Supported by Promius Pharma, LLC
Dermatology
Therapeutic Update
An informational newsletter for pediatricians
Editor’s Message
s a dermatologist who practices each week Atopic Dermatitis
A in the trenches seeing many patients, and
also as one who is heavily involved in clini-
cal research and many academic endeavors, I can
by James Q. Del Rosso, DO, FAOCD
topic dermatitis (AD) is a very common condition caused by a combina-
A
appreciate the difficulty in trying to translate new
scientific information into practical application at tion of genetic and environmental factors. Although many of the genetic
the bedside. Based on data from the National factors that predispose individuals to the disease are not yet known,
Center for Health Statistics (Centers for Disease many of the irritants and pathogens have been identified.1 The prevailing view
Control and Prevention), eczematous dermatoses, is that genetic factors cause a defect in the function of the immune system, lead-
ing to disease onset. However, research and our developing understanding of
including atopic dermatitis, comprise approximate-
the skin barrier point to a second theory in which genetic factors cause a defec-
ly six percent of annual visits to dermatology prac- tive skin barrier, leading to disease onset.
tices and one percent to all physicians—an astro- The inherent challenges faced by individuals with AD as they face the world
nomical number of individuals in the United States! each day are many.2,3 With regard to their skin, they typically demonstrate hyper-
In fact, atopic dermatitis is a global problem that is reactivity to several allergens and irritants leading to the common complaints of
on the rise regarding prevalence, and it does not frequent and severe “itching” along with recurrent “rashes.”3 It can be said that
spare any ethnicity or gender. “asthma is to over-reactive airways as AD is to over-reactive skin.” Many second-
As new information comes to light on pathologi- ary skin features occur, such as keratosis pilaris, pityriasis alba, and ichthyosis
cal mechanisms involved in atopic dermatitis, we vulgaris. Epidermal barrier dysfunction leads to increased transepidermal water
collect more pieces of the puzzle. Thanks to dedicat- loss, resulting in xerosis (“dry skin”).4 Abnormalities of naturally occurring
ed basic scientists, we have more information on antimicrobial peptides in skin lead to increased colonization with Staphylococcus
aureus, including involvement of the anterior nares.5 Despite some components
details related to aberrations in innate, cellular, and
of immune system hyper-reactivity, immunologic “blind spots” do occur, with
humoral immunity; defects in antimicrobial defense increased propensity for molluscum contagiosum infection and eczema her-
and host response; and epidermal barrier dysfunc- peticum. Beyond skin, individuals with AD commonly exhibit a hyperactive
tion. This latter factor is receiving significant atten- humoral immunity system characterized by increased serum levels of
tion in atopic dermatitis, especially due to recent immunoglobulin E (IgE).6 Many experience allergic response to aeroallergens,
information on alterations in skin lipids and defects manifesting as allergic rhinitis-sinusitis and/or asthma, and food allergens.
related to filaggrin within the stratum corneum. No As stated above, the challenges of individuals with AD are many, and the
pun intended, but this information is just “scratch- severity of each disease manifestation may vary over the course of their life-
ing the surface” of what we hope to uncover with times. It has recently been postulated that genetic factors cause a defect in the
additional research. skin barrier in AD, characterized by reduced levels of physiological ceramides
I hope this newsletter offers you valuable infor- continued on page 2
mation, especially related to epidermal barrier dys-
function and its relationship to atopic dermatitis.
Treatment of atopic dermatitis involves more than
just application of the appropriate topical corticos-
teroid to control disease flares. As atopic dermatitis Atopic dermatitis is
is associated with inherent tendencies of skin to be the most common
continually dry, and to develop exacerbations asso- childhood disorder in
ciated with pruritus and skin eruptions, optimal developing countries.
therapy addresses both short-term management of The most common
flares and long-term management to sustain skin behaviors among
barrier integrity. young children with
atopic dermatitis are
James Q. Del Rosso, DO, FAOCD
irritability, fussiness,
Dermatology Residency Director
Valley Hospital Medical Center crying, and loss of
Las Vegas, Nevada sleep.
Clinical Associate Professor
(Dermatology)
Touro University College of
Osteopathic Medicine
Henderson, Nevada, and
University of Nevada
School of Medicine
Las Vegas, Nevada
Las Vegas Skin & Cancer Clinics SUMMER 2009
Las Vegas and Henderson, Nevada
Dermatology Therapeutic Update
An informational newsletter for pediatricians
continued from page 1
and lipids. Treatment aimed at normal- References er in atopic dermatitis. In: Bieber T,
ization of the skin barrier corrects the 1. Maintz L, Novak N. Getting more and Leung DY, eds. Atopic Dermatitis.New
underlying biochemical defect and repre- more complex: the pathophysiology of York, NY: Marcel Dekker; 2002:
sents a rational approach to atopic thera- atopic eczema. Eur J Dermatol. 123–143.
py.2 Many topical preparations, including 2007;17:267–283. 5. Leung DY. Role of Staphylococcus
over-the-counter moisturizers and pre- 2. Elias PM, Hatano Y, Williams ML. aureus in atopic dermatitis. In: Bieber
scription barrier repair creams, are mar- Basis for the barrier abnormality in T, Leung DY, eds. Atopic Dermatitis.
keted, and it is difficult to differentiate atopic dermatitis: outside-inside-out- New York, NY: Marcel Dekker; 2002:
these agents with regard to their content side pathogenic mechanisms. J Allergy 401–418.
and therapeutic value. Some are well for- Clin Immunol. 2008;121:1337–1343. 6. Erwin EA, Platts-Mills TAE. Aero-
mulated, and in some cases are backed by 3. Wuthrich B, Schmid-Grendelmeier allergens. In: Bieber T, Leung DY, eds.
clinical studies. Others are not. This Peter. Definition and diagnosis of Atopic Dermatitis. New York, NY:
newsletter discusses scientific and clini- intrinsic vs. extrinsic atopic dermati- Marcel Dekker; 2002:357–374.
cal data related to a prescription barrier tis. In: Bieber T, Leung DY, eds. Atopic
repair cream, EpiCeram® Emulsion, which Dermatitis. New York, NY: Marcel
is formulated to help normalize the lipid Dekker; 2002:1–20.
barrier of the stratum corneum. 4. Proksch E, Elias PM. Epidermal barri-
Advances in Atopic Dermatitis Pathophysiology
by Peter Elias, MD
The prevalence of atopic dermatitis from the more traditional, inside-out cells that are constantly shed from the
(AD) has been difficult to determine part- theory. According to the inside-out surface.4 The structural organization of
ly because of age, remission, and the hypothesis, AD is caused by genetic fac- the stratum corneum (SC) can be viewed
uncertainty of the course of mild AD. It is tors that lead to defects in immune reg- as a two-compartment system termed the
generally estimated that AD affects 10 to ulation. This defective immune regula- brick and mortar model (Figure 1).
20 percent of children in industrialized tion is thought to be the primary driver The first compartment (bricks) consists
nations and three percent of adults.1,2 The of AD. Alternatively, the outside-in of layers of anucleated corneocytes that
prevalence of AD seems to be increasing hypothesis postulates that AD is caused provide a tough, resilient framework and
over the last few decades.1 In the United by genetic factors that lead to a defec- an ultraviolet (UV) barrier. Anucleated
States alone, there are more than 15 mil- tive skin barrier including ceramides corneocytes have a cornified cell envelope
lion people with the symptoms of AD, and and lipids. Inflammation, itch, and dry consisting of a cross-linked protein that
the direct cost of treating them is estimat- skin are consequences of a cascade of forms just below the cytoplasmic mem-
ed to exceed $1 billion.3 Dermatologists events that begins with an inherently brane and provides a scaffold for the
and researchers are continuing to investi- defective skin barrier. The immune organization of the extracellular lipid
gate the increasing prevalence of AD as response is still part of the theory, just lamellae.
they push for a better understanding of not the primary driver of the condition. The second compartment (mortar) is the
the pathophysiology of AD in hopes of extracellular matrix, which provides both
finding an optimal therapy. In recent The Structure of the Skin Barrier permeability and antimicrobial barriers.
years, the focus of research has shifted The outside-in theory developed as our The extracellular matrix consists primari-
from immunology to the relationship of understanding evolved of the skin as a ly of ceramides, cholesterol, free fatty
skin barrier function and AD. From this dynamic interface between a hostile out- acids, as well as specific proteins, such as
research, a new theory has emerged to side environment and the internal aque- antimicrobial peptides. These components
explain the pathophysiology of AD, the ous body. The skin accomplishes this by form a series of lipid bilayers that sur-
“outside-in” theory. producing a protective, semipermeable round the corneocytes (bricks). Protein
barrier constantly maintained by the bridges called corneodesmosomes connect
Pathophysiology reproduction of epidermal keratinocytes the corneocytes in the lower SC, but are
The newer theory of AD, the outside- that migrate to the skin’s surface as they progressively degraded, allowing the cor-
in theory, is not mutually exclusive transition into corneocytes to replace neocytes to be shed.
2
Dermatology Therapeutic Update
An informational newsletter for pediatricians
Outside-In Theory basophils, and eosino-
It is postulated that a genetic abnormali- phils, allowing them to Normal Skin Barrier
ty causes a defect in the skin barrier of recognize the antigen
patients with AD. This defect in turn has and secrete a variety of
three consequences. First, there is an inflammatory media-
increase in transepidermal water loss tors. These mediators
(TEWL), paralleled by increased allergen collectively cause in-
penetration into the SC, and finally, a stim- creased vascular perme-
ulation of the release of cytokines (IL-1α ability, vasodilation, and
and TNF-α) from the SC. The cytokines local inflammation. This
stimulate type 1 helper T cells (TH1) and cascade of events leads
macrophages, leading to an acute inflamma- to a vicious cycle that
tory response (Figure 2, Initial). increases clinical severi-
From this point on, the two views of AD ty of AD.
are highly similar (Figure 2, Ongoing).
Allergens that penetrate through the defec- Support of the
Figure 1. Schematic diagram of the epidermis. Epidermal differentiation is
tive skin barrier are encountered by den- Outside-In Theory accompanied by generation of corneocytes and extracellular lamellae
dritic cells that reside in the skin. The den- The failure of several lipids. The stratum granulosum secretes lamellar bodies containing lipids
dritic cells then stimulate naïve T cells to functions of the skin and enzymes that create mature lipid bilayers. The resulting skin barrier
regulates movement of water and exogenous material.
become TH2 cells. TH2 cells produce proin- barrier suggests that
flammatory cytokines (IL-4, IL-5, and IL- AD represents a disease
13), and stimulate B cells to produce anti- of broad barrier failure, rather than a is not merely a consequence of inflamma-
gen-specific IgE (Figure 2, Ongoing).5 defect in a single function.6 tion.7–9 Secondly, patients with AD have a
Increased production of proinflammatory Several lines of evidence support the out- decreased amount of lipids and ceramides
cytokines causes decreased production of side-in theory that AD is caused by a defect in both lesional and nonlesional skin.
ceramides, filaggrin, and antimicrobial pep- in the skin barrier. Disease severity corre- Again, this demonstrates that the defective
tides. The increased production of IgE fur- lates to the extent of the barrier abnormal- skin barrier of atopic patients is not limited
ther enhances hypersensitivity to the aller- ity even in uninvolved skin (Figure 3). to lesional skin with inflammation. Lastly,
gen exposure. IgE binds with mast cells, Thus, the defective regulation of water loss AD is linked to several mutations in the
Diagram of the Outside-In Theory of Atopic Dermatitis
Diagram Key
Figure 2. The outside-in theory of atopic dermatitis. A defect in the skin barrier permits increased exposure to allergens, increased transepidermal water loss, and
release of cytokines, leading to an allergic inflammatory response that can exacerbate skin damage.
3
Dermatology Therapeutic Update
An informational newsletter for pediatricians
A B C
Figure 3. Impaired barrier function in patients with AD. Transepidermal water loss (TEWL) and lipid content were measured in lesional and nonlesional skin of
patients with AD and in healthy controls. (A) TEWL was increased in nonlesional and lesional skin of patients with AD compared to the skin of normal controls
(N=8). (B) Total lipid content in patients with AD and healthy subjects. Stratum corneum (SC) was removed from the volar side of the forearms by tape stripping.
SC lipids were then extracted, separated by thin layer chromatography, charred, and quantified by photodensitometry.35 (C) Ceramide content in healthy subjects
and patients with AD.35
gene encoding filaggrin. Filaggrin plays an essential role in the 2. Williams H, Robertson C, Stewart A, et al. Worldwide variations in the
structure and hydration of corneocytes in the SC. Furthermore, prevalence of symptoms of atopic eczema in the International Study of
filaggrin degradation products contribute to acidification of the SC. Asthma and Allergies in Childhood. J Allergy Clin Immunol.
A reduction or loss of expression of filaggrin is a major predispos- 1999;103:125–138.
ing factor to AD. Four common mutations in the gene encoding 3. Bickers DR, Lim HW, Margolis D, et al. The burden of skin diseases: 2004.
filaggrin are present in approximately 10 percent of individuals of A joint project of the American Academy of Dermatology Association and
European origin.10 Therefore, a decreased filaggrin expression may the Society for Investigative Dermatology. J Am Acad Dermatol.
cause an increase in pH that adversely affects enzymatic activity 2006;55:490–500.
related to ceramide production within the extracellular spaces of 4. Madison KC. Barrier function of the skin: “la raison d’être” of the epider-
the SC. mis. J Invest Dermatol. 2003;121:231–241.
5. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. The adaptive
Clinical Applications of the Outside-In Theory immune system. In: Alberts B, Johnson A, Lewis J, Raff M, Roberts K,
Topical corticosteroids and topical immunomodulators, the stan- Walter P, eds. Molecular Biology of the Cell. 4th ed. New York, NY:
dard treatment options for the management of AD, address the Garland Science; 2005:1363–1421.
downstream inflammation and itch presenting in atopic patients. 6. Denda M, Sato J, Tsuchiya T, Elias PM, Feingold KR. Low humidity stim-
These agents are generally accepted as effective treatment ulates epidermal DNA synthesis and amplifies the hyperproliferative
options for a wide range of disease severity; however, they carry response to barrier disruption: implication for seasonal exacerbations of
safety concerns with long-term usage and usage within specific inflammatory dermatoses. J Invest Dermatol. 1998;111:873–878.
patient populations. The outside-in theory of AD predicts that a 7. Aberg KM, Man MQ, Gallo RL, et al. Co-regulation and interdependence
therapeutic product that truly addresses the defective skin barri- of the mammalian epidermal permeability and antimicrobial barriers. J
er could effectively manage AD. Research has shown that a novel, Invest Dermatol. 2008;128:917–925.
ceramide-dominant, triple lipid product (EpiCeram® Skin Barrier 8. Jensen JM, Fölster-Holst R, Baranowsky A, et al. Impaired sphingomyeli-
Emulsion, marketed by Promius Pharma, LLC) can manage the nase activity and epidermal differentiation in atopic dermatitis. J Invest
signs and symptoms of AD by helping to normalize the defective Dermatol. 2004;122:1423–1431.
skin barrier. In a clinical study, EpiCeram® Emulsion demonstrat- 9. Chamlin SL, Kao J, Frieden IJ, et al. Ceramide-dominant barrier repair
ed comparable efficacy to fluticasone propionate cream 0.05% lipids alleviate childhood atopic dermatitis: changes in barrier function
(Cutivate Cream) after 28 days of treatment. provide a sensitive indicator of disease activity. J Am Acad Dermatol.
2002;47:198–208.
References 10. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-
1. Larsen FS, Hanifin JM. Epidemiology of atopic dermatitis. Immunol function variants of the epidermal barrier protein filaggrin are a major
Allergy Clin North Am. 2002;22:1–24. predisposing factor for atopic dermatitis. Nat Genet. 2006;38: 441–446.
4
The Use of a Novel Nonsteroidal Therapy
in the Treatment of Atopic Dermatitis
by Jeffrey Sugarman, MD, PhD
Current treatment options for atopic der- for 28 days. Fifty-nine patients received Day 28 (P0.05). Both treatments
immunomodulators are considered highly The primary outcome was reduction from demonstrated a significant change from
effective, these agents may be associated baseline of clinical disease severity baseline at both time points.
with unacceptable long-term side effects. assessed by changes in SCORAD. SCO-
On the other hand, over-the-counter mois- RAD values are determined by the percent Secondary End Point:
turizers are considered to have an extreme- of the patient’s body covered by AD, the Improvement in Sleep Habits
ly good safety profile, but their efficacy as a severity of the lesions (erythema, excoria- Sleep habit scores were based on a 0 to
monotherapy has not been well estab- tion, edema, lichenification, oozing, and 10 scale, with 10 being great difficulty
lished. The limitations of these therapies xerosis), and the subjective scores of pruri- sleeping. Patients treated with EpiCeram®
have created a need for other therapeutic tus. Other secondary efficacy measures Emulsion demonstrated a significant
options that deliver efficacy comparable to included the reduction from baseline in improvement in sleep habits from base-
topical corticosteroids or immunomodula- pruritus and improvement in sleep habits. line—a 74-percent reduction at Day 28
tors with a safety profile closer to that of a (P0.05). Both treatments
potential to fill the therapeutic void by EpiCeram® Emulsion demonstrated a sig- demonstrated a significant change from
delivering efficacy comparable to a mid- nificant improvement in SCORAD from baseline at both time points.
potent topical steroid with an excellent baseline—a 56-percent decrease at Day 28
safety profile. In a clinical study, (P0.05). At Day 14, although both with comparable efficacy to fluticasone
patients with moderate AD.1 groups improved relative to control, signif- propionate cream 0.05% after 28 days of
icantly more patients in the fluticasone treatment.
Clinical Study Demonstrating the group had an excellent reduction in SCO- Based on the outside-in theory, patients
Efficacy of EpiCeram® Emulsion as a RAD (35% vs. 7.5%). with AD have a defective skin barrier
Treatment for Atopic Dermatitis caused by genetic abnormalities. This
The efficacy of EpiCeram® Emulsion was Secondary End Point: defective skin barrier is proposed to be the
evaluated in a prospective, randomized, Decreased Pruritus primary driver of AD and the first step in a
investigator-blinded, active-controlled, mul- Self-assessments of pruritus were based cascade of events that ultimately leads to
ticenter study and compared to fluticasone on a 0 to 10 scale, with 10 being the worst the signs and symptoms of AD. EpiCeram®
propionate cream 0.05% in 121 patients imaginable itching. Patients treated with Skin Barrier Emulsion is a prescription
with moderate AD. EpiCeram® Emulsion or EpiCeram® Emulsion demonstrated a sig- therapy that delivers an optimal 3:1:1 ratio
fluticasone propionate cream was applied nificant improvement in pruritus scores of ceramides, cholesterol, and free fatty
topically to all active areas of AD twice daily from baseline—a 59-percent reduction at acids to help repair this defective skin bar-
Figure 1. Mean SCORAD at Day 28 Figure 2. Mean subjective pruritus scores at Day 28
5
Dermatology Therapeutic Update
An informational newsletter for pediatricians
rier of patients with AD. It is postulated
that these physiological lipids traverse the
stratum corneum (SC), are absorbed by the
stratum granulosum, and are secreted into
extracellular spaces of the SC to correct
the underlying biochemical abnormality of
the skin barrier. This optimal ratio is
designed to help correct the barrier abnor-
mality in patients with AD. In one study in
mice, preparations that did not have these
ingredients in the proper ratio did not
accelerate barrier normalization and even
impeded repair (Figure 3).2 The graph seen
in Figure 3 demonstrates that not only is it
important to have the proper building
blocks of the lipid bilayer (ceramides, cho-
lesterol, and free fatty acids), but it is also
important that they be in an optimal ratio.
Too much of any one ingredient and the
formulation will not effectively reduce
TEWL. The clinical application of this was
demonstrated in the clinical trial.
Figure 3. Results from a study in which different proportions of lipids were applied to acetone-treated
mice. Transepidermal water loss was measured at two hours.
Treatment with EpiCeram® Emulsion
EpiCeram® Emulsion EpiCeram® Emulsion +/–
midpotent TCS or TIMs
OTC moisturizer EpiCeram® Emulsion
for maintenance for maintenance
EpiCeram® Emulsion EpiCeram® Emulsion +/–
midpotent TCS or TIMs
Figure 4. Proposed use. EpiCeram® Emulsion may be used as first-line therapy with the initial appearance of symptoms. Midpotent topical corticosteroid (TCS) or
TIMs may be used in combination with EpiCeram® Emulsion for more severe disease. Once the disease is well controlled, EpiCeram® Emulsion may be used as
maintenance therapy to minimize relapses. High-potency TCS may be reserved for major exacerbations.
6
Dermatology Therapeutic Update
An informational newsletter for pediatricians
EpiCeram® Emulsion was shown to have py in patients with mild-to-moderate AD and
comparable efficacy with fluticasone propi- a combination of EpiCeram® Emulsion with a
onate 0.05% cream in patients with moder- topical corticosteroid as initial therapy in MATRIX MEDICAL COMMUNICATIONS
ate AD at Day 28. patients with more severe presentations of publisher of
AD until initial control is achieved.
Conclusion
EpiCeram® Emulsion may be used as References
an alternative to the current standard of 1. Data on file. A prospective, randomized, investi- PRESIDENT
topical corticosteroids and topical gator-blind, controlled, pilot study comparing Robert L. Dougherty
immunomodulators for AD patients with the effect of EpiCeram® device versus conserva- rdougherty@matrixmedcom.com
mild-to-moderate severity and may tive standard of care therapy utilizing mid- PARTNER
decrease the need for topical corticos- strength topical steroid (fluticasone propionate Patrick D. Scullin
teroids and topical immunomodulators 0.05%) in the treatment of atopic dermatitis in pscullin@matrixmedcom.com
(Figure 4). Understanding the outside-in pediatric patients. Bridgewater, NJ: Promius VICE PRESIDENT, PUBLISHER
theory of AD leads a physician to believe Pharma, LLC; 2008. Joseph J. Morris
that all atopic patients should receive a 2. Man MQ, Feingold KR, Thornfeldt CR, Elias jmorris@matrixmedcom.com
treatment that addresses the defective PM. Optimization of physiologic lipid mixtures VICE PRESIDENT, EDITORIAL DIRECTOR
skin barrier of AD. Physicians should consid- for barrier repair. J Invest Dermatol. Elizabeth A. Klumpp
er using EpiCeram® Emulsion as monothera- 1996;106:1096–1101. eklumpp@matrixmedcom.com
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