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Treating Atopic Dermatitis

Treating Atopic Dermatitis

This is an exciting time in dermatology because for the first time in recent decades there is significant innovation, both in the understanding of atopic dermatitis and potentially with some therapeutics, according to Peter Lio, MD, assistant professor of clinical dermatology and pediatrics-dermatology at Northwestern University Feinberg School of Medicine. 

Atopic dermatitis is a complicated condition. Its definitive and succinct cause and ideal treatment have not been realized yet, said Dr. Lio, who spoke on the topic at the recent American Academy of Dermatology meeting in New York. Factors of the condition include the itch/scratch cycle, allergies and contactants playing a role, the inflammation aspect and the microbial effects. Dr. Lio outlined treatment options using a pyramid with 4 points: anti-inflammatory, moisturization, antipruritics and antibiotics (Figure 1).

Moisturization is one of the important cornerstones in the treatment of atopic dermatitis. “The filaggrin protein acts as a barrier component, provides structural support and keeps those junctions very tight, preventing water loss and keeping out bacteria, allergens and contactants. It also plays a role in natural moisturizing factor as it breaks down into hygroscopic amino acids pulling water in, keeping the skin in good homeostasis,” explained Dr. Lio, who practices at The Chicago Integrative Eczema Center in Chicago and also serves on the Scientific Advisory Board for the National Eczema Association.

“In addition, the filaggrin protein has an effect on some of the serum proteases, the enzymes that are chewing up other structural proteins in the skin. As filaggrin breaks down, it also is modulating skin pH, which turns out to be important both for structural integrity, but also for bacterial growth,” he added.1

If a patient lacks the filaggrin gene that is what causes their eczema. “We know that the genotype/phenotype connection is with ichthyosis vulgaris and these 2 diseases have a lot in common. When you work backwards, depending on the population being studied, you can say about 13% of patients with eczema have it due to a filaggrin gene mutation.1 Of course, there are other exciting structural proteins that may play a similar role. As we learn more about this, we might have other things that can explain more of it, but still, at least we have a minority of patients that we can say, this is what’s wrong fundamentally,” he said.

In other cases, a patient’s filaggrin genetics could be adequate, but problems still exist. Howell et al2 looked at the effective inflammatory cytokines in normal patients, and found that if they have sufficient filaggrin gene expression at baseline in the presence of inflammation, particularly interleukin (IL)-4 and IL-13, which are 2 important inflammatory cytokines in the pathogenesis of atopic dermatitis, inhibition of production of filaggrin can result. In these cases even if the patient does not have a primary mutation in this structural protein, they become functionally filaggrin-deficient.2 “This means something that all clinicians have known for a long time: that the barrier is still key in eczema,” he said.

Cork et al3 demonstrated that more emollient equals less eczema. “We know emollients can make a huge difference, and it is not glamourous to be cheerleading for our patients to put on more moisturizer, but it is really important,” he said.

Types of Moisturizer

Much debate surrounds which type of moisturizer is optimal. Lio and his colleagues conducted a study4 published in 2012 that evaluated various moisturizer formulations, including ointments, creams, water and oil emulsions and water-based lotions. The study introduced a hydrophilic index (HI) as a novel method of quantifying the aqueous content of topical emollients. When considered together with pH, the 2 indices are designed to guide providers in choosing the most suitable emollients for patients with skin diseases involving altered acid mantle and barrier disruption, such as atopic dermatitis. Their findings were similar to common clinical impressions: lotions generally have higher HI, while ointments have lower HI. The majority of the products tested were low HI, suggesting that a large percentage of the products may be rich in overall lipid content. The pH values range widely, from 3.7 to 8.2, with the majority of the products close to the physiologic skin pH of 4 to 6, according to the study. “There probably is no best moisturizer. A lot of it depends on what the patient likes,” he said. 

Another study from Simpson et al5 evaluated if moisturizers could prevent the development of eczema. The pilot study demonstrated that there might be a preventative aspect to moisturization if skin barrier repair was practiced from birth. 

“In general, greasier products are better for most people,” he added, noting that many patients prefer more cosmetically acceptable or elegant formulations and this area is worth studying.

Moisturization

Several practice pearls for patients with atopic dermatitis can help with moisturization dilemmas. “If the patients are complaining that the moisturizers are too cold, when they are in the bathtub at night, just take the sealed tub of moisturizer and float it in the bath with them. That will naturally warm it up,” he said.

Conversely, some patients are always feeling hot, which could cause sleep disturbances. “Put the tub of moisturizer in the refrigerator (not the freezer because sometimes that will separate the components) and then when you put that on the skin, it has a cooling effect, which feels good. There is evidence that cooling the skin has an important anti-inflammatory physical effect,” he noted.

For many moderate and severe eczema patients, Staphylococcus colonization can be a problem. Often these children place their hands (potentially covered in the bacteria) into the moisturizer jar repeatedly, thus increasing the likelihood of the amount of colonization in the jars. “If we can encourage them to use a clean spoon, a Popsicle stick or tongue depressor, that’s a great pearl just to keep some of that infection down,” he said, adding that if a patient cannot seem to shake Staphylococcus he recommends they throw away all the moisturizers and buy new ones. 

When to apply moisturizer is a topic of much debate although little evidence-based literature is available. A study by Chiang et al6 found that moisturizer applied within minutes of bathing results in a spike in epidermal hydration of the stratum corneum that degrades quickly over time. They also found moisturizer applied on dry skin (not with a bath) also results in a significant spike (although not quite as high as immediately after bathing), but it is much more sustained. “The moral of the story is apply it early after bathing and often,” he said. 

Antibacterials

Many patients with eczema experience numerous infections and significantly more of those patients are colonized with S aureus. “The most exciting thing in my practice in the past few years has been the implementation of dilute bleach baths. The results have been remarkable,” said Dr. Lio.

Huang et al7 conducted a randomized, controlled trial with 31 children with moderate-to-severe eczema that demonstrated patients who had a dilute bleach bath did better than those with the placebo bleach bath, and there were significant improvements in eczema severity at 1 and 3 months, which were sustained. “This is one of those things I don’t need any more data as a clinician. Clinically, it has changed everything. Since I’ve been doing this routinely, I almost never have to write prescriptions for antibacterials anymore. Now if they’re doing this, they just don’t get infected,” he said. 

The bleach is antibacterial and reduces the bacterial colonization, which helps prevent infection. Staphylococcus causes infection and the colonization drives inflammation. Leung et al8 demonstrated how S aureus on the skin acts as a super-antigen. They concluded that it pushes T cell and lymphocyte function into hyperdrive and causes inflammation.

Another study by Nakamura et al9 identified a delta toxin produced by S aureus, as a potent inducer of mast cell degranulation and suggests a mechanistic link between S aureus colonization and allergic skin disease. “This research makes dilute bleach baths really interesting because it is not only killing the bacteria from the infection, it is also killing the bacteria which is driving inflammation,” he said. (For more information, please visit, www.chicagoeczema.com/resource/dilute-bleach-baths/ for instructions for making a dilute bleach bath). 

In addition, Leung et al10 looked at a different model of radiation dermatitis and inflammation. The study showed that dilute sodium hypochlorite (the bleach) had an effect in wound healing and inflammation. 

“Dilute bleach therapy is an incredible game-changer. It’s super inexpensive and safe,” Dr. Lio said. 

Microbiome

Intestinal microflora is a hot topic. Recent research is looking at the diversity of gut microbes and evaluating a correlative link to eczema. Ismail et al11 showed you could predict at day 7 of life, if you do a swab of the gastrointestinal tract, which children were more likely to develop eczema, and it is because of the decreased diversity of gut microbes.12 “Those children who had better diversity were more likely not to have eczema,” said Dr. Lio, who notes that this avenue is worth exploring further. 

The skin microflora might also hold some clues to the process of atopic dermatitis. Kong et al13 modeled the microbial changes on the skin. The study showed at baseline there is significant microbial diversity and minimal Staphylococcus and the eczema is down. As the microbial diversity starts to decrease, Staphylococcus starts to inversely go up and then that triggers the flare. The flare-up occurs, then Staphylococcus gets reduced, then the microbial diversity comes up and the flare subsides. “This is a kind of symphony or concert of things happening in terms of inflammation, normal bacterial flora and S aureus all playing a role as a system,” Dr. Lio said. 

Anti-inflammatory Treatments

Inflammation is another important aspect of the pathogenesis of atopic dermatitis. Although numerous anti-inflammatory treatments are on the horizon, Dr. Lio noted that topical steroids are still going to be the mainstay treatment for atopic dermatitis. “Ointments, in general, are preferred. They have less preservatives, less potential for irritant and have a good barrier effect when we put them on,” he said, pointing out they are safe for short-term use under close monitoring. “The risks (atrophy, striae, dyspigmentation and hypertrichosis) must be weighed against the benefits.”

Maintenance Therapy

Off-label maintenance therapy has been shown to be beneficial (ie, improves quality of life, decreases the number of flare-ups, decreases the amount of medication used and decreases healthcare costs significantly.)14 For this type of therapy, a patient uses topical corticosteroids for a week to calm the flare-up of a particular area. Once the flare-up has abated, instead of stopping treatment, a low-potency steroid or topical calcineurin inhibitor (such as tacrolimus or pimecrolimus) is used. Data supports using both of these methods twice weekly for the trouble spots.15 

Synergy — using a topical steroid in the morning and a topical calcineurin inhibitor in the evening — is another type of therapy. A study of 13 cutaneous lupus patients showed the synergy between the 2 agents was better than either agent alone.16 

“I’ve had a few patients tell me that they do better if they use a topical corticosteroid once in the day, and then a topical calcineurin inhibitor (tacrolimus or pimecrolimus) the other time of day. You can get this synergy in some patients and it is a nice way to transition them off the steroid,” he explained, noting the patient can remain on the topical calcineurin inhibitor a little longer and then shift to the maintenance schedule.

Antipruritics

Antipruritics comprise the last aspect of the pyramid and traditionally have been a difficult area to see improvement. While antihistamines do not help the itch of eczema, sedating antihistamines can be helpful. Topical options are numerous; however, they are also overall unsatisfying, Dr. Lio said. 

Some newer research concerns investigational products that address nerve differences17 in patients with atopic dermatitis versus normal. Several nerve growth factor inhibitors show promise. 

Developing an Action Plan

Because a dermatologist’s time is limited and there is so much to explain regarding eczema, Dr. Lio advocates providing a written eczema action plan to patients and their caregivers. His original action plan design consisted of 3 categories: severe, mild or moderate and clear. The standard template was divided into face and body and then during the visit he would give instructions to the caregiver and circle the action needed (Figure 2). 

Despite the explanation and written action plan, parents called the office asking for more direction. So, he revised the action plan and numbered the steps so it can be more easily understood. “It has cut my phone calls by 95%,” he said.

 The updated bulleted sample eczema action plan is available at www.chicagoeczema.com/resource/bulleted-sample-eczema-action-plan/.

Overall, patients and caregivers report more satisfaction when they received the written action plan. A study of 37 adult patients or caregivers of pediatric patients with eczema found when verbal instruction was compared to a written action plan that was explained and then given to parents, the written action plan reduced anxiety significantly. Parents and caregivers noted they felt like they had increased understanding of the treatment and of the medications themselves.18

Overall, a multipronged approach and good communication provides optimal treatment options for patients. 

Disclosure: Dr. Lio reports no relevant financial relationships.

References

1. Brown SJ, Irvine AD. Atopic eczema and the filaggrin story. Semin Cutan Med Surg. 2008;27(2):128-137. 

2. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007;120(1):150-155. 

3. Cork MJ, Britton J, Butler L, Young S, Murphy R, Keohane SG. Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse. Br J Dermatol. 2003;149(3):582-589.

4. Shi VY, Tran K, Lio PA. A comparison of physicochemical properties of a selection of modern moisturizers: hydrophilic index and pH. J Drugs Dermatol. 2012;11(5):633-636.

5. Simpson EL, Berry TM, Brown PA, Hanifin JM. A pilot study of emollient therapy for the primary prevention of atopic dermatitis. J Am Acad Dermatol. 2010;63(4):587-593.

6. Chiang C, Eichenfield LF. Quantitative assessment of combination bathing and moisturizing regimens on skin hydration in atopic dermatitis. Pediatr Dermatol. 2009;26(3):273-278. 

7. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics. 2009;123(5):e808-814. 

8. Leung AD, Schiltz AM, Hall CF, Liu AH. Severe atopic dermatitis is associated with a high burden of environmental Staphylococcus aureus. Clin Exp Allergy. 2008;38(5):789-793. 

9. Nakamura Y, Oscherwitz J, Cease KB, et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature. 2013;503(7476):397-401. 

10. Leung TH, Zhang LF, Wang J, Ning S, Knox SJ, Kim SK. Topical hypochlorite ameliorates NF-κB-mediated skin diseases in mice. J Clin Invest. 2013;123(12):5361-5370.

11. Ismail IH, Oppedisano F, Joseph SJ, et al. Reduced gut microbial diversity in early life is associated with later development of eczema but not atopy in high-risk infants. Pediatr Allergy Immunol. 2012;23(7):674-681.

12.  Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low diversity of the gut microbiota in infants with atopic eczema. J Allergy Clin Immunol. 2012;129(2):434-440, 440.e1-2.

13. Kong HH, Oh J, Deming C, et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012;22(5):850-859.

14. Wollenberg A, Sidhu MK, Odeyemi I, et al. Economic evaluation of maintenance treatment with tacrolimus 0.1% ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol. 2008;159(6):1322-1330. 

15. Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy. 2008;63(6):742-750. 

16. Madan V, August PJ, Chalmers RJ. Efficacy of topical tacrolimus 0.3% in clobetasol propionate 0.05% ointment in therapy-resistant cutaneous lupus erythematosus: a cohort study. Clin Exp Dermatol. 2010;35(1):27-30.

17. Tominaga M, Takamori K. An update on peripheral mechanisms and treatments of itch. Biol Pharm Bull. 2013;36(8):1241-1247. 

18. Shi VY, Nanda S, Lee K, Armstrong AW, Lio PA. Improving patient education with an eczema action plan: a randomized controlled trial. JAMA Dermatol. 2013;149(4):481-483. 

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