Atopic Dermatitis

An Introduction to Atopic Dermatitis

Atopic dermatitis, also known as atopic eczema, is the most common form of eczema. It mainly affects children however it can continue into adulthood.

Eczema is a condition that causes the skin to become itchy, red, dry and cracked. Severe cases can also result in small levels of bleeding from affected areas. It is a long-term or chronic condition that can vary in severity but most people with the condition are only mildly affected. Atopic eczema commonly occurs in areas with folds of skin, such as: behind the knees, the inside of the elbows, on the side of the neck and around the eyes and ears.

Causes of atopic dermatitis

As of yet the cause of atopic dermatitis is unknown, although it can often occur in people who also suffer from unrelated allergies. The atopy means that a person has an existing predisposition to having a hypersensitivity towards allergens, therefore it usually runs in families and can occur alongside other conditions such as asthma and hay fever.

Atopic dermatitis tends to clear up or significantly improve in many children as they grow older. It is unusually common among children, and can affect up to 1 in 10 children at some point in their development. (24) Although the condition usually disappears during infancy, atopic eczema can carry onto adolescence or further into adult life. In the majority of cases atopic eczema is not due to an allergy.

Treatment of atopic dermatitis

Severe cases of atopic eczema can be very difficult for infants to live with and can have a significant impact on everyday life even for adult sufferers. There are a variety of treatments that can help to control and manage eczema, such as medication and skin treatments. The main methods for treating this condition are:

Emollients (moisturising treatments) which can be used continuously for dry skin.

Topical corticosteroids which are used to reduce swelling and redness. Different strength topical corticosteroids are available for various parts of the body which may be affected.

Antihistamines which can help with the itching caused by atopic eczema causes.

If the eczema is not infected then certain dressings known as wet wraps may also help keep the skin moisturised and prevent scratching. Specific types of dietary control and forms of complementary medicine may also prove beneficial, but advice from a medical professional is advised for these particular eczema treatments.

Section 1. THE PATHOGENESES OF ATOPIC DERMATITIS

1.1 DEFINITION

Atopic dermatitis is a chronic, pruritic inflammatory skin disease that occurs most frequently in children, but also affects many adults. It follows a relapsing course. Atopic dermatitis is often associated with elevated serum immunoglobulin (IgE) levels and a personal or family history of type I allergies, allergic rhinitis, and asthma. Atopic eczema is synonymous with atopic dermatitis. Atopic dermatitis appears to involve a genetic defect in the proteins supporting the epidermal barrier. Atopy, referring to "out of place", describes a group of disorders that include eczema, asthma, and allergic rhinitis. However such a link between atopic dermatitis and asthma and hay fever has been called into question and is now controversial. The terms "dermatitis" and "eczema" are frequently used interchangeably. When the term "eczema" isused alone, it usually refers to atopic dermatitis (atopic eczema). "Eczematous" also connotes some crusting, serous oozing, or blister formation as opposed to mere erythema and scale.

1.2 EPIDEMIOLOGY

Atopic dermatitis affects approximately 5 to 20 percent of children worldwide. The prevalence of atopic dermatitis in the United States is around 11 percent. (36) The incidence of atopic dermatitis appears to be increasing. It may occur in any race or geographic location, although there appears to be a higher incidence in urban areas and developed countries, especially western societies.The vast majority of atopic dermatitis has an onset before age five years, and prevalence data in children show a slight female to male preponderance.

1.3 PATHOGENESIS

Two major models currently exist to explain the pathogenesis of atopic dermatitis.The predominant model describes atopic dermatitis as a result of impaired epidermal barrier function due to intrinsic structural and functional abnormalities in the skin. In this model, the disease evolves from the outside in, with an abnormal epidermal barrier as the primary defect.

The second and traditional model views atopic dermatitis as primarily an immune function disorder in which Langerhans cells, T-cells and immune effector cells modulate an inflammatory response to environmental factors (fig. nr. 1 ).

Fig. nr. 1 Factors contributing to the pathogenesis of atopic dermatitis ( genetics, immunology, environment, skin barrier dysfunction).

dermnetnz.org/dermatitis/atopic-causes.

1.4 CLINICAL MANIFESTATIONS

Atopic dermatitis occurs in the first year of life in 60 percent of cases, and by the age of 5 years in nearly 85 percent of cases. Atopic dermatitis will clear in nearly 40 percent of patients by adulthood. There are three age-group stages of atopic dermatitis: infantile (from infancy to 2 years old), childhood (from 2 years old to 12 years old) and the adult stage for those older than 12 years. (29) Virtually all patients report dry skin. Pruritus is characteristic, and secondary changes in the skin due to chronic rubbing or scratching are frequently present.

The infantile stage may present with pruritic, red, scaly, and crusted lesions on the extensor surfaces and cheeks or scalp. There is usually sparing of the diaper area. Acute lesions can include vesicles and there can be serous exudates and crusting in severe cases.

The childhood stage is characterized by less exudation and often demonstrates lichenified plaques in a flexural distribution, especially of the antecubital and popliteal fossae, volar aspect of the wrists, ankles, and neck.

The adult stage of atopic dermatitis is considerably more localized and lichenified and has a similar distribution to the childhood stage, or may be primarily located on the hands and feet. Adult atopic dermatitis is characterized by thickened skin, increased skin markings (lichenification), and excoriated and fibrotic papules. In adults, the flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly involved; other common sites include the face, wrists, and forearms (fig. nr. 2).

Fig. nr. 2 Atopic dermatitis occurs in the first year of life in 60 percent of cases, and by the age of 5 years in nearly 85 percent of cases. Atopic dermatitis will clear in nearly 40 percent of patients by adulthood. There are three age-group stages of atopic dermatitis: infantile (from infancy to 2 years old), childhood (from 2 years old to 12 years old) and the adult stage for those older than 12 years.

In severe cases, any area of the body can be involved, although it is uncommon to see lesions in the axillary, gluteal, or groin area; lesions in these locations should prompt consideration of other diagnoses such as psoriasis. The presence of pustules within areas of dermatitis suggests secondary infection with Staphylococcus aureus.

1.5 DIAGNOSIS

Atopic dermatitis is diagnosed by observing its representative clinical features. The United Kingdom (UK) Working Party on atopic dermatitis published criteria for diagnosing atopic dermatitis that include the following. (17)

Evidence of pruritic skin, including the report by a parent of a child rubbing or scratching. In addition to itchy skin, three or more of the following are needed to make the diagnosis.

History of skin creases being involved. These include: antecubital fossae, popliteal fossae, neck, areas around eyes, fronts of ankles. The presence of generally dry skin within the past year. Symptoms beginning in a child before the age of two years. This criterion is not used to make the diagnosis in a child who is under four years old.Visible evidence of dermatitis involving flexural surfaces. For children under four years old, this criterion is met by dermatitis affecting the cheeks or forehead and outer aspects of the extremities.

The UK working group's analysis excluded allergy criteria as originally proposed by Hanifin and Rajka in 1980. The United Kingdom working group data have been validated by investigators from the Netherlands.

Laboratory testing, including IgE levels, are not used routinely in the evaluation of patients with suspected atopic dermatitis, and are not currently recommended.

When the diagnosis is uncertain, it is suggest that patients be referred to a specialist (eg, dermatologist,allergist).

1.6 DIFFERENTIAL DIAGNOSIS

The differential diagnosis of atopic dermatitis includes other eczematous disorders such as contact dermatitis, seborrheic dermatitis, and drug reactions.

In infants, considerations include psoriasis, scabies, Wiskott-Aldrich syndrome, hyperimmunoglobulin E syndrome, nutritional deficiencies, acrodermatitis enteropathica and Netherton's syndrome. (fig. nr. 3)

Fig. nr. 3 – differential diagnosis www.nhs.uk/…/eczema-(atopic)/…/introduction…

Section. 2 EPIDERMAL PERMEABILITY BARRIER

The epidermis is the first line of defense between the body and the environment. An intact epidermis keeps environmental irritants, allergens, and microbes from entering the body. Permeability of the epidermis is determined by complex interactions of differentiated keratinocytes on the surface of the skin called corneocytes and groups of structural proteins, such as filaggrin, regulatory enzymes, and lipids. Any disruption of these components through inherited defects, trauma, decreased humidity, alteration of pH, and infection can interfere with the ability of the epidermis to function as an effective barrier. Disruption allows antigenic and irritant agents to penetrate the barrier and come into contact with immune cells, leading to the release of proinflammatory mediators. This can then produce the clinical and pathologic findings of dermatitis.

1. Epidermal hydration

Hydration of the epidermis is a key factor in maintaining an intact barrier, and the stratum corneum layer of the epidermis plays a key role in the retention of water in the skin. Water absorption into the stratum corneum occurs as a function of stratum corneum natural moisturizing factor, which consists of a variety of molecules that promote water absorption, including amino acids derived from the proteolysis of epidermal filaggrin, urea, lactate and electrolytes. The stratum corneum also prevents epidermal water loss through the presence of an extracellular lipid barrier composed of ceramides, cholesterol, and free fatty acids.

Defects that affect filaggrin, epidermal lipids, or other key components of the stratum corneum can result in the creation of an inadequate epidermal barrier, leading to decreased water content in the epidermis. Increased rates of transepidermal water loss (TEWL) have been detected in skin of patients with atopic dermatitis, and an association between this finding and mutations in the gene for filaggrin have been reported. In addition, decreased levels of ceramides in the stratum corneum due to up regulation of sphingomyelin deacylase may contribute to increased transepidermal water loss in atopic dermatitis.

Abnormalities in the skin barrier that result in increased water loss likely contribute to the clinical findings in atopic dermatitis. Higher levels of transepidermal water loss in patients with atopic dermatitis have been associated with greater disease severity. In patients with atopic dermatitis, dry skin (xerosis) secondary to decreased epidermal water content may contribute to pruritus and scratching. Resultant cutaneous trauma from scratching can promote the release of proinflammatory mediators and inflammation, there by worsening pruritus. This “itch-scratch” cycle may play a role in the persistence of symptoms (fig. nr. 4)

Fig. nr. 4 The barrier to the penetration of irritants, allergents and drugs is located in the lower part of the stratum corneum. The structural integrity of the statum corneum is maintained of modified desmosomes (corneodesmosomes), which lock together the corneocytes. As the corneocytes move up trought the stratum corneum the corneum desmosomes are gradually broken down by the skin specific proteases, and unattached corneocytes can than be descuamated from the surface of the skin.

www.nationaljewish.org

2. Filaggrin

Filaggrin is encoded by the (FLG) gene on the 1q21 epidermal differentiation complex. Filaggrin is a protein that is produced by differentiating keratinocytes that functions to aggregate keratin filaments into a cytoskeleton that, in combination with other components, comprise the cornified cell envelope.

Mutations of filaggrin ( fig. nr. 5 ) have been demonstrated to cause ichthyosis vulgaris, the most common inherited disorder of keratinization. Ichthyosis vulgaris is characterized by many of the features that are included in the diagnostic criteria for atopic dermatitis including dry skin, keratosis pilaris, and palmar hyperlinearity and is frequently associated with atopic dermatitis.

Fig. nr. 5 (www.drjockers.com)

Two well characterized loss of function filaggrin mutations (R501X and 2282del4) have been shown to be responsible for moderate-severe ichthyosis vulgaris in those who carry two mutant alleles and mild disease in those with only one copy of the allele. One study examined the occurrence of atopic dermatitis in individuals with known mutations of the filaggrin (R501X and 2282del4) and ichthyosis vulgaris. Atopic dermatitis was found in higher frequency in those who had two mutated filaggrin alleles compared with those with one, and atopic dermatitis was completely absent in family members who had no copies of the mutated filaggrin. A number of independent studies in Ireland, Scotland, Denmark, and Japan corroborate these results. Many authorities now cite filaggrin defects as a major contributor to the development of atopic dermatitis.

3. Spink 5

Spink 5 is a serine protease inhibitor (Kazal-type 5 serine protease inhibitor) that is deficientin Netherton's syndrome (a rare autosomal recessive disorder characterized by severe atopic dermatitis). Spink 5 inhibits a well characterized protease stratum corneum chymotryptic enzyme (SCCE) that is involved in cleaving the intercellular attachments between corneocytes in normal desquamation process. Decreased Spink 5 results in upregulated stratum corneum chymotryptic enzyme function and increased cleavage of intercellular attachments and reduced corneocyte cohesion and compromised barrier function.

4. Epicutaneous sensitization

Immune responses to allergens, irritants, and microbes that enter the skin through a defective skin barrier may contribute to the development of local inflammatory responses and the cutaneous findings of atopic dermatitis. Antigen presenting cells in the skin, in particular IgE bearing Langerhans cells, can interact with environmental allergens, leading to the local Th2-mediated inflammatory responses that have been detected in the skin of patients with atopic dermatitis.

5. İmmune hypersensitivity

Another theory explaining the pathogenesis of atopic dermatitis proposes that the immune system is responsible for atopic disorders. Atopic dermatitis in this view may represent a cutaneous sign of a systemic disorder that is characterized by food allergy, asthma, andallergic rhinitis.

The discovery that defects in the filaggrin protein lead to a dysfunctional epidermal barrier and are the primary cause of atopic dermatitis has made this theory less plausible. Emphasis is now placed on the study of the epidermal barrier dysfunction as it relates to the abnormal epidermal architecture and how the immune system responds to the barrier failure.

Serum IgE levels vary among patients with atopic dermatitis. Patients with mild to moderate atopic dermatitis typically have much lower (or normal) serum IgE levels compared to patients with severe atopic dermatitis. This finding suggests that the systemic Th2 driven axis of the immune system detected in atopic dermatitis may be related to epidermal barrier dysfunction and the introduction of environmental antigens, rather than intrinsic immune hypersensitivity.

6. Genetics

Most experts believe that atopic dermatitis has a genetic basis. A genetic basis is suggested by twin studies that have found concordance rates of 80% for monozygotic twins compared to 20% for dizygotic twins.

7. Other genes

In addition to filaggrin, many other genes have been proposed as potential contributors to atopic dermatitis, including genes involved in the creation of the skin barrier or immune regulation. Linkage on chromosomes 3q21, 1q21, 17q25, and 20p, all of which correspond closely withknown psoriasis loci, have been reported.

In 2009, the first genome-wide association study of atopic dermatitis detected a strong association between atopic dermatitis and an allele on chromosome 11q13.5. The risk of atopic dermatitis wasapproximately 1.5 times greater in patients who were homozygous for the risk allele than in noncarriers (OR 1.47, 95% CI 1.29-1.68). The results of this genome-wide association study were supported by asubsequent case-control study of 511 children with atopic dermatitis and 1000 controls. The case-control study implicated the same susceptibility locus as a potential contributor to atopic dermatitis, andfound that the effect of the risk allele was independent of and supplementary to filaggrin mutations.Additional studies are necessary to determine how these findings apply to the pathogenesis of atopicdermatitis.

8. Staphylococcus aureus

Staphylococcus aureus colonization is common in patients with atopic dermatitis and may play a role in the development of this disorder

Suppression of the innate immune system of the skin by the inflammatory micromilieu of atopic dermatitis explains the colonization of the skin by S. aureus in more than 90% of patients with atopic dermatitis. This feature contributes to allergic sensitization and inflammation. (fig. nr. 6).

Fig. nr. 6 Multiple pathways of staphylococcus aureus- Driven Sensitization and İnflammation. By virtue of several mechanisms, S.aureus and its products provide signals that favor sensitization and inflammation. S.aureus – derived ceramidase increases the permeability of the stratum corneum, and the superantigenic capacity of S.aureus enterotoxins activates T celss in an allergen –independt manner. S.aureus induces the expression of the skin – homing receptor cutaneous lymphopoietin (TSLP) , and interleukin -31 secretion are induced and augmented by S.aureus enterotoxins. They also contribute to corticosteroid resistance in T cells and alter the activity of regulatory T cells S.aureus – specific IgE generated by the immune system can bind to Fc RI receptors on dendritic cellss and initiate an IgE-mediated reaction to this microbe.

S. aureus and its products provide signals that favor sensitization and inflammation. S. aureus–derived ceramidase increases the permeability of the stratum corneum, and the superantigenic capacity of S. aureus enterotoxins activates T cells in an allergen-independent manner.

Scratching increases the binding of S. aureus to the skin, and the increased amount of S. aureus–derived ceramidase can aggravate the defect in the skin barrier.

S. aureus enterotoxins increase the inflammation in atopic dermatitis and provoke the generation of enterotoxin-specific IgE, which correlates with the severity of the disease (nr. bibliografie corespunzator articolului).

Section 3. THE ROLE OF ALLERGIC DISEASE

Patients and caregivers often seek allergy assessment to find a single cause or trigger that could be eliminated to obtain ‘‘cure’’—or at least reduce the need for treatment. However, the role of allergens in eliciting and maintaining atopic dermatitis skin lesions is complex, further complicated by challenges in determining clinical relevance and their importance relative to other factors. Foods and inhalant/aeroallergens are common concerns, and along with contact allergens are the most relevant for discussion.

Food allergies

A fair number of children and a much smaller percentage of adult patients with atopic dermatitis have food allergies, particularly those of younger age and with more severe disease. The exact impact of food exposure on the course of atopic dermatitis remains unclear.

Asthma is a stronger risk factor for food allergy than Atopic Dermatitis. A true allergy is defined as ‘‘an adverse health event that results from stimulation of a specific immune response that occurs reproducibly on exposure.’’ Therefore, reproducible clinical symptoms or signs after food exposure/ingestion are necessary to diagnose food allergy, and broad panel allergy testing independent of a history of a reaction to foods is not recommended. Positive test results may reflect sensitization, associated with IgE reactivity, but have poor correlation with clinical allergic responses.

Moreover, exposure to allergenic foods may or may not induce eczematous dermatitis (a delayed reaction that typically occurs 6-48 hours later), but more often gives immediate/type I, nondermatitic reactions (usually within 2 hours) that include local or generalized urticaria, flushing, or itch. Food allergy may also present as gastrointestinal or respiratory symptoms, and at times, anaphylaxis. It is therefore important not only to establish presence of a true food allergy but also to determine if the food allergy is exacerbating atopic dermatitis, either directly via immune cell activation or indirectly via increased pruritus, or is instead a coexisting condition with non-Atopic Dermatitis manifestations.

The National Institute of Allergy and Infectious Diseases (NIAID) Food Allergy Expert Panel suggests consideration of limited food allergy testing (ie, cow’s milk, eggs, wheat, soy, and peanut) if a child\5 years of age has moderate to severe atopic dermatitis and the following: (1) persistent disease in spite of optimized management and topical therapy;

(2) a reliable history of an immediate allergic reaction after ingestion of a specific food;

(3) or both.

While food allergy is less common in older age groups, when suspected, the choice of food for testing should be made according to the clinical history and to the most prevalent allergies in a given population. Tree nuts, shellfish, and fish become relevant in subsequent childhood years. In older children, adolescents, and adults, pollen-related food allergy should be taken into account—for example, those with birch pollen allergy may developing itching in their mouth with exposure to apples, celery, carrots, and hazelnuts.

Tests often performed for evaluation include skin prick testing (SPT) and serum-specific IgE level determination, which assess for immediate/type I hypersensitivity reactions. skin prick testing is an in vivo test based on introducing allergen extracts that bind to specific IgE antibodies on mast cells, causing the release of histamine and other mediators that give rapid formation of a wheal and flare. Food-specific IgE levels may be measured in the serum by in vitro assays, such as radio allergosorbent (RAST) testing or immunoCAP testing. In cases of extensive eczematous lesions, prominent dermatographism, or the recent use of oral antihistamines, specific IgE measurement may be preferable over skin prick testing. With both tests, the negative predictive value is high (95%) and the specificity and positive predictive value are low (40-60%).

Negative test results are helpful to rule out food allergy, but positive results only signify sensitization and require clinical correlation and confirmation to establish presence of allergic disease and the exact type of allergic response. Higher specific IgE levels and larger wheal sizes ([8-10 mm) are associated with a greater likelihood of reaction on challenge. Measuring total serum IgE levels alone, or to compare with allergen-specific levels, is not helpful in determining food allergy. In recent years, atopy patch tests (APT) have been introduced to assess for type IV hypersensitivity/ eczematous reactions. These involve applying custom-made food material for 48 to 72 hours to the back using 8- to 12-mm test chambers.

Food atopy patch tests are not commonly used in the evaluation of patients in North America, but have been investigated in Europe. One European multicenter study found that atopy patch tests have a higher specificity than SPTs or specific IgE, particularly in the case of wheat, while other studies noted that atopy patch tests could not predict food hypersensitivity beyond that of SPT or specific IgE testing. These conflicting findings might be explained by the sometimes difficult interpretation of atopy patch tests because of nonspecific reactions. In addition, while Atopic Dermatitis patients have more reactivity than healthy controls, the results do not necessarily correlate with disease severity or clinical outcome, and atopy patch tests are therefore not recommended for routine use at this time.

Positive skin or blood tests ideally need to be verified by controlled food challenges. The criterion standard for diagnosing food allergy is a doubleblind, placebo-controlled oral food challenge. In this case, testing is performed after a washout period. Potential allergenic foods and placebo are given in a randomized, titrated fashion, and both the patient and observer are blinded to the test food. Because this may not always be practical, open-label or single-blind oral food challenges are more commonly used in clinical practice to screen for reactions. Such challenges should be performed under the guidance of well-trained medical personnel and with emergency equipment available.

Another alternative is careful assessment of the effects of a food elimination diet carried out in the absence of other exacerbating factors. Avoidance diets should be cautiously undertaken, however, and are further discussed below. Even if food allergies are present, effective treatment for Atopic Dermatitis is still centered on good skin care and topical therapies. In addition, children with clinically significant food allergy will often develop tolerance over time to milk, egg, soy, and wheat, and therefore these allergens should be retested with age. Food allergies in adults can reflect persistence of childhood allergies or de novo sensitization to allergens encountered after childhood. Although data are limited, there is a suggestion that food allergies starting in adult life tend to be persistent.

Inhalant/aeroallergens

In contrast to food allergy, reactivity to aeroallergens increases with age. Common aeroallergens include house dust mites, pollens, animal dander, and fungi, and higher rates of sensitization are noted in those with moderate to severe Atopic dermatitis. As with foods, true allergy to aeroallergens requires demonstration of an adverse health event that is reproducible on exposure, along with discernment of the clinical reaction. The exact role of aeroallergens in Atopic Dermatitis pathogenesis is controversial, because inhalation may induce the release of proinflammatory cytokines in the skin of sensitized patients, but avoidance measures have not consistently helped (discussed under Environmental Modifications). Skin contact with aeroallergens triggers eczematous skin lesions in some individuals but not others (5-45% positivity, depending on the allergen).

The diagnosis of allergy to an aeroallergen is based on a sequential workup and demonstration of clinical relevance. History can be helpful to identify pollens or animal dander as potential triggers, such as seasonal flares or exacerbation of Atopic Dermatitis lesions after contact. Aeroallergens may also be suspected if the dermatitis is more severe on exposed surfaces of the face, neck, arms, legs, and ‘‘V’’ area of the chest. In a second step, SPT or measurement of specific IgE antibodies can be performed to detect sensitization. atopy patch tests’s with epicutaneous application of aeroallergens on uninvolved atopic skin has also been used for testing. Positive eczematoid reactions have been observed in 30% to 50% of patients with Atopic Dermatitis, but only rarely in patients with respiratory allergy or healthy volunteers.

The major disadvantage with atopy patch tests, however, is the variability of methods and interpretation of results among investigators, along with the lack of a commercially available product. Standardization of the procedure has been proposed, but is hampered by the lack of a comparator gold standard test that establishes the diagnosis of aeroallergen-induced or exacerbated dermatitis.

Allergic contact dermatitis

The high prevalence of allergic contact dermatitis (Allergic contact dermatitis ) has been increasingly recognized in individuals with atopic dermatitis. Allergic contact dermatitis is a type IV/delayed hypersensitivity reaction to small environmental chemicals (ie, haptens or prehaptens) that come in direct contact with the skin. These bind to epidermal carrier proteins to form complete antigens, cause sensitization, and induce an inflammatory reaction on subsequent exposure. Because allergic contact dermatitis manifests as eczematous lesions, it is often clinically indistinguishable from atopic dermatitis and should be considered both as an alternative diagnosis to atopic dermatitis and as a concomitant condition.

Recent studies have found that allergic contact dermatitis is at least as common in patients with atopic dermatitis as in the general population (6-60% of subjects, depending on the study). The most common contact allergens in patients with atopic dermatitis include nickel, neomycin, fragrance, formaldehyde and other preservatives, lanolin, and rubber chemicals. A small subset of patients may even develop allergic contact dermatitis to some topical corticosteroids and can pose a diagnostic dilemma for the clinician. A diagnosis of allergic contact dermatitis is made by patch testing, whereby suspected allergens are placed on unaffected skin, typically the back, for 48 hours. Presence of a reaction should be assessed at the time of initial patch removal and again at a later time point, up to 7 days after application, for delayed reactions. Patch testing should be considered in cases where a history and/or physical examination is suggestive of allergic contact dermatitis, such as disease aggravated by topical medications or emollients or patterns that reflect application of, or exposure to, a consistent item, such as marked facial and/or eyelid involvement, increased severity at the flexures of the neck, and vesicular lesions on the dorsal surfaces of the hands and fingertips.

Testing may also be considered where there is an unusual and atypical distribution of lesions for atopic dermatitis (eg, on the sides of the feet), if there is later onset of disease or new significant worsening, if there is no family history of atopy, and in patients with persistent/recalcitrant disease that has not responded to standard atopic dermatitis therapies.

Even some cases of generalized dermatitis may involve allergic contact dermatitis, such as to fragrances, preservatives, cleansers, and textiles, but are a challenge to recognize and to test for if there is little uninvolved skin. The sensitivity of patch testing ranges from 60% to 80%. Positive patch tests only indicate contact sensitization and need demonstrated relevance to the patient’s active dermatitis and sometimes confirmation by repeat open application testing of products containing the allergen that have been in contact with the patient. Avoidance of the suspected allergen with resolution of the corresponding dermatitis confirms the diagnosis of allergic contact dermatitis. In summary, allergens may be pertinent to some atopic dermatitis patients but require a detailed history, careful evaluation, and correlation of allergy test results to determine clinical relevance. It is extremely rare to find one allergen responsible for Atopic Dermatitis, which is a complex multifactorial disease in which nonallergic factors, such as climate and secondary infection, may also be implicated. (fig.nr.7)

Fig. nr. 7 www.uptodate.com/…/treatment-of-atopic-der…

DIETARY INTERVENTIONS

Food elimination/avoidance diets

Large numbers of patients with atopic dermatitis, particularly children, are started on empiric food elimination/ avoidance diets. However, there is a frequent misattribution of Atopic Dermatits flares to food-related issues. Food allergies may coexist and represent important triggers in a small subset of individuals with atopic dermatitis (usually those with moderate to severe disease), but the true frequency of food allergies causing an isolated flare of disease is probably low.

Elimination diets should not be initiated based on presence of atopic dermatitis or a suspicious history alone. İt is concluded that there may be some benefit to an egg-free diet in infants with suspected egg allergy who also have positive specific IgE to eggs, but other exclusion diets (eg, milk-free, elemental, few-foods diets) were not found to be efficacious in unselected Atopic Dermatitis populations.

If allergy is suspected as a trigger of Atopic Dermatitis, a food diary recording symptoms and intake can be helpful in identifying a specific food. If there is consistent correlation of symptoms (with or without positive allergy testing), a diagnostic elimination diet for up to 4 to 6 weeks with the suspected food item(s) may be initiated. If the individual’s Atopic Dermatitis remains stable or even increases in severity, it is unlikely that the food is a relevant Atopic Dermatitis trigger and additional testing is not necessary. If there is an improvement of the symptoms during a diagnostic elimination diet, an oral food challenge should be performed under the guidance of anallergist, because the skin improvement may be coincidental or reflect a placebo effect. If a patient has positive allergy tests but no history of symptomatic food allergy, review with an allergist regarding the issue of true versus false positive tests (allergy vs only sensitization) is warranted, along with discussion of benefits and downsides of formal food challenge.

A retrospective study on the outcome of oral food challenges in children with Atopic Dermatitis after elimination diets primarily based on sensitization found that 84% to 93% of the avoided foods could be returned to the diet and could be tolerated. Multiple dietary restrictions and long-term dietary avoidance should only be undertaken with documented, clinically relevant food allergies. Excessively restrictive diets, especially in atopic children, have led to weight loss, poor growth, calcium deficiency, hypovitaminosis, and kwashiorkor.

Proper medical supervision, nutritional counseling from a dietician, and supplementation should be included if elimination/avoidance diets are pursued for any prolonged period of time. Even in those individuals with clinically relevant food allergy, avoidance diets are generally helpful to avoid the effects of IgE-mediated/immediate reactions but are unlikely to affect the course of Atopic Dermatitis.

Probiotics/prebiotics

The study of probiotics for Atopic Dermatitis management stems from the finding that the intestinal microbiota is different in those with and without Atopic Dermatitis. Probiotics are live microorganisms that modify the overall composition of this microbiota and potentially modulate the host immune response. However, studies have found limited evidence to support their use as a treatment for established Atopic Dermatitis.

Other dietary supplements

A deficiency of essential fatty acids in the skin has been proposed as having a role in Atopic Dermatitis. Fish oils are particularly rich in n-3 fatty acids, and are suggested to compete with n-6 fatty acids in a manner that reduces the inflammatory components of Atopic Dermatitis. There is, however, little supportive data for either. Evening primrose oil and borage oil have been tried orally because of their gamma-linolenic acid content, and these oils are considered to have antiinflammatory properties, and vitamins and minerals have also been tried. Some studies suggest a mild positive effect for vitamin D and E supplementation, but larger, well-controlled trials are warranted before any formal recommendations can be made.

ENVIRONMENTAL MODIFICATIONS

General recommendations are to avoid known mechanical and chemical irritants, such as wool, acids, bleaches, and solvents, and any clear triggers/exacerbants particular to the individual (eg, excessive heat).

Sensitization to house dust mite is commonly shown in Atopic Dermatitis patients, and exposure can also cause a worsening of allergic rhinitis and asthma in sensitized individuals. The evidence is limited, however, to support the routine use of house dust mite avoidance measures. Normal cleaning measures (such as washing bedding weekly and vacuuming frequently) only provide small decreases in house dust mite allergen present in the room.

There is a paucity of clinical studies on specific laundering techniques (such as double rinsing and other methods), detergents, or other laundry products and their impact on atopic dermatitis management. The use of ion exchange water softeners for bathing and laundering clothing was not of benefit. Products with low pH may be better because of potentially fewer negative effects on the skin barrier, while botanical products (ie, plant-derived extracts and herbs) may not be as they have irritant contact dermatitis and allergic contact dermatitis risks. Fabric softener with perfumes can cause irritation, but some data indicate that softened fabrics might help because of reduced frictional irritation. Smooth clothing and avoidance of irritating fabrics and fibers are favored to minimize skin irritation.

There are a small number of controlled studies indicating that specialty silk garments may improve severity scores, although at this time it is not clear whether silk and specialty silks impregnated with antibacterial agents provide significantly more improvement compared to soft cotton. Clothing impregnated with silver can decrease Staphylococcus aureus density, but did not improve disease severity more than soft cotton in 1 study. More research into this area is warranted before recommendations can be offered regarding specialized clothing fabrics, which are associated with higher cost.

OTHER ALLERGEN-BASED INTERVENTIONS

Allergen-specific immunotherapies have been used in the treatment of asthma and allergic rhinitis and are now being tested for atopic dermatitis management. Preliminary studies on sublingual immunotherapy for house dust mite’s yielded modest positive results, which may be more evident in those with milder cases of atopic dermatitis. The present evidence does not warrant routine recommendation of sublingual immunotherapy for house dust mite – sensitized atopic dermatitis patients. A series of small prospective studies on injection immunotherapy for house dust mite’s also had positive results. Injection immunotherapy for house dust mite -sensitized patients also cannot be routinely recommended at this time. Studies examining immunotherapy for other aeroallergens are even more limited in number, precluding recommendation for use.

COMPLEMENTARY THERAPIES

At this time, there are little data to support the majority of complementary therapies tried for atopic dermatitis management. Chinese herbal therapy (or traditional Chinese medicine [TCM]) has been the most extensively studied. While it may have some benefit for atopic dermatitis lesions, the of traditional Chinese medicine taken orally are conflicting, and reports of serious hepatotoxicity raise potential safety concerns. Some herbal creams have been found to be contaminated with topical corticosteroids.

The individualized and dynamic nature of this intervention (eg, a different herb is added or subtracted depending on the patient) also poses challenges to performing controlled studies. Acupuncture alone or in conjunction with traditional Chinese medicine decreases signs and symptoms of atopic dermatitis, but the evidence is confined to small studies of limited quality. Massage therapy may improve symptoms and associated patient and parental anxiety levels. While it is a safe intervention, studies to date are small and of limited quality, precluding recommendation at this time. Other complementary therapies lacking sufficient evidence include: aromatherapy, homeopathy, naturopathy, acupressure, and autologous blood injections.

PREVENTIVE MANAGEMENT

Because atopic dermatitis is a chronic, often lifelong condition, identification of precipitating factors or triggers is a high priority and their avoidance should be an ongoing process. Immunologic triggers of atopic dermatitis vary for different patients and can include various foods, aeroallergens, irritants and contactants, hormones, stress, climate, and microorganisms such as Staphylococcus aureus. Proper skin care may also help to minimize disease exacerbations. Hydration of the skin is particularly important to offset xerosis resulting from reduction in skin ceramide concentrations, which, in turn, leads to water loss across the epidermal skin layer.

This dryness creates microfissures and cracks in the skin, which allow for entry of pathogens, antigens, or irritants, and causes general irritation. Such irritation then predisposes the patient to scratching of lesions, thereby exacerbating (or perpetuating) the disease process. Several substances may worsen xerosis and should be avoided, including those detergents or soaps that promote significant defatting; smoke; toiletries that contain alcohol, preservatives, solubilizers, fragrances, or astringents; abrasive clothing; and various chemicals.

Appropriate clipping of nails and wearing of gloves also may minimize disease aggravation related to scratching, particularly during sleep. Proper hydration may include application of an occlusive emollient after showers or baths (which should be warm, not hot), use of hydrophilic ointments and ceramide-rich barrier repair mixtures, and the application of wet dressings in severely affected areas and chronic lesions.

Section 4. THE QUALITY OF LIFE SCALES AND DISEASE IMPACT MEASUREMENTS

DISEASE SEVERITY AND CLINICAL OUTCOMES ASSESSMENT

Disease severity scales

For the measurement of disease severity, 28 different scales were identified, without a single gold standard emerging. These scales are primarily used in clinical trials and rarely in clinical practice, as they were generally not designed for this purpose. Scale development in many cases included rigorous testing and evaluation of the following statistical properties: inter- and intrarater reliability, validity (ie, construct, content, and concurrent), internal consistency reliability, responsiveness to change, and minimal clinically important difference.

Recognizing the lack of uniformity in disease severity scale use, international efforts are underway to standardize measured outcomes. This includes development of a core set of valid measures of signs and symptoms that can be feasibly recorded in controlled trials, which is directed to ward improving comparisons across trials and facilitating metaanalyses.

Quality of life scales and disease impact measurements

Twenty-two different atopic dermatitis-specific, dermatologyspecific, and generic scales were identified that measure quality of life and other psychological outcomes in patients with Atopic Dermatitis.

These scales have been used to assess the impact of atopic dermatitis and the effects of interventions, as well as to make comparisons with the impact of other disorders. Careful consideration of the scale properties should occur before use, including validity (ie, content, construct, concurrent, and discriminative), reliability (ie, testeretest and internal consistency), responsiveness to change, and minimal clinically important difference.

Additional development and evaluation of practical clinical quality of life scales are needed. This could be done by modifying existing scales into short clinical versions or by testing existing scales in a clinic population. Of note, the inclusion of patient assessment of pruritus is critical given its central contribution to the morbidity of atopic dermatitis.

Ratings of itch intensity, whether made by parents for young children or by older individuals for themselves, significantly and inversely correlate with quality of life.

The difficulties associated with itching and the resultant scratching are typically the first to be mentioned by parents when asked about the effects of their child’s disease. The mechanisms underlying atopic dermatitis-associated itch remain unclear, and are an area of much active research. Sleep disturbance, the impedance of daily activities (including effects on work or school performance), and persistence of disease are other key measures of disease impact, and represent a patient’s status and overall well-being.

CLINICAL ASSOCIATIONS

Common associations/comorbidities of atopic dermatitis that have been supported by studies include other atopic conditions, namely food allergies, asthma, and allergic rhinitis/rhinoconjunctivitis. Some consider atopic dermatitis to be the start of the ‘‘atopic march, ’’ given the frequent subsequent development of one or more of the other atopic conditions.

However, the association of other atopic conditions with atopic dermatitis is complex and multifactorial, because this progression does not happen in all individuals. Patients living in humid climates or developing countries may manifest atopic dermatitis only after changing their locale and/or after the onset of respiratory allergies. Sleep disturbance is also common and stems in large part from the significant itch associated with Atopic Dermatitis.

Greater skin disease severity also appears to have an effect on mood. Depression has been noted in both teens and adults affected with atopic dermatitis. More recently, there has been a suggested association of atopic dermatitis with behavior disorders, including ADHD, especially in children. However, an association does not establish causality, and the precise nature of the relationship requires additional study, including the role of sleep disturbance and ADHD – like behaviors and the possibility of nonspecific linkage to any chronic disease of childhood.

Cancer and obesity have been inconsistently associated with atopic dermatitis. There does not appear to be an increased risk of skin cancer or of internal malignancies, although some data are suggestive of higher rates of lymphoma and lower rates of glioma.

At present, there are insufficient data to warrant special screening or caution. Atopic Dermatitis has been linked to obesity in a few epidemiologic studies. However, short stature and poor growth have also been documented, particularly in children who suffer from severe skin disease. (fig. nr. 8)

RISK FACTORS FOR DISEASE DEVELOPMENT

Fig. nr. 8 www.dyersburgskinandallergyclinic.com

Two risk factors appear to be consistently and strongly associated with the development of Atopic Dermatitis:

(1) a family history of atopy

(2) the loss of function mutations in the filaggrin gene.

Approximately 70% of atopic dermatitis patients have a positive family history of atopic diseases.

The odds of developing atopic dermatitis are 2- to 3-fold higher in children with 1 atopic parent, and this increases to 3- to 5-fold if both parents are atopic. A maternal history of atopic dermatitis is possibly more predictive. The Filaggrin gene encodes profilaggrin, which is degraded to filaggrin monomers, and these proteins play key roles in the terminal differentiation of the epidermis and formation of the skin barrier, including the stratum corneum. Filaggrin breakdown products are part of natural moisturizing factor, which contributes to epidermal hydration and barrier function. filaggrin null mutations confer a risk for earlier-onset atopic dermatitis , and for more severe, persistent disease. They also lead to an increased tendency for eczema herpeticum. Different defects in filaggrin have been noted in different ethnic populations with atopic dermatitis, showing its importance to pathogenesis. However, a significant number of patients with atopic dermatitis have no known filaggrin mutations, and conversely, approximately 40% of individuals with filaggrin null alleles do not develop atopic dermatitis .

The type of delivery during childbirth (ie, caesarean or vaginal) does not appear to alter atopic dermatitis risk. Elevated birth weights may be a risk factor for disease development, but the effect size is likely small because studies have been conflicting, with some showing a negative association. While patients with atopic dermatitis are often sensitized to certain foods, the timing of solid food introduction or withholding of allergenic foods does not appear to alter the risk for atopic dermatitis.

Most studies of dietary modification of the maternal or infant diet do not show a protective effect, although recently published studies of hydrolyzed formula and probiotic supplementation suggest that these approaches could have a beneficial effect in preventing disease development in some high-risk infants who are not exclusively breast fed.

At present, however, there is insufficient evidence to recommend any specific dietary or other measures as being effective for the primary prevention of atopic dermatitis. Breastfeeding for the first 6 months of life is encouraged for its other benefits for the infant and mother (eg, bonding and passive immunity). There are no consistent findings to suggest that male or female sex affects atopic dermatitis risk, but being of black race does appear to increase risk.

A higher level of parental education is a risk factor for disease, but the effect of socioeconomic status is unclear. Previous studies found a higher risk of atopic dermatitis in higher socioeconomic groups, but more recent studies failed to confirm these findings.

Living in urban areas appears likely to increase the risk of atopic dermatitis , but studies attempting to identify causative environmental agents have not been conclusive. Daycare may influence the risk of atopic dermatitis development, but studies that offer better control for confounders are needed before additional conclusions can be made. The effect of exposure to pets is unclear, with conflicting data. Two recent studies have shown that cat but not dog ownership enhanced the effect of filaggrin mutations in promoting the development of atopic dermatitis. While patients with atopic dermatitis are often sensitized to house dust mites, there is not strong evidence to show that dust mite avoidance strategies prevent atopic dermatitis . The most recent systematic review regarding early life microbial exposures found evidence that exposures to endotoxin, farm animals, and dogs may protect against atopic dermatitis. The consumption of unpasteurized milk and acquired helminth infections may also be protective, but are not recommended measures because of their potential associated health risks. No definitive conclusions can be drawn regarding early antibiotic exposure and the risk of atopic dermatitis . Although studies are inconsistent, personal and second hand/household smoking status do not appear to significantly affect atopic dermatitis development; however, smoking is detrimental to those with asthma and has many other negative health risks.

EDUCATIONAL INTERVENTIONS

The education of patients and care givers is itself an important form of intervention. Because atopic dermatitis has a complex pathogenesis and involves multiple (and sometimes rotating) therapies, it inherently requires much teaching and support to achieve and maintain good response. Increased knowledge of disease mechanisms and course, the appropriate use of therapies, and the goals of management can improve treatment adherence and lessen fears and misconceptions.

Educational methods vary greatly in scope, intensity, frequency, setting, and personnel used. Disease-directed teaching can be on an individual or group basis. Formal, structured multidisciplinary educational programs (ie, training programs or ‘‘eczema schools’’) for children and adults have already been established in some countries.

Comparison between programs is difficult because the contentis heterogeneous and outcome measures vary greatly between studies. Because physician time during clinic visits is often limited, workshops and nurse-led educational sessions can be of benefit to patients, improving the knowledge and use of topical treatments. One systematic review found increased patient satisfaction as a result of longer consultation and similar health outcomes to doctor-led care. Other educational methods include parental education via standardized video instruction.

In addition, video-assisted approaches were less time consuming. Written action plans also assist in reinforcing teachings. These facilitate communication and networking between affected patients and families, although their effects on Atopic Dermatitis outcomes have not been formally tested. Psychological interventions have also been used to help with coping with Atopic Dermatitis, and include autogenic training, biofeedback, brief dynamic psychotherapy, cognitive behavioral therapy, habit reversal behavioral therapy, and a stress management program. Most of these adjunctive therapies are limited to case series that use different outcome measures that preclude comparison.

Section 5. MANAGEMENT AND TREATMENT WİTH SYSTEMIC AGENTS AND PHOTOTHERAPY

Despite its relapsing and remitting nature, the majority of patients with atopic dermatitis can achieve clinical improvement and disease control with nonpharmacologic interventions, conventional topical therapies (including corticosteroids and calcineurin inhibitors), and environmental and occupational modifications. (fig. nr. 9).

Fig. nr.9 (www.aard.or.kr)

Phototherapy is recommended as a treatment for both acute and chronic atopic dermatitis in children and adults, after failure of the measures mentioned above. Systemic immunomodulatory agents are indicated and recommended for the subset of adult and pediatric patients in whom optimized topical regimens using emollients, topical anti-inflammatory therapies, adjunctive methods, and/or phototherapy do not adequately control the signs and symptoms of disease, and contact dermatitis has been considered.

Phototherapy and systemic immunomodulating agents may also be used in patients whose medical, physical, and/or psychological states are greatly affected by their skin disease, which may include negative impact on work, school performance, or interpersonal relationships. Despite their frequent use in clinical practice, oral antihistamines and systemic antimicrobials appear to be of benefit only for specific circumstances (detailed below), based on the scientific data to date.

5.1 SYSTEMIC AGENTS

Systemic immunomodulating medications are a prevalent treatment option for the management of chronic and/or severe inflammatory diseases. Their use in dermatology is common place for blistering disorders, granulomatous diseases, and most frequently, psoriasis. As discussed earlier, these agents are indicated and recommended in atopic dermatitis care for the subset of adult and pediatric patients in whom optimized topical regimens and/or phototherapy do not adequately control the disease, or when quality of life is substantially impacted. There are few studies in the literature that compare different systemic therapies with one another in a randomized, controlled fashion.

Thus, it is difficult to determine the relative efficacy of the available options. Prevailing literature suggests that cyclosporine, methotrexate (MTX), mycophenolate mofetil (MMF), and azathioprine (AZA) are used the most and are more efficacious in treating atopic dermatitis, whereas other agents (leukotriene inhibitors, oral calcineurin inhibitors) have limited data. Biologic drugs are relatively new and the lack of available data prevents a recommendation for use in atopic dermatitis at this time. The management of atopic dermatitis with systemic corticosteroids, although used frequently and shown to temporarily suppress disease, should generally be avoided because of short- and long-term adverse effects and an overall unfavorable risk-benefit profile. Short courses of oral corticosteroids may lead to atopic flares.

CYCLOSPORINE

Cyclosporin A (CSA) was discovered in the 1970s as an effective immunosuppressant of T cells and interleukin-2 production. From its original use as a graft antirejection medication in transplant recipients, its expanded therapeutic benefits have been proven in several immune-mediated skin diseases, including graft-versus-host disease and psoriasis. The treatment of refractory Atopic Dermatitis with Cyclosporin A was first reported in 1991. Cyclosporin A is an effective off-label treatment option for patients with atopic dermatitis refractory to conventional topical treatment.

Efficacy

Cyclosporin A is efficacious in treating atopic dermatitis , with most patients noting a significant decrease in disease activity within 2 to 6 weeks of treatment initiation. For example, one study randomized 46 patients with severe Atopic Dermatitis to Cyclosporin A or placebo therapy. (18) Patients who received Cyclosporin A had both a decrease in surface area of involvement and in the degree of inflammation of the remaining dermatitis at the 6-week time mark. These patients had a mean decrease in total body severity assessment of 55%, compared with an increase of 4% in patients taking placebo. The mean score for extent of disease, measured by the rule-of-nines area assessment, decreased by 40% in patients taking cyclosporine, compared with an increase of 25% in those taking placebo. The drug was deemed moderately beneficial relative to placebo. (25)

Dosage and scheduling

The dosage of Cyclosporin A used for Atopic Dermatitis treatment varies greatly, ranging from 3 to 6 mg/kg/d, standardly 150 to 300 mg/d in adults. Reports suggest that higher initial doses result in more rapid control of the disease and involved body surface area while improving quality of life measures, such as pruritus and sleep disturbance. The initial and maintenance dose of Cyclosporin A prescribed should be based on multiple factors, including the patient’s disease severity and other medical morbidities. Although all formulations of Cyclosporin A are effective in Atopic Dermatitis, the microemulsion formulation demonstrated more rapid onset of action and greater initial efficacy relative to the conventional formulation in 1 double-blind, cross-over study. (16) (17)

Modified microemulsion formulation of Cyclosporin A is not bioequivalent to the nonmodified formulation (both are available in oral capsules and solution), and the medications should not be used interchangeably. The long-term effectiveness of Cyclosporin A for Atopic Dermatitis cannot be determined based on the current literature. Data on relapse after Cyclosporin A discontinuation are limited. Lower dose protocols for a longer duration of treatment (maximum duration discussed below), independent of body weight, may be effective. In general, once clearance or near-clearance is achieved and maintained, Cyclosporin A should be tapered or discontinued, with maintenance of remission via emollients, topical agents, and/or phototherapy. Oral Cyclosporin A should be administered in divided doses twice daily and taken at the same time every day for maximum benefit.

Adverse effects and monitoring

The side-effect profile of Cyclosporin A is well known and is similar in patients with Atopic Dermatitis as with other cutaneous disorders. Potential adverse effects include: infection, nephrotoxicity, hypertension, tremor, hypertrichosis, headache, gingival hyperplasia, and increased risk of skin cancer and lymphoma. Thus, patients receiving Cyclosporin A should be monitored for such potential consequences. These adverse effects may occur regardless of daily dosage used, but high-dose groups and low-dose groups have only been compared and measured over short periods of time (up to 12 weeks). Some studies showed higher serum creatinine levels in patients given higher doses initially, but this trended downward over time to match the low-dose counterparts. (16)

Caution is advised when using Cyclosporin A in patients on other systemic medications because of drug interactions. Consulting up-to-date product information and drug reference resources is suggested before prescribing this medication or when adding other medications in the course of treatment, to determine the safety profile for an individual patient. The US Food and Drug Administration (FDA) recommended time limit for consecutive use of Cyclosporin A for psoriasis is currently 1 year, although longer-term use has been documented for other dermatologic conditions. (20, 21 )

Pediatric considerations

Cyclosporin A is an effective treatment for atopic dermatitis in the pediatric population, similar to adults. Both continuous long-term (up to 12 months) and Mycophenolate intermittent short-term dosing schemes (3- or 6-month courses) are efficacious. Although continuous dosing is associated with better efficacy and longer sustained effects relative to intermittent use, dosing regimens should be determined on an individual basis. As with adult patients, the lowest effective dose to achieve the desired results should be given.

AZATHIOPRINE

Azathioprine is a purine analog that inhibits DNA production, thus preferentially affecting cells with high proliferation rates, such as B cells and T cells during inflammatory disease states. Although it is FDA approved for the treatment of rheumatoid arthritis and renal transplant rejection prophylaxis, it is also used off-label to treat other inflammatory cutaneous and systemic disorders, including atopic dermatitis. Azathioprine is recommended as a systemic agent for the treatment of refractory atopic dermatitis.

Efficacy

Azathioprine is efficacious in treating atopic dermatitis. Meggitt et al 44 compared the effectiveness of azathioprine with placebo in a parallel-group, double-blinded trial of moderately to severely affected patients with atopic dermatitis. After 12 weeks, the azathioprine -treated group reported a 37% improvement in their dermatitis, relative to 20% improvement with placebo (17% difference; 95% confidence interval 4.3-29), as measured by the Six Area, Six Sign Atopic Dermatitis (SASSAD) scoring system. Similarly, a 2002 publication by Berth – Jones and al (9) found a Six Area, Six Sign Atopic Dermatitis score reduction of 26% in azathioprine -treated patients relative to 3% reduction while treated with placebo in their double-blind, placebo-controlled study (P\.01). These data demonstrate that azathioprine improves both quality of life and signs and symptoms of disease when used in patients with Atopic Dermatitis as monotherapy.

Dosage and scheduling

As with other systemic medications, the dose range of azathioprine given to patients with Atopic Dermatitis is variable, with most studies choosing a dose range between 1 to 3 mg/kg/d. Whether this range is optimal for patients with Atopic Dermatitis is yet unknown based on the available data. Graduated dosing to maximize benefit while limiting side effects is preferred, as a considerable number of patients develop intolerable nausea and vomiting at higher doses and electively discontinue the medication. Dosing using thiopurine methyltransferase (TPMT) activity level may also be helpful (discussed below). A delayed effect may be noted, with some patients needing 12 weeks or greater of medication to achieve full clinical benefit. Once clearance or near-clearance is achieved and maintained, azathioprine should be tapered or discontinued, with maintenance of remission via emollients and topical agents. Concomitant phototherapy is not advised because of increased risk of DNA damage and possible photocarcinogenicity, particularly with UVA exposure. Azathioprine is currently available in the United States in tablet form only, although liquid formulations can be compounded. It may be given once daily. (23, 32 )

Adverse effects and monitoring

The side-effect profile of azathioprine is well known and similar for patients with Atopic Dermatitis as for other patients taking the medication for cutaneous indications. Nausea, vomiting and other gastrointestinal (GI) symptoms (bloating, anorexia, cramping) are common while on azathioprine , and may cause patient dissatisfaction and noncompliance. Other side effects that have been variably reported include: headache, hypersensitivity reactions, elevated liver enzymes, and leukopenia.

These potential side effects must be taken into consideration in individual patients, with a thorough history, physical examination, and laboratory monitoring performed as deemed appropriate before and during therapy. Although an increased risk of infection, lymphoma, and nonmelanoma skin cancer development has been noted on some patients treated with azathioprine for other conditions, these patient populations usually require polypharmacy for their disorders, confounding the true relevance to azathioprine use. There are no studies to date that signify such a risk for patients with Atopic Dermatitis using long-term therapy, although the available data are largely uncontrolled and use is generally limited to a few years. The metabolism of azathioprine is dependent on an individual’s thiopurine methyltransferase activity level, a principle enzyme in the thiopurine pathway. Genetic polymorphisms in thiopurine methyltransferase activity are linked to a patient’s susceptibility to azathioprine toxicity, such that the homozygous carrier state of low or absent enzyme capacity poses the greatest toxicity risk.

Thus, baseline thiopurine methyltransferase level testing is strongly recommended before azathioprine initiation, with avoidance of use in those with very low or absent enzyme activity. Although thiopurine methyltransferase enzyme activity will not alter the risk of gastrointestinal intolerance or hypersensitivity syndrome, greater thiopurine methyltransferase activity reduces the risk of myelotoxicity. Testing for thiopurine methyltransferase may also enhance efficacy by preventing underdosing in those patients who have high enzymatic function. It should be noted thiopurine methyltransferase is an inducible enzyme, such that levels have been reported to change over time. Regular monitoring of the patient’s blood cell count and liver enzymes is also essential while taking azathioprine, regardless of thiopurine methyltransferase status.

Pediatric considerations

There is literature to support the use of azathioprine to treat Atopic Dermatitis in the pediatric population. Use is generally recommended for those children whose dermatitis is recalcitrant, or when there is significant psychosocial impact on the patient and family unit. Insufficient data exist to recommend an optimal dose, duration of therapy, or to predict the relapse rate upon discontinuation. However, the most common dosage given is 2.5 mg/kg/d, with a higher treatment range maximum of 4 mg/kg/d relative to adult dosing (maximum 3 mg/kg/d). thiopurine methyltransferase levels should be measured in pediatric patients at baseline, with repeated testing considered in cases of nonresponse or change in response. Evidence shows those children with higher thiopurine methyltransferase levels may respond less well to treatment but may have a greater risk of hepatotoxicity. Similarly, children with lower thiopurine methyltransferase levels may have improved clinical response on lower drug doses but may have an increased risk of myelosuppression.

METHOTREXATE

Methotrexate is an antifolate metabolite and blocks the synthesis of DNA, RNA, and purines. It is also thought to negatively affect T-cell function. It is currently FDA approved for several oncologic and inflammatory disorders, including dermatologic conditions such as advanced mycosis fungoides and psoriasis. Its many off-label uses include atopic dermatitis. Methotrexate is recommended as a systemic agent for the treatment of refractory atopic dermatitis.

Efficacy

The true efficacy of Methotrexate in the treatment of refractory atopic dermatitis is unknown, as there is inconsistency between studies regarding methods, dosing, and duration of therapy. One open-label, dose-ranging, prospective trial of Methotrexate for the treatment of moderate to severe atopic dermatitis in adults demonstrated a disease activity reduction of 52% from baseline via Six Area, Six Sign atopic dermatitis scoring (confidence interval 45%-60%).

The medication was given for 24 weeks, and patients were followed up for an additional 12 weeks after Methotrexate discontinuation. Methotrexate was well tolerated, and patients noted improvement in sleep and decreased pruritus. Mean disease activity remained at 34% below baseline at the end of the follow-up period. Another single blind – trial by Schram et al.(35) Another single-blind trial randomized individuals to take either Methotrexate (10-22.5 mg/wk) or azathioprine (1.5-2.5 mg/kg/d) over a 24-week period. At 12 weeks of therapy, both the Methotrexate group and the azathioprine group had statistically significant clinical improvement (severity scoring 42% and 39%, respectively, P = .52). No adverse events occurred in the study, and the medications were deemed equally efficacious in the treatment of severe atopic dermatitis. Lyakhovitsky et al. (28) There were successfully administered low-dose Methotrexate (10-25 mg per week) to 20 adult patients with Atopic Dermatitis, with improvements in both the SCORing Atopic Dermatitis (SCORAD) and the Dermatology Life Quality Index measurements. Methotrexate appears safe, well tolerated, and effective for controlling severe atopic dermatitis. Additional randomized, controlled studies are warranted to determine the optimal dose range and magnitude of response.

Dosage and scheduling

Methotrexate is readily available in solution (for intramuscular or subcutaneous injection) and oral tablet form. Patients typically prefer to avoid injection of the medication but bioavailability is better in this form; fortunately, 0.1 mL of the 25 mg/mL injection solution is equivalent to a 2.5 mg oral tablet, making conversion between the 2 formulations straightforward when necessary. Judicious measuring is strongly suggested to ensure that the appropriate amount of medication is given to the patient. Methotrexate is usually given as a single weekly dose.

The dose range for Methotrexate in patients with atopic dermatitis is extrapolated from its use in psoriasis, and is between 7.5 and 25 mg weekly.42 Divided dosing, given every 12 hours for 3 doses, is an alternative method for dosing methotrexate. The provider needs to adjust the dose appropriately if this schedule is to be used. As with other systemic medications, dosing should be tailored to the individual patient to achieve and maintain adequate disease control. The average time to maximum effect averages 10 weeks, with minimal to no further efficacy after 12 to 16 weeks with further dose escalation. Once clearance or near-clearance is achieved and maintained, Methotrexate should be tapered or discontinued, with maintenance of remission with emollients and topical agents and/or phototherapy. Nonresponding patients on a sufficient dose ( $ 15 mg/wk) of Methotrexate may consider discontinuing therapy after a 12- to 16-week trial.

Adverse effects and monitoring

There are very limited data that address the safety of methotrexate use in patients with Atopic Dermatitis specifically. The side-effect profile of methotrexate is well known, however, and thought to be similar in patients with atopic dermatitis as with others taking the medication for other cutaneous indications. Nausea and other gastrointestinal symptoms may preclude oral administration. Such symptoms usually abate when given parenterally. Severe adverse effects, including bone-marrow suppression and pulmonary fibrosis, can occur. Literature suggests bone-marrow suppression is often reversible upon methotrexate dose reduction or discontinuation. ( 28,31)

Risk for skin cancer and lymphoma has been reported, although some cases of lymphoma arising during low-dose treatment have regressed on drug discontinuation. Pulmonary fibrosis may occur with short- or long-term use of the medication, such that patients with pulmonary diseases (eg, asthma, chronic cough) may not be candidates. If methotrexate is considered in such patients, they should undergo pulmonary function studies in consultation with a pulmonologist before drug initiation. Although the cumulative dose of methotrexate given to an individual should be documented in the medical record, its relevance to monitoring for hepatic toxicity (including potential liver biopsy) in patients with atopic dermatitis is unclear and cannot be directly postulated from its relevance in patients with psoriasis.

In contrast to patients with atopic dermatitis , patients with psoriasis typically have more comorbidities, including obesity, and may practice polypharmacy to a greater extent than their atopic dermatitis counterparts. A 2009 Consensus Conference on Methotrexate use in patients with psoriasis suggests patients being considered for Methotrexate therapy be divided into 2 groups, those without underlying risk factors for hepatotoxicity, and those with risk factors. This group of experts advised liver biopsy should be considered in patients at low risk after a cumulative dose of 3.5 to 4 g. The aminoterminal peptide of procollagen 3 is used in Europe as a test for hepatic fibrosis, reducing the need for frequent liver biopsies. Folic acid supplementation is recommended for all patients with atopic dermatitis taking Methotrexate to reduce the likelihood of hematologic and gastrointestinal toxicity. Data do not support 1 specific regimen.

In general, expert consensus suggests 1 mg/d, with a possible escalation up to 5 mg/d, depending on a patient’s unique medical needs. Patients may skip folate supplementation on the day of Methotrexate intake.

Pediatric considerations

At the time of literature review, there were no prospective data on Methotrexate use in children for the treatment of atopic dermatitis . Since then, a 12-week study showed a slower onset of effect compared with low-dose cyclosporine, but increased time before relapse on discontinuation. (17) Multiple studies regarding its use in pediatric patients with psoriasis show methotrexate to be a safe, effective, and well-tolerated medication. (18) The side-effect profile for children on methotrexate commonly includes gastrointestinal symptoms such as stomatitis, nausea, and vomiting, but the same potential risks exist in children as they do in adults. Most adverse effects of methotrexate are reversible upon dose reduction, route modification, or altered dosing schedule. As with adult patients, the lowest effective dose to achieve the desired results should be given.

MYCOPHENOLATE MOFETIL

Mycophenolate mofetil is an immunosuppressant that blocks the purine biosynthesis pathway of cells via the inhibition of inosine monophosphate dehydrogenase. Mycophenolate mofetil selectively affects B cells and T cells, as other cells have purine scavenger mechanisms that compensate for this blockage, giving this medication a unique mechanism of action to treat inflammatory disorders. Although it is FDA approved solely for solid organ transplant rejection prophylaxis, it is recognized as an off-label systemic therapy option in patients with atopic dermatitis and should be considered as an alternative, variably effective therapy for refractory cases.

Efficacy

Aggregate data on mycophenolate mofetil use to treat atopic dermatitis are highly variable but overall suggest that mycophenolate mofetil is an alternative therapy for refractory atopic dermatitis. Efficacy is inconsistent. Haeck et al. (18) treated 55 adult patients with severe atopic dermatitis with CSA – cyclosporin A for 6 weeks, and then subsequently switched 24 of these patients from cyclosporin A to mycophenolate mofetil for 30 weeks. Both cyclosporin A – and mycophenolate mofetil -treated patients were monitored during this time period, and for 12 weeks after medication discontinuation. During the initial 10 weeks of mycophenolate mofetil use, the SCORAD measurements were better for the patients who remained on cyclosporin A, and 7 patients in the mycophenolate mofetil cohort required a limited oral corticosteroid course.

Thereafter, efficacy was equal in both treatment groups, and side effects were comparable, mild, and temporary. This suggests the initial response to mycophenolate mofetil was delayed, with improvement as drug levels increased. Clinical remission lasted longer for patients treated with mycophenolate mofetil relative to those treated with cyclosporin A upon medication discontinuation. In a retrospective chart analysis, there were reviewed 20 adult patients with moderate to severe atopic dermatitis who were treated with mycophenolate mofetil. Seventeen patients (85%) reported disease improvement within the first month of administration. Ten patients (50%) achieved disease clearance and were able to discontinue the medication.

Dosage and scheduling

Insufficient data exist to make recommendations regarding the optimal mycophenolate mofetil dosing or duration of therapy for patients with atopic dermatitis. Dosing ranges from 0.5 to 3 g/d.57 The relapse rate after withdrawal is also unknown. Mycophenolate mofetil is available in oral suspension, capsules, and tablets, and is given twice daily.

Adverse effects and monitoring

Mycophenolate mofetil is generally well tolerated, with nausea, vomiting, and abdominal cramping being the most common side effects. These gastrointesinal symptoms may improve if the patient takes the enteric-coated formulation. The development of gastrointestinal symptoms, along with headaches and fatigue, are not dose dependent and do not tend to negatively impact compliance. Rarely, hematologic (anemia, leukopenia, thrombocytopenia) and genitourinary (urgency, frequency, dysuria) symptoms have been reported. There is a theoretical risk of increased susceptibility to viral and bacterial infections while taking mycophenolate mofetil , as is clearly observed in patients with organ transplantation. The applicability of this risk to patients with atopic dermatitis is unknown. Similar to other immunosuppressive drugs, cutaneous malignancy and lymphoma are potential risks, although difficult to delineate for mycophenolate mofetil given many reports involve multidrug therapy.

Pediatric considerations

Mycophenolate mofetil should be considered a relatively safe alternative systemic therapy for pediatric patients with refractory atopic dermatitis. Patients aged 2 years and older have been treated with mycophenolate mofetil as monotherapy for severe Atopic Dermatitis with benefit and without hematologic, hepatic, or infectious sequelae. (23) The suggested dosing in children of 600 to 1200 mg/m2 is based on body surface area secondary to increased hepatic metabolism in this patient population. This equates to 40 to 50 mg/kg/d in young children and 30 to 40 mg/kg/d in adolescents. No long-term efficacy or safety profiles exist at this time, although use in children for up to 24 consecutive months has been reported for atopic dermatitis without deleterious effects.

INTERFERON GAMMA

Interferon gamma (IFN-G) is a cytokine with a principle role in the innate and adaptive immune system cascade, enhancing natural killer cell production and increasing macrophage oxidation. It is classified pharmacologically as a biologic response modifier, and is FDA approved for chronic granulomatous disease and malignant osteopetrosis. Interferon gamma is moderately and variably effective for severe atopic dermatitis in clinical trials, but may be considered as an alternative therapy for refractory atopic dermatitis in adults and children who have not responded to, or have contraindications to, other systemic therapies or phototherapy.

Efficacy

There are a few studies on interferon gamma that demonstrate its efficacy in the treatment of Atopic Dermatitis. One randomized, placebo-controlled, double-blinded trial published in 1993 compared 38 patients with atopic dermatitis receiving daily subcutaneous injections of interferon gamma with 40 patients receiving placebo injections over 12 weeks. (22) Statistically significant improvements were found in patients treated with interferon gamma versus placebo with regards to erythema (P = .035), excoriations and erosions (P = .045), and conjunctivitis (P \.002). A study treated 41 patients with interferon gamma via subcutaneous injection 3 times weekly for 12 weeks, versus 10 patients who received placebo injections. These patients treated with interferon gamma also had notable improvement in clinical disease activity compared with placebo (P \.05).

Dosage and scheduling

There is no recommended optimal dose of interferon gamma for the treatment of Atopic Dermatitis. Dosages for FDA-approved indications are based on body surface area, for both adults and children, and are usually administered 3 times weekly. Interferon gamma is available solely in solution form for subcutaneous injection.

Adverse effects

Constitutional side effects (fatigue, fever, nausea, vomiting, myalgia) have been documented with its use.

Monitoring

Recommended monitoring for those taking interferon gamma for chronic granulomatous disease or osteopetrosis includes pretreatment blood chemistries (complete blood cell count with differential, renal function serologies, hepatic function serologies) and urinalysis, repeated every 3 months during treatment. Similar monitoring should be considered for patients with atopic dermatitis receiving interferon gamma.

Pediatric considerations

There are no specific recommendations unique to the pediatric population.

SYSTEMIC STEROIDS

Corticosteroids are natural products of the adrenal gland, used to regulate the immune system and stress response in human beings. Although systemic steroids are used by some providers to treat atopic dermatitis because they rapidly improve clinical symptoms, caution is warranted to ensure their administration is time-limited and judicious. Rebound flare and increased disease severity is a commonly observed phenomenon upon discontinuation of systemic steroids. Thus, although temporarily effective, systemic steroids (oral or parenteral) should generally be avoided in adults and children with atopic dermatitis because the potential short- and long-term adverse effects, described below, largely outweigh the benefits. Systemic steroids may be considered for shortterm use in individual cases whereas other systemic or phototherapy regimens are being initiated and/or optimized.

Efficacy

The efficacy of systemic steroids to decrease clinical symptoms of atopic dermatitis is commonly accepted and frequently observed, but there are few reports in the literature to support it. A double-blind, placebo-controlled study by Schmitt et al (34) compared patients on prednisolone with those taking CSA or placebo. All patients remained on primary therapy, such as topical steroids and emollients. In this trial, only 1 patient of 27 taking prednisolone achieved a durable remission, defined as a greater than 75% improvement in baseline SCORAD measurement after 2 weeks of oral steroid therapy and a 4-week follow-up time period.

This study was also prematurely discontinued because of significant rebound flaring in the prednisolone group. Systemic steroids are discouraged for continuous or chronic intermittent use in atopic dermatitis but may be considered for acute usage as a transitional therapy in severe, rapidly progressive, or debilitating cases in adults or children, while nonsteroidal immunomodulatory agents or phototherapy is being initiated. Although immediate improvement of atopic dermatitis may be noted by patients and providers, other systemic medications with a more favorable side-effect profile should be considered in lieu of chronic systemic steroids.

Dosage and scheduling

The most commonly used formulations of systemic steroids in patients with atopic dermatitis are prednisone, prednisolone, and triamcinolone acetonide. Prednisone and prednisolone are available as a tablet or oral solution for enteral administration, whereas triamcinolone acetonide is available as a suspension for intramuscular injection. Dosing is based on body weight, but as a general principle most providers using a dosage range of 0.5 to 1.0 mg/kg. A taper is indicated to decrease the risk of adrenal suppression. Regardless of the taper schedule, flare of the dermatitis upon steroid discontinuation may be expected.

Adverse effects

The short- and long-term side effects of systemic steroids are well documented. The likelihood of undesired side effects in patients treated for atopic dermatitis is unknown but is thought to be similar to other patients taking the medication. These adverse effects include: hypertension, glucose intolerance, gastritis, weight gain, decreased bone density, adrenal suppression, and emotional lability. Pediatric patients experience decreased linear growth while on the medication. Patients on long-term protocols may need antibiotic prophylaxis for opportunistic infections, calcium and vitamin D supplementation, and immunizations according to a booster (‘‘catch-up’’) schedule. Patients with atopic dermatitis who experience a rebound flare upon steroid discontinuation may become frustrated when the disease is difficult to manage. When systemic steroids are given for an atopic dermatitis exacerbation or for another indication in a patient with atopic dermatitis, a taper schedule is required.

Monitoring

Patients on long-term systemic steroids may require blood pressure monitoring, ophthalmologic examination, hypothalamic-pituitary-adrenal axis suppression testing, bone-density evaluation (adults), and growth-velocity measurement (children).

Pediatric considerations

Children and adolescents given systemic steroids can experience decreased linear growth while on the medication. All potential adverse effects of systemic steroids in adults may also be observed in children. Systemic steroids are not recommended for children with atopic dermatitis unless they are required to manage comorbid conditions (eg, asthma exacerbations), or are given as part of a short-term transition protocol to nonsteroidal systemic immunomodulatory agents. Children on long-term systemic steroids may require booster immunization protocols because of a robust vaccination schedule relative to adults.

OMALIZUMAB

Limited data exist to determine the efficacy of omalizumab in the treatment of Atopic Dermatitis. One double-blind, placebo-controlled study did not show clinical improvement in Atopic Dermatitis with its use despite reducing free serum IgE levels.(23, 24)

ORAL CALCINEURIN INHIBITORS

Tacrolimus and pimecrolimus are available in topical formulations for the treatment of Atopic Dermatitis with proven efficacy. At this time, tacrolimus is available in the United States in oral capsule and intravenous solution formulations for transplant rejection prophylaxis. Pimecrolimus is currently available in topical form only. Insufficient data exist to recommend the use of systemic calcineurin inhibitors in the management of atopic dermatitis.

OTHER SYSTEMIC THERAPIES

There are insufficient data at this time to make a recommendation for the use of tumor necrosis factor-alpha inhibitors, intravenous immunoglobulin, theophylline, papaverine, or thymopentin in the management of atopic dermatitis.

5.2 ANTIMICROBIALS

Because of an impaired skin barrier, patients with atopic dermatitis are predisposed to secondary bacterial and viral infection, most commonly with Staphylococcus aureus and Herpes Simplex Virus (HSV). Although Staphylococuus aureus can be cultured from the skin of an estimated 5% of the population without dermatitis, this microbe is isolated from greater than 90% of adult patients with atopic dermatitis upon skin culture. The clinical relevance of bacterial overgrowth is patient dependent, as most patients with Atopic Dermatitis do not show increased morbidity from the Staphylococcus colonization. This can provide a diagnostic challenge to the provider, as the clinical appearance of active localized infection and active atopic dermatitis can be difficult to distinguish. Certain clinical signs, such as crusting, may be present in either localized infection or active dermatitis. The presence of purulent exudate and pustules on skin examination may suggest a diagnosis of secondary bacterial infection over inflammation from dermatitis.

Less frequently, the compromised skin barrier allows infection with Herpes Simplex Virus, referred to as ‘‘eczema herpeticum,’’ a dermatologic urgency because of its increased patient morbidity. Although the use of systemic antibiotics in the treatment of noninfected atopic dermatitis is not recommended, they can be recommended for use in patients with clinical evidence of bacterial infection. Antibiotics may be administered in addition to standard, suitable treatment for atopic dermatitis, including the concurrent application of topical steroids. Similarly, systemic antiviral agents should be used in the treatment of eczema herpeticum.

Efficacy

There are numerous studies addressing the efficacy of systemic antibiotics to decrease S aureus colonization rates in patients with atopic dermatitis; however, data on the impact of this treatment on atopic dermatitis disease outcomes are limited. A Cochrane analysis from 2010 was able to use 3 of the studies (involving 103 total patients). This review concluded that the use of systemic antistaphylococcal medications is warranted in overtly infected patients with atopic dermatitis only and the use of topical or systemic antibiotics as a therapy for uninfected or colonized dermatitic skin is controversial. The colony count is reduced in patients with Atopic Dermatitis treated with topical or systemic antibiotics, but counts return to previous levels within days to weeks of medication discontinuation.

Furthermore, antigens from Staphylococcus may persist for prolonged periods of time after eradication, and incomplete elimination may increase bacterial resistance to previously susceptible treatments. Thus, the judicious use of antibiotics, reserved for frank bacterial infections, is suggested. Skin culture with bacterial antibiotic susceptibility profiling may be appropriate for recurrent or nonresponsive infections. The treatment of eczema herpeticum with systemic antiviral medications has significantly altered the course of this once potentially fatal condition. Before the use of acyclovir, there was a 10% to 50% mortality for patients with untreated eczema herpeticum. Aronson et al (4) demonstrate in a retrospective chart review of 1331 children from 42 tertiary care pediatric hospitals that no deaths occurred from eczema herpeticum when patients received systemic antiviral therapy. Timing of acyclovir initiation was also directly related to length of hospital course, with earlier medication initiation decreasing length of stay, further supporting acyclovir’s efficacy in eczema herpeticum treatment.

Dosage and scheduling

There are several antibiotics that have antimicrobial properties against S aureus, with various mechanisms of action. Similarly, there are now multiple systemic antiviral medications for the treatment of Herpes Simplex Virus. Dosage and scheduling should be based on each individual medication’s drug profile.

Adverse effects and monitoring

Adverse effects from systemic antimicrobials, and the need for laboratory monitoring, are dependent on the medication chosen and the patient’s medical history. Consulting current product information and drug reference material is suggested before prescribing a particular medication to determine its safety profile, indications, and contraindications for an individual patient.

Pediatric considerations

There are no specific recommendations unique to the pediatric population.

5.3 ORAL ANTIHISTAMINES

Histamine is a protein secreted by mast cells and basophils as a component of the immune system response to foreign antigen presentation. The primary function of histamine is to stimulate local blood vessels and nerves, producing vasodilatation and pruritus. Patients with atopic dermatitis often report itch as burdensome, affecting their quality of life.

Secondary scratching not only intensifies pruritus (the ‘‘itchscratch cycle’’) but also further compromises the skin barrier. Oral antihistamines have been used in the management of pruritus in patients with atopic dermatitis in an effort to improve their quality of life by inhibiting these vascular and neurologic effects, but there is insufficient evidence to recommend the general use of antihistamines as part of the treatment of atopic dermatitis. Short-term, intermittent use of sedating antihistamines may be beneficial in the setting of sleep loss secondary to itch, but should not be substituted for management of atopic dermatitis with topical therapies

Efficacy

There are numerous randomized, controlled trials that have examined whether systemic antihistamines benefit atopic dermatitis as a disease process, and whether their effects specifically benefit patients with atopic dermatitis via itch relief. Both sedating and nonsedating medications have been studied. The evidence is mixed and favors no benefit, with many patients reporting as much improvement with placebo.It has been reviewed 16 randomized, controlled trials of various sizes and concluded that nonsedating histamines are ineffectual in Atopic Dermatitis management, whereas sedating forms may improve sleep quality. In the Early Treatment of the Atopic Child trial, infants 12 to 24 months of age were randomized to receive cetirizine or placebo for 18 months. Although cetirizine-treated patients had less urticaria during this time period, there was no statistically significant improvement in overall atopic dermatitis control. Similarly, a dose-ranging study of 178 adults demonstrated a 4-fold dose of cetirizine (40 mg daily) was necessary to significantly improve erythema, lichenification, body surface area involvement, and pruritus in their cohort. Doubling the recommended dose (20 mg daily) improved pruritus only. These results are attributed to a sedating effect of cetirizine when given in a dose higher than usually recommended.

Dosage and scheduling

Oral antihistamines are available both over-thecounter and by prescription, depending on which medication is selected. Dosage and scheduling should be based on each individual medication’s drug profile.

Adverse effects and monitoring

Adverse effects from systemic antihistamines are known and vary by the medication chosen and the patient’s medical history. Common side effects include undesired sedation and anticholinergic symptoms (dry mouth, blurred vision, tachycardia). No laboratory monitoring is required. If antihistamine toxicity is suspected, an electrocardiogram should be obtained to assess for a dysrhythmia. Consulting current product information and drug reference material is suggested before prescribing a particular medication to determine its safety profile for an individual patient.

Pediatric consideration: The use of sedating antihistamines in school-age children may negatively affect school performance, warranting attention to dosage and scheduling.

5.4 PHOTOTHERAPY

The use of light waves as a medical therapy began in the 1890s. The most relevant use of phototherapy in dermatology today is in the treatment of refractory or extensive psoriasis, first reported in 1925, with use of broadband (BB) ultraviolet (UV) B in combination with crude coal tar. Decades later, there were noticed patients with refractory atopic dermatitis improved in sunny climates, and thus attempted to treat these patients with oral psoralen and UV light, with success.

Fig. nr. 10 www.camberwellskin.com.au

Efficacy

Numerous studies document the efficacy of phototherapy for atopic dermatitis. Multiple forms of light therapy are beneficial for disease and symptom control, including: natural sunlight, narrowband (NB) UVB, BB-UVB, UVA, topical and systemic psoralen plus UVA (PUVA), UVA and UVB (UVAB).

Dosage and scheduling

Treatment protocols and parameters for the use of phototherapy in patients with Atopic Dermatitis are numerous, fluid, and heterogenous. Many providers, because of familiarity and ease of use, initiate therapy based on the phototherapy dosing protocols outlined in the AAD psoriasis. In general, patients are dosed according to their minimal erythema dose and/or Fitzpatrick skin type ( describes the most commonly used scheme to classify a person’s skin type by their response to sun exposure in terms of the degree of burning and tanning). Just as with other medical treatments, phototherapy protocols and their adjustments should be structured and reviewed by a medical provider knowledgeable in phototherapy techniques.

Dosing protocols differ for BB-UVB and NB-UVB ( similar to UVA irradiation, UVB radiation modulates and suppresses the immune system via T-cell apoptosis, decreases antigen presentation, and alteration of inflammtory mediators and cytokines. and are not interchangeable, and phototherapy equipment varies between manufacturers. Many pertinent variables will determine which light modality is chosen for a particular patient, including local availability and cost. Providers should also be diligent about the key components of the patient’s history and physical examination of relevance to phototherapy, including skin cancer history and the use of prescription and over-the-counter topical and oral products that may be photosensitizing.

Phototherapy can be administered on a scheduled but intermittent basis over time, or more continuously as maintenance therapy, for patients with refractory or chronic disease. Phototherapy can be used as monotherapy or in combination with emollients and topical steroids. The use of phototherapy with topical calcineurin inhibitors is cautioned, as the manufacturers suggest limiting exposure to natural and artificial light sources while using these topical medications. The use of light therapy may decrease the need for topical steroid and topical immunomodulator use. Risks and benefits, and pragmatic concerns (eg, cost, availability, patient compliance) should be considered when formulating the optimal treatment course for the patient.

Adverse effects

The true incidence of adverse events with provider-monitored phototherapy is unknown, but considered to be low. Available studies report minimal noncompliance rates secondary to side effects. Moreover, the majority of publications on phototherapy side effects address treatment of patients with psoriasis. How this relates to outcomes for patients with Atopic Dermatitis is unclear. Nonetheless, caution and due diligence are warranted as with any other medical therapy given to patients.

Different forms of phototherapy have distinct risk profiles that the clinician must take into account. Several common adverse effects include: actinic damage, local erythema and tenderness, pruritus, burning and stinging. Less common consequences of light therapy include: nonmelanoma skin cancer, melanoma (particularly with the use of PUVA), lentigines, photosensitive eruptions (especially polymorphous light eruption), folliculitis, photoonycholysis, herpes simplex virus (HSV) reactivation, and facial hypertrichosis. Cataract formation is a recognized side effect specific to UVA therapy, whereas the addition of oral psoralen to UVA treatment frequently causes patients to have headaches, nausea, and vomiting, and rarely hepatotoxicity. Oral psoralen also increases a patient’s photosensitivity, both cutaneous and ocular, for several hours after ingestion.

Pediatric considerations

Several studies document the safe and effective use of both UVA and UVB phototherapy in children and adolescents. Additional psychosocial factors must be anticipated and addressed to successfully treat younger patients, as lamps and machines can appear intimidating, and caregivers often have many questions and concerns. There are no known studies that report the long-term consequences of phototherapy use in children with Atopic Dermatitis. An increased risk of nonmelanoma skin cancer has been reported in children receiving PUVA treatment for psoriasis. Centered on 311 to 313 nm, NB-UVB is safe and effective for a number of photoresponsive dermatoses in children and is often considered as a first-line agent because of its ease of administration and safety profile relative to PUVA. Thus, phototherapy as a treatment for children with Atopic Dermatitis unresponsive to multimodal topical measures is appropriate. The wavelength selection and treatment course should be individualized.

Home phototherapy

The greatest barrier to more widespread use of phototherapy is frequent travel to a provider of this therapeutic modality. Home phototherapy would, no doubt, make this an excellent alternative before systemic treatments (fig. nr.10 ). However, there are no studies to date that document the efficacy or safety of home light therapy for patients with Atopic Dermatitis, or that contrast its use to in-office phototherapy.

Fig. nr.11 UVB 311nm Phototherapy – Psoriasis, Vitiligo, Eczema, Atopic Dermatitis Treatment – www.aliexpress.com

Home UVB treatment is not uncommonly used in the treatment of psoriasis. The PLUTO study (home versus outpatient ultraviolet B phototherapy for mild to severe psoriasis: pragmatic multicentre randomised controlled non-inferiority trial) by Koek et al(26) (26) demonstrated that patients with psoriasis treated with home NB-UVB phototherapy units experienced decreased burden of treatment and increased satisfaction versus in-office NB-UVB treatment, whereas Psoriasis Area and Severity Index score reduction, cumulative doses, and incidence of short-term side effects (up to 46 irradiations) were not significantly different. Although this study does not generalize to patients with Atopic Dermatitis , similar results might be expected. Therefore, home phototherapy under the direction of a physician may be considered for patients who are unable to receive phototherapy in an office setting.

Lasers and extracorporeal photochemotherapy

The successful use of UV light for Atopic Dermatitis has led to the investigation of laser light technology as another possible treatment. Various laser modalities, including excimer, diode, and pulsed dye lasers, have been tested in patients with atopic dermatitis, with some improvement in symptoms such as pruritus and quality of life. However, given a very limited number and quality of reports, lasers are not recommended for the treatment of Atopic Dermatitis at this time.

Extracorporeal photochemotherapy has been used in patients with generalized and erythrodermic Atopic Dermatitis to attempt to control disease severity and symptomatology. Response rates differ among patients, ranging from complete remission to no response. Given this lack of consistent improvement, extracorporeal photochemotherapy is not recommended for the routine treatment of Atopic Dermatitis.

Table 1. Treatment options for mild/moderate/severe atopic dermatitis

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Section 6. Management and treatment of atopic dermatitis with topical therapies

Topical agents are the mainstay of atopic dermatitis therapy. Even in more severe cases needing systemic or phototherapy, they are often used in conjunction with these modalities. Although discussed in separate subsections, topical agents from several classes are frequently used in combination, in part because they address different aspects of atopic dermatitis pathogenesis. Each class of treatment is discussed in regards to its mode of action and main use in therapy, and where possible, suggestions on dosing and monitoring are given based on available evidence.

NONPHARMACOLOGIC INTERVENTIONS

Moisturizers Xerosis is one of the cardinal clinical features of atopic dermatitis and results from a dysfunctional epidermal barrier. Topical moisturizers are used to combat xerosis and transepidermal water loss, with traditional agents containing varying amounts of emollient, occlusive, and/or humectant ingredients. Although they often include water as well, this only delivers a transient effect, whereas the other components provide the main benefits. Emollients (eg, glycol and glyceryl stearate, soy sterols) lubricate and soften the skin, occlusive agents (eg, petrolatum, dimethicone, mineral oil) form a layer to retard evaporation of water, whereas humectants (eg, glycerol, lactic acid, urea) attract and hold water.

The application of moisturizers increases hydration of the skin, as measured subjectively by patients and objectively by assessment of capacitance or conductance and with microscopy. In addition, a number of clinical trials have shown that they lessen symptoms and signs of atopic dermatitis, including pruritus, erythema, fissuring, and lichenification. Thus, moisturizers can themselves give some reduction in inflammation and atopic dermatitis severity. Furthermore, their use decreases the amount of prescription antiinflammatory treatments required for disease control.

Moisturizers can be the main primary treatment for mild disease and should be part of the regimen for moderate and severe disease. They are also an important component of maintenance treatment and prevention of flares. Moisturizers are therefore a cornerstone of atopic dermatitis therapy and should be included in management plans.

It is generally thought that liberal and frequent reapplication is necessary such that xerosis is minimal. Traditional moisturizers are formulated into a variety of delivery systems, including creams, ointments, oils, gels, and lotions. Although most ointments have the advantage of not containing preservatives, which may cause stinging when applied to inflamed skin, they may be too greasy for some patients with atopic dermatitis. Lotions have a higher water content that can evaporate and may be less ideal in those with significant xerosis.

Prescription emollient devices (PEDs) are a newer class of topical agents designed to target specific defects in skin barrier function observed in atopic dermatitis. They include preparations having distinct ratios of lipids that mimic endogenous compositions and creams containing palmitoylethanolamide, glycyrrhetinic acid, or other hydrolipids. They are generally recommended for 2 or 3 times daily use depending on the specific agent.

There are now several moisturizers containing ceramides and/or filaggrin breakdown products that are available over the counter, though the compositions are not necessarily equivalent to those of the prescription emollient devices. Head-to-head trials between specific moisturizing products are few in number, and those performed to date have not demonstrated one to be superior to others, including the prescription emollient devices.

Therefore, the choice of moisturizing agent is highly dependent on individual preference. The ideal agent should be safe, effective, inexpensive, and free of additives, fragrances, perfumes, and other potentially sensitizing agents. But regardless of the particular product used, moisturizing to address the defective barrier is an important therapeutic concept given our current understanding of atopic dermatitis pathogenesis. Trials are also underway to test if skin barrier protection and moisturizer use from birth reduces the likelihood of development of atopic dermatitis in genetically predisposed infants.

Bathing practices, including additives

Bathing can have differing effects on the skin depending on the manner in which it is carried out. Bathing with water can hydrate the skin and remove scale, crust, irritants, and allergens, which can be helpful for patients with atopic dermatitis. However, if the water is left to evaporate from the skin, greater transepidermal water loss occurs.

Therefore, application of moisturizers soon after bathing is necessary to maintain good hydration status. There are few objective data from which to determine best bathing practices, and most recommendations stem from expert consensus and personal experience.

There is no clear frequency or duration of bathing that is optimal for those with atopic dermatitis. However, it is generally recommended that up to once-daily bathing be performed to remove serous crust, as long as moisturizers follow as above; the duration should be limited to short periods of time (eg, 5-10 minutes) with use of warm water. If there are areas of significantly inflamed skin, soaking in plain water for 20 minutes followed by the immediate application of pharmacologic anti-inflammatory therapies (eg, topical corticosteroids [TCS]) to these sites, without toweling dry, is a helpful treatment measure. This ‘‘soak and smear’’ technique can improve response in cases where the topical antiinflammatory alone is inadequate.

Limited use of nonsoap cleansers that are neutral to low pH, hypoallergenic, and fragrance free is recommended. Soaps consist of surfactants that interact with stratum corneum proteins and lipids, but in a manner that causes damage, dry skin, and irritation. Most soaps are alkaline in pH, whereas the skin’s normal pH is 4 to 5.5. Instead, nonsoapbased surfactants and synthetic detergents (syndets) are often recommended for better tolerance, although this is based on only a few supportive clinical studies.

With the exception of bleach, which is discussed in detail below, data are limited on the addition of oils, emollients, and other related additives to bath water and their benefits for atopic dermatitis. The quantity of emollient deposited on the skin via a bath additive is likely to be lower than that from direct application. No published RCTs have tested the clinical benefit of combining bath emollients with directly applied emollients after bathing. Thus, at this time, the routine use of bath additives cannot be recommended. Use of acidic spring water for bathing (balneotherapy) also has limited supporting evidence.

The use of water-softening devices has also not been shown to have benefits over the use of normal water. Wet-wrap therapy (WWT) is one method to quickly reduce atopic dermatitis severity, and is often used in the setting of significant flares and/or recalcitrant disease. It may be performed on an ambulatory or inpatient basis. Most use a technique of a topical agent that is covered by a wetted first layer of tubular bandages, gauze, or a cotton suit, followed by a dry second/outside layer. For more generalized disease, 2 layers of nonirritating clothing can be similarly prepared. Wet-wrap therapy appears to help via occluding the topical agent for increased penetration, decreasing water loss, and providing a physical barrier against scratching. The wrap can be worn from several hours to 24 hours at a time, depending on patient tolerance. Most suggest several days of use, although a few studies continued Wet-wrap therapy for up to 2 weeks. In 2 comparative trials, the application of topical corticosteroids with wet wraps was more efficacious than using only moisturizers with the wraps.

Care should be taken, however, when mid- to higher- potency corticosteroids are applied under the wraps, as absorption is increased and may cause hypothalamic-pituitary-adrenal axis suppression, especially if used widely on the skin. The potential for increased risk of infection has been raised with the use of mid- to higher-potency topical steroids in Wet-wrap therapy, although the data are sparse and conflicting regarding its actual occurrence.

TOPICAL CORTICOSTEROIDS

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TCS (topical corticosteroids) are used in the management of atopic dermatitis in both adults and children and are the mainstay of anti-inflammatory therapy. They act on a variety of immune cells, including T lymphocytes, monocytes, macrophages, and dendritic cells, interfering with antigen processing and suppressing the release of proinflammatory cytokines. They are typically introduced into the treatment regimen after failure of lesions to respond to good skin care and regular use of moisturizers alone.

Efficacy

Topical corticosteroids have been used to treat atopic dermatitis for more than 60 years. Their efficacy has been demonstrated with a wide variety of preparations and strengths. They are generally the standard to which other topical anti-inflammatory therapies are compared. In addition to decreasing acute and chronic signs of atopic dermatitis, multiple trials have shown decreased pruritus with their application. Topical corticosteroids are used for both active inflammatory disease and for prevention of relapses. Comparative trials are limited in duration and scope, and as a result, there are no data to support one or a few specific agents as being more efficacious than others. Patient vehicle preference, along with cost and availability, often determine their selection.

Dosage

Topical corticosteroids are grouped into 7 classes, from very low/ lowest potency (VII) to very high potency (I), based on vasoconstriction assays. There is a paucity of studies that examine a range of topical corticosteroids doses in large numbers of patients and with the lack of an established optimum, great variability in dosing exists. Some use a short burst of a high-potency topical corticosteroids to rapidly control active disease, followed by a quick taper in potency, whereas others use the lowest-potency agent thought to be needed and adjust upward only if this fails.

No universal standard exists for quantity of application, although suggested methods include use of the adult fingertip unit (the amount from the distal interphalangeal joint to the fingertip, or approximately 0.5 g, being applied over an area equal to 2 adult palms), following the rule of 9’s that measures the percent affected area, and use of charts that propose amounts based on patient age and body site.

Children have a proportionately greater body surface area to weight ratio, and as a result, have a higher degree of absorption for the same amount applied. But during significant acute flares, the use of mid- or higher-potency topical corticosteroids for short courses may be appropriate to gain rapid control of symptoms, even in children.

However, for long-term management, the least-potent corticosteroid that is effective should be used to minimize the risk of adverse effects. Greater caution regarding topical corticosteroids potency is also needed when treating thin skin sites (ie, face, neck, and other skin folds), where there is greater penetration and higher likelihood for systemic absorption. It is important to monitor quantities of topical corticosteroids used over time, which may impact efficacy and safety.

Frequency of application

Most studies on the efficacy of topical corticosteroids in atopic dermatitis management involve twice-daily application. This is the most common clinical practice and also the generally recommended frequency. However, there is evidence to suggest that once-daily application of some potent corticosteroids may be as effective as twice-daily application. Some newer formulations also use once-daily application.

For acute flares, use of topical corticosteroids is recommended every day until the inflammatory lesions are significantly improved and less thick, for up to several weeks at a time. After obtaining control of an outbreak, the goal is to prolong the period until the next flare. Previously, topical corticosteroids use was stopped on improvement of symptoms and signs of disease, switching to the use of moisturizers alone and reinstituting the topical corticosteroids only with subsequent relapses. However, in recent years, a more proactive approach to maintenance has been advocated for those patients who experience frequent, repeated outbreaks at the same body sites.

This entails the scheduled application of a topical corticosteroids once to twice weekly at these particular locations, a method that has reduced rates of relapse and increased time to first flare relative to the use of moisturizers alone.

Adverse effects and monitoring

The incidence of reported side effects from topical corticosteroids use is low; however, most studies fail to follow up patients long term for potential complications. Cutaneous side effects include purpura, telangiectasia, striae, focal hypertrichosis, and acneiform or rosacea – like eruptions. Of greatest concern is skin atrophy, which can be induced by any TCS, though higher-potency agents, occlusion, use on thinner skin, and older patient age increase this risk.

Many of these side effects will resolve after discontinuing topical corticosteroids use, but may take months. Sites of treatment should be assessed regularly for these adverse effects, particularly with use of more potent agents. Continuous application of topical corticosteroids for long periods of time should be avoided, to limit the occurrence of negative changes. Proactive, once to twice weekly application of mid-potency topical corticosteroids for up to 40 weeks has not demonstrated these adverse events in clinical trials. topical corticosteroids application on atopic dermatitis lesions does reduce Staphylococcus aureus bacterial load, likely via decreasing the inflammatory cytokines that inhibit antimicrobial peptide production.

There is some worry that topical corticosteroids may impair the process of wound healing and re-epithelialization, although excoriated and fissured lesions should be included in treatment given that the underlying inflammation and pruritus lead to these secondary changes. Allergic contact dermatitis/type IV hypersensitivity can develop to topical corticosteroids or other ingredients in their formulations, such as propylene glycol and preservatives. This should be considered if lesions fail to respond as expected or worsen with application.

Patch testing is needed to determine if the allergen is the steroid compound itself or a component of the vehicle. Development of tachyphylaxis is of concern for some practitioners, where the efficacy is thought to decrease with repeated use of the same agent, although data are lacking to suggest that this is a significant clinical problem. Although there is documented risk with systemic corticosteroid use, an association between topical steroid use and the development of cataracts or glaucoma is not as clear.

Nonetheless, minimizing use at periocular sites may be prudent. Topically applied corticosteroids, particularly high- and very highepotency agents, can be absorbed at a degree sufficient to cause systemic side effects. The risk of hypothalamic-pituitary-adrenal axis suppression is low but increases with prolonged continuous use, especially in individuals receiving corticosteroids concurrently in other forms (inhaled, intranasal, or oral).

Children are more susceptible as a result of a greater body surface to weight ratio. There is also some concern for negative effects on linear growth, although reports have given mixed conclusions. Hyperglycemia and hypertension have rarely been reported. A systematic review concluded that topical corticosteroids overall have a good safety profile. No specific monitoring for systemic side effects is recommended for patients with Atopic Dermatitis at this time. However, if hypothalamic-pituitary-adrenal axis suppression is a concern, this can be assessed by performing a cortisol stimulation test to check for appropriate adrenal response.

Addressing concerns with topical corticosteroids use

Although judicious use of topical corticosteroids is certainly warranted, recognition of undertreatment as a result of steroid phobia is also important. One survey of 200 dermatology outpatients with Atopic Dermatitis found that 72.5% were worried about use of topical corticosteroids on their own or their child’s skin, with 24% admitting noncompliance with therapy as a result of these concerns. Other studies have shown that patient knowledge of steroid class potencies is poor and leads to inappropriate use.

Thus, to achieve good response, it is important to address such fears and incorrect beliefs. The risks associated with topical corticosteroids use do appear to be low with appropriate application and choice of potency, combined with periods of nonuse. A higher strength of recommendation (than actual level of evidence) is therefore placed on counseling, because the benefits outweigh the risks.

TOPICAL CALCINEURIN INHIBITORS

Topical calcineurin inhibitors (TCI) are a second class of anti-inflammatory therapy introduced in 2000. They are naturally produced by Streptomyces bacteria and inhibit calcineurindependent T-cell activation, blocking the production of proinflammatory cytokines and mediators of the Atopic Dermatitis inflammatory reaction. They have also been demonstrated to affect mast cell activation, and tacrolimus decreases both the number and costimulatory ability of epidermal dendritic cells.

Efficacy

Two topical calcineurin inhibitors are available, topical tacrolimus ointment (0.03% and 0.1% strengths) and pimecrolimus cream (1% strength). Both agents have been shown to be more effective than vehicle in short-term (3-12 weeks) and long-term (up to 12 months) studies in adults and children with active disease.

Physician global evaluation scores showed decline, as did the percent body surface area involved and patient evaluation of symptoms and signs of disease. Tacrolimus is approved for moderate to severe disease, whereas pimecrolimus is indicated for mild to moderate Atopic Dermatitis. Pimecrolimus cream has not been directly compared with low-potency topical corticosteroids, but is less efficacious than mid- and high-potency topical corticosteroids.

Dosing

Topical calcineurin inhibitors have the benefit of not carrying risk for cutaneous atrophy, with little negative effect on collagen synthesis and skin thickness. Topical calcineurin inhibitors can therefore be used as steroid-sparing agents and long-term studies to 12 months have shown that they do reduce the need for topical corticosteorids use. They have also been demonstrated to be more effective in reversing skin atrophy than vehicle. Topical calcineurin inhibitors have particular use at sensitive skin sites, such as the face and skin folds, where there is a greater adverse risk profile with topical corticosteroids.

Three studies of pimecrolimus noted greater improvement at the face and neck compared with other body sites and in 1 Randomised controlled trials (RCT), more subjects achieved clearance of eyelid dermatitis using pimecrolimus compared with vehicle (45% vs 19%). In a 3-week randomised controlled trials of tacrolimus 0.1% ointment compared with fluticasone 0.005% ointment in adults with moderate to severe facial Atopic Dermatitis in which conventional treatment was ineffective or poorly tolerated, tacrolimus gave greater improvement in the modified severity score. Fewer patients opted to switch from tacrolimus to fluticasone than vice versa. Tacrolimus 0.03% ointment and pimecrolimus cream are indicated for use in individuals age 2 years and older, whereas tacrolimus 0.1% strength is only approved in those older than 15 years. However, evidence from clinical trials supports the safe and effective use of topical tacrolimus 0.03% and pimecrolimus in children younger than 2 years, including in infants. The indications for tacrolimus were based on early studies that suggested that the 0.03% and 0.1% strengths were equally effective and safe in children, although the 0.1% strength showed superiority in adults.

Subsequent clinical experience with the off-label use of tacrolimus 0.1% in children has led many to believe it is more effective than the 0.03% formulation, but there is a need for additional formal comparative studies.

Frequency of application

Twice-daily application of the tacrolimus ointments and pimecrolimus cream are significantly more effective at decreasing signs of inflammation, affected body surface area, and associated pruritus of lesional areas on the head/neck and nonhead/neck locations than vehicle or once-daily application in adults, children, and infants. Proactive, intermittent application of topical calcineurin inhibitors 2 to 3 times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses. After gaining control of acute disease, topical tacrolimus (0.03% in children and 0.1% in adults) significantly reduced the number of exacerbations compared with vehicle, and increased the time to first exacerbation and the number of flare-free days.93-95 It has been used for up to 1 year using this strategy, without significant adverse events noted.

Adverse effects

The most common side effects seen are local reactions such as stinging and burning. These symptoms are more frequent than that seen with topical corticosteroids , but tend to lessen after several applications or when first preceded by a short period of topical steroid use.

Patients should be advised of these adverse effects to avoid premature discontinuation of treatment. There are scattered reports of allergic contact dermatitis and a rosacea-like granulomatous reaction caused by topical calcineurin inhibitors . Patients with flaring and/or severe Atopic Dermatitis are at risk for secondary infections as a result of the skin disease. The effect of continuation of topical calcineurin inhibitors treatment on infected lesions has not been studied, but the prescribing information advocates against their use during acute infection. As with topical corticosteorids, topical tacrolimus applied to noninfected lesions has been associated with reduced Staphylococcus aureus colonization, also likely a result of reduced inflammation and barrier dysfunction. No consistent increases in the prevalence of cutaneous viral infections have been demonstrated with continuous or intermittent use of topical calcineurin inhibitors for up to 5 years.

Topical calcineurin inhibitors boxed warning should be discussed with patients before use. Rare cases of malignancy (eg, skin cancer and lymphoma) have been reported in patients treated with these agents, although a causal relationship has not been established. This warning was added in response to widespread offlabel use in children younger than 2 years, and based on a theoretical risk from the use of high-dose oral calcineurin inhibitor therapy in patients posttransplantation and from animal studies with exposures 25- to nearly 50-fold the maximum recommended human dose.

Interim analyses of ongoing, 10-year surveillance studies to address these concerns have not found evidence of increased malignancy rates relative to that expected in the general pediatric population. Several studies, including a large case-control study of patients, have noted an increased risk of lymphoma that correlates with Atopic Dermatitis severity, but not with topical calcineurin inhibitors use. Overall, the topical calcineurin inhibitors have demonstrated a good safety profile to date when used as recommended, but continued assessment is needed. Proactive guidance on the content of the black-box warning can reduce anxiety on the part of patients and parents. There is no evidence to suggest a need for routine blood monitoring of tacrolimus or pimecrolimus levels in patients with Atopic Dermatitis. Both topical calcineurin inhibitors have shown consistently low to negligible systemic absorption after topical application, without any notable sequelae. Use in conditions with a much more severely impaired skin barrier that would give increased absorption, such as with Netherton syndrome, may warrant such monitoring.

Use with TOPICAL CORTICOSTEROIDS

Topical calcineurin inhibitors may be combined with topical corticosteroids use in a number of ways. Often topical steroids are used first for control of a flare, given greater potency and to reduce occurrence of some of the local symptoms associated with topical calcineurin inhibitors. Topical calcineurin inhibitors can then be used both to spare topical steroid use and to prevent relapse. Only a few comparative trials have formally tested the topical corticosteroids plus topical calcineurin inhibitors combination, which may be used sequentially or concomitantly. In 1 study, 4 weeks of topical betamethasone butyrate propionate and tacrolimus sequential therapy improved lichenification and chronic papules to a greater degree than betamethasone butyrate propionate and emollient sequential therapy.

Tacrolimus 0.1% ointment used concomitantly with desoximetasone ointment was superior to tacrolimus and vehicle and the combination of clocortolone 0.1% cream with tacrolimus 0.1% ointment was also superior to either topical agent alone. However, 1 study of pimecrolimus cream added to fluticasone 0.05% cream did not appear to offer any significant advantage in the treatment of Atopic Dermatitis flares.

Other studies have examined the use of continuous, daily topical calcineurin inhibitors therapy between flares, particularly with topical pimecrolimus. Pimecrolimus application led to more days without flare, a decreased number of days needing topical corticosteroids rescue, and an increased median time to first flare, compared with vehicle.

TOPICAL ANTIMICROBIALS AND ANTISEPTICS

https://www.nice.org.uk/guidance/..

Atopic individuals are predisposed to skin infections because of a compromised physical barrier, coupled with diminished immune recognition and impaired antimicrobial peptide production. Staphylococcus aureus, in particular, is a frequent culprit and colonizer of the skin in Atopic Dermatitis. Its presence, even without overt infection, appears to trigger multiple inflammatory cascades, via toxins that act as superantigens and exogenous protease inhibitors that further damage the epidermal barrier and potentiate allergen penetration. A 2010 Cochrane review of RCTs found a lack of quality trials to support the use of antimicrobial and antiseptic preparations to treat Atopic Dermatitis.

The review also did not find any clear benefit for topical antibiotics/ antiseptics, antibacterial soaps, or antibacterial bath additives in either the setting of clinical infection or uninfected Atopic Dermatitis, noting that even positive findings in studies often had poor reporting of details. Although the addition of a topical antibiotic to a topical steroid reduces the amount of Staphylococcus aureus isolated from the skin, the combination has not been found to improve either global outcomes or disease severity compared with the steroid alone. Thus, topical antimicrobial preparations are not generally recommended in the treatment of Atopic Dermatitis.

They can be associated with contact dermatitis, and there is also concern that their use could promote wider antimicrobial drug resistance. An exception to the above antimicrobial agents is the use of bleach baths with intranasal topical mupirocin. In 1 RCT of 31 children with moderate to severe Atopic Dermatitis, treatment of an infectious episode with oral cephalexin for 2 weeks followed by the addition of household bleach to bathwater plus intranasal application of mupirocin for 3 months led to a greater improvement in disease severity than simple bathing alone.

Enhanced clinical improvement was noted only in the skin submerged in the bath (not the head/face). Bleach baths may therefore be helpful in cases of moderate to severe disease with frequent bacterial infections, and particularly for maintenance, as cultures did not show clearance of the bacteria in the majority of patients. There is less concern about the development of bacterial resistance with use of dilute bleach relative to the use of topical and systemic antibiotics. Topical hypochlorite products are also available as an alternative to dilute bleach baths, but at higher cost and without any RCTs published to date. In children and adults with clinically uninfected Atopic Dermatitis, the use of underwear made of silver impregnated textile did not reduce the severity of the Atopic Dermatitis compared with cotton underwear. Use of silk fabric with a durable antimicrobial finish has limited positive data, and needs further investigation.

TOPICAL ANTIHISTAMINES

www.waojournal.org/content/6/1/6

Topical antihistamines have been tried for the treatment of Atopic Dermatitis but unfortunately have demonstrated little utility and are not recommended. Studies investigating topical doxepin have demonstrated a short-term decrease in pruritus in some cases, but with no significant reduction in disease severity or control. Treatment has local side effects, particularly stinging and burning, and can also cause sedation. There are multiple reports of allergic contact dermatitis secondary to the use of topical doxepin; however, the specific incidence of this outcome cannot be established with certainty based on the available data. There are no controlled studies on the use of topical diphenhydramine for Atopic Dermatitis. It may also cause allergic or photoallergic contact dermatitis. Widespread application, use on broken skin, and/or combined use with oral diphenhydramine are not advised because of risk for systemic toxicities such as toxic psychosis (eg, hallucinations, delirium), particularly in children.

OTHER TOPICAL AGENTS

Topical coal tar derivatives have been used for many years in the treatment of inflammatory skin diseases, particularly psoriasis. There are, however, very few trials of coal tar preparations and their efficacy in the treatment of Atopic Dermatitis. Has been investigated a preparation designed to be more cosmetically acceptable than traditional formulations and found it to be as effective as 1% hydrocortisone acetate cream on left/right paired comparison for mild to moderate disease. But given only a 4-week study and 5 of 30 patients reported itching and soreness, there are not adequate data to make a recommendation regarding the use of coal tar topical agents. A recent study of organotypic skin models from patients with Atopic Dermatitis and control subjects did find that coal tar activates the aryl hydrocarbon receptor signaling pathway, resulting in enhanced epidermal differentiation, increased levels of filaggrin, and inhibition of a major Atopic Dermatitis cytokine pathway (interleukin-4/signal transducer and activator of transcription (STAT)-6).

Topical phosphodiesterase inhibitors are another new class of anti-inflammatory treatments, but remain available only in clinical trials, also precluding any recommendations for or against their use at this time.

Table 2. Antipruritic therapies in Atopic Eczema. Recommendation for topical and systemical therapies based on clinical trials and expert opinion.

*as proven by randomised, controlled trials T, topically; o, orally. www.turkderm.org.tr/…

SUMMARY AND RECOMMENDATIONS

Atopic dermatitis is a disease of children and young adults that is widely spread and increasing in its prevalence worldwide. The main feature is pruritis triggered by dry skin, with treatment aimed at reducing it by several management strategies. Management should start with education of patient and parents about trigger factors and the need of avoiding them. Skin moisturization by emollients is an important procedure to control the condition. Topical steroids and oral antihistamines are of extreme importance as drug therapies. Due to the chronic nature of the disease, patients are followed up by the family physician, with referral to a dermatologist considered for those with secondary infections that need hospital care or for refractory cases that require potent therapies such as immunomodulators and phototherapy.

Atopic dermatitis is a chronic inflammatory skin disease that is considered familial with allergic features. In children, acute skin lesions that appear as intensely pruritic erythematous patches with papules and some scaling can be seen on the face, scalp, extremities, or trunk; diaper areas are usually spared.

The skin lesions in older individuals with more chronic disease are characterized by thickened skin, increased skin markings (lichenification), and excoriated and fibrotic papules. In adults, the flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly involved.

A key feature of atopic dermatitis is severe dryness of the skin caused by a dysfunction of the skin barrier with increased transepidermal water loss. This is typically accompanied by intense pruritus and inflammation. The regular use of emollients is important for addressing this problem, and together with skin hydration, it represents the mainstay of the general management of atopic dermatitis. Emollients should be applied continuously, even if no actual inflammatory skin lesions are obvious.

Education to enhance disease knowledge, psychologic improvement in disease perception, and scratch control behavior modification, together with regular daily treatment, will lead to better skin care. This improvement in disease control will restore family dynamics, and the patient and family will cope better and have an overall improvement in quality of life.

Education should be aimed at reducing doctor shopping, facilitating a better partnership between the doctor and the patient-parent, and decreasing the long-term costs of chronic disease treatment.