Download Summer 2014 - Dermatology Foundation

A DERMATOLOGY FOUNDATION PUBLICATION
SPONSORED BY VALEANT PHARMACEUTICALS NORTH AMERICA LLC
VOL. 33 NO. 2
SUMMER 2014
DERMATOLOGY
FOCUS
™
Also In This Issue
The DF Turns 50!
DF Clinical Symposia:
Proceedings 2014–Part II
ADVANCES IN DERMATOLOGY
The Dermatology Foundation presented its annual
3-day symposia series in February. This highly regarded
cutting-edge CME program provides the most clinically
relevant knowledge and guidance for making the
newest research advances accessible and usable. A
daily provocative keynote talk precedes topic-focused,
peer-reviewed–caliber presentations. This year’s topics
were: Difficult Diseases in Medical Dermatology;
Surgery and Aesthetics; Immunologic Skin Diseases;
Pediatric Dermatology; How to Avoid Harming Your
Patient: Safety Issues in Dermatology; Cutaneous
Oncology: Clinical Challenges; Infectious Diseases
and the Skin. The Proceedings appear in the Spring
(Part I) and Summer (Part II) issues.
Janet A. Fairley, MD, and
Jack S. Resneck, Jr., MD—Program Co-Chairs
KEYNOTE ADDRESS
Comparative Effectiveness of Psoriasis Therapies
Joel M. Gelfand, MD, MSCE
Introduction. Dr. Gelfand explained that efficacy and effectiveness have different and mutually exclusive meanings when evaluating therapeutic modalities. Comparative efficacy research
involves the familiar randomized controlled clinical trial, a shortterm and highly controlled format that shows how well a treatment
works in an ideal setting. Comparative effectiveness research—of
which very little exists so far in dermatology—addresses the far less
disciplined realities of daily practice, ie, when the full spectrum of
patients (with varied ages, behaviors, treatment histories, and comorbidities) living with a chronic disease are treated by a spectrum
of physicians (with varied backgrounds, knowledge, experience,
and attitudes) over the long term. The respective results are not
interchangeable, yet the randomized controlled clinical trial,
2015 Research Funding
Applications Due October 15
DF Welcomes 26
New LS Members
despite its obvious limitations, is considered the gold standard—
not just for earning FDA approval—but for making evidence-based
treatment decisions in real-world settings. Gelfand is among those
beginning to create a comparative effectiveness research (CER)
data base to support relevant, meaningful treatment decisions—
something that is becoming a major public health priority.
Effectiveness vs efficacy. In essence, CER asks how well
interventions and strategies for preventing, diagnosing, treating, and
What Is CER: AHRQ Definition
• Comparative effectiveness research is the conduct
and synthesis of research comparing the benefits
and harms of various interventions and strategies for
preventing, diagnosing, treating, and monitoring
health conditions in real-world settings.
PH Conway and C Clancy. NEJM. 2009;361:328–330.
Efficacy
• How well does it work
in ideal settings
(clinical trials)?
• Stringent patient
selection criteria to
optimize safety
• Highly motivated patients
with strict adherence to
research protocol
• Highly trained physicianinvestigators with expertise in the study drug
• Clinical response determined at arbitrary
“short-term” time point
• Maximize internal
validity
Effectiveness
well does it work
vs • How
in real-world use (routine
vs
vs
vs
vs
vs
clinical practice)?
• Patient population
more susceptible to
adverse events
• Variations in patient motivation and ability to adhere to prescribed regimen
• Variation in experience
and knowledge of the
drug by prescriber
• Clinical response determined in routine clinical
visits
• Maximize external
validity
(Continued on page 3)
2015 DF
Clinical Symposia
ADVANC ES IN D ER M ATO LO GY
February 4–8, 2015
The Ritz-Carlton, Naples, Florida
Registration Begins in September!
Visit www.dermatologyfoundation.org/symposia
RAVE REVIEWS
“ Chock full of cutting-edge knowledge—the most concentrated presentation
of new, pertinent information for dermatology.”
“ Great coverage of the modern scope of derm—balance of basic science,
clinical, surgical, and cosmetic.”
“ Great speakers and latest material in an efficient, high yield setting.”
“ Best meeting I attend all year.”
COMPELLING TOPICS
A spectrum of Mini-Symposia bring the latest advances to benefit your practice:
New Perspectives, Old Diseases
Melanocytic Lesions
Pediatric Dermatology
Dermatology and Women
CPC
Surgical Focus
Plus 3 provocative Keynote Talks
EXPERT FACULTY
David E. Cohen, MD
Emma Guttman-Yassky, MD, PhD
Misha A. Rosenbach, MD
New York University
Mt. Sinai School of Medicine
University of Pennsylvania
Lawrence F. Eichenfield, MD
James G. Krueger, MD, PhD
Diane M. Thiboutot, MD
University of California,
San Francisco
The Rockefeller University
Pennsylvania State University
Dirk M. Elston, MD
Mark G. Lebwohl, MD
Marta J. Van Beek, MD, MPH
Mt. Sinai School of Medicine
University of Iowa
Amy J. McMichael, MD
Heidi A. Waldorf, MD
Wake Forest University
Mt. Sinai School of Medicine
Seth J. Orlow, MD, PhD
Frank Wang, MD
New York University
University of Michigan
Ackerman Academy of
Dermatopathology
Andrew T. Goldstein, MD
The Centers for Vulvovaginal
Disorders
The DF Clinical Symposia provides 16 AMA PRA Category 1 Credits™. This activity has been
planned and implemented in accordance with the Essential Areas and policies of the Accreditation
Council for Continuing Medical Education (ACCME) through the joint sponsorship of
the Yale School of Medicine and the Dermatology Foundation. The Yale School of Medicine
is accredited by the ACCME to provide continuing medical education to physicians.
2
Summer 2014
Dermatology Foundation
monitoring health conditions work in a real-world practice rather than
ideal settings—“real-world information on which interventions are
most effective in which patients under which specific circumstances.”
A new psoriasis drug in clinical trial, for example, is typically assessed
at “the arbitrarily chosen brief interval of 12 weeks. We make our treatment decisions based on this,” yet patients living with a chronic disease are concerned with a drug’s impact “over a broad time frame.”
A collaboration of federal and academic organizations has
launched a major initiative to generate CER data and disseminate
such results to the medical community. The current combined
funding pool for this initiative exceeds $4 billion, and the recently
established Patient Centered Outcomes Research Institute (PCORI)
leads the way in funding and directing effectiveness research. The
Institute of Medicine’s top 100 priority list includes treatments for
psoriasis and for acne.
DCERN and psoriasis. “Because there is almost no comparative data on our increasingly numerous therapeutic options for patients with psoriasis, we have no way of choosing the best treatment
for a given patient.” Gelfand is taking the first steps with a substantial
challenge grant (from NIAMS) enabling him to establish a CER infrastructure—DCERN, the Dermatology Clinical Effectiveness Research
Network—and begin assessing the real-world effectiveness of psoriasis therapies. DCERN involves academic hubs at UPenn and the
University of Utah and a network of private practices across the U.S.
Currently, Gelfand and his colleagues are creating a detailed,
panoramic snapshot of current reality to answer: “how are our
patients doing?” Assessment of the ~2,000 patients with moderateto-severe psoriasis seen annually by DCERN’s clinical network includes multiple measures of patient treatment satisfaction and
quality of life, plus a variety of physician-reported outcome measures. Gelfand discussed the 713-person subset currently using a systemic treatment (most commonly methotrexate, the TNF inhibitors
adalimumab, etanercept, and ustekinumab, and narrow-band
phototherapy [NB-UVB]). Average treatment duration was 11
months. Adalimumab achieved the best control. Inappropriate
and ineffective treatment was unexpectedly common, eg, 36% of
patients on etanercept who were beyond the double-dose period
yet still being double-dosed; a large percentage of NB-UVB-treated
DERMATOLOGY FOCUS
A PUBLICATION OF THE DERMATOLOGY FOUNDATION
Sponsored by
Valeant Pharmaceuticals North America LLC
Editors-in-Chief
Mary M. Tomayko, MD, PhD—Assistant Professor of Dermatology
Yale School of Medicine, New Haven, CT
Heidi A. Waldorf, MD—Director, Laser and Cosmetic Dermatology
The Mount Sinai Medical Center, New York, NY
Executive Director
Sandra Rahn Benz
Deputy Executive Director
Christine M. Boris
Please address correspondence to:
Editors-in-Chief
Dermatology Focus
c/o The Dermatology Foundation
1560 Sherman Avenue, Evanston, Illinois 60201
Tel: 847-328-2256 Fax: 847-328-0509
e-mail: [email protected]
Published for the Dermatology Foundation by
Robert B. Goetz—Designer, Production
Sheila Sperber Haas, PhD—Managing Editor, Writer
This issue of Dermatology Focus is distributed without charge through
an educational grant from Valeant Pharmaceuticals North America LLC.
The opinions expressed in this publication do not necessarily reflect those of
the Dermatology Foundation or Valeant Pharmaceuticals North America LLC.
© Copyright
2014 by the Dermatology Foundation
patients who were significantly below effective dosing. Controlling
for all factors that could influence intertreatment differences
showed that biologics are superior to methotrexate based on physician-reported outcomes (such as body surface area affected), but
patient-reported outcomes (such as the dermatology life quality
index) showed that patients regarded all treatments as equivalent.
Deferred Giving:
The Benefits of a Bequest to the DF
Contributing to
the Dermatology
Foundation this year is the best way to ensure
that today’s new generation of physician-scientists
and investigators have the support they need to
initiate work that will continue to advance patient
care. A simple, effective way to provide this
much-needed funding well into the future is a
bequest to the Dermatology Foundation.
A bequest is your legacy to benefit future
generations of dermatologists and patients—
and what better time to arrange this future
support than the DF’s 50th anniversary year.
www.dermatologyfoundation.org
By reducing your estate, a bequest also has the
potential to reduce estate taxes. Once your attorney
and/or financial advisor helps determine the most
beneficial option for establishing a bequest, be
sure to identify the Dermatology Foundation, a
501(c)3 organization, as the gift recipient in your
will or other instrument. Please note that the DF
is able to accept only monetary donations.
If you have questions about establishing
a bequest to the Dermatology Foundation,
feel free to address them to Sandra Benz,
DF Executive Director, at 847-328-2256 or
[email protected].
Summer 2014
3
Adalimumab illustrates “the huge gap” between clinical trials
and the real world in physician-assessed treatment success. Although ~80% of patients are clear/almost clear at the end of a 12- to
16-week clinical trial, only ~48% were clear/almost clear during
routine follow-up in the real world. “In clinical practice only
~24–48% of patients on systemic treatments are clear/almost clear—
even at highly experienced clinical centers.” This actually “overestimates effectiveness” because those experiencing little to no
benefit had already stopped using the particular drug and were not
in the assessment. Study results also identify phototherapy as “an
example of health care gone wrong.” Although it is quite effective,
regarded as the safest psoriasis treatment, and cheap compared to
the biologics, travel time and co-pays make it costly for patients.
“We have to figure out why our safest and cheapest therapy is the
most expensive and inconvenient for those who need it.” And only
10% of patients were receiving phototherapy at a frequency (3
times/week) that maximizes efficacy while decreasing toxicity.
Gelfand also learned that patients typically stopped TNF inhibitors
because they lost effectiveness within a year, not for adverse effects. “This raises a significant issue for a disease requiring good
control for a lifetime.” Next, DCERN will explore persistence, the
various real-world factors that contribute to long-term treatment
success.
Conclusion. It is clear that data from 12-week clinical trials
can mislead care providers, and that real-world effectiveness data
are needed to guide our treatment decisions. The concept of treatment persistence may be the most informative marker for identifying the best drugs.
PGA Clearance: Real World vs RCT
• Most patients fail
to achieve longterm disease
control
• Durable response
rates are much
lower in clinical
practice compared
to short-term
RCTs
JM Gelfand et al. Arch Dermatol. 2012;148:487. J Takeshits et al. JID.
2013;133:S92.
4-year Drug Survival Rates in Denmark:
DERMBIO Database
• 4-year survival:
– 40% Etanercept
– 70% Infliximab
• Reasons for stopping treatment:
– Loss of effectiveness (75%)
– Adverse events
(12%)
• Protective factors:
– Male sex, no prior TNF failure, infliximab
R Gniadecki et al. Brit J Dermatol. 2011;164:1091–6.
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Summer 2014
MINI-SYMPOSIUM:
IMMUNOLOGIC SKIN DISEASES
Emerging Biologic Therapies for Psoriasis
Bruce E. Strober, MD, PhD
Introduction. A robust pipeline of self-injectable biologic
drugs for psoriasis should give us at least 8 approved biologics
within the next 5 years. Dr. Strober discussed 4 monoclonal antibodies in clinical trials. Their 12-week placebo-compared endpoint
enables us to “know the drug works better than placebo, and in a
significant manner.” Data given are for the highest dose.
Inhibiting the IL-17 pathway. Discovery of IL-17’s pathophysiologic role in psoriasis spurred several targeted drugs with
similarly high efficacy. Brodalumab blocks the IL-17 receptor
(impeding the signaling of all IL-17 isoforms). In phase II data, at
week 12 (biweekly dose), 82% achieved PASI-75 and 75% reached
PASI-90—“possibly a more relevant metric.” (Phase III trials are
in progress, including comparison with the IL-12/23 inhibitor
ustekinumab.)
Secukinumab and ixekizumab immobilize the primary isoform IL-17A. Phase III data for secukinumab—dosed weekly for 1
month, then taken monthly—included a 12-week placebo arm and
a 1-year etanercept arm (TNF inhibitor, administered at its standard, FDA-approved dosing). At week 12 with secukinumab, 77%
reached PASI-75, 60% attained PASI-90, and 30% reached PASI-100.
It consistently outperformed etanercept. Candida infection is the
one notable adverse effect (5% of the high-dose group) observed
with this agent (most cases were mild). Week-20 phase II data for
ixekizumab show ~82% of patients reached PASI-75, ~70% reached
PASI-90. Secukinumab approval is expected within a year; brodalumab and ixekizumab will follow.
Anti-IL23 p19 antibody. Tildrakizumab and guselkumab are
considered an “improvement” over the less precise ustekinumab.
(IL-23 collaborates with IL-17.) Ustekinumab’s target is p40, a molecule shared by both IL-12 and IL-23; tildrakizumab and guselkumab
bind exclusively to p19, found only in IL-23. Both of these IL-23 inhibitors demonstrate efficacy in phase II studies that is comparable
or better than that of ustekinumab. Whether the more selective drug
has better safety is unknown, but may be inconsequential compared
to a drug that “already seems pretty clean.”
Conclusions. Waning long-term efficacy will continue. Confident safety claims have to await post-marketing data. Because the
TNF inhibitors appear to surpass the newer medications for efficacy
for psoriatic arthritis, “one of these agents should probably be your
first-line biologic for such patients.”
Summary: Pipeline Biologic Drugs
• IL-17 inhibitors
– Selective for IL-17R—brodalumab
– Selective for IL-17A—secukinumab,
ixekizumab
• IL-23 inhibitors
– Selective for IL-23 p19—tildrakizumab
• High efficacy, self-injectable
• Good early data on safety
• Likely to have lesser efficacy for psoriatic arthritis
than the TNF inhibitors
(Continued on page 6)
Dermatology Foundation
www.dermatologyfoundation.org
Summer 2014
5
Vitiligo: What Do I Tell My Patients,
and Can I Make Them Better?
John E. Harris, MD, PhD
Introduction. Vitiligo, an autoimmune disease of the skin,
lacks effective treatments because the underlying molecular pathway has long been a mystery (although Dr. Harris is hot on its trail*).
“But this does not mean—as I tell my patients—that we cannot help
them. There is a lot we can do.” Harris noted basic elements in pigment loss and recovery, then characterized uncommon and rare
presentations of vitiligo before describing its basic workup and
treatment (all off-label).
Vitiligo basics. This relatively common disease (.50–1% of
the population) appears before age 20 in half the patients and can
create profound emotional distress. Small macules of depigmentation grow to patches that coalesce. Harris described various
locations and manifestations. He explained the importance of
pigmented hairs for repigmentation during treatment, but noted
that glabrous skin can repigment—albeit very slowly.
Depigmentation vs Hypopigmentation
to 20% in this population. Treatments work best in combination.
“Hands down, the most effective” combines narrow-band UVB
(NB-UVB) with topical corticosteroids. Harris uses clobetasol on
an alternate-week schedule, adding tacrolimus for the off weeks if
insurance covers it. Patient limitations are important—some have
no time for NB-UVB, some hate applying creams.
The good news. Let patients know they appear to be at a
lower risk for skin cancers. A recent study found a 3-fold lower risk
of melanoma and nonmelanoma skin cancers in this group. Harris
sees “a spectrum with vitiligo at one end and melanoma on the
other, with most people somewhere in the middle.”
*M Rashighi et al. “CXCL10 is critical for the progression and maintenance of depigmentation
in a mouse model of vitiligo.” Sci Transl Med. 2014;6. doi: 10.1126/scitranslmed.3007811.
MINI-SYMPOSIUM:
PEDIATRIC DERMATOLOGY
Recognizing Nutritional Deficiencies
in Children
James R. Treat, MD
Vitiligo + Progressive Macular Hypomelanosis
Combination Therapy Is Most Effective
Introduction. Significant nutritional deficiencies in children
occur in varied contexts: parents overzealously withdrawing possibly allergenic foods, children with autism spectrum disorders who
reject many foods, metabolic disorders, malabsorption, eating
disorders, and certain drugs. Dr. Treat discussed cases for which
the skin can aid the diagnosis. Treatment is repletion; improvement
is often rapid and dramatic.
Case discussions. Case 1: kwashiorkor. An 11-monthold with atopic dermatitis (AD) has a widespread dry and cracked
scaling rash that does not reflect AD, is somewhat edematous, and
is failing to thrive. The parents claim milk, soy, peanut, egg, and
wheat allergies. “As this child is failing to thrive, has a very restrictive diet, and widespread dry, cracked skin—consider a nutritional
deficiency.” The parents were using rice milk as his “formula,” ie,
sufficient nutrition, insufficient protein. Case 2: zinc deficiency.
An 8-month-old has a 2-month history of diaper and facial
eruption unresponsive to nystatins, zinc oxide, or substituting
fragrance-free diaper wipes. The eroded, crusted rash that is
poorly responsive to treatment is the primary clinical clue to zinc
deficiency. Other clinical clues include diarrhea, irritability, and
photosensitivity. Low alkaline phosphatase—a zinc-dependent
protein—is a rapid test, justifying initiating oral zinc while waiting
for zinc level results. Case 3: carotenemia. A 3-year-old with
trisomy 21 is fluorescent orange, yet his diet is exclusively
spaghetti without tomato sauce, chicken nuggets, and a multivitamin. The child’s carotene levels were 10 times normal due to
Ascorbic Acid Deficiency (Scurvy)
*NOTE: There are no FDA-approved treatments for vitiligo. ALL treatments are
used off-label. T Lotti et al. Dermatol Ther. 2008;21 Suppl 1:S24.
Workup and treatment. The workup is clear and straightforward, as there are few other possibilities. The Woods lamp is
indispensable in highlighting depigmentation. A review of systems
looks for coincident autoimmunity. Thyroiditis is increased from 3%
6
Summer 2014
• Often seen in patients with eating disorders, autism
spectrum disorders, or with extreme malnutrition
• Presenting signs of bleeding gums, gum hypertrophy,
perifollicular hemorrhage
• Can also have boney findings and pain as their
presenting sign (periosteal lifting, osteopenia)
• Repletion is rapidly beneficial
• Pediatric Bottom Line: Ask about diet, as there has
to be severe malnutrition to get scurvy
Dermatology Foundation
hypothyroidism (which impairs the conversion of carotene to
retinol), fairly common with trisomy 21. Case 4: phrynoderma. A colleague’s young patient with Crohn's disease had follicular hyperkeratosis. These widespread scaly papules indicate
phrynoderma, ie, severe vitamin A deficiency. GI illnesses and
malabsorption easily affect absorption of vitamins A, D, E, and K.
Case 5: scurvy. A child with autism spectrum disorder was diagnosed with vasculitis and sent to the emergency room for confirmation. He had red papules on his arms and legs and refused to
walk. A close look also showed perifollicular hemorrhage and
bleeding gums—all consistent with scurvy. The child would eat
only popcorn and chocolate milk, and was seriously vitamin
C-deficient. Testing for vitamin C is the sole assessment.
Nutritional Deficiencies:
Bottom Line
• Remember not only underserved populations, but
also those with restrictive diets—happens in autism
spectrum disorders, extreme or over-diagnosed food
allergies, eating disorders—and malabsorption
• Testing and therapy are extremely satisfying—
it just has to be on your differential diagnosis!
Neonatal Dermatology: Case-based Challenges
Ilona J. Frieden, MD
Introduction. Dr. Frieden discussed neonatal cases that are
relevant to the management of older patients.
Candidiasis. Although congenital and neonatal candidiasis
may involve features resembling those seen in immunocompromised hosts, some presentations are truly unique. Although congenital candidiasis usually presents with a widespread scaly
eruption on face and torso, this is one of the few eruptions characterized by small pustules where the palms and soles are typically
involved. Thus when this occurs, it can be particularly helpful in
diagnosis. Risk factors include prematurity, maternal history of
vaginal candidiasis, and amniotic rupture (overt or subclinical) that
creates a “Candida albicans bath.” Frieden discussed a spectrum of
disease in neonates, including the potential for life-threatening
disease in very preterm infants.
Face mask pressure-induced necrosis. A 32-week gestational age infant 7 weeks after birth had an area of skin necrosis
from face mask CPAP, which is being increasingly used in NICUs.
Mask CPAP is used commonly in adults and while reports of skin
effects are rare, they are probably under-recognized.
Subcutaneous fat necrosis (SCFN). Frieden discussed a
patient with extensive SCFN following therapeutic hypothermia for
perinatal asphyxia. Therapeutic hypothermia is a very important
treatment to improve neurologic outcome in asphyxiated newborns, but creates “the perfect storm” for SCFN risk because both
asphyxia and cold can each induce SCFN. Consider this diagnosis
if you see a newborn (or adult) who had this treatment. Extensive
SCFN requires monitoring for hypercalcemia for 4 to 6 months.
Perinatal scalp injury. Chronic scalp dermatitis can arise
after perinatal birth injury and in certain rare ectodermal dysplasias
such as Rapp-Hodgkin and Hay-Wells syndromes. These scalp dermatoses resemble so-called erosive pustular dermatosis seen in
elderly actinic-damaged scalps. In young infants, we hypothesize
that abnormal or damaged hair follicles act as a foreign antigen
and provoke an intense inflammatory reaction. Potent topical antiinflammatory medications can be helpful, as in the elderly.
www.dermatologyfoundation.org
Candida Infection in Newborns
• Most common–diaper or other skin folds
• Nail dystrophy
• Congenital candidiasis–widespread erythema,
pustules, and scale
– Present at birth or within 1–3 days
• Palmar pustules common
• Invasive candida in preemies–serious!
Cooling and SCFN: Take-home Points
• Cold temperatures cause SCFN
• Asphyxia is main risk for SCFN
• Asphyxia treated with cold could worsen
SCFN risk and extent of disease
• Therapeutic hypothermia used in older
children/adults: ? potential for injury
TP Wiadrowski et al. Austral J Dermatol. 2001;42: 217–9.
YM Liu et al. J Burn Care Res. 2014;35:e1846.
Perinatal Scalp Injury: Take-Home Points
• Erosive pustular dermatosis in elderly actinicdamaged scalps gave clues to infants
• Probable common pathway
– Damaged follicles/scarring/anatomic chaos
leading to strong inflammatory reaction
• Anti-inflammatory medications helpful in
improving process
KEYNOTE ADDRESS
Update on Melanoma Genetics
Hensin Tsao, MD, PhD
Introduction. “The molecular revolution is bringing about
a sea change” in the way we think about melanoma, and thus its
treatment, Dr. Tsao observed. Before this, we held overly simplified
notions of cutaneous melanoma and its genetic causality. And until
3 years ago, only 3 major genes—p16, CDKN2A, and CDK4—had
been identified in familial melanoma (10% of melanoma tumors),
discovered 20 years earlier.
But in the past 5 years, advances in the reach and speed of technology have enabled a vast jump shift in assessing the DNA from
melanoma families. In the last 3 years, 3 major new familial genes
have been identified (some also relevant to sporadic melanoma)
that fundamentally expand our awareness of the locus where mutations can reside, and illuminate cutaneous melanoma’s connections to other cancers. The concept of melanoma heritability goes
beyond cutaneous melanoma to melanoma and mixed cancer syndromes, and molecular patterns are replacing morphology in defining them. We are moving from phenotype to genotype in identifying
high-risk individuals. These new genes are TERT (telomerase
reverse transcriptase), BAP1 (BRCA1-associated protein-1), and
MITF (microphthalmia-associated transcription factor). Tsao
discussed them and the lessons we are learning from them.
TERT. Telomerase is encoded by the TERT gene. Telomerase
maintains the caps at chromosome ends to ensure proper chromosome division, and thus appropriate cell longevity. With too little
Summer 2014
7
New Members
Add Support for
Dermatology’s Future
The Dermatology Foundation extends a warm
welcome to the 26 newest Leaders Society members.
Their decision to participate at this level to help
advance the specialty’s future is especially important
in our environment of dramatically decreased federal
research funding. Each of these dermatologists contributed $1,500 this year to support the early research
of those individuals who can make a difference.
out to have a father with ocular melanoma and a brother with both
melanoma and kidney cancer. Their search led his team to BAP1,
which appears to be mutated in families with cutaneous and ocular
melanoma, and often mesothelioma. BAP1 is an important housekeeping enzyme. Normally, the cell’s “trash collection system”
places an ubiquitin tag on individual proteins earmarked for destruction; BAP1 removes ubiquitin groups to prevent inappropriate
protein destruction. If BAP1 does not work properly, there may be
overdestruction of growth-restraining proteins, insufficient removal
of growth-promoting proteins, or altered synthesis of these cancer
genes (ubiquitination may also be involved in transcription regulation). Having studied close to 300 melanoma families now, Tsao
Known Mutations
(As of July 22, 2014)
Neera Agarwal-Antal, MD
Christine Ambro, MD
Saundrett G. Arrindell, MD
Barbara S. Bopp, MD
Alexandra Cameli, MD
Janet F. Cheng, MD
Jeri Beth Foshee, MD
Scott D. Glazer, MD
Noah Gratch, MD
Earl G. Gross, MD
John E. Harris, MD, PhD
Suzanne P. Hess, MD
Kevin P. Hogan, MD, PhD
Tony Hsu, MD
William W. Huang, MD
Anne W. Lucky, MD
Gregory A. Nikolaidis, MD
Jeffrey North, MD
Gregory G. Papadeas, DO
Laura B. Pincus, MD
Elizabeth Faircloth Rostan, MD
Sarah K. Short Sarbacker, MD
Jeffrey B. Travers, MD, PhD
Eduardo H. Tschen, MD
Travis W. Vandergriff, MD
Caroline S. Wilkel, MD
telomerase, cells undergo senescence or chromosomal instability.
In a recent study, an upregulating TERT mutation was found to cosegregate with melanoma patients from one German family. Carriers
also developed other cancers—ovarian, kidney, bladder, and breast
cancers—thereby defining “a multi-cancer melanoma complex.” This
TERT variant sits in the promoter region of the TERT gene and creates
a new transcription factor binding site, which triggers the heightened
telomerase production. Tsao and others have since found a variety
of telomerase-upregulating changes “everywhere within TERT” in
74% of melanoma cell lines, one-third of primary melanomas, and in
a small number of liver and thyroid cancers—but in no other cancers.
And in 10% of melanomas, TERT itself is also amplified, driving
telomerase overproduction even higher. It is clear that alterations
outside the coding region can upregulate protein expression.
BAP1. The family that stimulated Tsao’s gene hunt involved a
young woman with superficial spreading melanoma who turned
8
Summer 2014
Melanoma Risk Alleles
Progress in Melanoma Genetics
• New concepts in melanoma heritability
– Melanoma/mixed cancer syndromes
– New mechanisms of cancer predisposition
– Gain of expression promoter variants (TERT)
– Altered ubiquitination (BAP1)
– Altered epigenetic reprogramming (MITF)
• NextGen sequencing will be game-changing
– Novel discovery strategies needed for the
deluge of variants
– “Missing heritability” may result from a
large number of low-prevalence mutations
Dermatology Foundation
The Thomas B. Fitzpatrick Legacy Fund
The Powerful Gift That Keeps on Giving
Established a decade ago to honor a DF
founder, these $100,000 gifts empower the
future that Dr. Fitzpatrick set out to build. Contributing to the
Fitzpatrick Legacy Fund during this 50th anniversary year is
an especially meaningful way to recognize what the DF has
already done while ensuring its full future potential. And
those 70½ or older this year can benefit from tax-free directfrom-IRA contributions capped at $100,000. Contact Sandra
Benz at the DF office for more information: 847.328.2256.
et al. have found a higher rate of inactivating BAP1 mutations in
families with mixed ocular and cutaneous melanoma—including
the one just described. Metastatic disease was common, and had
developed very quickly. “If BAP1 mutation carriers can be shown to
be at higher risk for metastatic, lethal ocular melanoma, I can envision a scenario in which mutation carriers may need to be screened
more aggressively.” Tsao has now identified a “new sort of syndrome” that links ocular and cutaneous melanoma with mesothelioma and renal cell carcinoma. “When we gather a family history
of melanoma, it must be broader than just cutaneous disease.”
MITF. A small region on chromosome 3—focally amplified in
melanoma tumors—contains the MITF gene, an epigenetic transcription factor that modifies the functions of existing proteins in
melanocytes and in retinal pigment cells. Mutant MITF can alter or
substitute the protein targets that are regulated. Since amplified
MITF was found in roughly 4% of melanomas, Tsao’s group became
part of an international consortium that identified a disease-causing
variant in MITF. This variant predisposes carriers to cutaneous
melanoma and/or renal cell carcinoma, with moderate risk.
Conclusion. To be determined: how exactly these mutations
cause cancer, and if there is a relationship between these mutations
and UV exposure. Tsao also noted the search for a larger percentage
of our melanoma families and a greater range of the genetic factors
accounting for melanoma heritability.
MINI-SYMPOSIUM: CUTANEOUS
ONCOLOGY: CLINICAL CHALLENGES
High-Risk Squamous Cell Carcinoma
Marc D. Brown, MD
Introduction. “The skin cancer keeping me awake at night
more than anything else—one I’ve seen change tremendously over
my 30 years in practice—is high-risk squamous cell carcinoma,” Dr.
Brown said. Metastasis occurs in 2–5% of all SCC, but in 20% of highrisk disease. The 10–15% lifetime risk for SCC is dramatically higher
past age 70, and in immunosuppressed patients.
Defining high risk. Tumor size and depth of invasion are the
two most important criteria. “Size matters”—tumors 4–6 mm deep, or
down to the deep subcutaneous tissue or beyond. Worrisome locations are the ear, lip, genitalia, cheek areas overlying the parotid gland,
balding scalp, back of the hand, and burn sites. Worrisome histology
includes poor differentiation and perineural invasion. Recurrent SCC
www.dermatologyfoundation.org
Current Members
Rex A. Amonette, MD
Susan V. Bershad, MD
Gordon J. Dow, PharmD
Harley A. Haynes, MD
James J. Leyden, MD
Robert L. Roschel, MD
Jonah Shacknai
Charles W. Stiefel
Eugene J. Van Scott, MD
Ruey J. Yu, PhD, OMD
Anonymous Donor
can be more aggressive. SCC in the immunosuppressed population
are typically high risk, intensely so in organ transplant patients.
Immunosuppression. This includes significant numbers of
patients living a lot longer with HIV or chronic lymphocytic
leukemia (CLL), and anyone on immunosuppressive medication—
which makes the organ transplant population especially vulnerable. This population has a 65-fold increase in SCCs, with tumors
Characteristics of SCC in
Organ Transplant Recipients (OTRs)
• Incidence ratios of skin cancer in OTRs
– Squamous cell carcinoma: 65-fold increase
– SCC of lip: 20-fold increase
– Basal cell carcinoma: 10-fold increase
– Melanoma: 3.4-fold increase
• Occur on an average of 30 years earlier
• More frequently multiple
• Increased rate of recurrence
• Increased rate of metastasis
• May have more rapid rate of growth
• Some patients with a tremendous number of tumors
Final Thoughts
1. Incidence of cSCC is increasing.
2. More patients with high risk SCC.
3. Predicting a patient’s risk for metastatic spread is
difficult—but assessment of defined risk factors
may help identify this subset.
4. Aggressive surgical excision with clear margins
is treatment of choice.
5. SLN Bx may provide prognostic and therapeutic
value, but is not well studied.
6. In high-risk patients, electively treating first
echelon nodes may improve survival, but high
level data are lacking.
7. Patients with metastatic nodal disease should
receive surgery and radiation.
Summer 2014
9
that occur an average of 30 years earlier, are significantly more
aggressive, and far more likely to recur and to metastasize.
Treatment. Brown relies on Mohs surgery with margins of 5–
10 mm instead of 2 mm. Radiation is suggested for patients who are
not surgical candidates. Roughly 50% of patients with clinically detectable nodal disease will die from metastatic disease, accounting
for at least 2,500 deaths annually in the U.S. There is no best treatment option. “We still do not have a good answer.” Brown noted appropriate situations for adjuvant radiation, discussed elective lymph
node dissection and sentinel lymph node biopsy, and noted modest
benefit at best with systemic drugs (retinoids, oral 5-FU, cetuximab).
Unusual Presentations of Cutaneous Lymphomas
Laura B. Pincus, MD
Case #1. A 29-year-old otherwise healthy woman with a 9-year
history of discrete small (1–5 mm) erythematous papules on her
forehead, bilateral temples, and chin was diagnosed with
acne/rosacea. Treatment was ineffective. Although a small biopsy
3 years after diagnosis showed a dense B-cell infiltrate pointing to
a low-grade B-cell lymphoma, a definitive diagnosis could not be
made in part because of the biopsy’s small size. Once the request
for further sampling was eventually agreed to, H&E and then
immunostaining confirmed the diagnosis of B-cell lymphoma,
follicle center type. Lesson: Add follicle center lymphoma to your
differential diagnosis of new-onset acne in an adult.
Case #2. A 54-year-old man saw his PCP for a nondescript erythematous patch on his thigh. It was diagnosed as a reaction to new
medication. Several months later, the patient developed nasal congestion that was unresponsive to treatment for allergic rhinitis (his
PCP), then for suspected polyps (ENT). Several months afterward, a
3.5-cm intranasal mass was detected and diagnosed as NK T-cell
lymphoma, nasal type, which is an aggressive T-cell lymphoma. The
thigh lesion was deemed unrelated—until body-wide papules and
nodules erupted after radiation for ostensible stage II disease. It had
in fact been his first manifestation of NK T-cell lymphoma, nasal type
in the skin. The patient actually had stage IV disease, and should
have received chemotherapy, not radiation. Lesson: Be aware that
this T-cell lymphoma can present with a subtle erythematous patch.
During staging, biopsy anything nonordinary or relatively new.
Case #3. A biopsy of a long-standing rash on a 76-year-old man
showed a granulomatous infiltrate in a nodular configuration, for
which the patient was diagnosed with sarcoidosis. Pincus saw the pa-
tient and discovered papules and plaques across his body, highly suspicious for MF. But “sarcoidosis is a great mimicker of MF,” so additional biopsies were taken. These more typically combined findings
of conventional MF with the granulomatous infiltrate, confirming a
diagnosis of granulomatous MF. Lessons: When granulomas form the
bulk of the histopathologic findings, added biopsies can be helpful.
Such cases are often misdiagnosed as granulomatous dermatitis.
Management of Challenging Pigmented Lesions
Hensin Tsao, MD, PhD
Introduction. Dr. Tsao discussed atypical Spitz tumors, noting the concern and uncertainty they engender. He noted that there
is no one way to manage an atypical Spitz tumor, and outlined
what he knows and what he does.
Spitz Tumors—Clinical Spectrum
Clinical Feature
Age
Location
Size
Shape
Border
Surface
Color
Classic Spitz Nevi
<10 yrs old
extremities, face, neck
<5–6 mm diameter
symmetric,
dome-shaped
well-defined
smooth
pink/reddish
S Luo et al. JAAD. 2011;65:1073–84.
Pathologic Spectrum
Atypical Spitz Tumors
Case #1: Follicle center lymphoma
• Can present as acneiform morphology on the face
• Excellent prognosis
• On the ddx of an adult acneiform eruption
• Follicular MF also on ddx of acneiform eruption
Case #2: NK T-cell lymphoma, nasal type
• Can present with erythematous patches
• Suspicious clinical lesions should be biopsied
• Ensure biopsy adequate for clinical lesion
Case #3: Granulomatous MF
• Granulomas present in biopsies
• Clinically indistinguishable from conventional MF
• Additional biopsies can be helpful
• Cases often misdiagnosed as sarcoid
10
Summer 2014
Classic
Haphazard, infiltrative
Asymmetric
Poorly circumscribed
Disrupted, ulcerated epidermis
Absent or few Kamino bodies
Lack of junctional clefting
Atypical Spitz
Subcutaneous involvement
Prominent, single-cell pagetoid spread,
beyond epidermal nests
Confluence, dense cellularity
Lack of zonation
Persistent, expansile deep nests
Mitoses ≤2–6/mm2
Take Home Points
Atypical Spitz Tumors
10–20 yrs old
back
>1 cm diameter
increasing
asymmetry
irregular
irregular, ulcerated
irregular
More heterogeneous cell types
Granular, dusty cytoplasm
High nuclear-to-cytoplasmic ratio
Hyperchromatism
Large eosinophilic nucleoli
Spitzoid Melanoma
S Luo et al. JAAD. 2011;65:1073–84.
Summary: Atypical Spitz Tumors
• Appear to metastasize more often in general
• Different genetics 씮 different biology 씮
different outcome
– Malignancy (lethality) ≠ Cancer (metastases)
– Borderline tumors 씮 developmental anomalies?
• Adult melanomas 씮 genetically injured melanocytes?
• Better survival than predicted with adults with
similar melanomas
• Re-excise to prevent local recurrence
Dermatology Foundation
What we know. Compared to common Spitz nevi, atypical
tumors involve an older population, larger size, asymmetry, greater
depth, and increased cellularity and mitotic rate. Although alterations in the HRAS gene had been described years ago, more recent
analyses have pinpointed activating translocations, rather than
point mutations, of receptor tyrosine kinases as common inciting
events. Similar rearrangements occur in both Spitz tumors and spitzoid melanomas, “and we do not understand how the same oncogenes lead to these different phenotypes.” Despite a 40% chance of
a positive SLNB, actual metastasis is rare. And when Tsao et al. followed all Spitz and atypical Spitz tumors at MGH for at least 10 years,
only 7 melanomas developed, always in addition to the Spitz tumor
rather than evolving from it. “So the Spitz tumor is behaving more
like a marker than a precursor,” and appears to confer an 8-fold
increase in risk for melanoma.
What we do—the Users Manual. Tsao avoids needless
anxiety for patients and parents, calling it simply “a lesion of interest” that is genetically distinct from melanoma. Re-excision is essential to prevent recurrence. Tsao clears a 5 mm–1 cm margin,
depending on size and degree of atypia. “Although there was a period of time when SNLB was performed on atypical Spitz tumors,
we’ve backed off on doing nodal sampling given the wave of recent
articles documenting a high microscopic nodal disease rate but low
survival impact.” Tsao avoids these procedures in children because
of completion dissection that ensues, and also the use of interferon
in young children espoused by many medical oncologists. “SNLB
does not appear to predict outcome, nor has interferon ever been
shown to alter the outcome of metastatic Spitz tumors.”
Conclusion. “I have gone from an enthusiastic molecular
geneticist who really believed in SNLB to a primary focus on trying
to reassure the parents, and making sure the tumor is re-excised.
We do very little for thin melanomas that do have a much higher
lethal potential, so why are we exaggerating what we do with these
atypical Spitz tumors?”
Recurrent SSTI. The poorly understood pathophysiology of
recurrent SSTIs and the paucity of good data for guidance makes
them “very tough to treat.” There is a complex and mystifying relationship between host, pathogen, and the household environment.
Decolonization data do not support bleach baths or chlorhexidine
washes. Schwartz has “had some reasonable results” with using
twice daily nasal mupirocin for 1 week/month. Systemic therapy is
generally a last resort.
Non-tuberculous mycobacteria (NTM). A woman with
multiple erythematous papules on her face after full-face fractional
laser treatment failed all treatments until a rapid-growing, acid-fast
bacillus was cultured post-biopsy and identified as NTM. NTM skin
infections have increased substantially in the past 30 years, especially recently. Half of Schwartz’s cases are post-procedure (cosmetic or biopsy); half follow a traumatic injury. Antibiotic treatment
alone may be effective, but surgical debridement is often needed.
Azithromycin plus TMP/SMX was curative in this case.
MINI-SYMPOSIUM:
INFECTIOUS DISEASES AND THE SKIN
Incidence of Cutaneous Non-tuberculous
Mycobacteria Infection (NTM) 1980–2009
Microbiology of Purulent SSTIs
GJ Moran et al. NEJM. 2006;355:666–74.
Skin Infections: The Perspective From
an Infectious Disease Specialist
Brian S. Schwartz, MD
Introduction. Dr. Schwartz emphasized that “there is no one
right way to treat many of these skin and soft tissue infections
(SSTI).” Representative cases introduced the important issues for
purulent, nonpurulent, and recurrent SSTIs, and he discussed the
literature and his treatment choices.
Purulent SSTI. A 32-year-old afebrile man had a 3-day-old
painful, enlarging thigh lesion—attributed to a spider bite—that appeared to be an abscess or furuncle. Data show no significant benefit from adding antibiotic therapy to incision and drainage (I&D).
“To be a good antimicrobial steward,” Schwartz typically omits antibiotics for a first infection (with exceptions), using them only with
a recurrence. Because 75% of the pathogens causing purulent SSTIs
are S. aureus, predominantly MRSA, he advises that empiric regimens include something active against MRSA.
Nonpurulent SSTI. An afebrile young woman presented with
a 2-day-old erythema of her left foot, an apparent cellulitis. Schwartz
opted to begin with cephalexin 500 mg QID, and add TMP/SMX if
no response occurred. He described the recent data supporting
␤-hemolytic strep as the primary pathogen in uncomplicated cellulitis, justifying the lack of MRSA coverage unless clearly needed.
www.dermatologyfoundation.org
AB Wentworth et al. Mayo Clin Proc. 2013;88:38–45.
Cellulitis & Pseudocellulitis
Daniela Kroshinsky, MD, MPH
Introduction. Although Dr. Kroshinsky discussed cellulitis, noting diagnostic challenges in both typical and variant presentations,
her primary focus was on “when it’s not cellulitis.” Her intense interest
in cellulitis mimickers was sparked when she began as a dermatology
hospitalist at Massachusetts General Hospital. She was struck by “the
significant number of consults for cases of cellulitis that remained
stubbornly unresponsive to treatment.” Reviewing records, she found
Summer 2014
11
Why Are You a Leader?
Tiffany C. Scharschmidt, MD:
“The DF Grows Our Specialty”
Dr. Scharschmidt
describes the Dermatology Foundation
as “a community of
dermatologists who
give of their personal
time and resources to further the specialty.
Those of us who become DF members give
to grow our specialty into the best that it can
be,” says Dr. Scharschmidt, a Young Leader*
and dermatologist at the University of
California, San Francisco who splits her time
between the research lab and clinic. “I feel
so fortunate to be a part of this specialty
and a DF research award recipient. It means
a lot to me to have a way to give back to the
Foundation early in my career.”
Dr. Scharschmidt completed her residency in
2012, joined the Leaders Society in 2013, and
became a new volunteer this year to encourage
other young dermatologists in her area to
join her in leadership giving. “When I was
approached about helping to bring in new members, it was an obvious decision to say yes. My
time as a new mother is valuable to me and I
don’t take on every opportunity that is offered,
but this is one I definitely wanted to be part of.”
Dr. Scharschmidt believes DF funding is critical—it supports early research experience and
data that are essential to compete successfully
for diminishing federal funds. “Dermatologists in
my generation have seen exciting advances over
the course of our training—including new biologics for psoriasis and targeted treatments for
melanoma. Continued research progress is growing more dependent on nontraditional funding
sources. I see the DF as an extremely important
resource in launching the careers of new faculty
members who want to make biomedical research
part of their career mission.”
Dr. Scharschmidt knew early on that she
liked science and medicine. As a kid, she loved
spending time in her physician-scientist dad’s lab
and regularly visiting her dermatologist mother’s
clinic. Then time in a complex medical dermatology clinic during her third year of medical school
awakened her recognition that dermatology was
perfect for her. “It’s a beautiful specialty. You can
see the skin to diagnose it. And for someone
interested in research—you have easy access
to tissue samples. The skin tells you so much
about the human body.”
Dr. Scharschmidt is personally grateful for
her recent research support from the DF. She
received a 1-year fellowship followed by a
Career Development Award to identify the cutaneous immunologic mechanisms that enable
us to live symbiotically with the commensal
organisms residing on our skin. She is now
preparing her first NIH grant application—and
as a Leaders Society member, is giving her
resources and time to help those who follow.
*The DF’s Leaders Society is an effective way to give back to the specialty, with an impact lasting well into the
future. A new Young Leader is a physician who begins this commitment within 5 years of completing residency.
that “85% of these calls turned out to be other diagnoses.” This inspired a 6-month retrospective study of all cellulitis cases that had presented to the hospital (excluding abscesses and atypical infections).
Kroshinsky summarized her results, then provided extensive examples and guidance from cellulitis mimickers she has seen.
Cellulitis overview. “As we do not have a good gold standard diagnostic technique, we use our clinical criteria.” Be prepared for many variants and exceptions. Kroshinsky discussed the
common pathogens, immunosuppressed patients, predisposing
traumas (including IV drug use), chronic ulcers and infection, and
several variants.
Cellulitis mimickers. In the 6-month retrospective review
of all hospital admissions for cellulitis, ~18%—“probably a conservative estimate”—were ultimately found to be other diagnoses. In
the internal medicine hospitalist service, cellulitis was the 15th
12
Summer 2014
reason for admission but the #1 reason for readmission within 30
days. In the outpatient setting, 80% of the cellulitis diagnoses
turned out not to be cellulitis. When Kroshinsky and her colleagues were called in to the outpatient setting for concern with
unresponsive cellulitis, “we were able to reduce antibiotic use by
82%.” She added that “this is an arena where we perform better
than all other specialties in being able to prevent morbidity and
unnecessary hospital admission for patients who really have other
skin diseases, and not cellulitis.”
Examples. For infections, Kroshinsky discussed tinea faciei incognito, erysipelas, Lyme’s disease, erythema migrans, early zoster,
brown recluse spider bite, osteomyelitis, and dental sinus. Patients
with noninfectious underlying conditions included subcutaneous fat
necrosis of the newborn, erythema nodosum, and Well’s syndrome.
(Continued on page 15)
Dermatology Foundation
FOR INTERDIGITAL TINEA PEDIS DUE TO TRICHOPHYTON RUBRUM
AND EPIDERMOPHYTON FLOCCOSUM IN ADULT PATIENTS
INTRODUCING LUZU
LU Z U FA ST:
2 W E E KS,
14 D O SE S
Efficacy demonstrated at
4 weeks post-treatment
The only topical azole
antifungal approved to treat
interdigital tinea pedis with
once-daily dosing over a
2-week period
Indications and Usage
LUZU (luliconazole) Cream, 1% is indicated for
the topical treatment of interdigital tinea pedis,
tinea cruris, and tinea corporis caused by the organisms
Trichophyton rubrum and Epidermophyton floccosum
in patients 18 years of age and older.
Important Safety Information
• LUZU is indicated for topical use only and is not
indicated for ophthalmic, oral or intravaginal use.
• LUZU should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Caution should be exercised when LUZU is prescribed
for nursing mothers.
Except as otherwise indicated, all product names, slogans,
and other marks are trademarks of the Valeant family of companies.
© 2014 Valeant Pharmaceuticals North America LLC.
DM/LUZ/13/0004
• The most common adverse reactions in clinical
trials were application site reactions, which
occurred in less than 1% of subjects in both
LUZU and vehicle arms. Most adverse reactions
were mild in severity.
Please see full Brief Summary of Prescribing
Information on adjacent page.
Reference: LUZU [prescribing information]. Bridgewater, NJ:
Medicis, a division of Valeant Pharmaceuticals; 2013.
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION
FOR LUZU (luliconazole)
This Brief Summary does not include all the information needed to use
LUZU safely and effectively. See full Prescribing Information for LUZU.
LUZU (luliconazole) Cream, 1% for topical use
Initial U.S. Approval: 2013
Rx Only
INDICATIONS
LUZU (luliconazole) Cream, 1% is an azole antifungal indicated for the topical
treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the
organisms Trichophyton rubrum and Epidermophyton floccosum, in patients
18 years of age and older.
DOSAGE AND ADMINISTRATION
For topical use only. LUZU Cream, 1% is not for ophthalmic, oral, or
intravaginal use.
When treating interdigital tinea pedis, a thin layer of LUZU Cream, 1%
should be applied to the affected area and approximately 1 inch of the
immediate surrounding area(s) once daily for two (2) weeks.
When treating tinea cruris or tinea corporis, LUZU Cream, 1% should be
applied to the affected area and approximately 1 inch of the immediate
surrounding area(s) once daily for one (1) week.
CONTRAINDICATIONS
None
ADVERSE REACTIONS
Clinical Trials 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.
In three Phase 3 clinical trials, 616 subjects were exposed to LUZU Cream, 1%:
305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with
interdigital tinea pedis or tinea cruris applied LUZU Cream, 1% or vehicle cream
once daily for 14 days or 7 days, respectively, to affected and adjacent areas.
During clinical trials with LUZU Cream, 1% the most common adverse reactions
were application site reactions which occurred in less than 1% of subjects in
both the LUZU and vehicle arms. Most adverse reactions were mild in severity.
Post-Marketing Experience
The following adverse reactions have been identified during post-marketing
use of luliconazole cream, 1%: contact dermatitis and cellulitis. 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 drug exposure.
DRUG INTERACTIONS
The potential of luliconazole to inhibit cytochrome P-450 (CYP) enzymes 1A2,
2C9, 2C19, 2D6, and 3A4 was evaluated in vitro. Based on in vitro assessment,
luliconazole at therapeutic doses, particularly when applied to patients with
moderate to severe tinea cruris, may inhibit the activity of CYP2C19 and
CYP3A4. However, no in vivo drug interaction trials have been conducted
to evaluate the effect of luliconazole on other drugs that are substrates of
CYP2C19 and CYP3A4.
Luliconazole is not expected to inhibit CYPs 1A2, 2C9 and 2D6 based on in vitro
assessment. The induction potential of luliconazole on CYP enzymes has not
been evaluated.
USE IN SPECIFIC POPULATIONS
Pregnancy: Pregnancy Category C.
to pregnant female rats. No treatment related effects on maternal toxicity or
malformations were noted at 25 mg/kg/day (3 times the MRHD based on BSA
comparisons). Increased incidences of skeletal variation (14th rib) were noted
at 25 mg/kg/day. No treatment related effects on skeletal variation were noted
at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons).
Subcutaneous doses of 4, 20 and 100 mg/kg/day luliconazole were
administered during the period of organogenesis (gestational days 6-18)
to pregnant female rabbits. No treatment related effects on maternal
toxicity, embryofetal toxicity or malformations were noted at 100 mg/kg/day
(24 times the MRHD based on BSA comparisons).
In a pre- and post-natal development study in rats, subcutaneous doses of
1, 5 and 25 mg/kg/day luliconazole were administered from the beginning
of organogenesis (gestation day 7) through the end of lactation (lactation
day 20). In the presence of maternal toxicity, embryofetal toxicity (increased
prenatal pup mortality, reduced live litter sizes and increased postnatal pup
mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted
at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). No
treatment effects on postnatal development were noted at 25 mg/kg/day
(3 times the MRHD based on BSA comparisons).
Nursing Mothers
It is not known whether luliconazole is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when
LUZU Cream, 1% is administered to women who are breastfeeding.
Pediatric Use
The safety and effectiveness of LUZU Cream, 1% in pediatric patients have
not been established. The number of pediatric patients ≥12 years of age
were too small to adequately assess safety and efficacy.
Geriatric Use
Of the total number of subjects in clinical studies of LUZU Cream, 1%, 8 percent
were 65 and over, while 1.4 percent were 75 and over. No overall differences
in safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified differences in
responses between the elderly and younger patients, but greater sensitivity of
some older individuals cannot be ruled out.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies to evaluate the carcinogenic potential of LUZU Cream,
1% have not been conducted.
Luliconazole revealed no evidence of mutagenic or clastogenic potential
based on the results of two in vitro genotoxicity tests (Ames assay and
Chinese hamster lung cell chromosomal aberration assay) and one in vivo
genotoxicity test (mouse bone marrow micronucleus test).
In a fertility study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day
luliconazole were administered prior to and during mating and through early
pregnancy. Treatment related effects on reproductive function were noted
in females (decreased live embryos and decreased corpus luteum) at 5 and
25 mg/kg/day and males (decreased sperm counts) at 25 mg/kg/day. No
treatment related effects on fertility or reproductive function were noted
at 1 mg/kg/day (0.1X MRHD based on BSA comparisons).
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information)
Inform patients that LUZU Cream, 1% is for topical use only.
LUZU Cream, 1% is not intended for intravaginal or ophthalmic use.
Manufactured for:
Medicis, a division of Valeant Pharmaceuticals North America LLC,
Bridgewater, NJ 08807
There are no adequate and well-controlled studies of LUZU Cream, 1% in
pregnant women. LUZU Cream, 1% should be used during pregnancy only
if the potential benefit justifies the potential risk to the fetus.
The animal multiples of human exposure calculations were based on daily dose
body surface area (BSA) comparisons (mg/m2) for the reproductive toxicology
studies described in this section and in Section 13.1. The Maximum
Recommended Human Dose (MRHD) was set at 8 g 1% cream per day
(1.33 mg/kg/day for a 60 kg individual which is equivalent to 49.2 mg/m2/day).
Systemic embryofetal development studies were conducted in rats and rabbits.
Subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were
administered during the period of organogenesis (gestational days 7-17)
Manufactured by:
DPT Laboratories, Ltd., San Antonio, TX 78215
Product of Japan
Issued: 11/2013
140127
DM/LUZ/13/0005(1)
Cellulitis
• Deep skin and subcutaneous fat infection
• Poorly demarcated erythema, warmth, tenderness,
edema
– Rubor, calor, dolor, tumor: inflammation
• 2.2% of all general practitioner office visits
• 400,000 bed days per year in the English National
Health Service, cost of £96 million ($157.2 million)
– U.S.: $98 million for U.S. hospitalization for
mouth cellulitis alone
• One of the most common infections resulting in
hospitalization
– Diagnostic criteria are poorly defined, variably
applied
Pseudocellulitis
• Dozens of clinical mimickers of cellulitis:
‘pseudocellulitis’
• Very little literature on pseudocellulitis, prevalence
or outcome measures
• Empiric use of aggressive antibiotics 씮 rising rates
of resistance in soft tissue infections
– ‘98–’04: MRSA soft tissue infections 26.2 씮 47.4%
Cellulitis: Bullous Variant
Case 4: A 10-year-old had fever, severe conjunctivitis, urethritis,
and crusted lips (the bottom lip had fully necrosed). It was Stevens
Johnson syndrome induced—not by a drug—but by a mycoplasma
infection. Because it was limited to mucosa, steroids were helpful.
Case 5: A 6-year-old presented with a thick crust on his scalp. Soaking it in saline to remove it allowed Treat to identify underlying
alopecia and “a really exuberant kerion,” an inflammatory fungal
infection that mimics bacterial infection. Oral antifungal therapy is
effective. Case 6: An immunosuppressed 10-year-old girl undergoing induction chemotherapy for new acute lymphoblastic leukemia
presented with an asymptomatic purple area on the back of one heel
that resembled irritation from her shoe. A biopsy with frozen section
showed a cutaneous mold infection. Because there is no inflammatory response to the pathogen, the infected area can be much
larger than initially thought. She also had other risk factors for mold
infections, and “you want to make your diagnosis immediately,
treat broadly, then if possible—restore the person’s immune system.”
Case 7: A 3-year-old returned from Costa Rica with his family with
what looked like impetigo. It turned out to be leishmaniasis. ■
Cutaneous Mold Infections
Patient Factors
• Prolonged neutropenia
• Prematurity
• Bone marrow transplant
High risk locations
• IV sites
• Areas of trauma
• Tape occlusion
Diagnosis/Treatment
• Emergent tissue for histopathology and culture
• Broad spectrum coverage including fungal
• Evaluation for surgical debridement if localized
• Consideration for granulocyte infusion or GMCSF
Leishmaniasis
Unusual Infections in Children
James R. Treat, MD
Introduction. Dr. Treat illustrated and discussed an extensive
variety of unusual infections in his patients.
Case Discussions. Case 1: A 6-month-old with atopic dermatitis presented with a widespread vesicular eruption. The vesicles
were all different sizes, which would be unusual for eczema herpeticum, and it was also on his buttocks. He was diagnosed with enterovirus A6, a type of Coxacki virus, that affects hand, foot, mouth
and buttocks. Many viruses can superinfect atopic dermatitis, including herpes, Coxackie virus, or varicella. Case 2: A 4-hour-old
healthy newborn in the nursery, after a vaginal birth following prolonged rupture of the membranes, had developed congenital Candidiasis after exposure to Candida-filled amniotic fluid for >24 hours.
Case 3: A 14-year-old with fevers, chills, malaise, and solitary enlarging ulcerated plaque had impressive lymphadenopathy in his axillary
area. Biopsy with culture diagnosed ulceroglandular tularemia
infection from an insect bite (a tick) that had initiated a localized
lymphadenopathy. IV gentamicin, then ciprofloxacin, were effective.
www.dermatologyfoundation.org
• Ask about travel!
• Parasite transmitted by sandflies
• 3 typical clinical presentations—cutaneous,
mucocutaneous, visceral—depending on the type
of Leishmania, which depends on geography
• Diagnosis is difficult!
– Special media, PCR
– Send to Walter Reed
or CDC
• Endemic areas include:
– Middle East
(Iran/Iraq/Afghanistan)
– South/Central America
(Costa Rica, Brazil,
– Peru, Bolivia)
– India
• Treatment is typically antimony for noncutaneous
disease, but in children amphotericin may have
better safety profile.
S Sundar et al. J Glob Infect Dis. 2010;2:159–66.
Summer 2014
15
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Summer 2014
Dermatology Foundation
2013 Corporate Honor Society
Partners in Shaping Dermatology’s Future
The Dermatology Foundation is grateful to the following corporations for their generous
contributions last year. Their support furthers the DF’s mission to develop and
retain tomorrow’s leaders in the specialty, enabling advancements in patient care.
Cornerstone Benefactor ($500,000 or more)
Platinum Benefactor ($200,000 or more)
A DIVISION OF VALEANT PHARMACEUTICALS
Gold Benefactor ($100,000 or more)
The Allergan Foundation
Silver Benefactor ($50,000 or more)
Avon Products, Inc.
DUSA Pharmaceuticals Inc.,
a Sun Pharma company
Ranbaxy Laboratories, Inc.
Stiefel, a GSK company
www.dermatologyfoundation.org
Summer 2014
17
2015 DF Research Funding
APPLICATIONS NOW BEING ACCEPTED
Deadline: October 15, 2014
The outstanding impact of the Dermatology Foundation’s Research Awards Program is
nationally recognized. They are effective and essential funding opportunities for advancing the
early research efforts and careers of talented new physician-scientists and investigators. The
dramatically cut federal grant programs makes these unique awards more essential than ever.
The DF’s program offers multi-year career development awards and one-year fellowships
and grants supporting research in all areas of modern dermatology and cutaneous biology.
Recipients have the capacity and desire to further the future of dermatology and patient care.
These awards are made possible by the generosity of the Foundation’s many members and
industry supporters.
Charles & Daneen Stiefel
Scholar Award
This award was introduced last year and is
designed to support outstanding investigators
committed to elucidating the basis, pathophysiology, clinical manifestations, and/or treatment
of autoimmune and/or connective tissue diseases affecting adults and/or children. A generous gift from Charles & Daneen Stiefel has
made possible an ample $100,000 in funding
for each of three years, and represents the first
Dermatology Foundation award intended for
early to mid-career investigators.
Career Development Awards (CDAs)
The nine categories of CDAs are designed
to enable physician-scientists and investigators
to transition from fellowship to established
researcher. These highly competitive and
effective awards provide an annual stipend of
$55,000 for up to three years of support.
Physician-Scientist CDA
Fellowships
Two one-year fellowships are offered—the
Dermatologist Investigator Research Fellowship
and the Fellowship in Pediatric Dermatology.
They provide salary stipends of $30,000 and
$45,000, respectively.
Research Grants
These one-year grants offer $20,000 in
seed money for research projects in a variety
of concentrations, including patient-directed
investigation, basic dermatologic research, and
dermatopathology. This year, special funding
is also available in the basic research grant
category for dermatopharmacology projects.
Program Development Grant
This unique grant provides $10,000 to
further the scientific infrastructure of an existing
dermatology division or department that has
not successfully competed for DF funding within
the last five years.
Clinical CDA in Dermatologic Surgery
Clinical CDA in Health Care
Policy/Public Health
Dermatopathology Research CDA
Medical Dermatology CDA
Science of Human Appearance CDA
Women’s Health CDA
Pediatric Dermatology CDA
Research CDA
18
Summer 2014
APPLY NOW!
Proposals are being accepted through October
15th for the funding year beginning July 1, 2015.
Visit dermatologyfoundation.org/rap
for everything you need:
eligibility criteria, application instructions,
and downloadable forms.
Questions are welcome: 847.328.2256 or
[email protected]
Dermatology Foundation
CLINICAL SYMPOSIA 2014 FACULTY
Proceedings—Part I
Marc D. Brown, MD
Professor
Departments of Dermatology and Oncology
University of Rochester
Ilona J. Frieden, MD
Professor
Departments of Dermatology and Pediatrics
University of California, San Francisco
Joel M. Gelfand, MD, MSCE
Associate Professor
Department of Dermatology
University of Pennsylvania
John E. Harris, MD, PhD
Assistant Professor
Division of Dermatology
University of Massachusetts
Corporate Supporters
2014 DF Clinical Symposia
Diamond Supporter
($100,000)
Galderma Laboratories, LP
Medicis,
a Division of Valeant Pharmaceuticals
Merz, Inc.
Emerald Supporters
($50,000)
Daniela Kroshinsky, MD, MPH
Assistant Professor
Department of Dermatology
Harvard Medical School
Ranbaxy Laboratories Inc.
Laura B. Pincus, MD
Assistant Professor
Departments of Dermatology and Pathology
University of California, San Francisco
Sapphire Supporters
Brian S. Schwartz, MD
Assistant Clinical Professor
Division of Infectious Disease
University of California, San Francisco
Bruce E. Strober, MD, PhD
Associate Professor & Vice Chair
Department of Dermatology
University of Connecticut Health Center
($25,000)
Amgen Inc.
Bayer HealthCare
DUSA Pharmaceuticals Inc.,
a Sun Pharma company
Taro Pharmaceuticals U.S.A., Inc.,
a Sun Pharma company
James R. Treat, MD
Assistant Professor
Departments of Pediatrics and Dermatology
University of Pennsylvania
Hensin Tsao, MD, PhD
Associate Professor
Department of Dermatology
Harvard Medical School
PROGRAM CO-CHAIRS
Janet A. Fairley, MD
Professor and Head
Department of Dermatology
University of Iowa
Jack S. Resneck, Jr., MD
Associate Professor and Vice Chair
Department of Dermatology
Core Faculty, Philip R. Lee Institute
for Health Policy Studies
University of California, San Francisco
www.dermatologyfoundation.org
The DF is pleased to
recognize Unilever for
their educational grant of
$300,000 supporting the
2014 DF Clinical Symposia
Resident Program.
2014 DF Clinical Symposia Faculty Disclosures
(Part II)
Marc D. Brown, MD: None. Ilona J. Frieden, MD: Anacor, Pierre Fabre
Dermatology. Joel M. Gelfand, MD, MSCE: AbbVie, Inc., Amgen, Eli Lilly,
Jansen, Merck, Novartis, Pfizer. John E. Harris, MD, PhD: AbbVie, Inc.,
Combe, Inc., Sanofi/Genzyme. Daniela Kroshinsky, MD, MPH: None.
Laura B. Pincus, MD: None. Brian S. Schwartz, MD: None. Bruce E. Strober,
MD, PhD: AbbVie, Amgen, Celgene, Janssen, Lilly, Maruho, Merck, Novartis,
Pfizer, UCB Pharma. James R. Treat, MD: None. Hensin Tsao, MD, PhD: None.
Summer 2014
19
Dermatology Focus
c/o Dermatology Foundation
1560 Sherman Avenue
Evanston, Illinois 60201-4808
Non-Profit
U.S. Postage
PAID
Permit No. 236
Melrose Park, IL
ADDRESS SERVICE REQUESTED
Giving Back—Profile of a DF Volunteer
“The Best Use of Our Money”
“I truly believe
that if research in
dermatology
doesn’t continue to
move forward, we
won’t have the
progress we need
Ali Moiin, MD
to improve our field
and the care we provide our patients,” Troy,
Michigan dermatologist Dr. Moiin asserts.
“Research funding has decreased so substantially that we have to step up to the plate and
help our specialty. This is why I support the DF,
and why I give my time to encourage other
dermatologists to do the same.”
Dr. Moiin’s support of the DF as a member
and a volunteer began early in his career as a
practitioner. He found it an easy decision to join
the Leaders Society in 2001, and the following
year volunteered to invite his colleagues to join
him. Then in 2010 he became an Annenberg
Circle member, and soon joined the Annenberg
Circle Committee to focus on increasing
membership at this level of giving.
Dr. Moiin explains that while his schedule is
full, his volunteer work allows him to give even
more to the specialty. He shares that he comes
from a family of physicians and has wanted to
be a dermatologist since he was 16 years old.
This clinical dermatologist now runs a busy
private practice, is Clinical Associate Professor
in Dermatology at Wayne State, and is the
chairman of medical education for the Michigan
Dermatological Society.
Dr. Moiin stresses to his colleagues that
“young investigators cannot apply for any federal
funding without having research experience
and solid early results. And funding for this initial
effort comes from the DF.”
He notes that many early-career DF research
awards have enabled significant progress,
including fundamental insights on the hair
follicle, the systemic nature of psoriasis,
and the cutaneous impact of cancer drugs.
“Funding from the DF was the crucial first step.
Giving to the DF is the best use of our money.”
The DF is exceptionally grateful to its many volunteers who work hard
and give generously of their time to keep dermatology at the forefront of medicine.
A DERMATOLOGY FOUNDATION PUBLICATION
SPONSORED BY VALEANT PHARMACEUTICALS NORTH AMERICA LLC
VOL. 33 NO. 2
SUMMER 2014