Atopic dermatitis (AD) continues to increase in prevalence. Less than half of AD patients have complete resolution by 7 years of age. In 30% to 40% of patients, this condition persists into adulthood. These statistics reflect poorly on the standard-of-care therapies that fail to address the root cause of AD and therefore cannot cure it. This overview describes treatment considerations that address the underlying cause, which is imperative to treatment success and patient satisfaction.
AD is one of the most common dermatological conditions seen in clinical practice. Its complex and multifactorial pathogenesis can make treatment difficult, lengthy, and often unsatisfactory. In 2006, the growing list of contributing factors for this condition expanded when a loss-of-function mutation in genes coding for filaggrin (FLG) was identified. FLG is a protein that facilitates the aggregation of keratin filaments supporting the barrier between the skin and the outside world. When the structural integrity of the outermost skin layer is compromised, as in the skin of those with a FLG mutation, pathogens, allergens, and toxins are able to pass through the hyperpermeable stratum corneum and create chronic inflammation.
This review article integrates this key finding into the multiple factors leading to the development of AD in susceptible individuals. When pathogens and allergens enter through the defective skin barrier, there is an initial cellular (Th1) response and production of inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor-β. Acute inflammation coupled with transepidermal water loss continually compromises the skin’s functional capacity as a protective barrier. Over time, there is a shift to a Th2 immunophenotype. Basophils, monocytes, eosinophils, and numerous cytokines propagate further inflammation and pruritis.1 An excessive Th2 response is the predominant immune feature of the atopic triad of AD, allergic rhinitis, and asthma.
The prevalence of FLG mutation is significant. Fifteen percent of AD cases are attributable to 30 or more FLG mutations. If a patient is born with 1 FLG mutation, the risk of AD is 40% to 50%.2 However, half of AD patients do not carry this mutation. Many other nongenetic risk factors have been implicated in AD, adding to the complexity of treating this condition. FLG mutations are not commonly tested for in clinical practice, as they are not relevant in treatment decision-making.
Ultraviolet light facilitates the conversion of the FLG breakdown product transurocanic acid into cisuronic acid, which is an immunosuppressive isotype that tames the inflammatory response. When researchers examined urban vs rural living, disease burden was shown to be higher in people living in cities when compared to rural dwellers.3 This is likely due to the detrimental effects of urbanization, such as traffic-related air pollution (nitric oxide and carbon monoxide) and tobacco smoke.4 Household irritants such as detergents, phthalates, dust mites, and even water hardness reduce natural moisturizing factor in the skin, increase the skin pH, and activate antigen-presenting cells in the epidermis. This leads to allergic sensitization, disease flares, and increases the risk of developing other atopic diseases in susceptible people.
The standard American diet (SAD), obesity, and lack of exercise play a significant role in most disease states, and this holds true in AD. A consistent protective effect for AD is found when patients consume fresh fruits, vegetables, and fish, whereas fast food consumption consistently shows the opposite.5,6 The SAD diet is low in antiinflammatory omega-3 polyunsaturated fatty acids and high in proinflammatory omega-6 fatty acids.7
There is a shifting paradigm in the treatment of atopic dermatitis to not only address [nutritional] deficiencies, but also to emphasize skin barrier repair.
Gastrointestinal health and function are compromised by broad-spectrum antibiotic exposure, more so than the exposure to the actual pathogen itself. There is a remarkable 41% overall increased risk of developing AD in those who received at least 1 course of antibiotics in early life and an additional 7% risk increase in each antibiotic course thereafter.8 There is no conclusive evidence that viral or bacterial pathogens themselves influence AD risk, with 1 exception: children who have had chicken pox have a 50% less chance of developing AD.9 Furthermore, there is again no definitive evidence that routine childhood vaccinations contribute to the risk of AD. These findings support the known conclusion that reduced diversity in gut flora is problematic as it heightens the immune response to allergens.10
The complex interplay among genetic, environmental, and immunological factors poses a challenge to practitioners who treat AD. With the discovery of FLG, we now have an improved understanding of the barrier dysfunction underlying AD that has led to better clinical outcomes, as the expression of AD is dependent on gene-environment interactions and epigenetic influences.11
Thymic Stromal Lymphopoetin
Another important environmental factor contributing to the immune dysfunction observed in AD is the triggering of thymic stromal lymphopoetic (TSLP) by phthalate exposure. TSLP is an IL 7‒like cytokine secreted by barrier-defective skin. High levels of TSLP are found in skin biopsies from AD lesions. TSLP in turn triggers Th2 commitment.12,13
Environmental exposure to phthalates may be a significant contributing factor to the rising incidence of AD. Pregnant women with high urinary levels of phthalates confer an increased risk of AD in their children. Children with AD have higher levels of urinary phthalates.14 The typical Western infant diet contains twice as much phthalates as considered safe (20 µg/kg body weight) by the US Environmental Protection Agency.15 Sources of phthalate exposure include red meat, poultry, and high-fat dairy products; cooking oils and margarine; contamination by packaging of meat, poultry, fish; chicken feed; and the practice of warming food in plastic containers. Phthalates are also prevalent in plastic toys, creams and lotions used by most women for personal care, and dust tracked into the home on the soles of footwear.16
Helicobacter pylori is another promoter of TSLP by gastric epithelial cells and induces dendritic cell-mediated inflammatory Th2 responses. H pylori immunoglobulin (Ig)G antibodies are positive in up to 70% of AD patients.17 Treatment of infection demonstrated by reduction in C-urea breath test and anti‒H pylori antibody titers resulted in partial improvement in patients with AD.18 It should be noted that antibodies titers persist long after H pylori eradication, and a breath test is the preferred method of testing for both presence and eradication of H pylori.
A defective skin barrier and increased intestinal permeability facilitate allergen sensitization.19 Avoidance of highly allergenic foods during infancy may prevent allergen sensitization and reduce severity of AD and food allergies.20 Clinically relevant food sensitivities can be identified with skin prick, serum IgE, and IgG4 tests, and/or food challenges; from there, appropriate dietary restrictions can then be initiated. In children, the most common foods that aggravate AD are cow’s milk products, eggs, peanuts, wheat, soy, and fish.21
Suboptimal and deficient vitamin D is also a recognized risk factor in AD.22 Children whose mothers have low levels of vitamin D during pregnancy are at higher risk of developing AD. Infants with the lowest levels of vitamin D at birth have the highest risk of developing AD by age 5.23 Every 4 ng/mL increase in vitamin D levels in newborns is associated with 13% lower risk of developing eczema.24 Both children and adults with AD are more likely to have low levels of vitamin D. Lower vitamin D levels are associated with more severe AD symptoms. People who have AD and low levels of vitamin D are more likely to get skin infections. Vitamin D supplementation increases antimicrobial proteins in the skin, which destroy pathogens, reduce inflammatory cytokines, and improve barrier function. Supplementation with 10,000 IU vitamin D daily has been found to be a safe and effective strategy to raise 25OHD levels to a target of 60 ng/dL to 65 ng/dL. Once this level achieved, it should be maintained with a lower dose: eg, 2,000 IU daily.25
It is well established that maternal probiotic supplementation during pregnancy and nursing are effective in the prevention and treatment of AD. A recent systematic review of controlled trials of probiotic supplements in 3,023 participants found that 8 out of 13 (61.5%) studies reported significant effect on prevention of AD after supplementation with probiotics and/or prebiotics, and 5 out of the 13 (38.5%) studies indicated significant reduction in the severity of AD after supplementation.26
Essential Fatty Acids
Linoleic acid (LA) and its derivatives (omega-6) play a central role in the structure and function of the stratum corneum permeability barrier (SCPB). LA is the most abundant fatty acid in the epidermis. Importantly, it is also the precursor to ceramides, a major component of the extracellular lipid matrix that forms the SCPB. The 3 components of the SCPB are the extracellular lipid matrix, the cornified envelope, and dense keratin fibrils aggregated by FLG. The extracellular lipid matrix is composed of 50% ceramides, 25% cholesterol, and 15% free fatty acids.27 Results of studies of omega-6 supplementation in AD have been conflicting and confusing. The most recent meta-analysis on this issue concluded that evening primrose oil is effective in a subset of patients with AD and elevated IgE levels.28
Derivatives of α-linolenic acid can modulate the immune response of the epidermis by influencing T lymphocytes, acting on toll-like receptors, and activating caspase cascades that influence the inflammation of AD.
Omega 3 fatty acids are ligands for an important class of transcription factors, the peroxisome proliferator-activated receptors, which are important in epidermal inflammation, immune regulation, and skin barrier homeostasis. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are not major constituents of the epidermis, which is likely a reflection of insufficient dietary consumption. Unlike LA, which plays a major structural role in the epidermis and SCPB, omega-3 fatty acids appear to play an immune-modulating role. EPA has been shown to reduce the expression of intercellular adhesion molecule-1, reduce T-lymphocyte proliferation, and dampen delayed-type hypersensitivity.29 Many studies have shown that breastfeeding has a protective effect against the development of AD. This again is likely a reflection of maternal nutrition because an increased incidence of AD was found in infants consuming breast milk rich in saturated fat and diminished omega-3 fats.30 This finding argues for the importance of DHA and EPA in early life. This recognition has led the US Food and Drug Administration to include the long-chain fatty acids, DHA, and arachidonic acid in infant formulas. A controlled trial of 5.4 g DHA daily for 8 weeks in adults with AD showed significant improvement clinically as well as in serum biomarkers.31
AD is often associated with emotional distress, insomnia, and significant discomfort; therefore, palliative therapy is often requested and employed. It is important to use a ceramide-containing emollient while treating the underlying cause. The goal of barrier therapy is to decrease symptoms of erythema and pruritis for the patient while reducing transepidermal water loss (TEWL) and inflammation, downregulating protease activity, and improving the integrity of the skin barrier. Two trials have shown that daily application of moisturizer during the first 32 weeks of life reduces the risk of AD in infants.32
An example of an excellent barrier repair and antiinflammatory cream is Topic Medis Body Cream (Kamedis, Tel Aviv, Israel), consisting of ceramides; herbal extracts of Rheum palmatum, Scutellaria baicalensis, and Cnidium monnieri; and dipotassium glycyrrhizinate. An antiinflammatory, antiallergic, antimicrobial, antipruritic, and barrier repair assessment of the skin condition in 20 volunteers with AD symptoms following treatment with this herbal cream for 3 weeks found the following:
- Dryness reduction of 46% in 75% of volunteers,
- erythema reduction of 49% in 70% of volunteers,
- oozing reduction of 70% in 50% of volunteers,
- significant reduction of 48% in level of pruritus, and
- significant reduction in TEWL by 14.3% and 28% increase in skin hydration (unpublished data).
Wet Wraps Therapy
Sleep is a reliable measurement of AD severity and treatment efficacy. Wet wraps applied at bedtime are an effective intervention for enhancing the benefit of topical therapy for AD. The largest study to date of wet wraps therapy (WWT) for pediatric patients with moderate-to-severe AD employed a validated outcomes tool. None of the patients required systemic immunosuppressive therapy, and only 31% were treated with an oral antibiotic. This study demonstrated the benefit of incorporating WWT as an acute intervention in a supervised multidisciplinary AD treatment program with benefit that lasted beyond 1 month after discontinuation of this intervention.33
Employ the following strategies to prevent AD in infants.
- If there is atopy in the family history of either parent, the pregnant mother should supplement with vitamin D (to reach 25OHD levels of 60 ng/dL), omega-3 1,000 mg to 2,000 mg daily depending on her dietary intake, and probiotic.
- Ceramide-containing emollient should be applied to infants’ skin from birth through infancy.
- Detoxification should be undertaken if urinary phthalates are elevated.
The effects of nutrient supplementation on AD have demonstrated clear benefits in preventing the development of AD and reducing its severity.34 There is a shifting paradigm in the treatment of AD to not only address these deficiencies, but also to emphasize skin barrier repair. With an understanding of FLG and its implications, the physician can help patients achieve and maintain relief from AD. Employing these strategies clinically will yield optimal results for patients with AD.