It is sobering to think that with the tremendous amount of sophisticated research on atopic dermatitis (AD)—a disease that affects some 20 percent of children in industrialized countries—the etiopathogenesis remains obscure.^1,2 The most current understanding involves multiple factors including impaired skin barrier function, abnormal nerve fibers, immune dysregulation, and microbiome abnormalities.^3,4

Fundamental questions remain unanswered, such as whether AD is truly an allergic disease. The existence of at least two distinct subtypes, variably referred to as “extrinsic vs. intrinsic,” or “atopic dermatitis vs. atopiform dermatitis,” highlight the large subgroup that has no allergic features and thus may not be truly atopic at all.⁵ When one considers the progression and variety of morphology and distribution of the disease, it becomes even more difficult to unify this somewhat protean syndrome: wet or dry, face or folds, erosions or lichenified plaques; at times it is like leaves scattering in the wind.

In thinking about AD, a tetrahedron with its four apices is useful to summarize the four cardinal aspects of AD and guide therapy choices (Figure 1), which include ant-inflammatory, moisturization, antibiotics, and antipruritics. When a patient presents with more severe disease, maximizing each area may lead to powerful synergies, which, in turn, may minimize the need for more potent and potentially toxic treatments.

Moisturization

The excitement surrounding the fairly recent discovery that mutations of the filaggrin gene (FLG) are associated with AD is justified. In fact, for some patients, this mutation is the answer to the question, “Why do I have eczema?"⁶ This protein is critical for epidermal barrier function, but it also degrades into Natural Moisturizing Factor (NMF) and helps maintain the acid mantle of the skin as well.⁷ Without sufficient filaggrin, the skin therefore becomes “leaky,” allowing increased water loss and enhanced penetration of allergens and irritants. It follows that restoring the skin barrier by moisturization is of paramount importance in AD. Fortunately, this is borne out clinically: It has been shown convincingly that increased moisturizer use strongly correlates with decreased eczema severity.⁸ Regular emollient use also appears to have a steroid- sparing effect and is associated with improved quality of life in AD as well.^9,10

Attention has been drawn, however, to those with normal filaggrin production: Would these patients also have barrier dysfunction, and if so, why? Although we may not have all the answers to this question yet, a very compelling paper in 2007 demonstrated that in the presence of inflammatory cytokines such as IL-4 and IL-13, there is significantly reduced filaggrin gene expression, even in genotypic normal skin.¹¹ This functional filaggrin deficiency likely results in the same “leaky” skin seen in patients with an abnormal FLG gene, underscoring the importance of moisturization for all patients with AD.

A recent pilot study suggested a potential ramification of maintaining the barrier through moisturization. The authors asked: “Can moisturizers prevent eczema in highrisk patients?” In the study, 22 neonates deemed high-risk for developing AD had moisturizer applied daily from birth. Excitingly, only 15 percent of these patients developed AD by two years of age, compared with a historic control prediction of 30 to 50 percent, suggesting a protective effect of moisturization.¹²

Despite these positive findings, many unanswered questions remain regarding moisturizers. Selection of an “optimal” moisturizer (if there is such a thing), is still elusive and there is minimal comparative evidence in this domain. Additives and innovations in moisturizers have more recently resulted in suspiciously drug-like claims, while socalled “barrier repair creams” walk the line precariously as 510(k) devices rather than actual drugs in the eyes of the FDA.¹³ On limited data—but bolstered by clinical experience— it seems that many mainstream over-the-counter moisturizers are comparable to the far more expensive barrier repair devices, and may even outperform them at a fraction of the cost.¹⁴

It is clear that skin barrier deficiency is at the root of AD and that moisturizers are currently our best way to address this aspect. In so doing, it seems plausible that beyond the improvement in symptoms, such treatment may actually alter the course of the disease as well.

Anti-inflammatory

Immune dysregulation and inflammation in the skin are defining characteristics of AD.¹⁵ As such, it has long been known that topical corticosteroids, and to a similar extent, the topical calcineurin inhibitors tacrolimus and pimecrolimus, can be used successfully to calm the inflammation and improve the skin. Notably, much of the literature is based on what might be called a “reactive” treatment approach: treating the skin when there is active inflammation and itch (a flare).¹⁶

Several studies, however, suggest that by changing the paradigm to a more “proactive” approach—i.e., treating the trouble areas twice per week, even in the absence of a flare—the number of disease exacerbations is reduced, overall cost is reduced, and quality of life is improved significantly.^17,18 Similar results were found with a topical calcineurin inhibitor or a low-mid potency topical corticosteroid used in this way. This proactive therapy, perhaps more than any other innovation, heralds a fundamentally new approach to managing AD and requires only wider adoption by clinicians. Analogous to the maintenance of asthma, moderate and severe cases of AD probably should be similarly maintained. Corticosteroid phobia (as well as concerns about topical calcineurin inhibitors) among patients and caregivers may limit this, however, and paradoxically result in more medication use over time due to poorly-controlled disease.¹⁹

Antibiotics

Frequent infections and abnormal colonization by bacteria such as Staphylococcus aureus are well-known features of AD.¹⁵ Several converging lines of evidence help elucidate the role of antimicrobial treatments in AD, even without overt signs of infection. Multiple studies show a correlation between staphylococcus colonization and AD severity, and even without infection, the secretion of exotoxins by the bacteria seem to directly fuel inflammation in the skin via superantigens.²⁰ A recent report suggests that a specific protein called δ-toxin acts to directly activate mast cells, promote IgE and IL-4 production, and directly contribute to inflammation in the skin, as well.²¹ Work done by Kong, et al., models a flare of AD as beginning with increased colonization of staphylococcus on the skin, followed by inflammation, and ending with decreasing numbers of staphylococcus leading into healing.⁵

From a therapeutics perspective, the use of dilute bleach (sodium hypochlorite) baths has been shown to decrease the severity of AD, presumably by decreasing colonization of the toxin-secreting bacteria.²² Clinically, the use of dilute bleach baths has dramatically decreased the frequency of infections, such that I find that I seldom need to prescribe oral antibiotics for my patients anymore. If dilute bleach baths were to become the standard of care, such a change could presumably result in massive cost savings, reduced adverse effects related to oral antibiotics, and decreased bacterial resistance from antibiotic overuse.

Antipruritics

AD is often known as “the itch that rashes,” highlighting the fact that pruritus is the primary symptom. Perhaps the most challenging task of all, then, is to quell the itch, which seems to be driven by all of the other factors at once: the dryness of the skin and the infiltration of allergens and irritants through a dysfunctional barrier; direct and indirect inflammatory mediators by staphylococcus bacteria on the skin; the inflammation itself, including IL-2 and mast cells; and changes both qualitatively and quantitatively in periperhal nerve fibers.^23,24

Because of the complexity of itch mechanisms, it is perhaps not surprising that there are few specific treatments able to break the itch-scratch cycle. While oral antihistamines are generally thought to be ineffective for the pruritus of AD, there may be some patients who benefit, particularly from the sedative effects during the night.²⁵ Generally, until more targeted antipruritic treatments are developed, the main strategy for itch control remains treating the other areas (moisturization, antibiotics, and anti-inflammatory) sufficiently until the itch is improved.

Ultraviolet light treatments (phototherapy) can address several of these aspects simultaneously, and remains an important therapeutic consideration for AD. Antiinflammatory, antimicrobial (via cathelicidin production, perhaps), and directly antipruritic, narrow-band ultraviolet B phototherapy is a powerful but safe option for moderate- to-severe AD.^26,27

Beyond this, we should consider systemic therapies, given the sufficient evidence available to justify use of cyclosporine, mycophenolate, azathioprine, and methotrexate in appropriate refractory cases.²⁵

Making a Plan

With so many aspects to a comprehensive treatment plan, it can be overwhelming to both the patient and clinician: soaks, cleansers, corticosteroids, calcineurin inhibitors, and emollients all must be juggled, for different areas of the body and depending on severity! There seems to be no other reasonable way to convey all of this information than an Eczema Action Plan. Modeled after the Asthma Action Plan, it can take a number of forms, but must—at the very least—account for the above list. Such a plan also allows for more complex regimens such as wet wrap therapy: a safe and powerful treatment for severe disease.²⁸ A blank template (as shown in Figure 2, also available at www.chicagoeczema.com) can be filled in with specific instructions for the patient.

A recent study demonstrated that written plans, in addition to being preferred by patients, reduces anxiety about the treatment approach, increases understanding of the regimen and its risks and benefits, and improves understanding of how to adjust medications based on disease severity.²⁹

Juggling Relief

Eczema continues to present a tremendous challenge to patients, their families, and their caregivers. The multiple subtypes under the heading of AD suggests that in time we will further refine our understanding of its etiopathogenesis which will hopefully lead to better, more targeted treatments. Until then, we continue to juggle the four major components, in order to maximize control of the disease: moisturization, antibiotics, anti-inflammatory, and antipruritics. In so doing, we aim to control the AD and its symptoms, in order to provide our patients with relief.

Peter A. Lio, MD is a Clinical Assistant Professor in the Department of Dermatology & Pediatrics at Northwestern University, Feinberg School of Medicine.

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