FLG (1q21); encoded protein: filaggrin
  • RAD50 (5q23-q32) encoded protein: RAD50
  • IL4 (5q31.1) Interleukin-4
  • IL4R (16p12.1-p1.2) Interleukin-4 receptor
  • IL5 (5q31.1) Interleukin-5
  • Il13 (5q31) Interleukin-13
  • IL18 (11q22.2-q22.3) Interleukin-18
  • IL31 (12q24.31) Interleukin
  • CSF2 (5q31.1) Granulocyte-macrophage colony stimulating factor
  • CCL5 (17q11.2-q12) CCL5/RANTES
  • FcεRI (1q32) high-affinity IgE receptor.

Disruption of the skin barrier: Disorders in filaggrin assembly play an important role in the reduction of epidermal integrity. Polymorphisms and loss-of-function mutations in the profilaggrin/filaggrin gene (FLG - this is located in the so-called epidermal differentiation complex - EDC - on chromosome 1q12.3), are observed 2-3 times more frequently in patients with atopic eczema (AE) than in healthy individuals. Filaggrin is a structural protein that crosslinks the disulfide bridges between keratinocytes in the skin barrier and thus has a reinforcing function. Due to a mutation, this function can no longer be guaranteed and the skin is more susceptible to mechanical stimuli. Theitch-scratch cycle ensures mechanical disruption of the barrier and maintains the cytokine-mediated inflammatory and pruritic response. Filaggrin mutant patients with AE have a significantly higher propensity to allergic bronchial asthma as well as ichthyosis vulgaris than those without this mutation. It is also possible that the demonstrated increased expression of aquaporin-3 in the keratinocytes of atopic patients plays a significant role in the impaired skin barrier function.

The allergens relevant for the atopic syndrome are grass pollen, house dust mites and animal dander. Because these proteins have a high molecular weight, they cannot penetrate through normal skin (only proteins < 1000 Daltons can). In atopic skin, however, molecules with a higher molecular weight can penetrate due to the barrier disorder. They are taken up there by dendritic cells. Concordant to this are clinical observations which prove an exacerbation of the atopical eczema after local provocation with grass pollen. Local exposure to cat epithelia also leads to an increased tendency to eczema in filaggrin-mutated newborns (!). That this is not only a matter of specific (local) reactions in the case of existing sensitisation is shown by the observation that eczema reactions can be induced by birch pollen, even in non-birch pollen-sensitised individuals. Other mechanisms are responsible for this, such as pollen-associated lipid mediators (PALMS), which stimulate an inflammatory reaction even non-specifically. Airborne particles are also able to penetrate the atopic skin.

Sensitizations:

  • Type I sensit izations: Tree and grass pollen: Apparently, there is an increased sensitizability via the skin in patients with AE. This also correlates with the observation of "flare-up" reactions in case of increased pollen count or house dust exposure.
  • Type IV sensit ization (see below contact allergy): Patients with atopic eczema seem to have a higher sensitization rate than non-atopics (most frequent contact allergens: nickel(II) sulfate and fragrance mix).

Microbial factors: Of pathophysiological relevance is Staph. aureus (high colonization density (> 80%) in the nasal mucosa and on weeping areas). Staphylococcus aureus produces high amounts of enterotoxins (enterotoxin A-D, toxic-shock-syndrome-toxin-1), which act as superantigens and are thus T-cell proliferative; patients continue to produce IgE antibodies against them, whereby the degree of sensitization and disease activity correlate. A disturbance of antimicrobial lipids and peptides is involved in the pathological colonisation of the skin (reduction of the antimicrobial peptides (AMP) cathelicidin LL-37, dermcidin (occurring in sweat) and beta-defensin-2), which are transported in the so-called "lamellar bodies" into the intercellular space of the str. corneum. This results in a reduction of antimicrobially effective free sphingosines: a 2-fold reduction in the str. corneum correlates with a > 100-fold increase in the colonization of Staph. aureus. There is evidence that Staph. aureus penetrates the atopic epidermis with subsequent expression of AE-related cytokines (IL-4, IL-13, IL-22 and others). This dermal dysbacteria could thus directly lead to an increase in inflammatory cytokines.

The colonization with Pityrosporum ovale plays a pathogenetic role in patients with the "head-and-neck" form of atopic dermatitis. Patients affected in this way benefit from an antimyotic local therapy.

Furthermore, there is evidence that focal infections (such as dental infections) seem to be involved in triggering or exacerbating atopic eczema. This is surprising in so far as such influences have not been assumed so far!

Hygiene hypothesis: Assumption that the increase in atopic eczema is related to a higher standard of living and improved hygienic conditions. A reduction of bacterial or viral infections leads to a decreased production of TH1 cytokines (e.g. interferon gamma) and thus to a decrease of the protective effect of the Th1 immune responses in favour of the Th2 responses characteristic for atopic diseases.

Farm animals as risk factors? Remarkable is an investigation in 5 European countries on 1063 children, in which it could be proven that children of mothers who spent their pregnancy in the environment of farm animals had a lower risk of developing atopic eczema in the first two years of life. In this context, not only immunostimulatory microbial factors play a role but apparently also non-microbial substances such as N-glycolylneuraminic acid (Neu5Gc) produced by animals, a sensitizing sialic acid whose degree of sensitization is inversely associated with wheezing and bronchial asthma.

Neuroimmunological factors: Stress and other emotional factors are often blamed as triggers. Neuropeptides such as "calcium-gene-related peptide" (CGRP), "proopiomelanocortin-derived-hormone" (alpha-MSH) act as anti-inflammatory regulators.

Various triggers:

  • Vitamin D- correlation: Reported inverse correlation between the severity of atopic eczema and the level of Vit.D level.
  • Climate, stress, post-traumatic stress disorder, exposure to pollutants may lead to onset or exacerbation of the disease.

Manifestation
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70% of patients with atopic eczema show an initial manifestation in infancy, usually after the 3rd month of life (see atopic eczema in infancy).

Late manifestations in adulthood are possible.

During pregnancy, an exacerbation of a pre-existing atopic eczema occurs in 20% of cases. see also Pregnancy dermatosis, atopic.

Localization
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Infancy: face, trunk, extensor sides (!) of the extremities diaper area remains free.

Childhood, adolescence: elbows, hollow of the knee (sweet itch).

Adulthood: elbows, knees, face, chest, shoulders, back of the hands.

Described as minus variants in different localisations (see above).

Clinical features
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Depending on the age of the patient and the acuteity of the disease, different stages and manifestations of eczema can be observed, ranging from weeping red plaques to pale, dry, possibly scaly, bran-like, mostly scratched skin.

Typical is a seizure-like, tormenting itching, which increases with sweating (especially stress sweating). Furthermore a wool intolerance. The clinical symptoms of atopic eczema vary considerably depending on age. In this respect, clinical subdivisions by age are useful.

According to Hanifin and Rajka, the following symptoms are defined as major and minor criteria. The advantage is a high sensitivity and a low specificity (80%).

I. Major criteria:

  1. Itching (intense, unsuppressible itching that is answered with bloody scratching (not rubbing but scratching with the fingernails)
  2. Eczema plaques (on the stretching side in infants and toddlers, on the flexing side in post-pubertal adolescents and adults)
  3. Chronicity (long-term, chronic or chronically recurrent course)
  4. Medical history (positive atopic signs of disease in EA and/or FA - e.g. rhintis allergica, allergic bronchial asthma)

II Minor criteria or optional symptoms:

  1. milkcrust (Crusta lactea)
  2. Xerosis cutis (general sebostasis of the skin, skin feels dry and brittle)
  3. Ichthyosis hand, foot ("I-hand"; hyperlinear pattern of the unusually cotton wool-like soft palms and soles)
  4. Dennie Morgan infraorbital fold (double eyelid crease; Grd 1 to the pupil, Grd 2 including the entire iris, Grd 3 entire eye)
  5. Earlobe rhagade (the so-called stubbornly torn earlobe)
  6. Atopic facial pallor (pale, grey-white facial colour; the halonated dark eyes also belong to the special atopic facial colouring)
  7. Dermographism albus
  8. keratosis pilaris
  9. Hertogesches sign (Rarefication of the lateral eyebrows)
  10. Fur cap-like hairline (the adult atopic patient very rarely suffers from androgenetic alopecia!)
  • Other associated atopy signs:
    • Intolerance to (animal) wool (not cotton)
    • Food intolerances (citrus fruits, strawberries, tomatoes = unspecified histamine liberators which cause itching shortly after ingestion)
    • itching through sweating
    • IgE increased (only for extrinsic type)
    • Positive prick or intradermal test (only for extrinsic type)
    • Detection of specific IgE (only for extrinsic type
      )Perlèche
    • Shiny nail (like polished looking fingernails).
    • Dermopathic lymphadenopathy with generalized infestation

Laboratory
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IgE increase(IgE > 150 kU/l) in > 25% of patients, specific IgE antibodies, frequent eosinophilia, disturbance of the cellular mediated immunity. IL-16 and ECP can be regarded as good serological parameters (good correlation to SCORAD).

Histology
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Picture of allergic contact eczema with superficial perivascular and interstitial lympho-histiocytic mastocytic dermatitis with mild spongiosis up to spongiotic blistering, acanthosis of varying degrees with parakeratosis (in chronic foci acanthosis with accompanying parakeratosis may be clearly pronounced) and (rather) low eosinophilia.

Diagnosis
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Diagnosis is based on specific criteria that take into account patient and family history and clinical manifestations. The overall severity of the disease must be determined by evaluating the objective signs and subjective symptoms.

Clinical picture, family history, self history (eczema history, rhinitis allergica, bronchial asthma, food allergies, viral and bacterial infection susceptibility).

Allergy score - varies according to Diepgen - (if atopy is suspected)

  1. White dermographism (dash test on the skin turns white)
  2. Hertoghe's sign (thin, light outer eyebrows)
  3. Dennie-Morgan wrinkle (transverse wrinkle (or two) parallel to the lower eyelid)
  4. Pityriasis alba (dry, finely scaly light patches)
  5. Eczema patches
  6. Palmary hyperlinearity
  7. Pulpitis sicca (dry eczematous fingers/toe tips)
  8. Dyshidrosis (hands/feet)
  9. Perleche (torn corners of the mouth)
  10. Ear rhagades (torn earlobes)

Results of an orienting prick and intradermal test

  • Extrinsic form
    • IgE > 150 kU/ml
    • ECP
    • Increased levels of TH2 cytokines (IL-4, IL-5, IL-13)
    • Specific IgE (food allergens, inhalation allergens, Pityrosporon ovale)
    • Atopy patch test
    • Omission diet and search diet ( food allergy, food intolerance)
    • Epicutaneous test to question contact sensitization (higher rate of contact allergy to topical agents, external ingredients, rubber materials, fragrance mix)

Differential diagnosis
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Complication(s)
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Increased incidence of (severe) viral and bacterial infections. S.a.u. Eccema herpeticatum; Eccema molluscatum; pyoderma, erythroderma.

Occasionally, in the course of atopic eczema, "light sensitisation" occurs with an intensification of the eczema reaction in light-exposed areas. S.u. Eczema atopic photoaggravated

Other complicated comorbidities are:

General therapy
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Skin dryness: xerosis, depending on the ambient temperature and humidity. Avoid excessive heating of the living quarters, increase humidity, optimal ventilation of the rooms. Due to the reduced alkaline neutralizing capacity, the use of soaps, detergents and rinsing agents should be reduced to a minimum. Re-greasing washing lotions are recommended (Eucerin 5% Urea washing lotion, Atopicontrol shower and bath oil, Lipoderm shower gel, Cetaphil washing lotion).

Sweating: Reduced perspiration leads to heat accumulation and itching crises due to high outdoor temperatures during physical exertion, but also in stressful situations.

Sun and UV: UV exposure usually has an alleviating effect on eczema. Occasionally there is increased UV sensitivity. See also photoaggravated endogenous eczema.

Contact allergies: Often grafted contact allergy, especially to nickel. Caution. Fashion jewellery!

Skin cleansing:

  • No commercially available perfumed soaps, bubble baths and syndets. Use of oils (Linola fat oil bath, Balneum Hermal oil bath).
  • Oil/surfactant combinations are excellent (e.g. Eucerin shower oil, Lipoderm shower gel).
  • As an alternative to bath oils also an O/W emulsion or hydrophilic oils can be used for cleansing. In case of very dry skin, after drying, apply an emulsion or cream (e.g. Ungt. emulsif. aq., Eucerin Lotio, Excipial U Lipolotio or Excipial U Hydrolotio etc.) according to the tolerance.

Choice of profession: Unsuitable are professions with intensive contact to water, detergents, oils, fats, drilling water, disinfectants, adhesives, leather, chemical products, animals, flour and dusts. Dry, clean occupations are recommended. Cave. Spread of mould via air conditioning!

Clothing: Breathable clothing, loosely woven cotton or also textiles made of silk (e.g. Dermsilk with an antimicrobial component: Patients with atopic dermatitis find silk fabrics pleasant on their skin and hardly irritating, cooling. In this clientele the risk of a "silk protein dermatitis" has to be taken into account. In this case, sericin is considered to be the main allergen. The solution to this problem situation is sericin-free silk fabrics which have been proven to be suitable for atopics (Koller DY et al. 2007).

Avoidance of animal materials (wool, skins), uneven rough fabrics, but also materials made of breathable synthetic fibres. Silver-coated textiles (e.g. Padycare) appear to have an inhibitory effect on staphylococcal colonisation of atopic skin.

Pollen sensitization: The skin reacts with eczema (type IV reaction) to pollen. It is recommended to apply pollen filters (Tesa Protect) to the windows. Apply a protective cream before leaving the living rooms, shower off after returning.

House dust mite allergy (see also mite allergens): Avoid dust catchers (carpet, curtains, soft toys, etc.), encasing with special mite-repellent covers (recommended e.g. Allergocover). When travelling, use a mite-repellent sleeping bag.

Indoor allergen reduction: use of air purifiers (e.g. Lifelight or Aclimat Silence A50 or Aclimat Air-Center C50).

Hyposensitization (SIT): Regarding type I sensitizations, the implementation of a SIT is controversially discussed in the literature with regard to its effectiveness. It is also discussed whether SIT contributes to the improvement of atopic eczema. In this regard, 26 robust randomized studies could be evaluated worldwide, in which no usable benefit for atopic eczema could be demonstrated compared to control collectives (Tam 2016). SIT is not approved for atopic eczema (without allergic asthma or rhinits).

Sports: According to physical capacity, avoidance of extreme perspiration, followed by showering with moisturizing shower gels.

Sauna: According to personal tolerance, avoidance of extreme temperatures.

Climatic therapy: The most effective measure with the fewest side effects to improve the symptoms of the disease, especially in the high seas (e.g. Borkum, Norderney or Sylt) or in a high mountain climate (altitude over 1500 m, e.g. Davos), especially in spring and autumn. Minimum recommended duration: 4 weeks. Application to health insurance companies or pension funds.

Nutrition: Blanket diets are to be condemned. Avoidance of allergologically relevant allergens after appropriate testing (rubbing, pricking and resting test), omission and provocation diet. Review the relevance of test results every 2 years.

Notice. The most important thing for the diet is the patient's self-awareness of his disease!

  • In case of cow's milk allergy, use cow's milk substitutes.
  • Caution! Deficiency symptoms due to iodine deficiency, bone decalcification, rickets, furthermore iron, vitamin and protein deficiency. Substitution may be necessary.
  • Remark! 20-30% of infants who are allergic to cow's milk are also allergic to soy milk!
  • The therapeutic effect of probiotics remains questionable according to recent findings.

External therapy
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Stage appropriate treatment of eczema, see below. Eczema. In milder forms with circumscribed foci, external therapy is usually sufficient. In severe forms, it should be used in addition to internal therapy. Only use individually tested ointment bases, especially hydrophilic ointments, hydrophilic creams and hydrophilic emulsions. Hydrophobic ointments tend to be less well tolerated due to their occlusive effect!

  • Glucocorticoids: The use of topical glucocorticoids is recommended in the guidelines, taking into account the benefit/side-effect profile. In acute exacerbation: Initial 1% hydrocortisone cream or hydrocortisone butyrate (e.g. Laticort cream or Crelo) in combination with moist compresses, e.g. cold black tea or physiological saline solution. In case of superinfection, antiseptic measures, e.g. dressings with octenidine (Octenisept).
  • Education about short-term steroid use is urgently needed. Recent studies suggest that patients with severe skin lesions in the acute stage benefit better from topical combination therapy (steroids with antibiotics) than from monotherapy (steroids).
  • Pimecrolimus, Tacrolimus (calcineurin inhibitors): Tacrolimus (Protopic 0.03% for children and 0.1% for adults) and Pimecrolimus (e.g. Elidel or Douglan) can be used as cell-selective immunomodulators/suppressors. Indication: acute, especially subacute eczema. Therapy over a longer period is possible, but often not necessary. Several long-term studies in children and adults show significant efficacy (Pimecrolimus) even after 6 and 12 months (no tachyphylaxis). Skin atrophies are not observed. Due to the galenics, Protopic is more suitable for the treatment of dry skin conditions, Elidel or Douglan can also be used in cases of still weeping eczema. Effects: Calcineurin inhibition; selective inhibition of T-cells and mast cells; eosinophils. Under Pimecrolimus the itching decreases significantly within the first three days of treatment, under Tacrolimus a slight irritation of the skin may occur during the first two days of treatment. Pimecrolimus and tacrolimus are approved from 2 years of age. Caveat. Due to carcinogenicity of pimecrolimus in animal experiments, calcineurin inhibitors can no longer be used safely but only as second-line therapy in case of failure of other therapy options, as no sufficient data on long-term effects in humans are available. Combinations with UV therapies as well as continuous therapies are also not recommended for the reasons mentioned. Dosage: Elidel 2 times/day; Protopic within the first three weeks 2 times/day, afterwards 1 time/day. Pay attention to light protection especially after application on the face. Caution! Treat possible infections (herpes, pyoderma)! Caution! After market introduction of the drugs, the occurrence of lymphomas was observed in patients treated topically with calcineurin inhibitors and steroids. However, this could not be confirmed in a study with more than 290,000 cases (for long-term safety of topical calcineurin inhib itors, see there). After healing of the acute episode, proactive therapy is recommended: 1-3 x/week further application of Pimecrolimus or Tacrolimus to the healed skin.
  • Ruxolitinib: So far, topical approaches with a 1.5% ruxolitinib cream have been experimentally successful (Gong X et al. 2021).
  • Polidocanol: Polidocanol is well tolerated and has an anesthetic and antipruritic effect. Major clinical studies are not available for this indication.
  • Tanning agents: The effect of tanning agents is based on their astringent action. Both synthetic (tamol-containing) and natural tanning agents (e.g., tea compresses) are available for use appropriate to the stage.
  • Zinc: Zinc-containing externals have an anti-inflammatory and astringent effect with good tolerability and are widely used. Controlled studies are not available for this indication (and will not be available in the future).
  • Vegetable oil additives: Good success under 15-20% evening primrose oil creams(e.g. Eucerin 12% Omega, Lipoderm Omega, Linola gamma, R177 ).
  • Urea: Application of hydrating additives such as 2-10% urea (e.g. R102 R104 R113, Basodexan lipid cream/ointment, Excipial U Lipolotio or Hydrolotio; Eucerin 5-10% urea cream/lotion) or 5% dexpanthenol) in combination with moist compresses, e.g. cold black tea or physiological saline solution. It should be noted that urea-containing topical preparations may cause burning sensations in highly inflamed skin.
  • Basic therapy, possible up to the age of 12 via health insurance prescription: SanaCutan basic cream (with 20% glycerine), Optiderm basic cream, Allergica basic cream, Linola fat.
  • Experimental: Crisaborol, a phosphodiesterase-4 inhibitor, which was tested positively in a 2% ointment form in 2 phase III studies. The effect is based on an inhibition of the enzyme phosphodiesterase-4, leading to an increase in cAMP and an inhibition of inflammatory cytokines.
  • Balneotherapy:
    • Bathing in cool, salty sea water with an intact skin surface is beneficial. Afterwards shower off and apply cream. Water with added chlorine is highly dehydrating, and there is a risk of infection with molluscum contagiosum viruses (see also Molluscum contagiosum) and HPV viruses (see also Papillomaviruses, human) in swimming pools.
    • Baths with added polidocanol (Balneum Hermal Plus). Severe itching crises can sometimes be alleviated with potassium permanganate baths (light pink). Caveat. Undiluted potassium permanganate is toxic and does not belong in the hands of children.
  • Balneophototherapy (see below radiation therapy)
  • Silver textiles:
    • The efficacy of silver-coated underwear (see also silver textiles) for atopic eczema has been proven in various studies.

      Note! The prescription at the expense of the GKV is mostly not possible!

  • In case of superinfection, quinolinol (e.g. quinosol 1:1000), R042 or potassium permanganate or octenidine can be used as supportive agents.
  • active probiotics with living bacteria to restore the balance of the skin microbiome (e.g. AktivaDerm®ND)

Radiation therapy
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Phototherapy (UV-Therapy):
  • UVA/UVB (see below UV rays) combinations or low-dose UVA1 therapy have proven to be effective, in the case of exacerbations also in higher doses.
  • Photosol therapy (hypertonic salt baths plus UVB). Cave! Possible danger of photoaggravated atopic eczema!
  • Photosoletherapy vs. narrow band UVB: In a larger prospective, randomized study with 160 patients a superiority of balneophototherapy could be shown in patients with severe to moderate atopic eczema. 10% brine solution!
  • PUVA Bath Therapy: In case of resistance to therapy, treatment with PUVA Bath Therapy or PUVA Therapy, systemic.
  • Narrowband UVB: According to a Brazilian study, narrowband UVB therapy is said to significantly reduce Staphylococcus aureus colonization on exacerbated skin.

Internal therapy
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In acute large-scale exacerbation, sub-/or erythroderma:

Chronic lichenified stage:

  • I.d.R. no systemic therapy is required. In cases of severe pruritus that cannot be controlled by external measures, antihistamines such as desloratadine (e.g. Aerius) 1-4 tbl/day or levocetirizine (e.g. Xusal) 1 film tbl/day can be given. If necessary, the dose can be set much higher than the manufacturer's instructions.

Severe atopic eczema that cannot be adequately treated topically:

  • Ciclosporin: (approved for atopic dermatitis from the age of 16) Numerous studies have shown good therapeutic success with ciclosporin (5 mg/kg bw/day for the first 2 weeks). The efficacy of ciclosporin (2.5-5 mg/kg bw/day) in severe atopic dermatitis has been demonstrated repeatedly in studies with good evidence. Creatinine increase and arterial hypertension have been reported as major adverse drug reactions. Recurrence (or rebound) in severe atopic eczema should be expected 4-5 months after ciclosporin discontinuation. According to the guidelines, ciclosporin A is suggested for the treatment of atopic eczema for a maximum of 2 years.
  • Dupilumab, trade name Dupixent ®: IL-4/13-R antibody (approved since 2017 for moderate to severe atopic eczema aged 12 years and older, or since December 2020 for children aged 6 to 11 years with severe atopic dermatitis). By blocking the IL-4 or IL-13 receptor, the initial response during the early phase of atopic inflammation (suppression of a Th-2 dominant development) is blocked. The Joint Federal Committee sees an additional benefit under the endpoint categories quality of life, itching, sleep disturbances, patient-reported symptoms and improvement of the EASI score, compared to standard therapy (consisting of: top. glucocorticoids, tacrolimus, ciclosporin). Adverse outcome was the development of ocular disease, including conjunctivitis. The additional benefit assessment and extension was based in part on data from the AD-1526, CHRONOS, LIBERTY AD PEDS study.
  • Baricitinib, trade name Olumiant®2 mg/4 mg Filmtbl.: Jak inhibitor, indication: treatment of moderate to severe atopic dermatitis, adults eligible with indication for systemic therapy. Dosage 4 mg / day, from 75 years of age 2 mg/day, also in chronic infections 2 mg/day. Control: if no response after 8 weeks, discontinuation of therapy.

  • Alternative: Methotrexate can be used as an alternative to ciclosporin(off-label use). The folic acid antagonist has not been studied at all in placebo-controlled trials so far! The efficacy of MTX was confirmed in 2018 in a smaller study (Gerbens et al. 2018). An analogous good clinical effect could also be demonstrated for azathioprine .
  • Alternative: Mycophenolate mofetil (off-label use): Several authors report good treatment success in severe and refractory atopic eczema with the preparation mycophenolate mofetil.
  • Alternative: In a smaller multicenter study (n=167), the JAK inhibitor upadacitinib achieved good clinical effects in atopic dermatitis (Guttman-Yassky E et al. 2019).
  • Alternative: Extracorporeal photopheresis: This treatment option is reserved for severe, otherwise refractory cases. The clinical effects can be considered good. The data situation is still unsatisfactory.
  • Experimental:
    • Anti-interleukin-5 therapy: Previous studies on this form of therapy for atopic eczema with monoclonal antibodies were unsatisfactory.
    • Omalizumab: Casuistic successes have been reported with the human anti-IgE antibody omalizumab(off-label use; so far approved only for the indication bronchial asthma), which could not be confirmed in a randomized, placebo-controlled double-blind pilot study.
    • Nemolizumab: A humanized interleukin-31 receptor antibody (nemolizumab) targeting IL-31 receptors (see below Interleukin-31), including IL-31 receptors on neurons was shown to significantly reduce itch and eczema severity with monthly administrations (Ruzicka T et al. (2017).
    • Experimental: more inerleukin antibodies are expected in the therapy of atopic dermatitis or there are already fully published studies: lebrikizumab, tralokinumab, fezakinumab, ustekinumab, baricitinib there are already fully published studies.

  • Experimental:
    • IVIG: The approaches to treat therapy-resistant atopic eczema with high-dose intravenous immunoglobulins (IVIG: doses 2.0/kgKG) must still be regarded as experimental. This applies in particular to patients with severe atopic eczema in whom immunosuppressive therapy is not possible for various reasons. There are a number of studies on this subject in both adults and children dating back to 1996. Turner PJ and co-workers describe in a restrospective study of 10 children with severe therapy-resistant atopic eczema clear positive effects of IVIG therapy. Side effects were not observed. The treatment took place once a month over a period of 1 year. At the same time, a previously necessary immunosuppressive therapy could be reduced. A research group was able to demonstrate a decrease in the IgE level in 50% of the patients. In a direct comparison in patients with severe atopic eczema between ciclosporin (4mg/kgKG) and IVIG (2g/kgKG) positive effects could be demonstrated in both groups with a superiority of ciclosporin. It is pointed out that both adults and children respond to IVG therapy, with a more pronounced positive effect in children than in adults. Remarkable the statement that in adults a combination therapy works better than a monotherapy, whereas children rather benefit from a monotherapeutic approach.
  • Outlook: further innovative therapeutic options for systemic treatment could bring substances whose development is at different stages. A monoclonal antibody targeting TH2 inflammation, Dupilumab, is already approved for the treatment of atopic dermatitis (see above). There are already fully published studies on 7 further substances for the therapy of neurodermatitis: Lebrikizumab, Tralokinumab, Nemolizumab, Fezakinumab, Ustekinumab, Baricitinib and ZPL3893787.

Progression/forecast
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Due to the high clinical variability, it is not possible to make an individual prediction about the course of the disease pattern. A chronic, intermittent course with relapses of varying duration and severity is to be expected.

Important: the disease can be significantly improved by therapeutic measures but not cured! Healing promises of miracle healers are charlatanry.

As a rule of thumb the third rule can be applied:

  • 1/3 loses the disease
  • 1/3 must expect the disease to persist
  • 1/3 must expect exacerbations.

An improvement of the skin symptoms is to be expected with increasing age. 75% of patients with atopic eczema show remissions in puberty. There is an increased susceptibility to viral, bacterial and mycotic infections due to impaired cellular immunity.

Prophylaxis
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Preventive measures in case of known atopic diathesis:

  • Breastfeeding(previously accepted attitude): Full breastfeeding of infants over 6 months, only then supplementary feeding. According to various meta-analyses, the "Breast is best! According to various meta-analyses, the "Breast is best!" approach should result in a 30% significant risk reduction! In the meantime, these results have been called into question by the results of a large Canadian study (final evaluation of 11,000 children), which found a higher sensitization rate in the breastfed children than in the control group. Also for allergic bronchial asthma no risk reduction could be proven in a larger study (n=335). An Italian study came to similar results.
  • Supplementary food: For years it was recommended to introduce potent food allergens as late as possible in infant feeding. This can no longer be deduced from the relevant studies on this topic. On the contrary, delayed introduction of complementary foods seems to increase the risk of later sensitization to aero- and food allergens at the age of 5 years.
  • Maternal diet during breastfeeding: The evidence base is relatively weak. Avoidance of potent allergens (milk, egg, fish, nut, wheat, soy) appears to have a beneficial effect on eczema prevention.
  • Food supplements ( probiotics ): The preventive effect of probiotics is controversially discussed and completely negated by several working groups due to insufficient studies. Proponents of probiotics have the following hypothesis: The intestines of allergy sufferers seem to be poorly colonized by lactobacilli. The addition of LGG (Lactobacillus Goldin and Gorbach = Lactobacillus rhamnosus GG) is said to lead to a significant reduction (68%) of the atopy rate in at-risk children, but has since been relativized to 21%. In a Dutch study with 138 children, the hydrolyzed protein formulations with indigestible oligosacchrids could be shown to have a formulation of the intestinal flora comparable to that of breastfed children (Wopereis H et al. 2018).
  • Vitamin D (high dose): High dose supplementation of vitamin D (4,400IU/day versus the current recommendation 400IU/day) resulted in immunomodulation of neonates in a randomized trial that may provide SCprotection against wheezing and bronchial asthma (Hornsby E et al. 2018).
  • Pet ownership: Individual epidemiological studies have found a significant association between the ownership of small rodents (rabbits, guinea pigs) and the prevalence of atopic eczema. Children at risk should avoid keeping these animals (including cats). There are no restrictive recommendations regarding the keeping of dogs. In case of sensitization and clinical symptoms ( rhinitis/conjunctivitis/asthma), direct contact should be avoided, also via contact persons.
  • Smoking: Do not smoke at home! In children whose mothers smoked during pregnancy, atopy stigmata occur significantly more often (52.2% in the verum group vs 37.7% in the control group). Maternal smoking doubles the risk of developing atopic eczema.
  • Mold (see below mold diseases ): Clean up living spaces from mold! Moisture and mold exposure indoors seems to be associated with an increased risk of eczema!
  • House dust mites: For at-risk children, minimize house dust mite exposure:
    • Remove dust traps from living rooms and bedrooms.
    • Keep bedrooms cool and clean. Do not carpet but prefer smooth, damp wipe surfaces.
    • Toys: Prefer washable toys (e.g. washable soft toys).
    • Bedding: Use washable bedding, remove bed springs. Frequent airing and cleaning of mattresses. The mite-proof mattress cover (see below Encasing) is an effective measure for mite minimisation in bedrooms. Alternatively, bedding made of microfibre can be used.

Occupations to avoid with atopic dermatitis(see below Occupational dermatoses):

  • Hairdresser, nursing professions, photographer, painter, machining professions (lathe operator/miller), manual professions in the metal and car industry, carpenter, bricklayer professions, work underground (miner), employment in leather tanning and leather processing, baker, confectioner, cook (food professions), professions with constant damp work (room cleaner; window cleaner, etc.).

Naturopathy
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Naturopathic treatment is suitable in the subacute and chronic stages.

Order therapy: The adequate lifestyle is essential, avoidance of allergens, extreme stress situations, see also therapy in general.

Climatic therapy: Allergen-poor stimulating climate (high sea climate, high mountain climate), long-wave UVA 1 irradiation, baths with locally disinfecting, skin-soothing additives such as lavender oil, alleviate the skin irritation. Caution: rare allergic reaction to lavender, especially linalool. Due to the disinfecting effect of lavender oil also suitable in case of superinfection. In the acute stage of eczema, cool moist compresses with black tea or oak bark extract (see tannins below) relieve the itching and inflammation. To prevent the skin from drying out, always apply the cream or care cream containing the active substance to the skin first.

Intestinal rehabilitation is becoming increasingly important in atopic eczema. Patients with atopic eczema tend to have a reduction of protective germs in the intestine, in particular enterococci. Frequently, especially after antibiotic therapies, Candida albicans overgrowth occurs and reactively triggers the atopic eczema. In addition to the reduction of Candida colonisation(Nystatin), the correction of the bacterial overgrowth should be carried out by means of symbiosis control after differentiation of the missing protective germ.

Locally, probiotic bacterial strains (bacterial complex Baplexin 621, which is
composedof lactobacilli, namely Lactobacillus gasseri, L. paracasei, L. plantarum, L. rhamnosus, L. reuteriL.
johnsonii, as well as bifidobacteria: Bifidobacterium lactis and B. longum, and streptococci: Streptococcus thermophilus)can be used.
Prebiotic ingredients inulin and maltodextrin are included with the bacteria, these are optimal nutrients for the probiotic bacterial strains.

Phytotherapy: Phytotherapeutically, especially the rational phytotherapeutics have proven to be effective, while the effect of some traditional plants could not be proven in studies.

Note: always test ointment compatibility! Caution: Wool wax alcohols

Traditional phytotherapy:

Dulcamaris (bittersweet stalk, Solanum dulcamara) from the nightshade family, positive monograph for supportive treatment of eczema, no confirmed studies to date, can be used locally (Cefabene ointment and gel, Dulcamaris ointment) as well as systemically (e.g. in Cefabene drops, cave contains ethanol and fortified wine). Extracts of the drug contain steroid saponins, which have steroid-like effects, tannins, and steroid alkaloid glycosides.

Hamamelis (witch hazel), positive Commission E/ESCOP monograph for use in skin lesions, mild inflammation, of skin and mucous membranes, haemorrhoids and varicose vein complaints
, in studies no superiority over placebo. Topically as ointments (e.g. Hametum® wound and healing ointment, Hamasana®, Hamadest®).

Calendula(marigold), composite plant, positive monograph of Commission E/ESCOP for use in inflammatory changes of the oral and pharyngeal mucosa, poorly healing wounds, ulcus cruris. To date no systematic studies in eczema, in prophylaxis of radiodermatitis superior to placebo. Topically as ointment (e.g. Calendumed ointment) or essence for the preparation of baths and compresses. Caution: Allergic potency, daisy!

Evening primrose oil: Seeds of Oenothera biennis (common evening primrose; see below evening primrose oil), consisting of 60-80% linoleic acid and 8-14% gamma-linolenic acid, an omega-6 fatty acid, no positive monograph, as not processed. Recognized by WHO for the indication atopic eczema, diabetic neuropathy, mastodynia. Efficacy not sufficiently proven in studies to date. Topically as cream (e.g. Eucerin Omega®, Allergika Night Seed Oil Cream®), systemically in capsule form (e.g. Epogam®, dosage: 2-3 g/day = 4-6 Kps).

Borage seed oil is also rich in gamma-linolenic acid and can be applied internally (e.g. Glandol®, borage oil capsules) or externally as a formulation.

Tormentillae rhizoma: A smaller positive application study is available on Tormentillae rhizoma (2% ) in a good spreadable oil/w base (Hoffmann 2015).

Ice Plant Ointment: A positive application study is available on a paraffin-based base care with the juice of the "edible ice plant (see below Mesembryanthemum edule)". The atopic children treated in this way had a significantly increased hydration of the str. corneum and a lower transpepidermal water loss after 16 weeks (Schario 2014).

Seed Oats (Medicinal Plant of the Year 2017): Extracts of oat herb (containing flavonoids and saponins) are used in medicinal baths with good success in atopic eczema.

Rational phytopharmaceuticals(placebo-controlled, partly double-blind studies):

Betulin, found in birch bark, shows antibacterial, antipruritic, anti-inflammatory, wound-healing and antitumor activity. In local application as a cream (Imlan® Creme pur and plus) it leads to a statistically significant rehydration of the horny layer, improvement of the skin barrier and significant reduction of transepidermal water loss (Laszczyk 2009).

Hypericum (St. John's wort): A positive, randomized, placebo-controlled study half-side comparison study is available on atopic eczema with a 1.5% cream application (Schempp 2003) with significant superiority compared to placebo. Local application (e.g. Bedan® cream), approved from the 6th month of life.

Cardiospermum-halicacabum leaves (balloon vine leaves) Extracts from the monk's head plant (not to be confused with the "monk's head" Infundibilicybe geotropa - an edible fungus of the larkspur family) have antieczematous effects due to their content of saponins, tannins, flavonoids and traces of alkaloids. Clinical studies with Cardiospermum halicacabum showed good anti-inflammatory effects comparable to the active ingredient Bufexamac. Preparations: Dermaplant® ointment, Halicar® cream or Halicar ointment. Dermaplant can be prescribed and reimbursed for children up to the age of 12 in cases of atopic eczema.

Liquiritiae radix (liquorice root) the 1% and 2% gel shows significant improvement of erythema, oedema and pruritus (improvement of 80%) in a double-blind placebo-controlled study. Trade name: Atopiclair, applicable from 6 months of age (Abramovits 2006).

Mahonia+pansy+water pennywortas a fixed combination in Ekzevowen® derma cream showed a statistically significant superiority to placebo only in winter.

Note(s)
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Atopy is derived from the Greek word "atopos" (= in the wrong place).

The importance of atopic eczema in everyday life is illustrated by the world's largest study of the impact of the disease on the lives of sufferers and relatives ( ISOLATE study).

Evaluation of the clinical course is possible using the SASSAD score.

The frequency of sensitisation to food allergens (see below food allergy) is particularly high in atopic children who have already developed atopic eczema in the first three months of life and lowest in children who do not show symptoms of atopic eczema until after the first year of life.

Specific immunotherapy: Specific immunotherapy should be discussed only in the presence of appropriate pulmo-conjunctival or bronchial symptoms. Caution. Worsening of the eczema. Possibly danger of floor change!

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