Current Treatment Strategies in Dermatology

Transcription

l
ia t
ec or
Sp ep
R
Supplement to
®
www.the-dermatologist.com
Practical and Clinical Insights into Today’s Dermatology Issues | August 2012
S
R pe
ep c
o i al
rt
Contents
3 Patient Resources
When treating patients who present to you with conditions like acne, rosacea, psoriasis, skin cancer and atopic dermatitis,
there are several great patient support groups and websites you can recommend.
Stefanie Tuleya, Executive Editor
7 Current Treatment Options for Acne Vulgaris and Acne Rosacea
A review of the proposed pathogenesis of these conditions as well as the many different treatment options available.
Lindsay C. Strowd, MD
15 The Therapeutic Approach to Psoriasis
Recent research has shown the role that the immune system plays in the pathogenesis of this disease, which may lead
to the development of immune-specific therapies. This article highlights current approaches in treating and managing
patients with psoriasis.
Alyssa S. Daniel, MD
24 Current Treatment Strategies for Skin Cancer
A review of novel approaches and combination therapies to effectively manage skin cancer.
Jenna L. O’Neill, MD
33 Current Trends in Atopic Dermatitis Treatment: More Than Just Steroids
As the cause of the condition is considered multifactorial, the treatment plan should include combination therapies and
avoidance of triggers.
Megan A. Kinney, MD, MHAM
41 New Products
42 Calendar of Events
HMP Communications
Editorial Staff
Design & Production
Business Staff
83 General Warren Blvd,
Suite 100
Malvern, PA 19355
Executive Editor
Stefanie Tuleya
Creative Director
Vic Geanopulos
Vice President/Group Publisher
Christopher Ciraulo
Assistant Editor
Julia Ernst, MS
Art Director
Karen Copestakes
Publishing Director
Michael F. DiBella
Special Projects Editor
Stephanie Wasek
Production Manager
Monica McLaughlin
Publisher
Sydney Slater
(800) 237-7285
(610) 560-0500
Fax (610) 560-0501
Copyright 2012 © HMP Communications, LLC
2
August 2012 The Dermatologist® Current Treatment Strategies in Dermatology
Patient Resources
When treating patients who present to you with conditions like acne, rosacea, psoriasis, skin cancer and
atopic dermatitis, there are several great patient support groups and websites you can recommend.
Stefanie Tuleya, Executive Editor
I
n an effort to help patients cope with a new diagnosis or a
chronic, long-term condition, referral to organizations or resources the patient can consult between office visits can be
extremely valuable. These organizations and resources can offer
educational materials, support through contact with other patients and answers to frequently asked questions. Here is a look at
some of the available resources to share with your patients.
Acne
The American Academy of Dermatology (AAD) offers AcneNet — www.skincarephysicians.com/acnenet — which
includes an overview of the causes of acne and articles about
treatment and skin care tips. The acne treatment section describes over-the-counter treatments and prescription medications, such as isotretinoin, oral antibiotics, oral contraceptives
and topicals, and also includes a discussion of physical procedures from chemical peels to phototherapy. There is also a
section of the site dedicated to acne scars, including frequently
asked questions and available treatments.
Another site, www.acnemonth.com, which is supported by
Galderma, contains information about National Acne Month,
which is held in June. On this site, patients can learn about
the causes of acne and treatments; it includes a section on
how to talk to doctors about acne, with suggested questions
they should ask and what questions from their doctors they
should be prepared to answer.The Acne: Facts or Fiction page
dispels several common acne myths.There are tips for patients
on how to care for their skin and take control of their acne.
In addition, there are videos from leading dermatologists that
offer tips for parents on how to help their teens with acne.
Atopic Dermatitis
Eczema, particularly moderate to severe atopic dermatitis,
can be very difficult for patients and their families to deal
with on a daily basis. The burden can be attributed to painful
flares, difficulty sleeping and sometimes embarrassment from
the highly visible physical signs and symptoms.
Helping patients understand the condition and the best
treatments and offering tips that help them comply with their
treatments will go a long way in helping them control flares
and cope, both physically and psychologically.
The National Eczema Association (NEA) organization supwww.the-dermatologist.com
Groups like the NEA are great resources for patients.
ports patients with eczema and associated conditions. Its mission, as described on its website (www.nationaleczema.org), is
to improve “the health and quality of life for individuals with
eczema through research, support and education.”
The NEA is a national, patient-oriented organization governed by a Board of Directors and guided by a Scientific Advisory Committee of physicians and scientists who donate
their time and expertise.
Through the site, visitors can sign up to receive the association’s newsletter, The Advocate. Patients can search the site
for tips from others who also have eczema, watch treatment
videos, find ways to get involved in advocacy, download educational pamphlets for parents as well as educators and find
information about current research.
The NEA also offers programs like The Eczema & Sensitive-Skin Education (EASE) Program and the Seal of Acceptance program, which are designed to help identify products
that are best for patients with eczema.
Through the organization’s website, patients can access educational references about skin care and treatment tips and a
3D eczema photo library.
The AAD also offers EczemaNet (www.skincarephysicians.
com/eczemanet), which includes background information on
eczema, definitions of types of eczema, how the condition is
diagnosed, treatment overviews, tips for preventing flare-ups,
3
Patient Resources
frequently-asked questions and news and articles on the topic.
Various sections include reference guides, such as bathing and
moisturizing guidelines, plus lists of products to avoid and tips
specifically for atopic dermatitis patients.
Psoriasis
The National Psoriasis Foundation (NPF), whose mission is “to find a cure for psoriasis and psoriatic arthritis
and to eliminate their devastating effects through research,
advocacy and education,” was established in October 1968.
However, the organization, according to press material
from the NPF, actually started on August 29, 1966, when
Beverly Foster’s husband placed a classified ad in a Portland,
OR, newspaper asking people with psoriasis to call her so
she would have others to talk with about her severe psoriasis. After receiving more than 100 calls in a week, Beverly
Foster began organizing meetings and initially formed the
Psoriasis Society of Oregon, which eventually became the
National Psoriasis Foundation, with a group of volunteers
who are raising money to increase awareness about psoriasis and help raise money and interest for more research
about the condition.
This organization, which patients can learn more about by
visiting www.psoriasis.org, offers several programs and services for patients with psoriasis, lobbies on Capitol Hill and
provides support to those living with psoriatic diseases.
On the website, patients can learn about psoriasis — from
types of psoriasis, treatment options and answers to frequently
asked questions to more information about their rights to
healthcare. There is information on how to get involved with
volunteer work, how to find a doctor and tips for navigating
the healthcare system.
The NPF works with insurance companies to reform restrictive policies that prevent psoriasis and psoriatic arthritis
patients from getting the care they need. One such initiative,
its Access Action Guide, is a step-by-step guide for patients to
access health care through insurance programs.
As a member of the NPF, patients can connect with others living with these conditions through message boards, networks, webcasts, mentoring programs and more. Patients can
also connect to the NPF through the organization’s social networking sites on Twitter (www.twitter.com/NPF) and Facebook (www.facebook.com/NationalPsoriasis.Foundation).
The NPS also has a site, www.psome.org, for children
who have psoriasis or psoriatic arthritis. On this site, patients and their parents can connect with others who are in
the same situation and they can also have access to downloadable resources like handouts for schoolmates, teammates and others in the community to help explain what
the conditions are.
Rosacea
The National Rosacea Society (NRS), which was started
in 1992 and celebrates its 20th anniversary this year, provides
support to the estimated 16 million Americans who live with
rosacea. According to the organization, which patients can
4
learn more about at www.rosacea.org, the NRS uses education and advocacy to meet its mission, which is:
• To raise awareness of rosacea.
• To provide public health information on the disorder.
• To encourage and support medical research that may lead to improvements in its management, prevention and potential cure.”
The NRS also offers a grants program to encourage and
support medical research to improve rosacea treatment, management and potential prevention. The program is supported
entirely by donations.
The group’s website offers patients everything from an
overview of treatment options to makeup tips and rosacea triggers to avoid. The NRS offers brochures, such as a
“Rosacea Diary: An Easy Way to Find and Avoid Your Personal Rosacea Triggers,” and its Rosacea Review newsletter,
both of which patients can order online. There are several
photos depicting the types of rosacea, as well and before
and after treatment photos.
Skin Cancer
Since its founding in 1979, the Skin Cancer Foundation
(www.skincancer.org) has worked to educate the public and
the medical profession about skin cancer, prevention by means
of sun protection, the need for early detection, and prompt,
effective treatment, according to its website.
Through the site, patients can access accurate information about diagnosis and treatment options — whether it’s
actinic keratosis, basal cell carcinoma, squamous cell carcinoma or melanoma. It offers skin cancer facts, video descriptions, news and more. And, since prevention is one of
the Foundation’s main goals, there is a significant amount
of information about self examinations, signs to look for
and information about sun protective clothes and sunscreens. Patients can also find the Skin Cancer Foundation
on Facebook (www.facebook.com/skincancerfoundation)
and Twitter (twitter.com/skincancerorg).
The Mayo Clinic also offers a skin cancer resource on
its
website
(www.mayoclinic.com/health/skin-cancer/
DS00190). This site organizes information by:
• Basic, which includes information about definitions,
symptoms, how patients can prepare for appointments,
treatment options, prevention tips and more.
• In-Depth, which offers more detailed information about
tests and diagnosis, how treatments like Mohs surgery
work, and answers about sunscreens.
• Multimedia, which includes images, videos and slideshows.
•E
xpert Answers, which offers a Q&A about tanning bed use.
• Resources, which includes information about Mayo Clinic
services and links to other sites.
The AAD offers SkinCancerNet, which patients can access at www.skincarephysicians.com/skincancernet. The site
includes recent news about advances in treatments, information about what skin cancer is, how it’s caused, prevention
tips and information about diagnosis and treatment. It has a
link for patients to sign up for a free, monthly e-newsletter
from the AAD. n
Current Treatment Options for Acne
Vulgaris and Acne Rosacea
A review of the proposed pathogenesis of these conditions as well as the many different treatment
options available.
Lindsay C. Strowd, MD
Figure 1. Inflammatory papules on the cheeks and periorbital skin. These papules are characteristic of both
acne vulgaris and the papulopustular variant of acne rosacea.
Photograph courtesy of Graham Library, Wake Forest Baptist Health Department of Dermatology.
A
cne vulgaris and acne rosacea are two distinct but
related entities that affect more than 60 million
Americans combined and cost upward of $3 billion yearly. These diseases have a significant, negative impact on quality of life.1 The terms acne vulgaris and
acne rosacea represent a group of diseases and disease subtypes with different clinical features and treatments. This article will briefly review the proposed pathogenesis of these
conditions and cover the many different treatment options
currently available.
7
Current Treatment Options For Acne Vulgaris And Acne Rosacea
Pathogenesis and Classification
The acne lesion originates from the pilosebaceous unit of the
skin, which explains its predilection for more sebaceous skin
like the face, chest and upper back. Shed keratinocytes form
a plug at the level of the hair infundibulum, which prevents
sebum from being extruded to the skin surface. The affected
pilosebaceous unit expands until the comedo ruptures, creating
inflammation. Because sebaceous glands are heavily influenced
by hormonal stimulation, increases in hormone levels (such as
with adrenarche) often precipitate the development of acne.
Proprionibacterium acnes (P. acnes) are Gram-positive rods found
within the pilosebaceous unit and contribute to acne formation by inducing comedo rupture and generating pro-inflammatory cytokines.2 Despite popular belief, there is no evidence
to suggest that exogenous factors such as make-up or skincare
products contribute to acne development.3
Acne vulgaris can be organized into two main categories
based on lesion morphology: inflammatory and non-inflammatory, or comedonal. While a minority of patients will have,
exclusively, one type of acne, the majority present with both
types of lesions. There is a wide spectrum of disease severity
among patients, ranging from mild comedonal acne to severe
nodulocystic scarring acne. Several acne variants exist and include acne conglobata, acne fulminans, drug-induced acne and
acne in the setting of syndromes like SAPHO (synovitis, acne,
pustulosis, hyperostosis, osteitis) and PAPA (pyogenic arthritis,
pyoderma gangrenosum, acne). Acne conglobata, defined as
severe nodulocystic acne without systemic manifestations, is
often associated with dissecting cellulitis of the scalp, hidradenitis suppurativa and pilar cysts, collectively known as the
tients with rosacea tend to be fair-skinned individuals in the
third decade of life and older. Key elements of pathogenesis
include the presence of inflammation in vascular and skin tissue
and vascular hyperreactivity. New studies are focusing on the
presence of antimicrobial and proinflammatory canthelicidins
and their impact on the altered immune response seen in rosacea patients. Infectious agents such as Demodex folliculorum mites
and Proprionibacterium acnes have also been implicated.5
Compared to acne, rosacea has more variable presentations, and, in contrast to acne vulgaris, rosacea can have
ocular involvement. Erythematotelangiectatic rosacea is
the most common variant and is characterized by episodic
flushing and the presence of facial telangiectasias, giving the
skin an overall ruddy appearance. Patients often complain of
stinging and burning sensations. Papulopustular rosacea is
the second most common subtype and more closely mimics acne vulgaris, with multiple inflammatory papules and
pustules on the face. Phymatous rosacea is less common but
can be extremely disfiguring, with nodular enlargement of
the nose along with increased sebaceous gland production.
Ocular rosacea can accompany other forms of rosacea or
be the only clinical manifestation of disease. Patients complain of itching, burning and redness of the conjunctiva and
lid margin. Several rare variants of rosacea exist, analogous
to acne variants discussed above. Granulomatous rosacea
is a rare variant in which patients develop indurated firm
papules and nodules on the face that can lead to scarring.
Rosacea fulminans is another rare rosacea variant that, like
acne fulminans, can have systemic complications and lead to
severe scarring and disfigurement.6
Topical Treatments
Compared to acne, rosacea has
more variable presentations,
and, in contrast to acne
vulgaris, rosacea can have
ocular involvement.
follicular occlusion tetrad. Acne fulminans is the most severe
form, with large, draining, ulcerated nodules accompanied by
systemic signs and symptoms such as fever, malaise, leukocytosis and elevated inflammatory markers. Drug-induced acne
has been reported with numerous medications but is relatively
common with the use of steroids and steroid-derivatives, as
well as lithium, iodides and bromides.4
Rosacea is another adnexal inflammatory disorder that often mimics acne vulgaris clinically but differs in epidemiology,
pathogenesis and subtypes.While acne typically affects younger
patients with any Fitzpatrick skin type, the vast majority of pa8
Numerous topical medications have been studied and used
extensively in the treatment of acne and rosacea.Topical treatments are the cornerstone of therapy for these conditions and
are beneficial in that they deliver the drug directly to the skin
while minimizing the side effects of systemic medications.
There is a significant body of literature available on different
topical medications for these entities, but there are relatively
few head-to-head, double blind, randomized, controlled trials comparing different topical acne and rosacea medications.
Many studies compare an active drug to placebo, thereby
making it difficult to say whether one topical medication is
truly more efficacious than another.
The first group of medications used for acne and rosacea
are topical antibiotics. This class of medications includes topical clindamycin, erythromycin, metronidazole and dapsone.
Topical antibiotics exert anti-microbial effects on P. acnes as
well as anti-inflammatory effects.2 These medications are
more commonly prescribed for inflammatory lesions of acne
and rosacea as opposed to comedonal lesions.
Topical clindamycin 1% is available in foam, gel, solution
and lotion formulations as well as in combination topical
medications with benzoyl peroxide and with tretinoin. Topical clindamycin tends to be well tolerated by patients with
Figure 2. Open comedones of acne vulgaris on periorbital skin.
minimal irritation and dryness. Systemic absorption is minimized with topical application, which greatly decreases the
risk of serious side effects such as pseudomembranous colitis.
Topical erythromycin is an older acne and rosacea medication that also works by inhibiting the growth of P. acnes.
Erythromycin is available in a 2% concentration as an ointment, gel, solution and in pads as well as in a 3% concentration
combined with benzoyl peroxide.
Both topical clindamycin and erythromycin products have
been widely used for acne and, to a lesser degree, rosacea;
however, there is growing evidence and concern about the
development of P. acnes strains, which were resistant to these
antibiotics. The body of evidence is somewhat conflicting regarding increasing rates of resistant bacteria, but most providers use these topical antibiotics as short-term treatment and
usually avoid them as monotherapy.
Topical metronidazole is an FDA-approved first-line treatment for rosacea, especially the papulopustular variant. Several
studies have shown metronidazole to be significantly more effective than placebo in treating rosacea.7,8 Both 0.75% and 1%
concentrations are available in cream, gel and lotion formulations. Studies have shown that once-daily application of either
concentration is equally efficacious to twice-daily application
with no difference in efficacy between the two strengths.
Topical dapsone is the newest topical antibiotic to be FDAapproved for the treatment of acne. Dapsone downregulates tumor necrosis factor, prostaglandins and leukotrienes and inhibits
neutrophil function and migration. It is used in both oral and
topical preparations for dermatologic conditions, although oral
dapsone has serious potential risks, including methemoglobinemia and hemolytic anemia. Topical dapsone minimizes these
side effects while still targeting inflammatory acne lesions. In
one study, twice-daily application of topical dapsone 5% gel
resulted in a 50% decrease in inflammatory lesions.2,9
Topical retinoids have been used for decades for both acne
vulgaris and acne rosacea. Retinoids treat acneiform lesions by
reducing follicular keratinization, which prevents microcomdone and comedone formation.2 Many studies have shown
that combining topical retinoids with other topical medications such as topical antibiotics and topical benzoyl peroxide
or salicylic acid have a synergistic effect on acne lesions.
Three topical retinoids are currently approved by the FDA
for acne: adapalene, tretinoin and tazarotene.
Adapalene is a third-generation retinoid that comes in 0.1%
and 0.3% concentrations and in several vehicles, including gel
and lotion. Adapalene is also available in a combination product with benzoyl peroxide and has shown synergistic effects on
acne lesions.10 Studies show adapalene has similar efficacy to
other topical retinoids but causes significantly less skin irritation,11 which is critically important when considering patient
adherence to a topical treatment regimen.
Tretinoin is a first-generation retinoid that is available in
multiple concentrations, including 0.025%, 0.04%, 0.5% and
0.1% as well as liquid, cream and gel vehicles. It is also available
9
Figure 3. Histologic demonstration of a comedonal lesion. Large amounts of keratinaceous debris fills a plugged
pilosebaceous unit, associated with significant surrounding inflammatory infiltrate.
as a combination product with topical clindamycin 1%. Combining tretinoin and clindamycin results in greater reduction
of acne lesions than either medicine used alone.12 Micronized
tretinoin is a newer topical formulation designed for better skin
penetration and reduced UV degradation along with less severe
skin irritation.13,14
Tazarotene is the third topical retinoid approved for acne
treatment and is a third-generation retinoid. Tazarotene comes
in 0.05% and 0.1% concentrations and is available as a cream or
gel. Though older studies initially showed topical tazarotene to
be superior to the other topical retinoids in acne lesion reduction, newer studies suggest it has similar efficacy to topical tretinoin and adapalene but is associated with significantly more
skin irritation.15,16
Topical retinoids are used much less frequently in acne rosacea and there is little evidence to provide direct support for
their use for this condition.17 Recently, one article showed
that topical tretinoin and clindamycin used in combination
may improve the erythematotelangiectatic subtype but not
the papulopustular subtype.18
Benzoyl peroxide and salicylic acid are two topical medications often used in combination with topical antibiotics, topical
10
retinoids or both for treatment of acne. The synergistic effect
of these medications is evident in the literature and reflected in
the increasing number of combination acne medications.19,20
Benzoyl peroxide is thought to improve acne via its antibacterial actions against P. acnes, while salicylic acid acts as both a
keratolytic and an anti-inflammatory molecule.21 The keratolytic properties of benzoyl peroxide may enhance the penetration of topical agents like antibiotics when applied in combination.22 Combination therapy with benzoyl peroxide and an
antibiotic has also been shown to decrease the emergence of
resistant strains. One study that compared a 5% benzoyl peroxide/clindamycin gel and clindamycin monotherapy showed a
> 1600% increase of clindamycin-resistant P. acnes from baseline
in the monotherapy group over a 16-week period.23 Benzoyl
peroxide combined with topical erythromycin reduced papular
lesions and Demodex populations and was comparable to topical metronidazole in rosacea patients.20
Both benzoyl peroxide and salicylic acid can result in skin
irritation and dryness. Benzoyl peroxide is now an over-thecounter product and comes in a wide range of concentrations
from 1% to 10%. Benzoyl peroxide is available as a topical
gel, cream, lotion and solution as well as a wash. Physicians
should warn patients that benzoyl peroxide bleaches dyed fabrics. Studies have also shown benzoyl peroxide can produce an
orange discoloration when combined with sulfur-containing
products and with topical dapsone24 and can oxidize clindamycin over time.2 Salicylic acid is also available over-the-counter
in a range of concentrations. Concentrations typically used
on the face for acne are on the weaker end of this spectrum
(0.5% to 3%). One study showed combining benzoyl peroxide
and salicylic acid resulted in the greatest reduction of acne lesions, more than topical clindamycin or combination topical
clindamycin and benzoyl peroxide.20
Several other topical medications are used for acne and rosacea. Azaleic acid is a topical medication available in a 15%
gel and a 20% cream for inflammatory acne and rosacea lesions. Currently, only the 15% concentration is FDA approved
for rosacea. Azelaic acid has anti-proliferative effects on keratinocytes, antimicrobial properties against P. acnes and decreases
sebum production. Studies have also shown azelaic acid to
scavenge reactive oxygen species and inhibit UVB-produced
pro-inflammatory cytokines.25 Several studies have shown azelaic acid to be significantly more effective than placebo in the
treatment of rosacea.7,8 Azelaic acid has the added benefit of
being pregnancy class B, allowing for use in pregnant patients.
Sulfur-sodium sulfacetamide (SSS) is an older medication
that has been approved by the FDA for acne and rosacea since
the 1950s. Sulfur and sodium sulfacetamide possess both anti-inflammatory and anti-bacterial properties against P. acnes
with moisturizing effects.26 Along with topical metronidazole
and azelaic acid, topical SSS has been extensively tested in rosacea patients. SSS is available in a lotion, cream, cleanser and
foam. Newer formulations like the foam reduce lesion counts
in both acne and rosacea patients while minimizing the unpleasant sulfur odor associated with older formulations.26,27,28
Azelaic acid and SSS are alternative products for patients who
cannot tolerate more irritating medications. They can also be
used in combination with other topical agents.
Finally, topical calcineurin inhibitors are sometimes prescribed for patients with steroid-induced rosacea for their antiinflammatory properties. Topical pimecrolimus 1% cream and
topical tacrolimus 1% ointment both significantly decrease lesion counts in rosacea and are well-tolerated.29 Other studies
have reported topical calcineurin inhibitors can induce rosacealike dermatitis.30 Topical zinc is a lesser known adjunct treatment for acne, but there are few studies examining its effectiveness.31 Botanical products have not been extensively studied in
acne and rosacea patients; most of the studies available are small
case series or are underpowered. Topical tea tree oil 5% gel has
been shown to be comparable to 5% topical benzoyl peroxide,
but, again, no large studies have been completed.7
Oral Treatment Options
Oral medications are another major treatment option for
acne and rosacea.32 Oral antibiotics are commonly prescribed
for both conditions and are considered first-line therapy for
moderate to severe disease. Due to their popularity, there is a
Figure 4. Multiple inflammatory papules and nodules
coalescing into plaques on the cheeks and chin of this
patient with severe nodulocystic acne.
Photograph courtesy of Graham Library, Wake Forest
Baptist Health Department of Dermatology.
concern about whether prolonged antibiotic therapy leads to
development of antibiotic-resistant P. acnes. Most prescribers
try to minimize the risk of resistance by combining oral antibiotics with topical retinoids and benzoyl peroxide and giving
these medications for a limited time.33,34
Several different classes of oral antibiotics have been
studied, including tetracyclines. Tetracyclines are a class of
antibiotics, which, when given at anti-microbial doses, bind
to the 50S ribosome subunit of bacteria such as P. acnes
and are bactericidal. Tetracyclines also have important antiinflammatory effects; they downregulate inflammatory cytokines, impede neutrophil chemotaxis and inhibit certain
matrix metalloproteinases.2
Doxycycline is a second-generation tetracycline that
comes in 50-mg, 75-mg and 100-mg tablets and is available in an enteric-coated form. Doxycycline has been shown
to be more effective than placebo in the treatment of both
acne and rosacea. Originally, doxycycline was prescribed in
100-mg to 200-mg daily doses, but studies have shown that
lower doses of doxycycline, such as 40 mg daily, are just as
effective at treating rosacea but with less toxicity.8 A subantimicrobial dose of doxycycline is available specifically for
acne and rosacea use (40-mg tablet) and is FDA approved
11
Figure 5. This patient suffers from rhinophymatous
rosacea with erythema and enlargement of the
sebaceous glands in the nose causing nasal deformity.
Photograph courtesy of Graham Library, Wake Forest
Baptist Health Department of Dermatology.
for use for up to 12 months. Doxycycline can cause gastrointestinal symptoms in up to a third of patients but can be
taken with food. Other side effects include photosensitivity,
candidiasis, esophagitis and benign intracranial hypertension.
Tetracyclines are contraindicated in children under 8 years
of age due to risk of teeth discoloration.2,35
Minocycline is another second-generation tetracycline used in
both acne and rosacea. Minocycline comes in 50-mg and 100mg tablets or capsules and is typically dosed at 100 mg to 200
mg daily.There is now an extended-release version that is meant
to be dosed at 1 mg/kg/day and, therefore, comes in a variety of
strengths (45-, 55-, 65-, 80-, 90-, 105, 115-, 135-mg tablets). Minocycline can cause vertigo, photosensitivity, benign intracranial
hypertension, drug-induced lupus and skin pigmentation.2
Macrolide antibiotics used to be commonly prescribed for
acne patients, but increasing P. acnes resistance has limited their
use.2 Azithromycin is a second-generation macrolide with a
long half-life (68 hours) and comparable efficacy to doxycycline. It is considered safe to use in pregnant and breastfeeding women and is Pregnancy Class B. Cephalexin and
12
clindamycin are also occasionally used for acne treatment, but
risk of pseudomembranous colitis prevents them from being
first-line agents.
Oral hormonal agents have gained popularity in off-label
use for acne, particularly in older patients. Adult acne tends to
affect the lower face and neck and most women with adult
acne actually have normal levels of circulating androgens.3
Anti-androgens are the most common class of hormonal
agents and include androgen receptor blockers, inhibitors of
peripheral androgen metabolism and inhibitors of androgens
via effects on the ovaries or pituitary gland.31 One metaanalysis of anti-androgen medications used for acne suggested
ethinyl estradiol plus cyproterone acetate was the most effective agent; however, all agents studied were significantly better
than placebo.33 Oral spironolactone is an aldosterone antagonist that was originally used as a potassium-sparing diuretic
but is also an anti-androgen that inhibits sebaceous gland
activity. Spironolactone decreases 5-alpha reductase activity,
which is increased in acne-prone skin. Spironolactone also
increases steroid hormone binding globulin, which decreases
levels of free testosterone.3 These effects make spironolactone
a good choice for women with hormonal acne. Spironolactone is dosed between 25 mg and 200 mg daily, though most
women will respond to 75-mg/day to 100-mg/day dosing.
Side effects include hypotension, diuresis, hyperkalemia, gynecomastia and decreased libido. There is a black box warning on spironolactone regarding the risk of breast carcinoma,
though long-term studies have not shown an increased risk.3
Oral isotretinoin is a first generation retinoid with a halflife of 20 hours that has been used for decades to treat severe
acne that is resistant to topical and other oral medications.
This medication is usually dosed between 40 mg to 80 mg per
day for 4 to 6 months, with the goal cumulative dose being
150 mg/kg. Oral isotretinoin works on acne by decreasing the
activity of sebaceous glands as well as providing anti-proliferative effects on keratinocytes. The benefit of this medication is
that it has a very high response rate in patients who have failed
other first and second-line treatments.
However, isotretinoin use comes with many potential side
effects and is Catergory X, strictly contraindicated in pregnancy due to high rate of birth defects. Due to its potential
teratogenicity, all patients in the United States on this medication must enroll in the government drug-monitoring program iPledge, and females must be on two forms of contraception while on isotretinoin. The most common side effects
are dry skin, dry lips and mucosal surfaces, arthralgia and hypertriglyceridemia; these tend to be dose-dependent. Numerous other side effects have been reported with isotretinoin,
including pseudotumor cerebri, inflammatory bowel disease
and increased suicidality.
The increased risk of suicide is hotly debated in the literature. In a large cohort study from Sweden, the risk of suicide
peaked 6 months after starting treatment with isotretinoin
and fell to expected levels 3 years after treatment. Patients in
this study with a history of suicide attempts before starting
Table 1. Medications Commonly Employed for Acne
Drug Category
Active Drug
Common Brand Names
Topical retinoid
Tretinoin +
Retin-A 0.025%, 0.05%, 0.1%; Avita 0.025%;
Atralin 0.05%
Adapalene +
Differin 0.1%, 0.3%
Tazarotene *
Tazorac 0.05%, 0.1%; Fabior
Topical antibiotic
Erythromycin
Akne-Mycin, Erygel, Emgel
Clindamycin
Cleocin T, Evoclin
Benzoyl peroxide
Benzoyl peroxide
Numerous: Proactiv, Clearasil, Oxy, others
Benzoyl peroxide + erythromycin
Benzamycin
Benzoyl peroxide + clindamycin
Benzaclin, Duac, Acanya
Benzoyl peroxide + retinoid
Benzoyl peroxide + adapalene
Epiduo
Retinoid + antibiotic
Tretinoin + clindamycin
Ziana, Veltin
Oral antibiotic
Erythromycin
EES, Eryped, Ery-tab
Tetracycline
Sumycin
Doxycycline
Vibramycin, Doryx, Adoxa
Fixed combination products
Benzoyl peroxide + antibiotic
Systemic retinoid
Minocycline
Dynacin, Minocin, Solodyn
Isotretinoin
Accutane, Amnesteem, Sotret, Claravis, Absorica
Source: Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/)
+ Pregnancy category C; *Pregnancy category X
isotretinoin made fewer attempts during treatment than those
whose behavior started during treatment.31 In reviewing the
literature, there is no direct evidence showing a clear link between isotretinoin and increased suicidality.
See Table 1 above for list of medications commonly used
to treat acne.36
Procedural Treatment Options
Epidemiologic data shows the vast majority of acne and
rosacea patients are treated with topical and oral medications.
There is a growing body of literature to support procedural
treatments as adjunctive therapy in these conditions. Photodynamic therapy (PDT) uses a combination of a photosensitizer and UV light to produce reactive oxygen species, which
target specific cells. P. acnes produce protophorphyrin IX and
coproporphyrin III within sebaceous glands, acting as an endogenous photosensitizer.
Exposure to certain light wavelengths causes destruction of
P. acnes with resolution of inflammatory acne lesions. Peak absorption of porphyrins occurs in the blue light spectrum (415
nm) and red light spectrum (630 nm). Both blue and red light
have been studied in treatment of acne and both have demonstrated significant improvement.37 Multiple studies have
examined the use of exogenous 5-aminolevulinic acid (ALA)
as a photosensitizer followed by laser treatment for acne. One
study showed using ALA prior to intense pulsed light (IPL)
laser was more effective than IPL alone for acne lesions.
Other studies show that relatively short incubation with ALA
(15 to 60 minutes) followed by blue light is also an effective acne
treatment. Other procedures use lasers, which directly destroy
sebaceous glands for acne and rosacea. These lasers are nearinfrared lasers with spectra between 1300 and 1600 nm. One
study using an infrared laser showed 98% reduction of inflammatory acne lesions after four treatments. Diode lasers (810-900
nm) have also shown to effectively destroy sebaceous glands.37
IPL effectively treats telangiectasias and flushing seen in erythematotelangiectatic rosacea.38 Phymatous rosacea can be difficult
to treat using topical and oral medications. Many patients can
benefit from ablative laser resurfacing with Erb:YAG or carbon
dioxide laser. Salicylic acid peels, glycolic acid peels and microdermabrasion have all been published as treatments for acne, although there are few randomized studies or studies comparing
these treatments to topical acne medications.39-42
Conclusion
Acne and rosacea are common dermatologic conditions that
have a major psychosocial impact on patients. Over the past several decades, new research has helped elucidate pathogenic factors
important in these conditions, although the exact pathogenesis
remains unknown.43,44 First-line treatment for both conditions
involves the use of topical and oral medications. Often, topical
and oral medications used in combination achieve better, more
rapid lesion clearance. Topical retinoids, antibiotics and many
other compounds like benzoyl peroxide, salicylic acid, azelaic acid
and sulfur sulfacetamide have proven efficacious. Oral antibiotics,
particulary tetracyclines, can be used at antimicrobial doses for
acne and at sub-antimicrobial doses for rosacea. Careful thought
needs to be given to the treatment duration with oral antibiot-
13
ics to prevent P. acnes resistance. For severe acne, oral isotretinoin
remains an excellent treatment option but requires careful discussion of toxicity and meticulous follow-up. Procedural treatments
are a growing trend in the management of acne and rosacea, with
photodynamic therapy and lasers targeting vessels and sebaceous
glands showing significant efficacy. Knowledge of all the different
treatment options for acne and rosacea allows the provider to tailor each individual’s treatment regimen and to provide significant
improvement in these disease entities. n
Dr. Strowd is with the department of dermatology at Wake Forest
University School of Medicine in Winston-Salem, NC.
Disclosure: Dr. Strowd does not have any industry relationships
or financial conflicts of interest to disclose.
References
1.Thomas DR. Psychosocial effects of acne. J Cutan Med Surg. 2004;8 Suppl 4:3-5.
2. Mays RM, Gordon RA, Wilson JM, Silapunt S. New antibiotic therapies
for acne and rosacea. Dermatol Ther. 2012 Jan-Feb; 25(1):23-37.
3. Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: Practical considerations for the clinical based on
current data and clinical experience. J Clin Aesthet Dermatol. 2012 March;
5(3):37-50.
4. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology 2nd Edition, Elsivier,
England; Chapter 37: Acne Vulgaris, p. 495-508.
5. Forton FM. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol. 2012 Jan;
26(1):19-28.
6. Bolognia J, Jorizzo JL, Rapini RP eds. Dermatology 2nd Edition, Elsivier,
England; Chapter 38: Rosacea and Related Disorders, p. 509-516.
7. Emer J, Waldorf H, Berson D. Botanicals and anti-inflammatories: natural
ingredients for rosacea. Semin Cutan Med Surg. 2011 Sep; 30(3):148-155.
8. Van Zuuren EJ, Kramer SF, Carter BR, Graber MA, Fedorowicz Z. Effective and evidence-based management strategies for rosacea: Summary of a
Cochrane systematic review. Br J Dermatol. 2011 Oct; 165(4):760-781.
9. Stotland M, Shalita AR, Kissling RF. Dapsone 5% gel: A review of its
efficacy and safety in the treatment of acne vulgaris. Am J Clin Dermatol.
2009;10(4):221-227.
10. Kircik LH. Synergy and its clinical relevance in topical acne therapy. J Clin
Aesthet Dermatol. 2011 Nov; 4(11): 30-33.
11. Goh CL, Tang MB, Briantais P, Kaoukhov A, Soto P. Adapalene gel 0.1%
is better tolerated than tretinoin gel 0.025% among healthy volunteers of
various ethnic origins. J Dermatol Treat. 2009;20(5):282-288.
12. Jarrat MT, Brundage T. Efficacy and safety of clindamycin-tretinoin gel
versus clindamycin or tretinoin alne in acne vulgaris: a randomized, doubleblind, vehicle-controlled study. J Drugs Dermatol. 2012 Mar;11(3):318-326.
13. Del Rosso JO, Harper J, Pillai R, Moore R. Tretinoin photostability: comparison of micronized tretinoin (0.05%) gel and tretinoin (0.025%) gel following exposure to ultraviolet a light. J Clin Aesthet Dermatol. 2012 Jan; 5(1):27-29.
14. Lucky AW, Sugarman J. Comparison of micronized tretinoin gel 0.05%
and tretinoin gel microsphere 0.1% in young adolescents with acne: a post
hoc analysis of efficacy and tolerability data. Cutis 2011 Jun; 87(6):305-310.
15. Thiboutot D, Arsonnaud S, Soto P. Efficacy and tolerability of adapalene
0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris.
J Drugs Dermatol. 2008 Jun;7(6 Suppl):s3-10.
16. Kakita L.Tazarotene versus tretinoin or adapalene in the treatment of acne
vulgaris. J Am Acad Dermatol. 2000 Aug;43(2 Pt 3):S51-54.
17. Parodi A, Drago F, Paolino S, Cozzani E, Gallo R. Treatment of rosacea.
Ann Dermatol Venereol. 2011 Nov;138 Suppl 3:S211-4.
18. Chang AL, Alora-Palli M, Lima XT, et al. A randomized, double-blind,
placebo-controlled, pilot study to assess the efficacy and safety of clindamycin
1.2% and tretinoin 0.025% combination gel for the treatment of acne rosacea
over 12 weeks. J Drugs Dermatol. 2012 Mar; 11(3):333-339.
14
19. Oztürkcan S, Ermertcan AT, Sahin MT, Afşar FS. Efficiency of benzoyl
peroxide-erythromycin gel in comparison with metronidazole gel in the
treatment of acne rosacea. J Dermatol. 2004 Aug;31(8):610-617.
20. Seidler EM, Kimball AB. Meta-analysis comparing efficacy of benzoyl peroxide, clindamycin, benzoyl peroxide with salicylic acid, and combination benzoyl peroxide/clindamycin in acne. J Am Acad Dermatol. 2010 Jul;63(1):52-62.
21.Van Scott EJ,Yu RJ. Hyperkeratinization, corneocyte cohesion, and alpha
hydroxyacids. J Am Acad Dermatol. 1984 Nov; 11(5): 867–879.
22. Waller JM, Dreher F, Behnam S, et al. ‘Keratolytic’ properties of benzoyl
peroxide and retinoic acid resemble salicylic acid in man. Skin Pharmacol
Physiol. 2006;19(5):283–289.
23. Cunliffe WJ, Holland KT, Bojar R, Levy SF. A randomized, double-blind
comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a
matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther. 2002;24(7):1117–1133.
24. Dubina MI, Fleischer AB. Interaction of topical sulfacetamide and topical dapsone with benzoyl peroxide. Arch Dermatol. 2009;145(9):1027-1029.
25. Mastrofrancesco A, Ottaviani M, Aspite N, et al. Azelaic acid modulates
the inflammatory response in normal human keratinocytes through PPARgamma activation. Exp Dermatol. 2010 Sep;19(9):813-820.
26. Del Rosso JQ. The use of sodium sulfacetamide 10%-sulfur 5% emollient foam in the treatment of acne vulgaris. J Clin Aesthet Dermatol. 2009
August; 2(8):26-29.
27. Draelos ZD. The multifunctionality of 10% sodium sulfacetamide, 5%
sulfur emollient foam in the treatment of inflammatory facial dermatoses. J
Drugs Dermatol. 2010 Mar;9(3):234-236.
28. Trumbore MW, Goldstein JA, Gurge RM. Treatment of papulopustular
rosacea with sodium sulfacetamide 10%/sulfer 5% emollient foam. J Drugs
Dermatol. 2009 Mar;8(3):299-304.
29. Kim MB, Kim GW, Park HJ, et al. Pimecrolimus 1% cream for the treatment of rosacea. J Dermatol. 2011 Dec;38(12):1135-1139.
30. Teraki Y, Hitomi K, Sato U et al. Tacrolimus-induced rosacea-like dermatitis: A clinical analysis of 16 cases associated with tacrolimus ointment
application. Dermatology. 2012 May 22. (Epub ahead of print).
31. Gamble R, Dunn J, Dawson A, et al. Topical antimicrobial treatment of acne
vulgaris: an evidence-based review. Am J Clin Dermatol. 2012 Jun 1; 13(3):141-52.
32. Korting HC, Schöllmann C. Current topical and systemic approaches to
treatment of rosacea. J Eur Acad Dermatol Venereol. 2009 Aug; 23(8):876-882.
33. Simpson RC, Grindlay DJ, Williams HC. What’s new in acne? An analysis
of systematic reviews and clinically significant trials published in 2010-2011.
Clin Exp Dermatol. 2011 Dec; 36(8):840-843.
34. Leyden JJ, Preston N, Osborn C, Gottschalk AR. In-vivo effectiveness of
adapalene 0.1%/benzoyl peroxide 2.5% gel on antibiotic-sensitive and resistant Propionibacterium acnes. J Clin Aesthet Dermatol. 2011 May; 4(5):22-26.
35. Schnopp C, Mempel M. Acne vulgaris in children and adolescents. Minerva Pediatr. 2011 Aug;63(4):293-304.
36. Ho B, Friedlander SF. Developing an acne treatment plan for pediatric
and adolescent patients. Derm for the Pediatrician. 2012 Aug;1(2):19-25.
37. Gold MH. Acne and PDT: new techniques with lasers and light sources.
Lasers Med Sci. 2007 Jun; 22(2):67-72.
38. Bikowski JB, Goldman MP. Rosacea: where are we now? J Drugs Dermatol. 2004 May-Jun; 3(3):251-261.
39. Garg VK, Sinha S, Sarkar R. Glycolic acid peels versus salicylic-mandelic
acid peels in active acne vulgaris and post-acnescarring and hyperpigmentation: a comparative study. Dermatol Surg. 2009 Jan;35(1):59-65.
40. Lee SH, Huh CH, Park KC, Youn SW. Effects of repetitive superficial
chemical peels on facial sebum secretion in acne patients. J Eur Acad Dermatol
Venereol. 2006 Sep;20(8):964-968.
41. Kempiak SJ, Uebelhoer N. Superficial chemical peels and microdermabrasion for acne vulgaris. Semin Cutan Med Surg. 2008 Sep;27(3):212-220.
42. Dréno B, Fischer TC, Perosino E, et al. Expert opinion: efficacy of superficial chemical peels in active acne management--what can we learn from
the literature today? Evidence-based recommendations. J Eur Acad Dermatol
Venereol. 2011 Jun;25(6):695-704.
43. Fleischer AB Jr. Inflammation in rosacea and acne: Implications for patient
care. J Drugs Dermatol. 2011 Jun;10(6):614-620.
44. Yamasaki K, Gallo RL. Rosacea as a disease of cathelicidins and skin innate immunity. J Investig Dermatol Symp Proc. 2011 Dec;15(1):12-15.
The Therapeutic
Approach to Psoriasis
Recent research has shown the role that the immune system plays in the pathogenesis of this disease,
which may lead to the development of immune-specific therapies. This article highlights current approaches in treating and managing patients with psoriasis.
Alyssa S. Daniel, MD
Figure 1. Clinical view of plaque-type psoriasis with well-demarcated plaques and overlying adherent scale.
P
soriasis is a chronic, immune mediated, inflammatory
skin condition with a genetic susceptibility pattern
and several environmental triggers. It is characterized
by the hyperproliferation of keratinocytes, dilation of
blood vessels and an inflammatory infiltrate, all of which are
potential targets for treatment. Psoriasis is associated with
key comorbidities including cardiovascular disease, metabolic dysfunction, depression and psoriatic arthritis.1 There has
been a great deal of research recently to elucidate the role
that the immune system plays in the pathogenesis of this dis-
ease and to develop immune-specific therapies. This article
will highlight current approaches in treating and managing
patients with psoriasis.
Epidemiology
The prevalence of psoriasis was most recently approximated
to affect around 3% of the US population.2 This figure varies considerably worldwide. In certain Asian, African, AfricanAmerican and Norwegian Lapp populations, the prevalence
may be much lower.3 Psoriasis has a bimodal age distribution
15
The Therapeutic Approach to Psoriasis
Figure 2. Histology of psoriasis.
with a peak in the 2nd and 6th decades of life.3-7 Three quarters of new cases occur before the age of 40.7 The prevalence
of the disease appears to be equal among women and men.
Early childhood psoriasis is relatively rare but there are reported cases of even infantile psoriasis.8
Psoriasis is a polygenetic disorder. Approximately 70% of
children with psoriasis have a positive family history.9 Many
gene linkage studies and more recent genome-wide association studies have identified at least nine gene loci that are
associated with a higher risk for developing psoriasis. These
are designated PSORS1-PSORS9.10-20 The natural history of
psoriasis is variable, usually chronic with intermittent flares.21
Pathogenesis
The underlying etiology of psoriasis is still at the center
of heated debates. Prior to the 1980s, psoriasis was regarded
as a disease of epidermal dysfunction with several epidermal
mediators being at the center of the pathogenesis, including
cyclic AMP, eicosanoids, protein kinase C, phospholipase C,
polyamines and transforming growth factor (TGF)-α.22 More
recently, the pathogenesis has been clearly related, in some part,
to T-cell immune dysfunction. Studies looking at the association between psoriasis and major histocompatibility complex
(MHC) alleles and disease improvement with therapies that
16
affect T-cell function make it apparent that T cells likely play a
direct role.23,24 Additional support for this correlation include
animal models showing that xenograft transplantation of uninvolved human psoriatic skin can induce psoriatic lesions on
immunodeficient mice when given the donors’ activated T
cells.25 Barrier maintenance may be a contributing factor in
the pathogenesis as well.26
Clinical Implications
Psoriasis is a papulosquamous skin condition with hallmark
erythematous, well-demarcated, silver-scaling papules and
plaques.These plaques can localize to sights of trauma, a clinical finding referred to as the Koebner phenomenon.27 There
are several clinical variants, including chronic plaque, guttate,
erythrodermic, pustular and inverse psoriasis. Locations such
as the scalp, nails and tongue, also known as annulus migrans,
can also be affected by psoriasis.
Comorbidities are frequently seen at increased rates in
psoriatic patients compared to the general population. These
patients have higher rates of hypertension, left ventricular hypertrophy, obesity and diabetes. They also are more likely to
engage in risky behaviors such as smoking and alcohol use.28
Psoriatic arthritis is also a complication. Approximately
one-third of patients with psoriasis will also develop pso-
Biologics for Psoriasis: A Review of Recent Research and News
A
recent observational study, published online ahead of print in the Journal of Dermatologic Treatment, compared
clinical improvement and treatment satisfaction with biologic versus other therapies in patients with plaque psoriasis.
A group of European dermatologists reported disease severity before and after starting current therapy; dermatologists
and patients reported treatment satisfaction. Of 2,151 patients, 453 were undergoing treatment with topicals, 666 with
phototherapy, 683 with conventional systemic therapies and 349 with biologics. A significantly greater improvement in
disease severity was observed in the biologics group (70% before to 15% after treatment) compared to topicals (22%
to 10%), phototherapy (20% to 11%) and conventional systemic therapy (49% to 15%) (all P≤0.03). A greater number
of patients and dermatologists also reported greater satisfaction with biologic therapy over other therapies. Significantly
more patients (59%) receiving biologics were satisfied with treatment versus topicals (45%), phototherapy (34%), or conventional systemic treatment (50%) (all P<0.001). Significantly more dermatologists were satisfied with biologics (60%)
versus topicals (35%), phototherapy (26%) or conventional systemics (42%) (all P<0.001).
Long-term Safety and Efficacy of Biologics
Results of a study published in the August 2012 issue of the Journal of the American Academy of Dermatology found
that etanercept is well tolerated with no sign of risk of dose-related or cumulative toxicity over time. David M. Pariser,
MD, of Virginia Clinical Research Inc. in Norfolk, VA and colleagues evaluated integrated adverse event (AE) data from
etanercept trials to assess short- (up to 12 weeks from controlled trials) and long-term (up to 144 weeks from uncontrolled
extension studies) safety of etanercept doising of 25 mg once weekly to 50 mg twice weekly.
According to the abstract, long-term data were stratified by treatment regimens, and rates of noninfectious and infectious
AEs and standardized incidence ratios for malignancies were determined.
The evaluation showed that rates of noninfectious and infectious AEs and serious noninfectious AEs were comparable
for both placebo and etanercept groups for the short-term analyses. Both the short- and long-term analyses found no
dose-related increases in any of these events. Dr. Pariser and colleagues found no significant differences in cumulative
event rates for serious infections across dose groups or over time. There was no significant difference in the standardized
incidence ratios for malignancies (excluding non-melanoma skin cancer). No increase in overall malignancies was seen
with etanercept treatment compared to the psoriasis population. Lymphoma, demyelination, congestive heart failure and
opportunistic infection were rare.
Data presented at the 9th Annual European Academy of Dermatology and Venereology Spring Symposium in Verona,
Italy, in June showed that maintenance treatment with ustekinumab for up to five years resulted in consistent, significant
clinical response in adults with moderate to severe plaque psoriasis.
This new efficacy and safety data come from the Phase III PHOENIX 1 study, one of two pivotal registration trials for
ustekinumab. Patients were randomized to receive placebo or ustekinumab 45 mg or 90 mg at weeks 0 and 4. Following assessment of Psoriasis Area and Severity Index (PASI) 75 at week 12, the primary endpoint, ustekinumab-treated
patients continued to receive treatment every 12 weeks. At week 40, PASI 75 responders were re-randomized to receive
maintenance therapy with ustekinumab or to withdraw from treatment and only receive retreatment with loss of response.
More than two-thirds (n=517) of all ustekinumab-treated patients (n=753) in PHOENIX 1 continued to receive ustekinumab
through the last scheduled 5-year dose. Among the responders who continued treatment from week 40 through the end
of the study, 48% and 59% had PASI 90 in the ustekinumab 45-mg and 90-mg groups, respectively, with up to 5 years
of treatment. Efficacy was similarly maintained in an overall analysis of the study population, with 63% and 72% of all
PHOENIX 1 participants achieving PASI 75, and 40% and 49% achieving PASI 90, among those individuals receiving
ustekinumab 45 mg or 90 mg, respectively. Investigators also reported a consistent benefit-to-risk profile for ustekinumab
through 5 years and observed treatment with the biologic therapy to be generally well-tolerated with rates of adverse
events (AEs), including infections, malignancies and cardiovascular events, remaining stable over time.
— Stefanie Tuleya, Executive Editor
17
riatic arthritis.29 This usually presents after skin lesions are
first seen, but, in a minority of patients, the arthritis precedes
the skin lesions. The most common presentation is that of a
mono- and asymmetric oligoarthritis leading to the classic
sausage digit deformity.30
Topical Therapies
Vitamin D Analogues
Topical vitamin D3 analogues were first introduced in
the 1990s. The mechanism of action is not entirely understood, but they seem to affect the proliferation and
differentiation of keratinocytes and have immunomodulating effects as well. They may also induce apoptosis of
psoriatic keratinocytes.31
Most studies of topical D3 have examined patients with
chronic plaque psoriasis, but there should be caution in using this in patients who have extensive body surface area
involvement, as there is an increased risk of hypercalcemia
and hypercalciuria. Otherwise, the medication is safe and
well tolerated (although there may be some irritation) and
should be considered first line in most patients with mild to
moderate plaque psoriasis.32 A systematic review that aimed
A review of the literature
on the efficacy of clobetasol
propionate ointment
compared to other clobetasol
preparations found no
difference in efficacy
rates among the different
formulations.
to provide evidence-based recommendations about the use
of vitamin D analogues found them to be a cost effective,
safe treatment, but efficacy is increased nearly twice as much
when topical corticosteroids were added as concomitant
therapies.33 Calcipotriol/calcipotriene is available in the
United States in cream, ointment, foam and solution forms.
Calcitriol ointment is available in the United States, while
tacalcitol and calcitriol are available in Europe and may be
more potent than calcipotriol/calcipotriene. Calcipotriol/
calcipotriene is typically used twice daily at the concentration of 50 μg/g. Most studies with calcipotriol have limited
the use to no more than 100 grams/week to protect against
side effects. It is pregnancy category C.
18
Topical Steroids
Topical corticosteroids are among the oldest treatments
available for psoriasis. Corticosteroids bind to the cytoplasmic
corticosteroid receptor and translocate into the nucleus; this
downstream effect inhibits transcription of key genes needed
to promote the inflammatory response. Corticosteroids also
act to inhibit proliferation and promote vasoconstriction.34
A systematic review examined 51 randomized controlled
trials of mild to severe chronic plaque psoriasis where topical
corticosteroids were used as the initial treatment. Most treatment time for studies was 4 weeks. The results were highly
variable, with 30% to 90% of patients showing at least 50%
initial improvement for mild to severe psoriasis, 7% to 85%
achieving at least 75% improvement and 55% to 85% experiencing at least 90% improvement. Occlusive measures were
associated with better response, and intermittent maintenance
therapy appeared to provide longer remission times.35
More potent topical steroids are being used than in the
past,36 although it’s not clear if higher potency steroids are
actually more effective. One study estimated that the effective
concentrations in the skin of hydrocortisone 2.5% ointment,
triamcinolone 0.1% ointment, clobetasol 0.05% foam and betamethasone 0.1% cream to oral prednisone. Hydrocortisone
2.5% ointment, triamcinolone 0.1% ointment and clobetasol
0.05% foam were predicted to provide greater levels of potency in the skin in comparison to oral prednisone.37
There are a wide variety of formulations of topical corticosteroids, including ointments, creams, solutions, foams, gels
and sprays. It was once common practice to choose the ointment formulation, as it was thought to be more potent and,
thus, more efficacious. A review of the literature on the efficacy of clobetasol propionate ointment compared to other
clobetasol preparations found no difference in efficacy rates
among the different formulations.The authors concluded that
patient preference should be forefront in decision making
because, ultimately, patient compliance with the formulation
that is chosen will largely dictate how effective treatment is.38
The side effects of topical steroid therapy include skin
atrophy, telangiectasias, easy bruising, acneiform eruptions,
increased risk for skin infections and allergic contact dermatitis. There has been much debate about the risks of suppression of the hypothalamic-pituitary-adrenal axis.38,39 In a
recent review on the risk for adrenal suppression and skin
atrophy by Castela et al, higher-potency steroids were associated with measurable decreased levels of morning cortisol
levels, thus suggesting adrenal suppression; however, none
of these measurable cases had any clinical manifestations of
adrenal suppression. With once-daily application of topical
steroids, the incidence of skin atrophy was 1.9%.40 Topical
steroids are pregnancy category C.
Topical Retinoids
Retinoids are vitamin A derivative hormones. Retinoids
decrease epidermal proliferation and reduce inflammation.
The only topical retinoid approved for psoriasis is tazarotene;
Brief Summary of Prescribing Information for STELARA® (ustekinumab)
STELARA® Injection, for subcutaneous use
See package insert for Full Prescribing Information
INDICATIONS AND USAGE: STELARA® is indicated for the treatment of adult
patients (18 years or older) with moderate to severe plaque psoriasis who are
candidates for phototherapy or systemic therapy. CONTRAINDICATIONS:
Clinically significant hypersensitivity to ustekinumab or to any of the excipients
(see Warnings and Precautions). WARNINGS AND PRECAUTIONS: Infections
STELARA® may increase the risk of infections and reactivation of latent
infections. Serious bacterial, fungal, and viral infections were observed in
subjects receiving STELARA® (see Adverse Reactions). STELARA® should not be
given to patients with any clinically important active infection. STELARA® should
not be administered until the infection resolves or is adequately treated. Instruct
patients to seek medical advice if signs or symptoms suggestive of an infection
occur. Exercise caution when considering the use of STELARA® in patients with
a chronic infection or a history of recurrent infection. Serious infections requiring
hospitalization occurred in the psoriasis development program. These serious
infections included cellulitis, diverticulitis, osteomyelitis, viral infections,
gastroenteritis, pneumonia, and urinary tract infections. Theoretical Risk for
Vulnerability to Particular Infections Individuals genetically deficient in IL-12/
IL-23 are particularly vulnerable to disseminated infections from mycobacteria
(including nontuberculous, environmental mycobacteria), salmonella (including
nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious
infections and fatal outcomes have been reported in such patients. It is not
known whether patients with pharmacologic blockade of IL-12/IL-23 from
treatment with STELARA® will be susceptible to these types of infections.
Appropriate diagnostic testing should be considered, e.g., tissue culture, stool
culture, as dictated by clinical circumstances. Pre-treatment Evaluation for
Tuberculosis Evaluate patients for tuberculosis infection prior to initiating
treatment with STELARA®. Do not administer STELARA® to patients with active
tuberculosis. Initiate treatment of latent tuberculosis prior to administering
STELARA®. Consider anti-tuberculosis therapy prior to initiation of STELARA® in
patients with a past history of latent or active tuberculosis in whom an adequate
course of treatment cannot be confirmed. Patients receiving STELARA® should
be monitored closely for signs and symptoms of active tuberculosis during and
after treatment. Malignancies STELARA® is an immunosuppressant and may
increase the risk of malignancy. Malignancies were reported among subjects
who received STELARA® in clinical studies (see Adverse Reactions). In rodent
models, inhibition of IL-12/IL-23p40 increased the risk of malignancy (see
Nonclinical Toxicology). The safety of STELARA® has not been evaluated in
patients who have a history of malignancy or who have a known malignancy.
Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis
and angioedema, have been reported post-marketing. If an anaphylactic or other
clinically significant hypersensitivity reaction occurs, discontinue STELARA®
and institute appropriate therapy (see Adverse Reactions). Reversible
Posterior Leukoencephalopathy Syndrome One case of reversible posterior
leukoencephalopathy syndrome (RPLS) was observed during the clinical
development program which included 3523 STELARA®-treated subjects. The
subject, who had received 12 doses of STELARA® over approximately two years,
presented with headache, seizures and confusion. No additional STELARA®
injections were administered and the subject fully recovered with appropriate
treatment. RPLS is a neurological disorder, which is not caused by demyelination
or a known infectious agent. RPLS can present with headache, seizures,
confusion and visual disturbances. Conditions with which it has been associated
include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and
immunosuppressive therapy. Fatal outcomes have been reported. If RPLS is
suspected, STELARA® should be discontinued and appropriate treatment
administered. Immunizations Prior to initiating therapy with STELARA®, patients
should receive all immunizations appropriate for age as recommended by
current immunization guidelines. Patients being treated with STELARA® should
not receive live vaccines. BCG vaccines should not be given during treatment
with STELARA® or for one year prior to initiating treatment or one year following
discontinuation of treatment. Caution is advised when administering live
vaccines to household contacts of patients receiving STELARA® because of the
potential risk for shedding from the household contact and transmission to
patient. Non-live vaccinations received during a course of STELARA® may not
elicit an immune response sufficient to prevent disease. Concomitant Therapies
The safety of STELARA® in combination with other immunosuppressive agents
or phototherapy has not been evaluated. Ultraviolet-induced skin cancers
developed earlier and more frequently in mice genetically manipulated to be
deficient in both IL-12 and IL-23 or IL-12 alone (see Nonclinical Toxicology).
ADVERSE REACTIONS: The following serious adverse reactions are discussed
elsewhere in the label: Infections (see Warnings and Precautions); Malignancies
(see Warnings and Precautions); and RPLS (see Warnings and Precautions).
Clinical Studies Experience Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug and may
not reflect the rates observed in practice. The safety data reflect exposure to
STELARA® in 3117 psoriasis subjects, including 2414 exposed for at least
STELARA® (ustekinumab)
6 months, 1852 exposed for at least one year,1650 exposed for at least two
years, 1129 exposed for at least three years, and 619 exposed for at least four
years. Adverse reactions listed below are those that occurred at a rate of at least
1% and at a higher rate in the STELARA® groups than the placebo group during
the placebo-controlled period of STUDY 1 and STUDY 2 (see Clinical Studies).
The numbers (percentages) of adverse reactions reported for placebo-treated
patients (n=665), patients treated with 45 mg STELARA® (n=664), and patients
treated with 90 mg STELARA® (n=666), respectively, were: Nasopharyngitis: 51
(8%), 56 (8%), 49 (7%); Upper respiratory tract infection: 30 (5%), 36 (5%), 28
(4%); Headache: 23 (3%), 33 (5%), 32 (5%); Fatigue: 14 (2%), 18 (3%), 17 (3%);
Diarrhea: 12 (2%), 13 (2%), 13 (2%); Back pain: 8 (1%), 9 (1%), 14 (2%);
Dizziness: 8 (1%), 8 (1%), 14 (2%); Pharyngolaryngeal pain: 7 (1%), 9 (1%), 12
(2%); Pruritus: 9 (1%), 10 (2%), 9 (1%); Injection site erythema: 3 (<1%), 6 (1%),
13 (2%); Myalgia: 4 (1%), 7 (1%), 8 (1%); Depression: 3 (<1%), 8 (1%), 4 (1%).
Adverse reactions that occurred at rates less than 1% in the controlled period of
STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis
and certain injection site reactions (pain, swelling, pruritus, induration,
hemorrhage, bruising, and irritation). One case of RPLS occurred during clinical
trials (see Warnings and Precautions). Infections In the placebo-controlled period
of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for
placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects), 27%
of STELARA®-treated subjects reported infections (1.39 per subject-year of
follow-up) compared with 24% of placebo-treated subjects (1.21 per subjectyear of follow-up). Serious infections occurred in 0.3% of STELARA®-treated
subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated
subjects (0.02 per subject-year of follow-up) (see Warnings and Precautions). In
the controlled and non-controlled portions of psoriasis clinical trials (median
follow-up of 2.6 years), representing 6791 subject-years of exposure, 70% of
STELARA®-treated subjects reported infections (0.98 per subject-years of
follow-up). Serious infections were reported in 2% of subjects (0.01 per subjectyears of follow-up). Malignancies In the controlled and non-controlled portions
of psoriasis clinical trials (median follow-up of 2.6 years, representing 6791
subject-years of exposure), 1.3% of STELARA ®-treated subjects reported
malignancies excluding non-melanoma skin cancers (0.62 per hundred subjectyears of follow-up). Non-melanoma skin cancer was reported in 1.3% of
STELARA®-treated subjects (0.61 per hundred subject-years of follow-up) (see
Warnings and Precautions). The most frequently observed malignancies other
than non-melanoma skin cancer during the clinical trials were: prostate,
colorectal, melanoma in situ, breast. Malignancies other than non-melanoma
skin cancer in STELARA®-treated patients during the controlled and uncontrolled
portions of studies were similar in type and number to what would be expected
in the general U.S. population according to the SEER database (adjusted for age,
gender and race). Immunogenicity The presence of ustekinumab in the serum
can interfere with the detection of anti-ustekinumab antibodies resulting in
inconclusive results due to assay interference. In STUDIES 1 and 2, antibody
testing was done at time points when ustekinumab may have been present in
the serum. Table 2 summarizes the presence of anti-ustekinumab antibodies in
STUDY 1 through Year 3 and STUDY 2 through Year 4. In STUDY 1 (N=746),
antibody results were found to be positive, negative, and inconclusive in 39 (5%),
124 (17%), and 583 (78%) patients, respectively. In STUDY 2 (N=1202), antibody
results were found to be positive, negative, and inconclusive in 65 (5%), 150
(12%), and 987 (82%) patients, respectively. The data reflect the percentage of
subjects whose test results were positive for antibodies to ustekinumab in a
bridging immunoassay, and are highly dependent on the sensitivity and
specificity of the assay. Additionally, the observed incidence of antibody positivity
in an assay may be influenced by several factors, including sample handling,
timing of sample collection, concomitant medications and underlying disease.
For these reasons, comparison of the incidence of antibodies to ustekinumab
with the incidence of antibodies to other products may be misleading.
Post-marketing Experience Adverse reactions have been reported during postapproval use with STELARA®. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to STELARA® exposure.
Immune system disorders: Serious hypersensitivity reactions (including
anaphylaxis and angioedema), other hypersensitivity reactions (including rash
and urticaria). DRUG INTERACTIONS: Drug interaction studies have not been
conducted with STELARA®. Live Vaccines Live vaccines should not be given
concurrently with STELARA® (see Warnings and Precautions). Concomitant
Therapies The safety of STELARA® in combination with immunosuppressive
agents or phototherapy has not been evaluated (see Warnings and Precautions).
CYP450 Substrates The formation of CYP450 enzymes can be altered by
increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during
chronic inflammation. Thus, STELARA®, an antagonist of IL-12 and IL-23, could
normalize the formation of CYP450 enzymes. Upon initiation of STELARA® in
patients who are receiving concomitant CYP450 substrates, particularly those
with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for
warfarin) or drug concentration (e.g., for cyclosporine) should be considered and
the individual dose of the drug adjusted as needed (see Clinical Pharmacology).
STELARA® (ustekinumab)
Allergen Immunotherapy STELARA® has not been evaluated in patients who
have undergone allergy immunotherapy. STELARA® may decrease the protective
effect of allergen immunotherapy (decrease tolerance) which may increase the
risk of an allergic reaction to a dose of allergen immunotherapy. Therefore,
caution should be exercised in patients receiving or who have received allergen
immunotherapy, particularly for anaphylaxis. USE IN SPECIFIC POPULATIONS:
Pregnancy Pregnancy Category B There are no studies of STELARA® in pregnant
women. STELARA® should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. No teratogenic effects were observed in
the developmental and reproductive toxicology studies performed in cynomolgus
monkeys at doses up to 45 mg/kg ustekinumab, which is 45 times (based on
mg/kg) the highest intended clinical dose in psoriasis patients (approximately
1 mg/kg based on administration of a 90 mg dose to a 90 kg psoriasis patient).
Ustekinumab was tested in two embryo-fetal development toxicity studies.
Pregnant cynomolgus monkeys were administered ustekinumab at doses up to
45 mg/kg during the period of organogenesis either twice weekly via
subcutaneous injections or weekly by intravenous injections. No significant
adverse developmental effects were noted in either study. In an embryo-fetal
development and pre- and post-natal development toxicity study, three groups
of 20 pregnant cynomolgus monkeys were administered subcutaneous doses of
0, 22.5, or 45 mg/kg ustekinumab twice weekly from the beginning of
organogenesis in cynomolgus monkeys to Day 33 after delivery. There were no
treatment-related effects on mortality, clinical signs, body weight, food
consumption, hematology, or serum biochemistry in dams. Fetal losses occurred
in six control monkeys, six 22.5 mg/kg-treated monkeys, and five 45 mg/kgtreated monkeys. Neonatal deaths occurred in one 22.5 mg/kg-treated monkey
and in one 45 mg/kg-treated monkey. No ustekinumab-related abnormalities
were observed in the neonates from birth through six months of age in clinical
signs, body weight, hematology, or serum biochemistry. There were no
treatment-related effects on functional development until weaning, functional
development after weaning, morphological development, immunological
development, and gross and histopathological examinations of offsprings by the
age of 6 months. Nursing Mothers Caution should be exercised when STELARA®
is administered to a nursing woman. The unknown risks to the infant from
gastrointestinal or systemic exposure to ustekinumab should be weighed against
the known benefits of breast-feeding. Ustekinumab is excreted in the milk of
lactating monkeys administered ustekinumab. IgG is excreted in human milk, so
it is expected that STELARA® will be present in human milk. It is not known if
ustekinumab is absorbed systemically after ingestion; however, published data
suggest that antibodies in breast milk do not enter the neonatal and infant
circulation in substantial amounts. Pediatric Use Safety and effectiveness of
STELARA® in pediatric patients have not been evaluated. Geriatric Use Of the
3117 psoriasis subjects exposed to STELARA®, a total of 183 were 65 years or
older, and 21 subjects were 75 years or older. Although no differences in safety
or efficacy were observed between older and younger subjects, the number of
subjects aged 65 and over is not sufficient to determine whether they respond
differently from younger subjects. OVERDOSAGE: Single doses up to 4.5 mg/kg
intravenously have been administered in clinical studies without dose-limiting
toxicity. In case of overdosage, it is recommended that the patient be monitored
for any signs or symptoms of adverse reactions or effects and appropriate
symptomatic treatment be instituted immediately. PATIENT COUNSELING
INFORMATION: “See FDA-approved patient labeling (Medication Guide).”
Instruct patients to read the Medication Guide before starting STELARA® therapy
and to reread the Medication Guide each time the prescription is renewed.
Infections Inform patients that STELARA® may lower the ability of their immune
system to fight infections. Instruct patients of the importance of communicating
any history of infections to the doctor, and contacting their doctor if they develop
any symptoms of infection. Malignancies Patients should be counseled about the
risk of malignancies while receiving STELARA®. Allergic Reactions Advise
patients to seek immediate medical attention if they experience any symptoms
of serious allergic reactions.
Prefilled Syringe Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044,
License No. 1864 at Baxter Pharmaceutical Solutions, Bloomington, IN 47403
Vial Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, License No.
1864 at Cilag AG, Schaffhausen, Switzerland
© Janssen Biotech, Inc. 2012
25ST12104
20
it is as effective as topical vitamin D analogues but more irritating.41 Using tazarotene in combination with topical steroids
appears to be more effective and decreases the irritation seen
with topical retinoids alone.34 Tazarotene comes in 0.05% and
0.01% as a cream, gel or jelly.
Only up to 20% of body surface area should be treated,
which makes this less useful for patients with diffuse disease.
Because it is irritating, tazarotene should not be used in patients who are eythrodermic. It is pregnancy category X; regular pregnancy tests are very important, as well as counseling
any woman of childbearing potential about contraception.
Topical Calcineurin Inhibitors
Calcineurin inhibitors hinder the activity of calcineurin,
a phosphorylase enzyme that is needed for successful T-cell
differentiation. Calcineurin inhibitors inhibit T-cell function and inflammation. Calcineurin inhibitors are effective
for facial and flexural psoriasis.42 It is a safe treatment but
should be avoided in patients with skin barrier dysfunction,
as they are at risk for increased systemic absorption. It is
pregnancy category C.
Anthralin
Anthralin is one of the oldest psoriatic medications. It inhibits epidermal and T-lymphocyte proliferation. The use of
this medication is limited because of the complexity of ap-
[Calcineurin inhibitors are]
a safe treatment but should
be avoided in patients with
skin barrier dysfunction, as
they are at risk for increased
systemic absorption.
plication and the propensity of anthralin to stain whatever it
touches. Short-contact 0.3% anthralin ointment for 10 minutes daily combined with a topical steroid, retinoid or UV
light regimen seems to have beneficial results.43 Anthralin
comes in a cream formulation.The limitations include patient
compliance, local skin irritation and mess of application. This
drug is pregnancy category C.
Phototherapy
Phototherapy has long been a very useful treatment option for psoriasis. Treatment options range from broad-band
ultraviolet B therapy (BB-UVB), narrowband ultraviolet B
therapy (NB-UVB), photochemotherapy with UVA and ei-
ther an oral or topical dose of psoralen UVA1. More recently,
excimer laser has gained FDA approval.
NB-UVB is more effective at sub-erythmogenic doses than
BB-UVB.44 The efficacy of psoralen UVA (PUVA) therapy
and NB-UVB has also been compared; PUVA is better at
clearing psoriasis, fewer sessions are needed and longer-lasting
clearance is achieved.45 However, there is an increased risk of
carcinogenicity following PUVA treatment.46 The safety data
for NB-UVB has not been fully determined due to a lack of
prospective studies. Excimer (308 nm) laser is a safe and effective treatment for psoriasis; a number of different protocols
evaluated by Mudigonda et al showed no significant differences in the protocol used to initiate treatment.47
Systemic Medications
Systemic medications for severe psoriasis include methotrexate, cyclosporine and oral retinoids. Methotrexate inhibits
dihydrofolate reductase, inhibiting keratinocyte proliferation
and immune function. Methotrexate is indicated for severe
plaque psoriasis and psoriatic arthritis and is administered by
once-weekly dosing. Side effects include gastrointestinal upset, leucopenia, thrombocytopenia, renal failure, photosensitivity, fatigue and alopecia.48 Pulmonary toxicity may occur.
Side effects can be lessened by folic acid supplementation,49
although more recent conflicting reports note the efficacy of
methotrexate may be decreased secondary to folic acid supplementation.50 Hepatotoxity is a risk associated with cumulative dose. It used to be common practice to obtain liver
biopsies once a cumulative dose of 1.5 grams was reached,
but more recent evidence shows this is excessive in patients
with no risk factors for liver disease.51 Monitoring blood cell
counts, serum creatinine levels and liver enzymes is recommended.52 Methotrexate is pregnancy category X.
Cyclosporine is a calcineurin inhibitor administered systemically and is indicated for severe plaque psoriasis. Lowdose cyclosporine, 2 mg/kg/day is useful; with the addition
of topical corticosteroids, patients do significantly better still.53
It is a medication that works well as an initial therapy until
a safer maintenance therapy can be implemented. Cyclosporine has nephrotoxic effects; blood pressure and renal function
should be closely monitored while on this medication. The
dermatologist should also monitor liver function tests, serum
lipids and serum electrolytes, especially magnesium levels.52
Cyclopsorine is pregnancy category C.
Systemic retinoids have the same mechanism of action and
effects as topical retinoids. Acitretin is available in the United
States and is indicated for severe psoriasis. In a study looking at the use of high-dose therapy, defined as approximately
50mg/day versus low-dose therapy, patients in the low-dose
treatment group had better results, likely secondary to better
tolerability and adherence.54 Serum triglyceride levels, liver
enzymes, serum creatinine and screening for the development
of hyperostosis is important.52 Retinoids have teratogenic effects, so screening for pregnancy is crucial and counseling is
very important. With so many other non-teratogenic treatwww.the-dermatologist.com
The contraindication of using
methotrexate in combination
with oral retinoids has been
reevaluated. The combination
may provide benefit for
patients with recalcitrant
disease.
ments available, the use of acitretin in women of childbearing
potential is discouraged.
The contraindication of using methotrexate in combination with oral retinoids has been reevaluated. The combination may provide benefit for patients with recalcitrant disease.
There may be no added toxicity of using the combination, as
long as care in monitoring patients is taken.55
Biologic Therapies
An important group of biologic therapies, tumor necrosis
factor alpha (TNF-α) inhibitors, have made an enormous impact in the treatment of patients with severe psoriasis. Etanercept was approved for psoriatic arthritis in 2002 and for
moderate to severe psoriasis in 2004. It is a fusion protein
TNF-α receptor to the Fc portion of IgG1.56 The recommended dosing regimen starts with twice-weekly 50-mg
subcutaneous injections and decreases to once a week after
12 weeks.57 Adalimumab was approved by the FDA for psoriatic arthritis in 2005 and for moderate to severe psoriasis in
2008. It is a fully human anti-TNF monoclonal antibody.56
The recommended dose is an 80-mg subcutaneous loading
dose followed by subcutaneous doses every other week of 40
mg.55 Infliximab, a mouse-human IgG1 chimeric anti-TNF
monoclonal antibody, was approved for psoriatic arthritis in
2005 and for moderate to severe plaque psoriasis in 2006.54
Recommended dosing starts at a dose of 5 mg/kg via intravenous infusion at weeks 0, 2 and 6 and then continued every
8 weeks.57 Golimumab is, at the time this article was written,
FDA-approved for psoriatic arthritis only. It is a human IgGk
antibody. The recommended dosing is 50 mg injected subcutaneously at monthly intervals.58
Ustekinumab gained FDA approval for the treatment of
moderate to severe plaque psoriasis in 2009. It is a human
IgG1 monoclonal antibody that binds the p40 subunit of IL12 and IL-23.59 IL-23 promotes the differentiation and proliferation of Th17 cells.60 The effectiveness of ustekinumab
highlighted the importance of Th17 cells in the pathogenesis
of psoriasis. The recommended dosing is 45 mg injected subcutaneously for patients weighing less than 100 kg and 90 mg
21
for patients weighing greater than 100 kg. This dose is repeated at week 4 and then maintenance doses are given every
12 weeks thereafter. 61
In terms of efficacy, adalimumab and infliximab appear
to be more effective than etanercept and methotrexate.62,63
Although the approved biologics are considered safe, effective and well tolerated, serious complications may occur, including demyelinization, infection, tuberculosis, malignancy,
lymphoma, cardiovascular outcomes and hepatitis.64 The approved biologics for psoriasis are all pregnancy category B.
Alefecept and efalizumab were previously approved biologic
therapies. Alefecept was voluntarily discontinued and efalizumab was withdrawn after four reported cases of progressive multifocal leukoencephalopathy. 57
Special Considerations
Scalp Psoriasis
A review of 18 randomized control trials about the success of topical corticosteroid therapy for scalp psoriasis shows
that 40% to 70% of patients experienced more than 75%
improvement and 43% to 90% experienced more than 90%
initial improvement.Topical steroids still seem to be a successful treatment option in these patients.There may also be a role
for adding excimer 308 nm lasers.65
Nail Psoriasis
Nail psoriasis often is very concerning for the patient and
one of the most difficult forms of psoriasis to treat. Methotrexate is frequently used to treat nail psoriasis. With the
emergence of biologics, recent data suggests that they also are
effective in treating nail psoriasis. 66,67
Conclusion
The therapeutic approach to psoriasis needs to be individualized to each patient, as there are many different, effective
treatment options available. Generally, combination therapies
allow for the synergistic effects of multiple therapies and fewer side effects with lower doses. This will, hopefully, increase
patients’ compliance with any regimen. The risk vs. benefit
from any medication must be discussed and unique patient
characteristics must be incorporated when choosing a medication to decrease adverse effects. n
Dr. Daniel is with the department of dermatology at Wake Forest
Disclosure: Dr. Daniel has no conflicts of interest to report.
References
1. Onumah N, Kircik LH. Psoriasis and its comorbidities. J Drugs Dermatol.
2012; 11(5 suppl):s5-10.
2. Kurd SK, Gelfand JM. The prevalence of previously diagnosed and undiagnosed psoriasis in US adults: results from NHANES 2003-2004. J Am Acad
Dermatol. 2009; 60(2):218-224.
3. Christophers E. Psoriasis - epidemiology and clinical spectrum. Clin Exp
Dermatol. 2001;26(4):314-320.
4. Burch PR, Rowell, NR. Mode of inheritance in psoriasis. Arch Dermatol.
1981;117(5):251-252.
22
5. Smith AE, Kassab JY, Rowland Payne CM, Beer WE. Bimodality in
age of onset of psoriasis, in both patients and their relatives. Dermatology.
1993;186(3):181-186.
6. Ferrandiz C, Pujol RM, Garcia-Patos V, Bordas X, Smandia JA. Psoriasis of
early and late onset: a clinical and epidemiologic study from Spain. J Am Acad
Dermatol. 2002;46(6):867-873.
7. Hanseler T, Christopher E. Psoriasis of early and late onset: characterization
of two types of psoriasis vulgaris. J Am Acad Dermatol. 1985;13(3):450-456.
8. Dibi A, Jabourik F, Bentahila A. Psoriasis in infants about five cases. Arch
Pediatr. 2012;19(2):220-223.
9. Morris A, Rogers M, Fischer G, Williams K. Childhood psoriasis: a clinical
review of 1262 cases. Pediatr Dermatol. 2001;18(3):188-198.
10. Capon F, Bijlmakers MJ, Wolf N, et al. Identification of ZNF313/
RNF114 as a novel psoriasis susceptibility gene. Hum Mol Genet.
2008;17(13):1938–1945.
11. Capon F, Novelli G, Semprini S, et al. Searching for psoriasis susceptibility
genes in Italy: genome scan and evidence for a new locus on chromosome 1.
J Invest Dermatol 1999;112(1):32-35.
12. Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association
study confirms IL12B and leads to the identification of IL23R as psoriasis
risk genes. Am J Hum Genet. 2007;80(2):273–290.
13. Ellinghaus E, Ellinghaus D, Stuart PE, et al. Genome-wide association
study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat Genet.
2010;42(11):991–995.
14. Huffmeier U, Uebe S, Ekici AB, et al. Common variants at TRAF3IP2
are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet.
2010;42(11):996–999.
15. Nair RP, Henseler T, Jenisch S, et al. Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by
genome-wide scan. Hum Mol Genet. 1997;6(8):1349-1356.
16. Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case
Control Consortium 2, Strange A, Capon F, et al. A genome-wide association
study identifies new psoriasis susceptibility loci and an interaction between
HLA-C and ERAP1. Nat Genet. 2010;42(11):985–990.
17. Stuart PE, Nair RP, Ellinghaus E, et al. Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat Genet.
2010;42(11):1000–1004.
18. Sun LD, Cheng H, Wang ZX et al. Association analyses identify six
new psoriasis susceptibility loci in the Chinese population. Nat Genet.
2010;42(11):1005–1009.
19. Tomfohrde J, Silverman A, Barnes R, et al. Gene for familial psoriasis
susceptibility mapped to the distal end of human chromosome 17q. Science.
1994;264(5162):1141-1145.
20. Zhang XJ, Huang W,Yang S et al. Psoriasis genome-wide association study
identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet.
2009;41(2):205–210.
21. Farber EM, Nall LM. The natural history of psoriasis in 5600 patients.
Dermatologica 1974;148(1);1-18.
22.Voorhees JJ: Pathophysiology of psoriasis. Annu Rev Med. 1977;28:467-473
23. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 2010;445(7130):866–873.
24. Schwarz T. 25 years of UV-induced immunosuppression mediated by T
cells-from disregarded T suppressor cells to highly respected regulatory T
cells. Photochem Photobiol. 2008;84(1):10–18.
25. Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces
psoriasis. J Clin Invest .1996;98(8):1878–1887
26. Bergboer JG, Zeeuwen PL, Scalwijk J. Genetics of psoriasis: Evidence of
epistatic interaction between skin barrier abnormalities and immune deviation. J Invest Dermatol. May 2012. doi: 10.1038/jid.2012.167.
27. Waisman M. Historical note: Koebner on the isomorphic phenomenon.
Arch Dermatol. 1981;117(7):415.
28. Fernandez-Torres RM, Paradela S, Fanseca E. Psoriasis in patients older
than 65 years. A comparative study with younger adult psoriatic patients. J
Nutr Health Aging. 2012;16(6):586-591.
29. Catanoso M, Pipitone N, Salvarini C. Epidemiology of psoriatic arthritis.
Reumatismo. 2012; 64(2):66.
30. Moll JMH: Psoriatic arthropathy. In: Mier PD, van de Kerkhof PCM, ed.
Textbook of Dermatology, Edinburgh: Churchill Livingstone; 1986:55-82.
31. Tiberio R, Buzzo C, Pertusi G, et al. Calcipotriol induces apoptosis in psoriatic keritinocytes. Clin Exp Dermatol. 2009;34(8):e972-974.Epub 2009 Sep 15.
32. Berth-Jones J, Hutchinson PE. Vitamin D analogues and psoriasis. Br J
Dermatol. 1992;127(2):71-78.
33. Devaux S, Castela A, Archier E, et al.Topical vitamin D analogues alone or
in association with topical steroids: a systemic review. Acad of Venereol. 2012;26
Suppl 3:52-60.
34. Noris D. Mechanisms of action of topical therapies and the rationale for
combination therapy. J Am Acad Dermatol. 2005;53(1 Suppl 1):S17-25.
35. Castela E, Archier E, Devaux S, et al. Topical corticosteroids in plaque
psoriasis: a systemic review of efficacy and treatment modalities. J Eur Acad
Dermatol Venereol. 2012;26 Suppl 3:36-46.
36. Strowd L, Yentzer D, Fleischer A, Feldman SR. Increasing use of more
potent treatments for psoriasis. J Am Acad Dermatol. 2009;60 (3):478-481.
37. McClain RW, Yentzer BA, Feldman SR. Comparison of skin concentrations following topical versus oral corticosteroid treatment: reconsidering the
treatment of common inflammatory inflammatory dermatoses. J Drugs Dermatol. 2009;8(12);1076-1079.
38. Warino L, Balkrishnan R, Feldman SR. Clobetasol propionate for psoriasis: are ointments really more potent? J Drugs Dermatol. 2006;5(6):527-532.
39. Katz HI, Hien NT, Prawer SE, Mastbaum LI, Mooney JJ, Samson CR.
Superpotent topical steroid treatment of psoriasis vulgaris- clinical efficacy
and adrenal function. J Am Acad Dermatol. 1987;16(4):804-811.
40. Castela E, Archier E, Devaux S, et al.Topical corticosteroids in plaque psoriasis: a systemic review of risk for adrenal axis suppression and skin atrophy. J
Eur Acad Dermatol Venereol. 2012;26 Suppl 3:47-51.
41. Bailey J, Whitehair B. Topical treatments of chronic plaque psoriasis. Am
Fam Phsyician. 2010;81(5):596.
42. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the
treatment of intertriginous psoriasis: a double blind, randomized study. J Am
Acad Dermatol. 2004;51(5):731-738.
43. Lowe N, Ashton R, Koudsi H, Verschoore M, Schaefer H. Anthralin for
psoriasis: short-contact anthralin therapy compared with conventional topical
steroid and conventional anthralin. J Am Acad Dermatol. 1984;10(1)1:69-72.
44.Walters IB, Burack LH, Coven TR, Gilleaudeau P, Krueger JG. Suberythmogenic narrow-band UVB is markedly more effective than conventional UVB
in treatment of psoriasis vulgaris. J Am Acad Dermatol. 1999;40(6 Pt 1):893-900.
45. Archier E, Devaux S, Castela E, et al. Efficacy of psoralen UVA therapy vs
narrowband UVB therapy in chronic plaque psoriasis: a systematic literature
review. J Eur Acad Dermatol Venereol. 2012;26 Suppl3:11-21.
46. Archier E, Devaux S, Castela E, et al. Carcinogenic risks of psoaralen UVA
therapy and narrowband UVB in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26 Suppl3:22-31.
47. Mudigonda T, Dabade TS, Feldman SR. A review of protocols for 308 nm
excimer laser phototherapy in psoriasis. J Drugs Dermatol. 2012;11(1):92-97.
48. Gilani S, Khan D, Kahn F, Ahmed M. Adverse effects of low dose
methotrexate in rheumatoid arthristis patients. J Coll Physicians Surg Pak.
2012;22(2):101-104.
49. Morgan SL, Baggott JE. Folate supplementation during methotrexate therapy for rheumatoid arthritis. Clin Exp Rheumatol. 2010;28(5 Suppl
61):S102-109.
50. Salim A, Tan E, Ilchyshyn A, Berth-Jones J. Folic acid supplementation
during treatment of psoriasis with methotrexate: A randomized, double-blind,
placebo-controlled trial. Br J Dermatol. 2006;154(6):1169-1174.
51. Thomas JA, Aithal GP. Monitoring liver function during methotrexate
therapy for psoriasis: are routine biopsies really necessary? Am J Clin Dermatol.
2005;6(6):357-363.
52. Dubertret L. Retinoids, methotrexate and cyclopsporine. Curr Probl Dermatol. 2009;38:79-94.
53.Vena G, Galluccio A, Pezza M,Vestita M, Cassano N. Combined treatment
with low-dose cyclosporine and calicipotriol/ betamethasone dipropionate
ointment for moderate-to-severe- plaque psoriasis: a randomized control
open label study. J Dermatolog Treat. 2012;23(4):255-260.
54. Haushalter K, Murad EJ, Dabade TS, Rowell R, Pearce DJ, Feldman SR.
Efficacy of low-dose acitretin in the treatment of psoriasis. J Dermatolog Treat.
2011 Jul 25. [epub ahead of print].
55. Searles AD, Lee AD, Feldman SR. Is concomitant use of methotrexate and
oral retinoids dangerous? A review of the data regarding this combination. J
Am Acad Dermatol. 2011;64(4):791-793.
56. Mössner R, Schön MP, Reich K. Tumor necrosis factor antagonists in the
therapy of psoriasis. Clin Dermatol. 2008;26(5):486-502.
57. Herrier RN. Advances in the treatment of moderate-to-severe plaque
psoriasis. Am J Health Syst Pharm. 2011;68(9):795-806.
58. Boyce EG, Halilovic J, Stan-Ugbene O. Golimumab: Review of the efficacy and tolerability of a recently approved tumor necrosis factor-α inhibitor.
Clin Ther. 2010;32(10):1681-1703.
59. Kurzeja M, Rudnicka L, Olszewska M. New interleukin-23 pathway inhibitors in dermatology: ustekinumab, briakinumab, and secukinumab. Am J
Clin Dermatol. 2011;12(2):113-125.
60. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp
Med. 2004;199(1):125-130.
61. Krulig E, Gordon KB. Ustekinumab: an evidence-based review of its effectiveness in the treatment of psoriasis. Core Evid. 2010;5:11-22.
62. Singnorovitch JE, Wu EQ,Yu AP, et al. Comparative effectiveness without
head-to-head trials: a method for matching-adjusted indirect comparisons
applied to psoriasis treatment with adalimumab or etanercept. Pharmaoconomics. 2010;28(10):935-945.
63. Bansback N, Sizto S, Sun H et al. Efficacy of systemic treatments for moderate to severe plaque psoriasis. Dermatology. 2009;219(3):209-18.
64. Papp KA, Dekoven J, Parsons L, et al. Biologic therapy in psoriasis: perspectives on associated risks and patient management. J Cutan Med Surg.
2012;16(3):153-168.
65. Wong JW, Kamangar F Nguyen R, Koo Y. Excimer laser therapy for hairline psoriasis: a useful addition to the scalp psoriasis treatment algorithm. Skin
Therapy Lett. 2012;17(5):6-9.
66. Kahl C, Hansen B, Reich K. Nail psoriasis — An ignored disorder. Pathogenesis, diagnosis and therapy. Hautarzt. 2012;63(3):184-191.
67. Sánchez-Regaña M, Sola-Ortigosa J, Alsina-Gibert M, Vidal-Fernández
M, Umbert-Millet P. Nail psoriasis: a retrospective study on the effectiveness
of systemic treatment (classical and biological therapy). J Eur Acad Dermatol
Venereol. 2011;25(5):579-586.
23
Current Treatment Strategies for
Skin Cancer
A review of novel therapuetic approaches and combination treatments to effectively manage skin cancer.
Jenna L. O’Neill, MD
however, these treatment modalities are not without potential
side effects. Novel therapeutic approaches and combination
therapies are often utilized in the treatment of skin cancer,
which may be challenging but rewarding.
Non-Melanoma Skin Cancer
Figure 1. Basal cell carcinoma.
Photo courtesy of Daniel Pearce, MD
S
kin cancer is the most common type of cancer worldwide.The incidence rates of both melanoma and nonmelanoma skin cancers (NMSC) are increasing,1-3
which is a significant public health problem. The biologic behavior of skin cancer ranges from slow-growing, locally invasive cutaneous malignancy to locally aggressive tumors
that may metastasize. Melanoma is associated with significant
mortality when not treated early, and death from melanoma
tends to occur at a younger age than for many other cancers.4
If detected early, skin cancer is curable by surgical excision or destructive modalities. The ideal treatment for NMSC
should provide complete tumor eradication with the lowest
risk of recurrence and use the most cost effective method
with acceptable cosmetic outcome.5 Mohs micrographic surgery is used for intraoperative margin assessment and for tissue
preservation in cosmetically sensitive areas such as the face.
Despite the success of surgical intervention for skin cancers,
there are drawbacks, such as the need for local anesthesia, potential risk of infection and scarring. Patient and/or tumor
characteristics may necessitate other treatment methods if surgical intervention is not a viable option.Treatment options for
melanoma and NMSC targeting molecular defects in tumor
cells may allow for treatment without the need for surgery;
24
Basal cell carcinoma
Basal cell carcinoma (BCC) is the most common malignancy worldwide, with an incidence of 146 per 100,000 individuals in the United States.6 BCC typically affects middle
age and older adults, most commonly on the head and neck,
followed by the trunk. Ultraviolet (UV) radiation is thought
to play a role in the development of both BCC and squamous cell carcinoma (SCC). A higher incidence of NMSC
is reported in fair-skinned individuals, in those with greater
outdoor exposure and in latitudes closer to the equator.7,8 The
incidence of BCC is increased in patients with basal cell nevus
syndrome, also known as Gorlin syndrome, in which mutations in the PTCH gene result in upregulation of the sonic
hedgehog signaling pathway and subsequent development of
multiple BCCs beginning in childhood or early adulthood.
Treatment of BCC may vary by clinical subtype. Superficial
BCC, which presents as an erythematous, scaling telangiectatic plaque often on the trunk or extremities, may be treated
with topical therapy or via electrodesiccation and curettage,
while nodular BCC is typically excised surgically. More aggressive or poorly defined tumors are best treated with Mohs
micrographic surgery. While BCC has an exceedingly low
potential for metastasis, local tissue destruction may be extensive in advanced or aggressive malignancies and may result in
considerable morbidity.
Squamous cell carcinoma
SCC presents as a scaling, pink to red papule, plaque or
nodule that may be crusted or ulcerated, most frequently on
the head and neck or other chronically sun-exposed sites.The
development of SCC is more strongly linked to UV exposure
in comparison to BCC, in particular to chronic sun exposure. It is generally accepted that SCC occurs on a continuum
with premalignant lesions confined to the epidermis, such
as actinic keratoses (AKs).9 Patients with AKs are 10 to 15
times more likely to develop SCC compared to those without AKs. Bowen’s disease, a form of SCC in situ, typically
Current Treatment Strategies In Dermatology: Skin Cancer
Table I. Indications for Mohs Micrographic Surgery
Recurrent tumor
High-risk anatomic location (periorificial)
Anatomic sites where tissue preservation is imperative (eg, digits, genitalia)
Aggressive histologic subtype
Size > 2cm in diameter
Poorly defined clinical borders
Perineural invasion
Figure 2. Keratoacanthoma type squamous cell
carcinoma.
Figure 3. Melanoma on the right lower eyelid.
Photo courtesy of Graham Dermatopathology Library
Photo courtesy of Daniel Pearce, MD and Philip Williford, MD
presents as a well-demarcated, brightly erythematous scaling
plaque. Keratoacanthoma (KA) may be a well-differentiated
form of SCC, which rapidly enlarges over several weeks and
may spontaneously involute. Due to their propensity to cause
tissue destruction and reports of metastasis, KAs are often
treated surgically. Human papillomavirus is another important pathogenic factor implicated in some, if not all, cases of
SCC. In addition, SCC is more common than BCC in immunosuppressed patients, including transplant recipients and
individuals with HIV. In contrast to BCC, SCC is associated
with a small but significant risk of metastasis, typically to regional lymph nodes. Prompt treatment with negative surgical
margins is essential to minimize morbidity of both the malignancy and its treatment.
Surgical Treatment
Wide local excision is the primary treatment for NMSC,
with a cure rate approaching 90% or greater at 5 years.10,11
Optimal margins for excision of SCC are 4 mm for lesions
less than 2 cm in greatest diameter and 6 mm for lesions
larger than 2 cm. National Comprehensive Cancer Network
(NCCN) guidelines recommend 4-mm margins for excision
of primary low-risk BCC.12 A meta-analysis recommended
3-mm surgical margins for BCC, with a cure rate of 95% for
lesions less than 2 cm in diameter.5 Curettage and electrodessication is another treatment modality that involves tumor destruction and has a comparable cure rate to excision for treatment of low-risk NMSC.13 NCCN guidelines recommend
curettage and electrodesiccation for low-risk primary BCC
or SCC on non hair-bearing sites. If curettage is performed
to the level of subcutaneous fat, complete surgical excision
should be undertaken.
Mohs micrographic surgery is a specialized surgical and
pathologic technique that offers intraoperative histologic examination of 100% of the tissue margins. This is a distinct
advantage over conventional excision with frozen or paraffin
embedded sections, in which only a small proportion of the
total peripheral margin is examined via thin, cross-sectional
slices of tissue in a “bread loaf ” technique. Mohs micrographic
surgery offers the lowest recurrence rate and smallest defect
size in the treatment of BCC and SCC and is the treatment
of choice for recurrent tumors.10,11,14,15 Generally accepted
indications for Mohs micrographic surgery also include: size
> 2cm in diameter, high-risk anatomic location, perineural
invasion and poorly defined clinical borders (see Table I).16
Mohs surgery is time-consuming and very expensive and may
require coordination with another physician to perform the
reconstruction after negative margins are attained. Therefore,
25
Mohs surgery should be reserved for high-risk tumors or
when excision with standard margins would result in excessive tissue loss at sensitive anatomic sites.
Non-Surgical Treatment
Radiation therapy (RT) is a valuable adjunctive therapy in
patients with residual positive tumor margins after extensive
Mohs surgery or wide excision or in patients with high-risk
tumors or extensive perineural tumor infiltration.17 Narrow
radiation field margins of 1 cm to 2 cm are utilized; examples
of dose and treatment schedules are provided in the NCCN
guidelines for treatment of NMSC.12 RT is also utilized in
patients in whom surgical intervention is not a viable option,
either due to patient or tumor characteristics or both. A recent retrospective study demonstrated a 10-year relapse-free
survival of 80.4% in patients with inoperable SCC treated
with superficial radiotherapy.18 Irradiation of nodal basins in
conjunction with regional lymph node dissection improved
Prevention and early detection
of NMSC are key. Frequent
monitoring of patients with
NMSC, including full skin
examination and counseling
about the importance of daily
sun protection, is imperative.
survival compared to surgery alone in one study of 122 patients with metastatic spread of SCC to lymph nodes.19 Adjuvant RT may also be utilized in cases of inoperable lymph
node disease.
Photodynamic therapy (PDT) is a novel therapeutic method that uses a photosensitizing agent such as δ-aminolevulinic
acid (δ-ALA), which preferentially localizes to diseased cells.
Topical application is followed by exposure to a light source
with resultant selective cytotoxicity of tumor cells. PDT is
FDA-approved for the treatment of actinic keratoses and has
also demonstrated efficacy in the treatment of SCC in situ20,21
and superficial BCC.22,23 Methyl-aminolevulinic acid (MAL),
the methyl ester of ALA, has been used after curettage for
nodular BCC, with equivalent recurrence rates to standard
excision.24,25 PDT has been used more recently as adjunctive
therapy in the treatment of large non-melanoma skin cancers
prior to surgical removal.26 Intraoperative PDT has been proposed as a means to decrease recurrence rates of NMSC after
Mohs surgery in patients with extensive field cancerization.27
26
Cryosurgery may also be utilized for superficially invasive NMSC, either as monotherapy or in combination
with topical chemotherapeutic agents. Cryosurgery and
curettage has an excellent cure rate and cosmetic outcome
for select tumors.28,29 A combination of cryosurgery and
topical imiquimod, termed “immunocryosurgery,” has
been employed with acceptable response rates.30,31 Topical imiquimod 5% cream is an immune response modifier
that activates the innate and adaptive arms of the immune
response via toll-like receptor 7 (TLR7). Imiquimod has
been used alone in the treatment of nodular BCC, with
complete clearance rates of 78% even with intensive daily
dosing regimens.32,33 Response rates for nodular BCC are
greatly improved with pre-treatment curettage followed by
imiquimod 5 times a week for 6 weeks.34 Immunocryosurgery35,36 or imiquimod alone37-39 may also be used for SCC
in situ with excellent results.
Vismodegib, a novel oral small-molecule inhibitor of smoothened (SMO), was recently approved by the FDA for metastatic
or locally advanced BCC. SMO is normally inhibited by patched
homologue 1 (PTCH), which is mutated in the majority of BCC
and in patients with Gorlin syndrome. This mutation results in
constitutive activation of the Hedgehog signaling pathway and
unchecked tumor growth. Vismodegib is administered orally at
a dose of 150 mg daily. Early studies in patients with metastatic
and locally advanced BCC demonstrated promising results, with
response rates of 30 % and 43%, respectively, in 96 patients in an
open-label, Phase II trial.40,41 A randomized, double-blind, placebo-controlled trial of vismodegib in 41 patients with Gorlin
syndrome demonstrated a decrease in new BCCs as well as a
decrease in size of existing BCCs.42 Treatment with vismodegib
is associated with a high rate of adverse events, most commonly
dysgeusia and hair and weight loss, which necessitated discontinuation of therapy in 54% of patients enrolled in the latter study.42
The potential benefits of treatment must be weighed with these
potentially serious adverse events. Careful patient selection will
be imperative when utilizing this agent.
Oral retinoids, specifically acitretin, have been used as
chemoprevention in patients at risk for developing multiple
or aggressive SCCs, especially solid organ transplant recipients.43-45 Acitretin is typically administered at the lowest effective dose in order to minimize side effects, which include
cheilitis, headache, photosensitivity, palmoplantar desquamation, epistaxis, musculoskeletal symptoms and elevated triglycerides.44 Abnormalities in liver enzymes were not observed in a systematic review of controlled trials of acitretin
for chemoprevention in transplant recipients.45 Importantly,
after discontinuation of acitretin, SCC development recurs. In
organ transplant recipients at high risk for NMSC, changing
the immunosuppressive regimen from a calcineurin inhibitor to sirolimus, a mammalian target of rapamycin (mTOR)
inhibitor with anti-tumor effects, may reduce the number of
new cutaneous malignancies.46
Prevention and early detection of NMSC are key. Frequent monitoring of patients with NMSC, including full
Table II. Major Prognostic Factors for Melanoma
Breslow depth: >1mm high risk
Male gender
Advanced age
Ulceration
Anatomic site: head/neck and trunk high risk vs. extremities
Number of involved lymph nodes
Site of distant metastases: visceral metastases high risk vs. skin, subcutaneous, lymph nodes
Table III. Surgical Margins for Primary Melanoma
Thickness
Margins (cm)
In situ
0.5
< 1 mm
1
1– 4 mm
1 to 2*
> 4 mm
≥ 2cm
* AAD Task Force suggests a 1 cm margin for tumors < 2 mm in depth.
skin examination and counseling about the importance
of daily sun protection, is imperative. Daily use of broadspectrum sunscreen with SPF 30 or greater is recommended
by the American Academy of Dermatology; sun-protective
clothing and avoidance during peak sun hours also play an
important role. Melanoma
It is estimated that 76,250 men and women will be diagnosed with, and 9,180 will die from, melanoma in 2012.2 The
incidence and mortality rate from melanoma have increased
in recent decades.1 Melanocytes are neural crest-derived cells
that normally reside in the basal layer of the epidermis and
produce melanin. The pathogenesis of melanoma is complex
and is thought to involve evasion of the host immune response by cancer cells.When detected early, melanoma is curable by wide excision. Delays in diagnosis and treatment may
result in local invasion of melanoma and distant metastases,
typically to regional lymph nodes and visceral organs including the lungs, liver, bones and brain. In contrast to most other
solid organ tumors, melanoma recurrence may present many
years after initial diagnosis and complete surgical resection.
Metastatic melanoma is exceptionally resistant to treatment
with conventional chemotherapy and the prognosis remains
very poor, despite advances in our knowledge of melanoma
28
pathogenesis. Recent molecular genetic studies have revealed
mutations in melanoma cells that may be specifically targeted
in the treatment of advanced melanoma. The mitogen-activated protein kinase (MAPK) pathway plays a crucial role in
regulating cell proliferation, survival and differentiation. The
BRAF gene, which encodes a protein kinase upstream regulator of MAPK, harbors an activating mutation in 40% to 60%
of melanomas.47,48
Like other malignancies, the development of invasive melanoma is thought to progress through a step-wise process with
accumulation of mutations within melanoma cells, which are
influenced by both genetic and environmental factors. Melanoma in situ (MIS) is a proliferation of atypical melanocytes
confined to the epidermis and may precede the development
of melanoma. Melanoma may arise within a pre-existing nevus, but more than half of melanomas arise de novo. Four
major subtypes have been described: superficial spreading,
nodular, acral lentiginous and lentigo maligna melanoma. Regardless of subtype, prognosis is primarily determined by the
Breslow thickness, or depth of invasion, of the tumor. Breslow depth is important for determining excisional margins
and tumor staging and is the strongest predictor of melanoma
mortality. Additional predictors of poor prognosis in melanoma are male gender, presence of ulceration and distant metastases (see Table II).
Psychosocial Issues In Familial Melanoma
T
he Skin Cancer page from the National Cancer Institute (NCI) offers patients with both non-melanoma skin cancer
(NMSC) and melanoma a variety of resources, including information about treatment, clinical trials, statistics and
more. The page on the genetics of skin cancer includes information about the structure and function of the skin, clinical
presentations of NMSC and melanoma, rare skin cancer syndromes and psychosocial issues in familial melanoma.
The information on the psychosocial issues was updated very recently, at the end of July 2012, and discusses interest
in and motivation for genetic testing to determine risk of melanoma and the behavior of individuals found to be at a
high risk for the most serious type of skin cancer. The update comes on the heels of a number of new studies about
genetic and lifestyle factors that may contribute to melanoma risk, as well as a new app that may aid in personal skin
cancer screenings.
Limited Data, Conflicting Results
The review of the psychosocial issues in individuals with a family history of melanoma is written for healthcare professionals and is intended to help elucidate the factors involved in an individual’s perception of his or her risk, desire to
undergo genetic testing, and prevention practices, all in an effort to decrease the rates of melanoma among family
members of patients.
According to the authors of this review, the motivations for and interest in genetic testing for melanoma have not been
extensively studied, but the general findings note there is a high — but not universal — interest in genetic testing, and
individuals at a high risk for melanoma are able to articulate the benefits of testing. They also note ‘a relative lack’ of
examination of the potential limitations of testing and reasons to forgo testing. The most important factor that influences
an individual’s desire to be tested for melanoma susceptibility is being a parent; many studies reveal that individuals
with children are more likely to be tested, primarily to determine the relative risk to their offspring. The research that
focuses on individuals who have undergone genetic testing for melanoma reveals conflicting evidence. Most studies
have shown no increase in psychological distress, like anxiety and depression.
Protective behaviors before and after screening for genetic susceptibility have been examined slightly more extensively.
Generally, individuals who are identified as having an increased risk for melanoma from genetic testing are more likely
to increase the frequency of several protective behaviors: sunscreen use, self-exams for skin changes and skin checks
by a physician.
Several demographic factors may increase these proactive behaviors in an individual who has been identified by
genetic testing for a higher risk of melanoma. Adoption of protective behaviors is more likely in individuals with a
familial risk of melanoma who are older, female and more confident in their ability to practice such behaviors. In addition, regular sunscreen use has been correlated to higher levels of education, higher self-efficacy for sun protection
and higher perceived melanoma risk.
The Psychosocial Issues in Familial Melanoma page briefly discusses the efficacy of interventions about sun protection
and screening in family members of melanoma patients. The results of existing studies are also inconsistent. One study
with siblings utilized telephone messages and tailored print materials about risk reduction and screening recommendations; the control group received standard-of-care physician recommendations that patients tell family members about
their diagnosis. That study showed an increase in knowledge about melanoma, confidence in seeing a dermatologist
for a skin check and greater self-exam practices in the intervention group. Another study that utilized a similar intervention in family members of melanoma patients showed a near two-fold increase in skin examinations by a healthcare
provider in the intervention group but failed to show a change in sunscreen behaviors in either group.
To learn more about this data from the NCI, and for additional resources, please visit www.cancer.gov/cancertopics/
types/skin. For more information about the recent developments in the understanding of the genetic and lifestyle risk
factors for NMSC and melanoma, please visit www.the-dermatologist.com.
— Julia Ernst, MS, Assistant Editor
29
Surgical Treatment
Biopsy technique is essential in evaluating a suspicious
lesion for accurate diagnosis and measurement of Breslow
depth in the event of a melanoma diagnosis. Excisional biopsy technique with narrow margins of surrounding skin
is preferred, unless lesion size or location prevents it. Following histologic diagnosis, wide local excision is the preferred treatment method, with margins based on Breslow
depth (see Table III). The use of Mohs micrographic surgery in the treatment of melanoma remains controversial,
due, in part, to concern about the difficulty in detecting
abnormal melanocytes in frozen sections. Various modifications have been proposed to address this issue, including
the use of intraoperative immunostaining for melanoma
markers such as MelanA/MART149 and the use of modified or “slow” Mohs with permanent paraffin-embedded
tissue sections for tumors with ill-defined margins or for
tissue sparing in sensitive anatomic sites.50 Local tumor recurrence, sometimes after many months or years, continues
after these techniques.
Skin cancers may be curable
when detected early and
adequately treated, but the
prognosis for advanced
cutaneous malignancies
is poor.
Patients with melanomas greater than 1 mm in thickness
may be considered for sentinel lymph node biopsy (SLNB),
which provides prognostic information by detecting melanoma spread to regional lymph nodes.51 This practice remains
controversial among dermatologists, as subsequent complete
lymph node dissection for metastatic disease is not without
potential morbidity and has not demonstrated survival benefit
over observation.52
Adjuvant Therapies
Non-invasive methods for treating lentigo maligna (a type
of MIS) with ill-defined tumor margins or extensive involvement of sensitive anatomic sites have been proposed as a tissue-sparing technique. A review of treatment options for lentigo maligna recommends the use of imiquimod cream with
great caution due to short follow-up times and the possibility
of an invasive component not detected on biopsy.53 Radia30
tion therapy (RT) has also been proposed for large lentigo
maligna or lentigo maligna melanoma lesions on the face or
in elderly patients who may not be able to tolerate surgery,
with reported cure rates greater than 90%.54,55 Palliative RT
may be used in patients with symptomatic metastatic disease,
particularly inoperable brain metastases. Curative resection of
stable metastatic lesions, such as distant nodes or isolated visceral tumors, should be considered for appropriate patients.
Several approaches to systemic adjuvant therapy have been
tried in patients with high risk or metastatic melanoma, including traditional chemotherapy, immunotherapy and vaccination. Unfortunately, these treatments have generally failed
to show any significant survival benefit.
In 2011, the FDA approved two targeted therapies for
metastatic melanoma, representing a significant advance in
melanoma treatment. Ipilimumab is a monoclonal antibody
directed against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), which downregulates T cell activation.
By blocking CTLA-4, ipilimumab promotes T-cell mediated anti-tumor immunity. Ipilimumab is administered by
intravenous infusion once every 3 weeks for a total of four
doses. A randomized phase III trial demonstrated prolonged
survival in 676 patients with advanced melanoma treated
with ipilimumab compared to patients receiving a peptide
vaccine (10 months vs 6.4 months, respectively, P<0.001),
but the proportion of patients with an objective response
(10.9%) was disappointing.56 Another study of 502 patients
with metastatic melanoma demonstrated that ipilimumab
plus dacarbazine improved survival compared to dacarbazine
alone.57 More than 60% of patients experienced toxicity in
the form of autoimmune phenomena such as vitiligo, elevated liver enzymes and colitis, which can be life-threatening.
Vemurafenib, an oral inhibitor of mutated BRAF kinase,
has also demonstrated survival benefit over conventional chemotherapy in controlled trials.Vemurafenib has high specificity for BRAF harboring a V600E mutation, resulting in substitution of glutamic acid for valine at codon 600; this error
is present in 90% of melanomas with BRAF mutations.58 In
675 patients with metastatic melanoma, overall survival was
84% in patients receiving vemurafenib versus 64% in dacarbazine-treated patients at 6 months, with an overall response
rate of 48%.59 Treatment with vemurafenib is associated with
a number of potentially serious side effects that may require
modification or discontinuation of therapy; fatigue, alopecia,
arthralgia and muscle spasms, rash, squamous cell carcinoma
and gastrointestinal toxicity were noted most frequently. In
another study of 132 patients with previously treated metastatic melanoma, an overall response rate of 53% was noted
with a median duration of response of 6.7 months.60 Initial
treatment responses are marred by the emergence of resistant
cancer cells, which may acquire a mutation allowing for reactivation of the MAPK pathway. The mechanism of development of resistance is currently under investigation.
These novel targeted therapies are an exciting advance in
the field of melanoma treatment. Further research is needed
to develop therapies that provide sustained responses and high
response rates with favorable side effects profiles. A final note
is the importance of close follow-up to detect recurrent or
metastatic melanoma; patients diagnosed with melanoma are
at an increased risk of developing a second primary melanoma. Counseling melanoma patients and their first-degree
relatives about this risk and the importance of daily sun protection is essential.
Conclusion
Skin cancer is the most common cancer worldwide,
causing significant morbidity and consuming substantial
healthcare resources. Skin cancers may be curable when
detected early and adequately treated, but the prognosis for
advanced cutaneous malignancies is poor. Various surgical
and non-surgical therapeutic options exist for both melanoma and NMSC, with novel targeted therapies emerging
for patients with advanced disease. The choice of therapy
and determination of therapeutic goals and expectations
should be discussed with the patient and his or her family to optimize treatment outcomes. A multidisciplinary
approach is often critical for patients with advanced cutaneous malignancy, with input from oncology, radiology,
surgery and otolaryngology colleagues. Finally, prevention
of skin cancer is paramount; every patient encounter may
be viewed as an opportunity to educate patients about the
importance of daily sun protection.n
Dr. O’Neill is with the department of dermatology at Wake Forest
Disclosure: Dr. O’Neill does not have any industry relationships
or financial conflicts of interest to disclose.
References
1. Lens MB, Dawes M. Global perspectives of contemporary epidemiological
trends of cutaneous malignant melanoma. Br J Dermatol. 2004;150:179-185.
2. U.S. National Institutes of Health. SEER stat fact sheets: Melanoma of the
skin. National Cancer Institute 2011. Accessibility verified June 22, 2012. Available at: http://seer.cancer.gov/statfacts/html/melan.html#incidence-mortality
3. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide
incidence of nonmelanoma skin cancer. Br J Dermatol. 2012;166:1069.
4. Weinstock MA. Epidemiology, etiology and control of melanoma. Med
Health R I. 2001;84:234-236.
5. Gulleth Y, Goldberg N, Silverman RP, Gastman BR. What is the best surgical margin for a basal cell carcinoma: A meta-analysis of the literature. Plast
Reconstr Surg. 2010;126(4):1222-31.
6. Staples M, Marks R, Giles G. Trends in the incidence of nonmelanoma
skin cancer (NMSC) treated in Australia 1985-1995: Are primary prevention
programs starting to have an effect? Int J Cancer. 1998;78:144-8.
7. Urbach F. Incidence of nonmelanoma skin cancer. Dermatol Clin.
1991;9(4):751–5.
8. Gloster HM, Brodland DG Jr. The epidemiology of skin cancer. Dermatol
Surg. 1996;22(3):217–26.
9. Czarnecki D, Meehan CJ, Bruce F, Culjak G. The majority of cutaneous squamous cell carcinomas arise in actinic keratoses. J Cutan Med Surg.
2002;6(3):207-9.
10. Rowe DE, Carroll RJ, Day CL Jr. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: Implications for patient fol-
low-up. J Dermatol Surg Oncol. 1989;15(3):315-28.
11. Mosterd K, Krekels GA, Nieman FH, et al. Surgical excision versus Mohs
micrographic surgery for primary and recurrent basal-cell carcinoma of the
face: A prospective randomised controlled trial with 5-years’ follow-up. Lancet
Oncol. 2008;9(12):1149-56.
12. Miller SJ, Alam M, Andersen J, et al. Basal cell and squamous cell skin
cancers. J Natl Compr Canc Netw. 2010;8:836-64
13. Reschly MJ, Shenefelt PD. Controversies in skin surgery: Electrodessication and curettage versus excision for low-risk, small, well-differentiated
squamous cell carcinomas. J Drugs Dermatol. 2010;9(7):773-6.
14. Stegman SJ, Tromovitch TA. Modern chemosurgery--microscopically
controlled excision. West J Med. 1980;132(1):7-12.
15. Rowe DE, Carroll RJ, Day CL Jr. Mohs surgery is the treatment of choice
for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol.
1989;15(4):424-31.
16. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. St. Louis, Missouri:
Mosby/Elsevier, 2008. Second edition.
17. Han A, Ratner D. What is the role of adjuvant radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion? Cancer.
2007;109(6):1053-9.
18. Barysch MJ, Eggmann N, Beyeler M, Panizzon RG, Seifert B, Dummer R.
Long-term recurrence rate of large and difficult to treat cutaneous squamous
cell carcinomas after superficial radiotherapy. Dermatology. 2012;224(1):59-65.
19. Wang JT, Palme CE, Morgan GJ, Gebski V, Wang AY,Veness MJ. Predictors
of outcome in patients with metastatic cutaneous head and neck squamous
cell carcinoma involving cervical lymph nodes: Improved survival with the
addition of adjuvant radiotherapy. Head Neck. 2011 Nov 23. doi: 10.1002/
hed.21965. [Epub ahead of print]
20. Morton CA, Whitehurst C, Moseley H, McColl JH, Moore JV, Mackie
RM. Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen’s disease. Br J Dermatol. 1996;135:766-771.
21. Cox NH, Eedy DJ, Morton CA. Guidelines for management of Bowen’s
disease: 2006 update. Br J Dermatol. 2007;156:11-21.
22. Marmur ES, Schmults CD, Goldberg DJ. A review of laser and photodynamic therapy for the treatment of nonmelanoma skin cancer. Dermatol Surg.
2004;30:264-271.
23. Morton CA, McKenna KE, Rhodes LE. Guidelines for topical photodynamic therapy: Update. Br J Dermatol. 2008;159:1245-1266.
24. Horn M, Wolf P, Wulf HC, et al. Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications
and poor cosmetic outcome with conventional treatment. Br J Dermatol. 2003;
149: 1242-1249.
25. Vinciullo C, Elliott T, Francis D, et al. Photodynamic therapy with topical methyl aminolaevulinate for “difficult-to-treat” basal cell carcinoma. Br J
Dermatol. 2005;152:765-772.
26. Jeremic G, Brandt MG, Jordan K, Doyle PC, Yu E, Moore CC. Using
photodynamic therapy as a neoadjuvant treatment in the surgical excision of
nonmelanotic skin cancers: Prospective study. J Otolaryngol Head Neck Surg.
2011; 40 Suppl 1: S82-9.
27. Marmur ES, Nolan KA, Henry M. Intraoperative photodynamic therapy:A
description of a new adjuvant technique for patients with nonmelanoma skin
cancer. Dermatol Surg. 2012 May 18. doi: 10.1111/j.1524-4725.2012.02433.x.
[Epub ahead of print]
28. Peikert JM. Prospective trial of curettage and cryosurgery in the management of non-facial, superficial, and minimally invasive basal and squamous cell
carcinoma. Int J Dermatol. 2011;50(9):1135-8.
29. Lindemalm-Lundstam B, Dalenbäck J. Prospective follow-up after curettage-cryosurgery for scalp and face skin cancers. Br J Dermatol.
2009;161(3):568-76.
30. Gaitanis G, Nomikos K,Vava E, Alexopoulos EC, Bassukas ID. Immunocryosurgery for basal cell carcinoma: Results of a pilot, prospective, open-label
study of cryosurgery during continued imiquimod application. J Eur Acad
Dermatol Venereol. 2009;23(12):1427-31.
31. Gaitanis G, Alexopoulos EC, Bassukas ID. Cryosurgery is more effective
in the treatment of primary, non-superficial basal cell carcinomas when applied during and not prior to a five week imiquimod course: A randomized,
prospective, open-label study. Eur J Dermatol. 2011;21(6):952-8.
31
32. Eigentler TK, Kamin A, Weide BM, et al. A Phase III, randomized, open
label study to evaluate the safety and efficacy of imiquimod 5% cream applied
thrice weekly for 8 and 12 weeks in the treatment of low-risk nodular basal
cell carcinoma. J Am Acad Dermatol. 2007;57(4):616-21.
33. Shumack S, Robinson J, Kossard S, et al. Efficacy of topical 5% imiquimod
cream for the treatment of nodular basal cell carcinoma: comparison of dosing regimens. Arch Dermatol. 2002;138(9):1165-71.
34. Neville JA, Williford PM, Jorizzo JL. Pilot study using topical imiquimod
5% cream in the treatment of nodular basal cell carcinoma after initial treatment with curettage. J Drugs Dermatol. 2007;6(9):910-4.
35. Gaitanis G, Mitsou G, Tsiouri G, Alexis I, Bassukas ID. Cryosurgery during imiquimod cream treatment (“immunocryosurgery”) for Bowen’s disease
of the skin: A case series. Acta Derm Venereol. 2010;90(5):533-4.
36. MacFarlane DF, El Tal AK. Cryoimmunotherapy: Superficial basal cell
cancer and squamous cell carcinoma in situ treated with liquid nitrogen followed by imiquimod. Arch Dermatol. 2011;147(11):1326-7.
37. Rosen T, Harting M, Gibson M. Treatment of Bowen’s disease with topical
5% imiquimod cream: Retrospective study. Dermatol Surg. 2007;33(4):427-432.
38. Patel GK, Goodwin R, Chawla M, et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ (Bowen’s disease):
A randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol.
2006;54(6):1025-1032.
39. Mackenzie-Wood A, Kossard S, de Launey J, Wilkinson B, Owens ML.
Imiquimod 5% cream in the treatment of Bowen’s disease. J Am Acad Dermatol. 2001;44:462-70.
40. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog
pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164-72.
41. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib
in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-9.
42. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal cell nevus syndrome. N Engl J Med.
2012;366(23):2180-2188.
43. Bouwes Bavinck JN, Tieben LM, van der Woude FJ, et al. Prevention of
skin cancer and reduction of keratotic skin lesions during acitretin therapy
in renal transplant patients: A double-blind, placebo-controlled study. J Clin
Oncol. 1995;13:1933-1938.
44. George R, Weightman W, Russ GR, Bannister KM, Mathew TH. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant
recipients. Australas J Dermatol. 2002;43:269–73.
45. Chen K, Craig JC, Shumack S. Oral retinoids for the prevention of skin
32
cancers in solid organ transplant recipients: A systematic review of randomized controlled trials. Br J Dermatol. 2005;152(3):518-23.
46. Campbell SB, Walker R, Tai SS, Jiang Q, Russ GR. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant. 2012 May;12(5):1146-56. doi:
10.1111/j.1600-6143.2012.04004.x. Epub 2012 Mar 15.
47. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-54.
48. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations
in melanoma. N Engl J Med. 2005;353:2135-47.
49. Zalla MJ, Lim KK, Dicaudo DJ, Gagnot MM. Mohs micrographic excision of melanoma using immunostains. Dermatol Surg. 2000;26(8):771-84.
50. Shumaker PR, Kelley B, Swann MH, Greenway HT Jr. Modified Mohs
micrographic surgery for periocular melanoma and melanoma in situ: Longterm experience at Scripps Clinic. Dermatol Surg. 2009;35(8):1263-70.
51. Morton DL, Chan AD. The concept of sentinel node localization: How it
started. Semin Nucl Med. 2000;30:4-10.
52. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or
nodal observation in melanoma. N Engl J Med. 2006;355(13):1307-17.
53. Erickson C, Miller SJ. Treatment options in melanoma in situ: Topical and radiation therapy, excision and Mohs surgery. Int J Dermatol.
2010;49(5):482-91.
54. Farshad A, Burg G, Panizzon R, Dummer R. A retrospective study
of 150 patients with lentigo maligna and lentigo maligna melanoma and
the efficacy of radiotherapy using Grenz or soft X-rays. Br J Dermatol.
2002;146(6):1042-6.
55. Schmid-Wendtner MH, Brunner B, Konz B, et al. Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients. J Am
Acad Dermatol. 2000;43(3):477-82.
56. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-23.
57. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for
previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-26.
58. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs
broad target blockade in BRAF-mutant melanoma. Nature. 2010;467:596-9.
59. Chapman PB, Hauschild A, Robert C, et al. Improved survival with
vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med.
2011;364:2507-16.
60. Sosman JA, Jim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-14.
Current Trends in Atopic Dermatitis
Treatment: More Than Just Steroids
As the cause of the condition is considered multifactorial, the treatment plan should include combination therapies and avoidance of triggers.
Megan A. Kinney, MD, MHAM
A
topic dermatitis is a common chronic or chronically relapsing inflammatory skin disease that affects approximately 18% to 25% of the pediatric
population and causes psychosocial morbidity,
impaired quality of life and a heavy economic burden. The
disease presents with pruritus plus an eruption consisting
of scaly to lichenified plaques most commonly manifesting
in the skin creases (although in infants it is more common
on the face), and, generally dry skin and possible associated allergic symptoms (see Figures 1 and 2). In fact,
the progression from atopic dermatitis to asthma to allergic
rhinitis is called the “atopic march,” though patients can
present with these conditions in any order or all at once.
While AD much more characteristically develops in childhood, a small portion of patients may develop the disease
in adulthood. AD can be associated with elevated IgE levels and multiple gene mutations that can cause changes in
the skin barrier itself. The condition is likely a product of
gene-environment interaction.
Traditional treatment of AD is multifactorial and based on
severity. Patients should avoid triggers such as allergens, rough
clothing, stressors and bacteria on the skin through the use of
bleach baths and antibacterial soaps, and practice good skin
care habits with frequent application of emollients and use of
mild soaps. For the aforementioned plaques, topical corticosteroids are first-line treatment with potency based on severity
and thickness of plaques. Most agree that supplementation of
topical calcineurin inhibitors like pimecrolimus and tacrolimus, can aid in long-term management of moderate AD. Light
therapy may also be of benefit. For severe recalcitrant AD,
oral systemic medications may be necessary, with cyclosporin, azathioprine, mycophenolate mofetil and methotrexate
used most commonly. Smaller numbers of patients have also
been treated with biologics. Prednisone is generally not recommended for AD unless done in a shorter taper to another
steroid-sparing systemic agent, given its side effect profile and
propensity to cause AD to flare more severely with its discontinuation. Multiple integrative treatments are also employed in
the treatment of AD.1
A review of current literature shows that current studies
trend away from topical steroids and toward novel modalities,
Figure 1. Lichenified, excoriated eczematous plaques
in a child with atopic dermatitis.
Figure 2. The antecubital region is a common place
for atopic dermatitis.
some of which may be unexpected. Since the cause of the
disease is considered multifactorial, a treatment plan should be
implemented in lieu of a single miracle cream.This article will
explore these current trends in categories.
33
Current Trends in Atopic Dermatitis Treatment: More Than Just Steroids
Cornified cell envelope
-80% Loricrin
-Involucrin
Amino acids
Filaggrin
Endoproteases
Profilaggrin
Lipid bilayer
Corneocyte
Stratum corneum
Corneodesmosomes
Granular layer
Lamellar granules
-Lipid precursors
-Antimicrobial peptides
Spinous layer
-Proteases
Basal layer
Figure 3. Skin Barrier
Within the stratum corneum, the lipid bilayer between the corneocytes is created by planar lamellae sheets
of ceramides, cholesterol and free fatty acids. Within the cornified cell envelope is loricrin and involucrin.
Profilaggrin is cleaved by proteases at the junction of the granular layer and the stratum corneum to create
filaggrin which bundles keratin and flattens corneocytes. The filaggrin is then broken down into amino acids which
aid in retaining moisture. Corneodesmosomes create the tight junctions holding the corneocytes together.
Skin Barrier
Protecting and rebuilding the skin barrier has become
part of the bread-and-butter treatment regimen for atopic
dermatitis. Many patients with AD have been shown to have
a mutation in FLG, which codes for filaggrin, which aggregates keratin, a large component of the stratum corneum
(see Figure 3). In between the cells of the epidermis, the
keratinocytes, there are lipid molecules — including ceramides — that fill in the gaps and help to maintain the barrier.
With less filaggrin, the barrier becomes broken allowing for
water loss and the entry of antigens and infectious organisms. Recent studies have demonstrated that applying ceramide-containing emollients can help restore the skin barrier. These studies evaluated the ceramide topical in all age
groups, but a recent study evaluated this topical solely in the
pediatric population and further supported incorporation
of ceramide-dominant topicals as an integral component in
AD therapy either as monotherapy or combination therapy.2
These topicals not only replace what is lost; they actually
improve keratinocyte lipid biosynthesis, which may further
improve the epidermal barrier.3 This molecule has so far
only been available in lotion or cream form, but recently a
ceramide hyaluronic acid foam has been developed that may
have the benefits of ceramides with increased compliance
given the foam vehicle.4 Alternatively, patients may be able
to obtain the benefits of ceramides even without applying
a topical therapy. Consuming dietary sphingolipids has suggested an upregulation in the synthesis of ceramides in skin.5
Also, an oral collagen tripeptide has undergone initial animal
studies and shown improvement in skin dryness.6
34
While ceramides have been the primary focus, other possible molecules to enhance the skin barrier are also being
studied. Topical urea may enhance barrier function because it
has anti-microbial properties; it also upregulates filaggrin and
production of other components of the skin barrier.7
Recent studies suggest that upregulating filaggrin levels in
the skin by 5% to 10% may improve clinical management of
patients with AD; this may, therefore, become a more focused
therapeutic target for treatment. Several compounds already
shown to increase FLG gene expression include oleanolic
acid and ursolic acid.8
While FLG is most prominent in the literature, known upregulated genes in AD include involucrin, a small protein-rich
region (SPRR) 2C gene and alternative pathway keratin 16.
All were shown to be decreased in lesional skin after treatment with pimecrolimus. Treatments targeting genes lends to
a new avenue to improve the skin barrier.9
Lastly, recent studies in standard treatments of care have determined that while topical corticosteroids may be a more
effective anti-inflammatory, they reduce the rate limiting enzymes for lipid synthesis and the expression of involucrin and
SPRRs in the skin (which covalently binds ceramides), thus
inhibiting the restoration of the skin barrier. This confirms
that calcineurin inhibitors (such as pimecrolimus, which was
the comparison treatment in this study) are a better option for
long-term maintenance therapy.10
Fighting Infectious Organisms
Breakdown of the skin barrier allows easier access for infectious organisms. Practitioners offer many recommendations
for decreasing bacteria generally on the skin, including antibacterial soaps, oral and topical antibiotics and bleach baths.
Children with atopic dermatitis have been found to be
more prone to infectious diseases in general; they are more
frequently hospitalized than children without AD, and the
most common reason for hospitalization is pneumonia. Children with AD also commonly suffer from chronic diarrhea,
and studies have confirmed that Staphylococcus aureus is more
commonly found in their stool. Some believe that S. aureus in
the GI tract can stimulate atopic skin changes.11
Probiotic supplementation has been suggested as a way to
deliver additional microorganisms to the GI tract and, in several studies, have been shown to prevent AD.12,13 Addition of
other microorganisms may aid in eliminating the intestinal
overgrowth of S. aureus. Following a similar belief, Jang et al
argue that the addition of lactic acid bacteria (LAB) may also
aid in prevention and treatment of allergic diseases. Previous
studies have shown the LAB, Lactobacillus plantarum, isolated
from the traditional Korean food kimchi, reduce allergen-induced airway hypersensitivity and histamine release. By isolating Lactobacillus plantarum K-1, they found that proinflammatory cytokines and scratching behavior in mice was reduced,
indicating this may be a future treatment for allergic conditions such as AD.14
While the changes in the gut mentioned above are new
discoveries, it is well known that high levels of S. aureus are
found on the skin of patients with atopic dermatitis. A recent
study analyzed the susceptibilities of the S.aureus isolated on
patients with superinfected AD versus controls and found that
there is increased resistance to clindamycin (the most commonly prescribed antibiotic for these patients) on the skin of
patients with AD in comparison to controls. This may lead to
changes in clinical practice to prescribe something else like
trimethoprim/sulfmethoxazole as a first line empiric antimicrobial choice, although culture-driven antibiotic choices for
superinfected AD should be encouraged.15
However, others do not necessarily recommend the use of
oral antibiotics for secondarily impetiginized AD, even with
culture-proven MRSA. In an argument supporting decreased
antimicrobial peptides associated with AD, one group treated
patients with impetiginized AD with a combination therapy
of topical corticosteroids, antihistamines and oral cephalexin
(which would not cover MRSA). They saw improvement
even in patients harboring cephalexin-resistent MRSA. This
supports the belief that S. aureus is a trigger for AD and that
calming inflammation restores natural anti-microbial peptides
(AMPs) that can then adequately fight off the secondary impetiginization. This was supported by a quantified increase in
defensins after treatment.16
A new alternative that may be on the horizon is the addition of an antimicrobial component to clothing. In one study,
chitosan was incorporated into cotton clothing.The chitosanimpregnated clothing significantly reduced S. aureus bacterial
content specifically and not all bacteria. 17
In addition to secondary infection by bacteria, viral exwww.the-dermatologist.com
anthems may also be associated with eczema; molluscum
contagiosum is commonly seen in conjunction with atopic
dermatitis. In some patients, this eczematous eruption may
be a secondary id reaction to the primary infection. Given
the vicious cycle of topical steroids causing progression of
the molluscum when trying to treat the associated eczematous reaction, it is recommended to treat the id reaction with
topical emollients. If patients are severely symptomatic, short
courses of topical steroids may be used, but limiting their
duration is important, as steroid use can delay the resolution
of molluscum contagiosum.18
Environment
While environment provides the source for all infectious
agents, it can also affect patients with AD in other ways. Epidemiologic studies have shown that higher-income countries
have a decreased frequency of infections and an increased rate
of allergic diseases.12 Some argue that better hygiene has led
to less exposure to antigens early in life.
In addition to frequency, a recently published questionnaire study revealed several environmental factors associated
with severity of AD. Though a causal relationship could not
be demonstrated, these environmental factors could perhaps
trigger an individual’s genetic predisposition for the disease.
Factors associated with AD severity included indoor remodeling, those living in an apartment, higher household income
and higher educational status of the mother.19 Another study
found that, in children with AD, cat and daycare exposure actually reduced the risk of developing asthma in early childhood.20 Another study showed allergic AD may be more of
a result of house mites entering through the defective skin
barrier, stimulating an immune response. There is much controversy over whether food allergies contribute to AD; this
will be discussed in a later section.21
The use of humidifiers is often recommended, as they can
moisten the dry air, especially associated with heating, in the
home. Studies from Korea discuss an instance where biocides
mixed in the water of humidifiers caused a fatal pulmonary
syndrome in both children and pregnant women. While it is
not suggested that patients are at risk for inhaled biocides, it
is important for the clinician to remember that patients with
AD may have more of a chance of exposure to humidified
aerosols when compared with the general population.22
Psychological Issues
Sleep Deprivation
AD is not just a skin disease. The pruritus associated with
AD and the appearance of skin lesions can have a significant
impact psychologically. Recent studies in itch with AD confirm that intensity of pruritus correlated with declining quality of life and depressive symptoms. In addition, patients experiencing sleep deprivation with AD attributed it to nighttime
itch. Sleep deprivation can even occur at the onset of the
disease.23 Use of sleeping pills has been shown to improve
quality of life and depressive symptoms greatly.24
35
ADHD
A study in Taiwan recently found an increased risk of attention-deficit/hyperactivity disorder (ADHD) in patients
with pediatric allergy disorders. Of note, the main contributing disorder was allergic rhinitis, but bronchial asthma was
also determined to be a risk factor for ADHD. Atopic dermatitis was only determined to be a risk factor in association
with allergic rhinitis but was not an independent risk factor.25 Because of the atopic triad, clinicians should be aware
of this psychiatric co-association.
Stress
While there are no randomized controlled studies,
stress has been suspected to worsen AD. Multiple techniques of relaxation are present in the literature including massage, hypnosis, biofeedback and progressive muscle relaxation. Small studies have indicated improvement
in AD with massage. 13
One study looked at Dead Sea climatotherapy. In this study,
patients were treated at a spa hotel near the Dead Sea. Treatment consisted of bathing in the Dead Sea and then exposing
the skin to UV radiation.The treatment environment was also
kept stress-free. Using the SCORAD index for disease severity and the Skindex-29 score for quality of life, the treatment
regimen did show significant improvement in both modalities, but confounding variables such as feeling as though one
is on vacation may skew these results.26
In addition to causing
the patient psychological
distress, AD also causes
family stress.
In addition to causing the patient psychological distress,
AD also causes the family stress. Patient education programs
have shown to be successful in improving patient disease and
psychological well being. Schut et al recently demonstrated
that parents with little social support or parents with high
active problem solving behavior would likely benefit more
from such programs and that such patients and their parents
should be offered this additional education for greater success
in treating AD.27
Positive Reinforcement
Because AD is more commonly a pediatric disease, psychological approaches to treatment should also take the
child’s mindset into account. Most children strongly dislike
36
the sticky ointments and gooey creams prescribed. Poor adherence to topical treatments leads to worse outcomes and
possibly progression to a systemic medication with greater
side effects. Using positive reinforcement techniques may
increase motivation to use topical medications. For example,
sticker charts have been shown to improve outcomes in other chronic diseases that require long-term compliance with
treatment regimens.28
Integrative Medicine
There are scores of recommendations when one considers integrative treatments. We will focus on some of the most
recent research on oatmeal, silk, clothing and traditional Chinese medicine (TCM).
Oatmeal
Oatmeal has been shown to inherently possess antioxidant
and anti-inflammatory properties, and studies have shown
that using a topical formulation of colloidal oatmeal, avenanthramide, restores the cutaneous barrier, alleviating symptoms.
Some studies offer this as adjunctive treatment to limit topical
steroids, but others suggest that applying oatmeal to a damaged epidermal barrier may lead to oat allergy.29-32
Silk and Other Textiles
Silk and similar materials have been a mainstay in integrative
medicine. Recently, oral administration of silk peptides to mice
was shown to decrease IgE levels in an atopic dermatitis mouse
model.This may be an indication that silk has the ability to modulate the immunological T-helper cell (Th1/Th2) balance.33
Studies have also looked at more traditional use of silk as
textiles. Certain fabrics can be irritating to the skin. Some have
proposed silk as a softer alternative; in atopic dermatitis, however, this textile is not always practical, as it can reduce transpiration and may still cause irritation. Knitted silk alternatives,
however, some impregnated with an antimicrobial component,
have been shown to, at times, demonstrate a reduction in pruritus and severity of AD by SCORAD index. This initial success
spawned the development of a synthetic silk-like fabric, which
has been cleared by the FDA as a Class I medical device for use
by patients with AD. The fabric is even being used in bedding
and has been marketed to prevent bacterial infections (as they
have an antimicrobial coating), absorb perspiration and serous
exudates and reduce skin irritation. leading to reduced disease
severity and pruritus and improved quality of life.34
A silver-loaded cellulose fabric with incorporated seaweed
was also shown to decrease the modified SCORAD atopic
dermatitis index, trans-epidermal water loss and the patient’s
subjective severity of their AD compared to cotton clothing.35
Traditional Chinese Medicine
There has been an increasing trend in medicine to use herbal
medications. and trends in the treatment of atopic dermatitis are no different. TCM is based in more than 2,000 years
of experience in herbal medicines, acupuncture, massage and
diet. The difficulties with examining the safety and efficacy of
the medications is that many herbs are combined and dosed
differently with each individual patient, making randomized
controlled studies difficult. Standardized treatment across the
board contraindicates the individualized treatment that is the
basis of TCM. Of the randomized controlled studies that do
exist, some benefit has been seen and most authors offer TCM
as an alternative treatment for refractory AD. It must be noted
that TCM can still have adverse effects.The most common side
effect with oral medications was an elevation in liver function
tests. Also, secondary to a lack of monitoring by the FDA, some
topical formulations have actually been found to contain dexamethasone at varying concentrations with no indication on the
label that they include corticosteroids. Some were even found
to have concentrations of topical corticosteroids higher than
the highest potency steroid available in the United States. This
could be hazardous, especially if used in conjunction with a
potent prescribed topical steroid.13 A novel herbal medication,
KIOM-MA and its fermented product, KIOM-MA128, consist of a mixture of herbs including Glycyrrhizae radix, Polygoni
cuspidati rhizoma, Sophorae radix, Cnidii rhizoma, and Arctii fructus.
This oral medication was tested in an atopic dermatitis mouse
model and was shown to improve AD by decreasing plasma IgE,
scratching behavior and skin severity. The fermented version
was found to actually be more effective. Topical formulations
are also in development.36
tus and quality of life with AD, but larger trials would have to
be completed to make any recommendations to the general
public.39 Another study showed that a combination supplement containing five polyunsaturated fatty acids, vitamin C,
vitamin E and zinc demonstrated significant improvement in
patient symptoms. The idea behind supplementing polyunsaturated fatty acids is that they have been employed in restoring the stratum corneum and skin barrier.13 Other supplements such as vitamin B6, vitamin D, folic acid, vitamin
B12 and zinc have been studied in solitary. Vitamin B6 or
Nutrition
pyroxidine is an essential cofactor for many biochemical reactions in the body and it was suspected that a diet deficient
in this vitamin might lead to AD. While deficiencies themselves were not studied, there was no improvement in AD
with supplementation of vitamin B6. Vitamin D has been
thought to be promising in the treatment of AD, as it can
induce keratinocytes, increase synthesis of platelet-derived
growth factor, facilitate wound healing, decrease synthesis of
inflammatory cytokines, and promote cathelicidin expression. Studies have confirmed that patients with milder AD
do have higher levels of vitamin D and that supplementing
vitamin D stimulates production of cathelicidin. However,
there have been inconsistencies with both supplementation
of vitamin D for treatment of AD and vitamin D deficiency
associated with AD.40
Another study looked at folic acid versus IgE levels in patients with atopic dermatitis. IgE levels were correlated with
AD severity and were most increased in patients with allergic
rhinitis. Previous studies have suggested that low serum folate
levels may contribute to the risk of high IgE levels. This study,
however, did not find similar results, although patients with
AD did have lower levels of folic acid than controls. More
studies would need to be done in order to recommend folic
acid supplementation in patients with AD.41 Kiefte-de Jong
looked at plasma levels of both folic acid and vitamin B-12
during pregnancy and found that elevations during the first
trimester were associated with the development of atopic dermatitis in offspring, but not wheezing or shortness of breath.
Nutrition and its relationship with AD is a controversial
topic with dermatologists and primary care physicians. In
the literature, discrepancies remain about when to introduce new foods and which foods to expose to the newborn.
Roduit et al found that introduction of diverse complementary foods and yogurt within the first year of life actually
might have a protective effect against the development of
AD. A reduction in the risk of AD onset after the first year of
life was found.37 Early introduction of cow’s milk and different infant formulas and their association with the development of AD is also controversial. For breast-feeding mothers,
maternal diet supplementation has also been investigated.
Upon review of current literature, the American Academy
of Pediatrics suggests that lactating mothers avoid peanuts
and tree nuts in infants with a high risk for developing AD.
They should also consider elimination of eggs, cow’s milk
and fish. The World Health Organization (WHO) recommends breastfeeding children up to age 2. Limited research
in the area has not determined whether or not breastfeeding
has a protective role against development of AD.38
A recent review of studies using dietary supplements in
children with atopic dermatitis unfortunately showed no
benefit in improving AD with oral supplementation of olive
oil, corn oil, oral zinc sulphate, selenium, selenium plus vitamin E, vitamin D, sea buckthorn seed oil, sea buckthorn pulp
oil, hempseed oil, sunflower oil and DHA. Two small studies
with fish oil did indicate some slight improvement in pruriwww.the-dermatologist.com
Nutrition and its
relationship with AD is a
controversial topic with
dermatologists and primary
care physicians.
37
Though similar studies have shown conflicting results, they
bring to light that this should be taken into consideration
before institution of government-mandated folic acid fortification.42 Vitamin B12 or cobalamin has also been theorized to
treat AD through its known function of suppressing inflammatory cytokines. A study with topical vitamin B12 demonstrated improvement in AD. It has also been suggested that
patients with AD may have decreased zinc levels.
New Tricks
Pruritus, which is commonly associated with AD, can
be difficult to control. Oral antihistamines are not usually effective, as the itch associated with AD is not generally mediated by histamine release. Topical corticosteroids
are also not always effective and there is the added effect
of thinning the normal skin with chronic use. Chronic
itching can cause atopic dermatitis to worsen, re-starting
the itch-scratch cycle after induction therapy is complete.
Takeuci et al compared the use of tacrolimus versus emollients as maintenance therapy in patients who had already
undergone induction therapy with topical steroids. They
found that 100% of the emollient group had recurrence of
pruritus, while only 24% of the tacrolimus group did. This
argues that tacrolimus may be a better option for maintenance therapy in patients with AD.43
Tacrolimus is already a mainstay treatment in AD as a
non-steroid ointment that does not have the same side effect profile as topical steroids. Despite this, patients have
difficulty applying the sticky ointment and some complain
of local side effects like burning, warmth and redness with
the medication. To alleviate some of these local side effects,
a study compared tacrolimus-loaded lipid-nanoparticles
head-to-head with standard tacrolimus. The tacrolimusloaded lipid-nanoparticles better targeted the deeper layers of the skin, which is desirable. The worry with deeper
penetration is more systemic side effects, but this didn’t
seem to be the case in animal models. These nanoparticles,
which were delivered in a gel vehicle, may be a better alternative to a greasy ointment.44
Ustekinumab, a relatively new biologic FDA-approved for
psoriasis, is a monoclonal antibody with affinity for the p40
subunit of interleukin 12 (IL-12) and IL-23. These interleukins promote proliferation of IL-17 through stimulation of
T-helper 17 (TH17) cells. AD is also associated with TH17
cells, possibly suggesting a common pathway for both inflammatory conditions. Puja et al speculated this to be the
case and had success in treating one patient with resistant
AD with ustekinumab.45
Monitoring Severity of AD
Many have noted the presence of an infra-auricular fissure in
patients with AD. Kwatra et al took this clinical finding a step
further and found depth of the fissure to be associated with the
severity of AD.This bedside clinical assessment has been found to
be helpful assessing AD severity across all age groups.46
38
Severe Cases
A pilot study was recently completed with apremilast, an oral
phosphdiesterase (PDE) inhibitor, for the treatment of AD in
adults. Results were promising, with reductions in pruritus,
Eczema Area Severity Index (EASI) and the Dermatology Life
Quality Index (DLQI) scores depending on dosing at 3 and
6 months. The leukocytes in patients with AD have elevated
levels of PDE type 4 when compared to controls and this elevation leads to hyperactivity of leukocytes and inflammation.
Oral PDE4 inhibitors have been studied for other conditions
such as asthma, psoriasis, psoriatic arthritis and chronic obstructive pulmonary disease (COPD), but this is the first use of this
medication for AD.47
Extracorporeal photochemotherapy is a procedure where
the patient’s blood goes through a process called leukophoresis, which removes the patient’s white blood cells while
the red blood cells and plasma are returned to the patient.
The white blood cells are treated with UVA radiation for
several cycles and then returned to the patient. The process
has been a treatment for cutaneous T-cell lymphoma, but
Considering the environment
outside patients’ bodies and
also what they are putting into
their bodies through nutrition
may help in preventing flares
or the disease itself.
has more recently been studied as a potentially successful
long-term treatment to stabilize AD in patients with severe
disease that has been resistant to other systemic therapies
without the immunosuppression that makes other systemic
medications risky.48
Cyclosporin is a systemic agent used for the treatment
of severe resistant atopic dermatitis. Subcutaneous allergen
immunotherapy (SCIT) is a process of subcutaneously administering gradually increasing doses of allergens to patients with allergic conditions to reduce clinical symptoms
from exposure to the allergen over time. Allergic responses
to common environmental allergens can be responsible
for the chronicity of AD. Using house dust mite extract in
patients with known hypersensitivity for SCIT combined
with cyclosporine, Nahm and Kim saw clinical improvements in all patients treated offering this initial study for
this combined treatment option.49
On the Horizon
Recent studies have suggested that sprouting of epidermal nerves is seen with the pruritus associated with AD.
Nerve growth factor (NGF), released by keratinocytes, is
a major growth factor regulating these new nerve connections, and increased levels of this molecule have been
seen in AD patients. A nerve repulsion factor, epidermal
semaphorin 3A (Sema3A), acts in opposition to NGF
and the two are said to work together as axonal guidance
molecules. Sema3A is found in decreased concentrations
in AD patients and could be a new target for calming
pruritus associated with anti-histamine resistant itch. Initial animal studies with an ointment containing Sema3A
have so far shown positive results. 50
In a separate study, Samukawa et al looked at another possible new treatment modality, red ginseng extract (RGE), and
its effect on NGF. In a study where 2,4-dinitrofluorobenzene
was applied to mouse ears to induce pruritus, the 1% RGE
was shown to be just as effective as tacrolimus in attenuating
NGF, while dexamethasone was less effective. RGE also inhibited histamine-induced vascular permeability and the same
result was observed clinically, with a decrease in scratching
behavior by mice.51
Fucoidan, a sulphated polysaccharide extracted from
brown seaweed known to have anti-allergic and immunologic activities, was recently tested for the treatment of
AD in a mouse model. It was compared topically headto-head with dexamethasone and was shown to be just as
effective both symptomatically and histologically, showing a decreased number of mast cells and decreased thickness of epidermis.52
Peroxisome proliferator-activated receptors (PPARs) are
nuclear receptors that have long been known to be associated with adipocytes and involved in insulin sensitization
and adipogenesis, but have more recently been seen to be involved in anti-inflammatory activity. In an AD mouse model, topical application of a PPARα activator showed clinical
improvement in dermatitis, reduced inflammatory infiltrate
in the dermis and decline of serum IgE elevation. Therefore,
a topical PPARα activator could be a topical steroid alternative in the future.53
Lastly, a new non-steroidal topical medication currently referred to as WBI-1001 has been shown to be efficacious in
treating mild to severe atopic dermatitis after completion of
a multi-center Phase IIB randomized, parallel-group, doubleblind, placebo-controlled trial. Only a single-center, 4-week
trial had been completed previously, so, after further testing, this
may be a new non-steroidal topical treatment on the horizon.54
Conclusions
For patients with AD, the future looks promising. While
this update only skims the surface of the current literature
exploring new and different treatment modalities in AD,
considering a treatment plan — versus a single ‘miracle’
cream — and focusing on rebuilding the skin barrier seem
to be the current treatment trends. Finding medications
that patients will use with a lesser side effect profile than
topical and oral corticosteroids and going back to our
roots in medicine with TCM and integrative medicine may
cause less co-morbidities to our patients. Considering the
environment outside patients’ bodies and also what they
are putting into their bodies through nutrition may help in
preventing flares or the disease itself. It is also important to
consider the psychological effects of AD on both patients
and those around them when trying to implement successful treatment. Finding new ways of using the tried and true
medications and treatment modalities can help recalcitrant
cases. Lastly, better understanding of AD on the molecular
and genetic level gives us a positive outlook of what’s on
the horizon. n
Dr. Kinney is with the Wake Forest Baptist Health Department
of Dermatology in Winston-Salem, NC.
Disclosure: Dr. Kinney has no conflicts of interest to report.
References
1. Bieber T, Bussmann C. Atopic dermatitis. In: Bolognia JL, Jorizzo, JL, Schafer JV. Dermatology (3rd Edition). Elsevier; 2012.
2. Kircik LH, Del Rosso JQ. Nonsteroidal treatment of atopic dermatitis
in pediatric patients with a ceramide-dominant topical emulsion formulated with an optimized ratio of physiological lipids. J Clin Aesthet Dermatol.
2011;4(12): 25-31.
3. Popa I, Remoue N, Osta B, et al. The lipid alterations in the stratum corneum of dogs with atopic dermatitis are alleviated by topical application of
a sphingolipid-containing emulsion. Clin Exp Dermatol. 2012;37(6):665-71.
4. Pacha O, Hebert AA. Treating atopic dermatitis: safety, efficacy, and patient
acceptabolity of a ceramide hyaluronic acid emollient foam. Clin Cosmet Investig Dermatol. 2012;5:39-42.
5. Duan J, Sugawara T, Hirose M, et al. Dietary sphingolipids improve skin
barrier functions via the upregulation of ceramide synthases in the epidermis.
Exp Dermatol. 2012;21(6):448-52.
6. Okawa T, Yamaguchi Y, Takada S, et al. Oral administration of collagen
tripeptide improves dryness and pruritus in the acetone-induced dry skin
model. J Dermatol Sci. 2012;66(2):136-43.
7. Grether-Beck S, Felsner I, Brenden H, et al. Urea uptake enhances barrier
function and antimicrobial defense in humans by regulating epidermal gene
expression. J Invest Dermatol. 2012;132(6):1561-72.
8. McGrath J. Profilaggrin, dry skin, and atopic dermatitis risk: size matters. J
Invest Dermatol. 2012;132(1):10-1.
9. Grzanka A, Zebracka-Gala J, Rachowska R, Bozek A, Kowalska M, Jarzab J.
The effect of pimecrolimus on expression of genes associated with skin barrier
dysfunction in atopic dermatitis skin lesions. Exp Dermatol. 2012;21(3):184-8.
10. Jensen JM, Scheer A, Wanke C, et al. Gene expression is differently affected by pimecrolimus and betamethasone in lesional skin of atopic dermatitis.
Allergy. 2012;67(3):413-23.
11. Rotsztejn H, Frankowska J, Kamer B,Trznadel-Grodzka E. Infection cases
in infants and small children with atopic dermatitis-own observations. Postepy
Hig Med Dosw. 2012;66(0):96-103.
12. Pelucchi C, Chatenoud L, Turati F, et al. Probiotics supplementation during pregnancy or infancy for the prevention of atopic dermatitis: a metaanalysis. Epidemiology. 2012;23(3):402-14.
13. Dinicola C, Kekevian A, Chang C. Integrative medicine as adjunct therapy in the treatment of atopic dermatitis- the role of traditional chinese medicine, dietary supplements, and other modalities. Clin Rev Allergy Immunol.
2012 Jun 4 (online).
39
14. Jang SE, Trinh HT, Chung YH, Han MJ, Kim DH. Inhibitory effect of
lactobacillus plantarium K-1 on passive cutaneous anaphylaxis reaction and
scratching behavior in mice. Arch Pharm Res. 2011;34(12):2117-23.
15. Bell MC, Stoval SH, Scurlock AM, Perry TT, Jones SM, Harik
NS. Addressing antimicrobial resistance to treat children with atopic
dermatitis in a tertiary pediatric allergy clinic. Clin Pediatr. 2012 Apr
18 (Epub).
16. Travers JB, Kozman A,Yao Y, et al. Treatment outcomes of secondarily imptiginized pediatric atopic dermatitis lesions and the role of oral antibiotics.
Pediatr Dermatol. 2012;29(3):2809-96.
17. Tavaria FK, Soares JC, Reis IL, Paulo MH, Malcata FX, Pintado ME.
Chitosan: antimicrobial action upon staphylococci after impregnation onto
cotton fabric. J Appl Microbiol. 2012;122(5):1034-41.
18. Naetchiporouk E, Cohen BA. Recognizing and managing eczematous
id reactions to molluscum contagiosum virus in children. Pediatrics, 2012;
129(4):e1072-5.
19. Lee JH, Suh J, Kim EH, et al. Surveillance of home environment in
children with atopic dermatitis: a questionnaire survery. Asia Pac Allergy.
2012;2(1):59-66.
20. Gaffin JM, Spergel JM, Boguniewicz M, et al. Effect of cat and daycare
exposures on the risk of asthma in children with atopic dermatitis. Allergy
Astham Proc. 2012;33(3):282-8.
21. Fujano N, Incorvaia C. Dissecting the causes of atopic dermatitis in children: less foods, more mites. Allergol Int. 2012;61(2):231-43.
22. Kim EH, Ahn K, Cheong HK. Use of humidifiers with children suffering
from atopic dermatitis. Environ Health Toxicol. 2012;27:e2012004.
23. Anuntaseree W, Sangsupawanich P, Osmond C, Mo-Suwan L,Vasiknanonte
P, Choprapawon C. Sleep quality in infants with atopic dermatitis: a community-based, birth cohort study. Asian Pac J Allergy Immunol. 2012;30(1):26-31.
24. Chrostowska-Plak D, Reich A, Szepietowski JC. Relationship between
itch and psychological status of patients with atopic dermatitis. J Eur Acad
Dermatol Venereol. 2012 May 23 (Epub).
25. Shyu CS, Lin HK, Lin CH, Fu LS. Prevelence of attention-deficit/hyperactivity disorder in patients with pediatric allergic disorders: a nationwide,
population-based study. J Microbiol Immunol Infect. 2012;45(3):237-42.
26. Adler-Cohen C, Czarnowicki T, Dreiher J, Ruzicka T, Ingber A, Harari
M. Climatotherapy at the dead sea: an effective treatment modality for atopic dermatitis with significant positive impact on quality of life. Dermatitis.
2012;23(2):75-80.
27. Schut C, Mahmutovic V, Gieler U, Kupfer J. Patient education programs
for childhood atopic dermatitis: who is interested? J Dtsch Dermatol Ges. 2012
Apr 18 (Epub).
28. Luersen K, Davis SA, Kaplan SG, Abel TD, Winchester WW, Feldman SR.
Sticker charts: a method for improving adherence to treatment of chronic
disease in children. Pediatr Dermatol. 2012;29(4): 403-408.
29. Pazyar N, Yaghoobi R, Kazerouni A, Feily A. Oatmeal in dermatology:
a brief review. Indian J Dermatol Venereol Leprol. [serial online] 2012[cited 2012 Jun 19];78(2):142-5. Available from: http://www.ijdvl.com/text.
asp?2012/78/2/142/93629.
30. Sur R, Nigam A, Grote D, Liebel F, Southall MD. Avenanthramides, polyphenols from oats, exhibit anti-inflammatory and anti-itch activity. Arch Dermatol Res. 2008;300:569-74.
31. Pigatto P, Bigardi A, Caputo R, et al. An evaluation of the allergic contact dermatitis potential of colloidal grain suspensions. Am J Contact Dermat.
1997;8:207-9
32. Boussault P, Léauté-Labrèze C, Saubusse E, et al. Oat sensitization in children with atopic dermatitis: Prevalence, risks and associated factors. Allergy.
2007;62:1251-6;quiz 82-3
33. Ikegawa Y, Sato S, Lim G, Hur W,Tanaka K, Komori M,Takenaka S,Taira
T. Amelioration of the progression of an atopic dermatitis-like skin lesion
by silk peptide and identification of functional peptides. Biosci Biotechnol
Biochem. 2012;76(3):473-7.
34. Ricci G, Neri I, Ricci L, Patrizi A. Silk fabrics in the management of
atopic dermatitis. Skin Therapy Lett. 2012;17(3):5-7.
40
35. Park KY, Jang WS,Yang GW, et al. A pilot study of silver-loaded cellulose
fabric with incorporated seaweed for the treatment of atopic dermatitis. Clin
Exp Dermatol. 2012;37(5): 512-5.
36. Chung TH, Kang TJ, Cho WK, et al. Effectiveness of novel herbal
medicine, KIOM-MA, and its bioconversion product, KIOM-MIA128,
on the treatment of atopic dermatitis. Evid Based Complement Alternat Med.
2012;2012:762918 (Epub).
37. Roduit C, Frei R, Loss G, et al. Protection Against Allergy-Study in Rural Environments study group. Development of atopic deratitis according to
age of onset and association with early-life exposures. J Allergy Clin Immunol.
2012;130(1):130-136.
38. Lien TY, Goldman RD. Breastfeeding and maternal diet in atopic dermatitis. Cam Fam Physician. 2011;57(12):1403-5.
39. Bath-Hextall FJ, Jenkinson C, Humphreys R, Williams HC. Dietary
supplements for established atopic eczema. Cochrane Database Syst Rev.
2012;2:CD005205.
40. Benson AA, Toh JA, Vernon N, Jariwala SP. The role of vitamin D in the immunopathogenesis of allergic skin diseases. Allergy.
2012;67(3):296-301.
41. Shaheen MA, Attia EA, Louka ML, Bareedy N. Study of the role of serum
folic acid in atopic dermatitis: a correlation with serum IgE and disease severity. Indian J Dermatol. 2011;56(6):673-7.
42. Kiefte-de Jong JC, Timmermans S, Jaddoe VW, et al. High circulating
folate and vitamin B-12 concentrations in women during pregnancy are associated with increased prevalence of atopic dermatitis in their offspring. J
Nutr. 2012;142(4):731-8.
43. Takeuchi S, Saeki H, Tokunaga S, et al. A randomized, open-label, multicenter trial of topical tacrolimus for the treatment of pruritus in patients with
atopic dermatitis. Ann Dermatol. 2012;24(2):144-50.
44. Pople PV, Singh KK. Targeting tacrolimus to deeper layers of skin with
improved safety for treatment of atopic dermatitis- Part II: In vivo assessment of dermatopharmacokinetics, biodistribution and efficacy. Int J Pharm.
2012;434(1-2):70-9.
45. Puya R, Alvarez-López M,Velez A, Casas Asuncion E, Moreno JC. Treatment of severe refractory adult atopic dermatitis with ustekinumab. Int J Dermatol. 2012;51(1):115-6.
46. Kwatra SG, Tey HL, Dabade T, Chan YH, Yosipovitch G. The infra-auricular fissure: a bedside marker of disease severity in patients with atopic
dermatitis. J Am Acad Dermatol. 2012;66(6):1009-10.
47. Samaro A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral
phosphodiesterase inhibitor (Apremilast) for atopic dermatitis in adults. Arch
Dermatol. 2012 Apr 16 (Epub).
48. Rubegni P, Poggiali S, Cevenini G, et al. Long term follow-up results on
severe recalcitrant atopic dermatitis treated with extracorporeal phototherapy.
J Eur Acad Dermatol Venereol. 2012 Apr 28 (Epub).
49. Nahm DH, Kim ME. Treatment of severe atopic dermatitis with a combination of subcutaneous allergen immunotherapy allergen immunotherapy
and cyclosporin. Yonsei Med J. 2012;53(1):158-63.
50. Negi O, Tominaga M, Tengara S, et al. Topically applied semaphorin 3A ointment inhibits scratching behavior and improves skin inflammation in NC/Nga mice with atopic dermatitis. J Dermatol Sci.
2012;66(1):37-43.
51. Samukawa K, Izumi Y, Shiota M, et al. Red ginseng inhibits scratching
behavior assicated with atopic dermatitis in experimental animal models. J
Pharmacol Sci. 2012;118(3):391-400.
52.Yang JH.Topical application of fucoidan improves atopic dermatitis symptoms on NC/Nga mice. Phytother Res. 2012 Mar 19 (Epub).
53. Chiba T, Takeuchi S, Esaki H, et al. Topical application of PPAPα
(but not β/δ or ϒ) suppresses atopic dermatitis in NC/Nga mice. Allergy.
2012;67(7):936-42.
54. Bissonnette R, Poulin Y, Zhou Y, et al. Efficacy and safety of topical WBI1001 in patients with mild to severe atopic dermatitis; results from a 12-week,
multicentre, randomized, placebo-controlled double-blind trial. Br J Dermatol.
2012;166(4):853-60.
New Products
Topix Pharmaceuticals Introduces Replenix
Clarifying Brightening Polish
The new Replenix Clarifying
Brightening Polish from Topix
Pharmaceuticals is a mild cleanser
with exfoliating microbeads that
is designed to refine skin “gently
and effectively.”
The Brightening Polish has
smoothing, softening, exfoliating,
brightening and purifying qualities and includes ingredients such as
glycolic and salicylic acids, arbutin,
bisabolol, CoQ10, green tea polyphenols and vitamin C.The Brightening Polish helps slough away surface skin cells in order to enhance
texture, suppleness and moisture
levels while diminishing fine lines
and wrinkles, all without irritation.
The new Brightening Polish from
Topix Pharmaceuticals is both paraben-free and non-comedogenic. It is
suitable for all skin types.
Replenix Clarifying Brightening Polish sells for $32.40 and
can be purchased through a variety of websites.
For more information, please visit www.topixpharm.com. n
Liftactiv Serum 10 from
Vichy Laboratories
LiftActiv Serum 10 is a new antiaging serum from Vichy Laboratories
that firms, tightens and softens the skin.
LiftActiv Serum 10 combines
Rhamnose in a 10% concentration
with hyaluronic acid, ceramides and
antioxidant-rich Vichy Thermal Water.
Rhamnose is a naturally derived plant
sugar that is proven to stimulate rejuvenation of all skin surface layers simultaneously, according to the company.
LiftActiv Serum 10 results in a clinically proven reduction of
the appearance of the four main types of facial wrinkles (eye
contours, crow’s feet, forehead wrinkles and laugh lines) after
one month, according to the company. In addition, the new
LiftActiv Serum 10 from Vichy Laboratories reduces the appearance of pores.The Serum is gentle enough for all skin types.
The Vichy LiftActiv Serum 10 will be available in September 2012 for $52. It can be purchased at select CVS, Duane
Reade and Walgreens locations.
For more information, please visit www.vichyusa.com. n
Polish and Plump Peel is a TwoStep Anti-Wrinkle System
The new Polish and Plump Peel from HydroPeptide is a microdermabrasion peel system that includes two anti-wrinkle systems.
The first peel, Anti-Wrinkle Polishing Crystals, contains
vitamin C for collagen support and works to destroy reactive
oxidizing agents and promote skin tone consistency by inhibiting melanin production. The second peel, the Anti-Wrinkle
Plumping Activator, contains lactic acid, which sloughs away
dead skin cells, diminishes dryness, promotes a more uniform
complexion and primes the skin for hydration, and has an additional wrinkle-smoothing boost because of the trylagen and
SNAP 8 peptides, according to the company.
The new Polish and Plump Peel from HydroPeptide is
available for $68. It can be purchased at spas nationwide and
online at www.hydropeptide.com.
For more information, please visit www.hydropeptide.com. n
Glytone Anti-Aging
Night Cream Improves
Deep Lines, Wrinkles
Glytone has released its new AntiAging Night Cream, a new night
cream indicated for daily use.
The Anti-Aging Night Cream, the
latest addition to Glytone’s antioxidant anti-aging range of products, is
formulated with natural peptides,
antioxidants and glycolic acid. The
Anti-Aging Night Cream is designed
to improve the appearance of deep lines and wrinkles and
increase the production of the proteins that preserve and
strengthen the epidermal layers of the skin.
The new Anti-Aging Night Cream from Glytone is available exclusively through physicians. It has a suggested retail
price of $89 for 1.0 fl. oz./30 mL.
For more information, and to locate a physician, please visit
www.glytone-usa.com. n
41
Calendar of Events
September 27 to 30, 2012
Prague, Czech Republic — The 21st European Academy of Dermatology and Venereology Congress - Skin is Vital - to be held at
the Prague Congress Centre in Prague, Czech Republic. The 21st EADV Congress offers a platform for disseminating scientific and
practical knowledge among dermato-venereology professionals.
For more information, please visit www.eadv.org.
October 4 to 7, 2012
Las Vegas, NV — The Fall Clinical Dermatology Conference to be held at the Encore at the Wynn in Las Vegas, NV. This 4-day
conference is designed to provide increased knowledge for the practicing dermatologist by presenting a comprehensive update on
the diagnosis and treatment of a variety of conditions related to medical, surgical and cosmetic dermatology. The program offers daily
lectures, panels, live patient workshops and Q&A sessions.
For more information, please visit www.clinicaldermconf.org.
Atlanta, GA — The 2012 Annual Meeting of the American Society for Dermatologic Surgery to be held at the Hyatt Regency
in Atlanta, GA. This is an educational forum for dermatologists committed to excellence in cosmetic, medical, reconstructive and
Mohs procedures.
For more information, please visit www.asds.net.
San Francisco, CA — The Women’s & Pediatric Dermatology Seminar 2012 to be held at the Grand Hyatt San Francisco in San
Francisco, CA. This conference will explore the chief clinical topics relevant to skin diseases in women and children. Dermatologists,
pediatricians, OB/GYNs and other healthcare providers who manage these conditions are invited to attend.
For more information, please visit http://bit.ly/xB89a3.
Durban, South Africa — The International Society of Dermatology’s 3rd Annual Continental Congress of Dermatology and the 65th
National Congress of the DSSA to be held in Durban, South Africa. This conference allows dermatologists from all over the world to
interact and attend sessions encompassing all fields of dermatology, with information presented by leading dermatologists.
For more information, please visit www.pedsderm.net.
Calendar of Events Submissions
Send information to:
Stefanie Tuleya
The Dermatologist
83 General Warren Blvd., Ste. 100
Malvern, PA 19355
[email protected]
42
, LLC
™

Current Treatment Strategies in Dermatology

Transcription

Similar documents

What`s New in Dermatology

Sports Dermatology

Eczema - Ipswich and East Suffolk CCG

PRODUCT REVIEWS

Skin Diseases and the Eye - Texas Optometric Association

RAVLIN CONGREGATE CENTER

psychodermatology march 15.cdr

Rosacea

See here for more details

PDF handout