Supplement to Seminars in Cutaneous Medicine and Surgery

Transcription

A CME/CE CERTIFIED SUPPLEMENT TO
SUPPLEMENT 4
VOL. 34, NO. 4S
JUNE 2015
EDITORS
Kenneth A. Arndt, MD
Philip E. LeBoit, MD
Bruce U. Wintroub, MD
Highlights of Skin Disease Education
Foundation’s 39th Annual Hawaii
Dermatology Seminar
GUEST EDITORS
Joseph F. Fowler, Jr, MD
Christopher B. Zachary, MBBS, FRCP
Roger I. Ceilley, MD
Kristina Callis Duffin, MD, MS
Kenneth B. Gordon, MD
Linda F. Stein Gold, MD
Jerry K. L. Tan, MD, FRCPC
IntroductionS61
Fungus: New Treatment Options for S62
Toenail Onychomycosis and Tinea Pedis
Using the Anti-TNF Agents in Psoriasis S65
Impact of Psoriasis Therapy on Comorbid Conditions S69
What’s New in Acne S72
Rosacea: Pathogenesis and Therapy S75
Tattoo Treatment: Current State of the Art S78
Post-Test and Evaluation Form S80
Highlights of Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology Seminar
Original Release Date: June 2015
Most Recent Review Date: June 2015
Expiration Date: June 30, 2016
Estimated Time to Complete Activity: 2.0 hours
To get instant CME/CE credits online, go to http://tinyurl.com/39HawaiiSupp.
Upon successful completion of the online test and evaluation form, you will be
directed to a Web page that will allow you to receive your certificate of credit via
e-mail or you may print it at that time. If you have any questions or difficulties with
this activity, please contact the Global Academy for Medical Education office at
info@globalacademycme.com.
Inquiries may be directed to Global Academy for Medical Education
info@globalacademycme.com or (973) 290-8225.
Accreditation Statements
Physicians: 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 providership of Rutgers, The State University
of New Jersey, and Global Academy for Medical Education, LLC.
Rutgers, The State University of New Jersey, is accredited by the ACCME to provide
continuing medical education for physicians. Rutgers, The State University of
New Jersey, designates this enduring material for a maximum of 2.0 AMA PRA
Category 1 Credits™. Physicians should claim only the credit commensurate
with the extent of their participation in the activity. Nurses: Rutgers, The State University, Center for Continuing and Outreach Education
(CCOE) is an approved provider of continuing nursing education by the New Jersey State
Nurses Association, an accredited approver by the American Nurses Credentialing
Center’s Commission on Accreditation. Provider Number P173-12/12-15.
This activity is awarded 2.66 contact hours (60 minute CH). Nurses should only
claim those contact hours actually spent participating in the activity.
Target Audience
This activity has been designed for dermatologists, primary care physicians,
and other physicians, residents, nurses, nurse practitioners, physician assistants,
pharmacists, and fellows who treat patients with skin diseases.
Statement of Need
The growing body of evidence about the pathophysiology of skin diseases
has broadened our understanding of these diverse conditions, as well as their
effects on other aspects of health and quality of life. Psoriasis is an inflammatory
disease that increases the risk of many other conditions. The provider managing
the patient’s psoriasis must consider these potential and actual comorbidities
when choosing psoriasis therapy and monitoring patients. The range of anti-tumor
necrosis factor agents and other treatments for psoriasis increases the opportunity
to tailor therapy to the patient’s responses, characteristics, comorbidities if any,
and preferences.
Studies have shed light on the immune system underpinnings of rosacea in recent
years, and new therapies have received US Food and Drug Administration approval
for treatment of this condition. New agents also have been introduced for tinea pedis,
toenail onychomycosis, and acne. Clinical trials have examined and validated some
agents long used to treat skin conditions. Dermatologists also are called upon to
remove tattoos; newer methods can reduce the time required for treatment and may
improve results.
Learning Objectives
By reading and studying this supplement, participants should be better able to:
• Differentiate the characteristics of the tumor necrosis factor (TNF) inhibitors
approved for use in treating psoriasis and apply that information to clinical practice.
• Demonstrate familiarity with the impact of comorbid conditions on patients
with psoriasis and incorporate the effect of psoriasis therapy on those
comorbidities into patient management.
• Integrate new therapies for rosacea into practice and describe current theories
about rosacea pathophysiology.
• Explain the use of new treatments for tinea pedis and toenail onychomycosis.
• Apply current knowledge about anti-acne antibiotic dosing, maintenance
therapy, topical therapy, and diet to clinical practice.
• Identify current and updated techniques to improve tattoo removal.
Disclosure Declarations
Individuals in a position to control the content of this educational activity are
required to disclose: 1) the existence of any relevant financial relationship with any
entity producing, marketing, re-selling, or distributing health care goods or services
consumed by, or used on, patients with the exemption of nonprofit or government
organizations and non–health care related companies, within the past 12 months;
and 2) the identification of a commercial product/device that is unlabeled for use
or an investigational use of a product/device not yet approved.
Jointly provided by
Faculty
Roger I. Ceilley, MD, Consultant: Ferndale Pharma Group, Inc, DUSA Pharmaceuticals,
Inc., LEO Pharma Inc., Valeant Pharmaceuticals North America LLC, Xoft Inc.;
Speakers Bureau: DUSA and LEO Pharma; Advisory Board: Ferndale, DUSA, Xoft Inc.
Kristina Callis Duffin, MD, MS, Grant/Research: AbbVie Inc., Amgen Inc., BristolMyers Squibb Company, Eli Lilly and Company, Janssen Biotech, Inc., Novartis
Pharmaceuticals Corporation, Pfizer Inc., Stiefel Laboratories, Inc., and XenoPort,
Inc.; Consultant: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis,
Pfizer, and XenoPort; Advisory Board: Eli Lilly and Janssen.
Joseph F. Fowler, Jr, MD, Grant/Research: AbbVie, Allergan, Inc., Amgen, Anacor
Pharmaceuticals, Inc., Celgene Corporation, Chugai Pharma USA LLC, Eli Lilly,
Galderma Laboratories, L.P., Genentech Inc, Janssen, Johnson & Johnson, Merck &
Co., Inc., Novartis, Onset Dermatologics LLC, Pfizer, Regeneron Pharmaceuticals, Inc,
SmartPractice Dermatology/Allergy,Taisho Pharmaceutical Co., Taro Pharmaceutical
Industries Ltd, and Valeant; Consultant: Bayer Healthcare, Galderma, Johnson &
Johnson, Medimetriks Pharmaceuticals Inc, Ranbaxy Laboratories Limited, and
SmartPractice; Speakers Bureau: Galderma, SmartPractice, and Valeant.
Kenneth B. Gordon, MD, Grant/Research: AbbVie, Amgen, Celgene, Eli Lilly, Novartis,
and Pfizer; Consultant: AbbVie, Amgen, Celgene, Eli Lilly, Novartis, and Pfizer.
Linda F. Stein Gold, MD, Consultant: Allergan, Anacor Pharmaceuticals, Celgene,
Eli Lilly, Galderma, LEO Pharma, Novartis, and Valeant; Speakers Bureau:
Celgene, Galderma, LEO Pharma, Novartis, Taro, and Valeant; Advisory Board:
Allergan, Anacor Pharmaceuticals, Celgene, Eli Lilly, Galderma, LEO Pharma,
Novartis, Promius Pharma, LLC, and Valeant; Medical Legal Advisor: HoffmannLa Roche Inc.
Jerry K. L.Tan, MD, FRCPC, Grant/Research: Allergan, Bayer, Cipher Pharmaceuticals
Inc, Dermira, Galderma, and Valeant; Consultant: Cipher Pharmaceuticals,
Galderma, GlaxoSmithKline Pharmaceutical Company, Hoffmann-La Roche, Stiefel,
and Valeant; Speakers Bureau: Cipher Pharmaceuticals, Galderma, Pierre-Fabre,
and Valeant.
Christopher B. Zachary, MBBS, FRCP, Consultant: Cutera, Inc. and ZELTIQ
Aesthetics, Inc.; Speakers Bureau: Cynosure, Inc. and Solta Medical, a division of
Valeant; Advisory Board: ZELTIQ.
In order to help ensure content objectivity, independence, and fair balance, and
to ensure that the content is aligned with the interest of the public, CCOE has
resolved all potential and real conflicts of interest through content review by a nonconflicted, qualified reviewer.This activity was peer-reviewed for relevance, accuracy
of content, and balance of presentation by: Zac Handler, MD, Brian Lee, MD, and
Vijay Vanchinathan, MD, from Rutgers New Jersey Medical School, Department
of Medicine, Division of Dermatology, Newark, NJ, and Geraldine Bocchieri, RN,
BSN, Department of Dermatology, Rutgers Robert Wood Johnson Medical School,
New Brunswick, NJ. Dr Handler, Dr Lee, Dr Vanchinathan, and Ms Bocchieri have no
relevant financial relationships to disclose.
Field Testers: This activity was pilot-tested for time required by Physicians:
Zac Handler, MD, Brian Lee, MD, and Vijay Vanchinathan, MD; Nursing: Kathleen
Brown, LPN, Claudia Carron, MSN, RN, NE-BC, and Carol Ruland, RN. The field
testers have no relevant financial relationships to disclose.
CCOE Staff: Tristan Nelsen, MNM, CMP, and Elizabeth Ward, MSJ, have no relevant financial relationships to disclose.
Global Academy for Medical Education Staff: Shirley V. Jones, MBA; Sylvia H.
Reitman, MBA, DipEd; and Eileen McCaffrey, MA, have no relevant financial
relationships to disclose.
Off-Label/Investigational Use Disclosure
This activity discusses the off-label use of the following approved agents: adalimumab, cyclosporine ophthalmic emulsion, doxycycline, etanercept, fluconazole,
isotretinoin, itraconazole, ketoconazole, methotrexate, minocycline (oral and foam),
secukinumab, ustekinumab, and tumor necrosis factor inhibitors as a class.
This continuing education supplement was developed from faculty presentations at Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology
Seminar, held March 1-6, 2015, in Kauai, Hawaii. The Guest Editors acknowledge the editorial assistance of Global Academy for Medical Education and
Eileen McCaffrey, medical writer, in the development of this supplement. The
manuscript was reviewed and approved by the Guest Editors as well as
the Editors of Seminars in Cutaneous Medicine and Surgery. The ideas and
opinions expressed in this supplement are those of the Guest Editors and do
not necessarily reflect the views of the supporters, Global Academy for Medical
Education, Rutgers, or the Publisher.
Supported by educational grants from
AbbVie Inc., Amgen Inc., Bayer Healthcare,
and Valeant Pharmaceuticals North America LLC.
STATEMENT OF PURPOSE
Seminars in Cutaneous Medicine and Surgery presents
well-rounded and authoritative discussions of important
clinical areas, especially those undergoing rapid change in
the specialty. Each issue, under the direction of the Editors
and Guest Editors selected because of their expertise in
the subject area, includes the most current information
on the diagnosis and management of specific disorders of
the skin, as well as the application of the latest scientific
findings to patient care.
Seminars in Cutaneous Medicine and Surgery (ISSN 1085-5629) is
published quarterly by Frontline Medical Communications Inc.,
7 Century Drive, Suite 302, Parsippany, NJ 07054-4609. Months of issue
are April, June, September, and December. Periodicals postage paid at
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RECIPIENT: To change your address, contact Subscription Services at
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EDITORS
Kenneth A. Arndt, MD
Clinical Professor of Dermatology,
Emeritus
Harvard Medical School
Adjunct Professor of Surgery
Dartmouth Medical School
Hanover, New Hampshire
Adjunct Professor of Dermatology
Brown Medical School
Providence, Rhode Island
Philip E. LeBoit, MD
Professor of
Clinical Dermatology
University of California,
San Francisco
San Francisco, California
Bruce U. Wintroub, MD
Associate Dean
Professor and Chair
of Dermatology
School of Medicine
University of California,
San Francisco
San Francisco, California
Editorial correspondence should be addressed to Kenneth A. Arndt, MD,
Skincare Physicians of Chestnut Hill, 1244 Boylston St, Suite 302,
Chestnut Hill, MA 02467. Correspondence regarding subscriptions or
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Publication of an advertisement in Seminars in Cutaneous Medicine and
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The ideas and opinions expressed in Seminars in Cutaneous Medicine
and Surgery do not necessarily reflect those of the Editors or Publisher.
Publication of an advertisement or other product mention in Seminars
in Cutaneous Medicine and Surgery should not be construed as an
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Seminars in Cutaneous Medicine and Surgery is indexed in Index Medicus/
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June 2015, Vol. 34, No. 4S
TABLE OF CONTENTS
Highlights of Skin Disease Education Foundation’s
39th Annual Hawaii Dermatology Seminar
S61Introduction
S62 Fungus: New Treatment Options for
Toenail Onychomycosis and Tinea Pedis
S65 Using the Anti-TNF Agents in Psoriasis
S69 Impact of Psoriasis Therapy
on Comorbid Conditions
S72 What’s New in Acne
S75 Rosacea: Pathogenesis
and Therapy
S78 Tattoo Treatment:
Current State of the Art
S80 Post-Test and Evaluation Form
GUEST EDITORS
Clinical Professor of Dermatology
The University of Iowa
West Des Moines, Iowa
Assistant Professor, Dermatology
University of Utah
Salt Lake City, Utah
University of Louisville
Louisville, Kentucky
Professor of Dermatology
Northwestern University
Feinberg School of Medicine
Chicago, Illinois
Director of Dermatology Research
Henry Ford Health System
Detroit, Michigan
Adjunct Professor
Department of Medicine
University of Western Ontario
London, Ontario, Canada
Professor and Chair
Department of Dermatology
University of California, Irvine
Irvine, California
Vol. 34, No. 4S, June 2015
INTRODUCTION
T
he breadth and diversity of dermatology, the speed at which our understanding of skin pathophysiology has improved, and the
introduction of new therapies combine to make this field interesting and challenging. The expanding scope of our specialty also
creates a broad range of educational needs for practicing clinicians.
Skin Disease Education Foundation’s 39th Hawaii Dermatology Seminar offers updates from experts addressing a broad range of
skin diseases, and covers advances in both medical and aesthetic dermatology. The articles in this educational supplement summarize
the highlights of clinical sessions presented during the CME/CE conference by leading experts in the field of dermatology.
Tumor necrosis factor (TNF) inhibitors are the cornerstone of treatment for psoriasis, but choice of agent can be confusing.
This supplement includes a comparison of the TNF inhibitors approved by the US Food and Drug Administration (FDA) for
the treatment of psoriasis. Psoriasis has been linked to an elevated risk of several comorbidities. Can choice of psoriasis therapy
alleviate any of these conditions? Our faculty evaluates how risk or presence of comorbid conditions might inform the choice of
psoriasis therapy, and whether control of psoriasis can alleviate any coexisting conditions.
Accumulating evidence suggests that rosacea, like psoriasis, is a disorder of the immune system – specifically, of innate rather
than adaptive immunity. This CME/CE supplement summarizes those findings. It also reviews studies of new therapies for this
condition, as well as new evidence validating the use of a commonly prescribed agent.
Moving from the face to the feet and from immune disorders to fungal infection, our faculty addresses the diagnosis and therapy
for tinea pedis and toenail onychomycosis. The FDA last year approved two topical therapies developed specifically for toenail
onychomycosis, and in 2013 approved a treatment for interdigital tinea pedis. These highlights summarize the evidence for these
therapies, and also cover other publications about diagnosis and management of these infections.
Acne is a common problem in dermatological practice. Our faculty reviews recent studies addressing topics such as antibiotic
dosing, maintenance therapy, diet, and treatment of acne on the trunk of the body.
In the realm of aesthetic medicine, this educational supplement addresses techniques for reducing the number of sessions
required for tattoo removal and newer lasers that may improve removal of certain types of tattoos.
The broad range of dermatology care and new therapies for skin conditions challenge the busy clinician to remain abreast of the
latest information. We hope that you can apply these updates from our seminar to your clinical practice.
Publication of this CME/CE article was jointly provided by Rutgers,
The State University of New Jersey, and Global Academy for Medical
Education, LLC with Skin Disease Education Foundation (SDEF)
and is supported by educational grants from AbbVie Inc., Amgen Inc.,
Bayer Healthcare, and Valeant Pharmaceuticals North America LLC.
Dr Fowler and Dr Zachary have received an honorarium for their
participation in this activity. They acknowledge the editorial assistance of
Eileen McCaffrey, MA, medical writer, and Global Academy for Medical
Education in the development of this continuing medical education
journal article.
University of Louisville
Louisville, Kentucky
Skin Disease Education Foundation Director
Medical Dermatology
Professor and Chair
Department of Dermatology
University of California, Irvine
Irvine, California
Skin Disease Education Foundation Director
Aesthetic and Procedural Dermatology
Joseph F. Fowler, Jr, MD, Grant/Research: AbbVie, Allergan, Inc.,
Amgen, Anacor Pharmaceuticals, Inc., Celgene Corporation, Chugai
Pharma USA LLC, Eli Lilly and Company, Galderma Laboratories, L.P.,
Genentech Inc, Janssen Biotech, Inc., Johnson & Johnson, Merck & Co.,
Inc., Novartis Pharmaceuticals Corporation, Onset Dermatologics LLC,
Pfizer Inc., Regeneron Pharmaceuticals, Inc, SmartPractice Dermatology/
Allergy, Taisho Pharmaceutical Co., Taro Pharmaceutical Industries
Ltd, and Valeant; Consultant: Bayer, Galderma, Johnson & Johnson,
Medimetriks Pharmaceuticals Inc, Ranbaxy Laboratories Limited, and
SmartPractice; Speakers Bureau: Galderma, SmartPractice,
and Valeant.
Christopher B. Zachary, MBBS, FRCP, Consultant: Cutera, Inc. and
ZELTIQ Aesthetics, Inc.; Speakers Bureau: Cynosure, Inc. and Solta
Medical, a division of Valeant; Advisory Board: ZELTIQ.
Address reprint requests to: Christopher B. Zachary, MBBS, FRCP,
Dermatology, UC Irvine Health, 118 Med Surge I, Irvine, CA 92697,
czachary@uci.edu.
1085-5629/13/$-see front matter © 2015 Frontline Medical Communications
doi:10.12788/j.sder.2015.0152
Vol. 34, No. 4S, June 2015, Seminars in Cutaneous Medicine and Surgery S61
Fungus: New Treatment Options for Toenail
Onychomycosis and Tinea Pedis
Roger I. Ceilley, MD*
■ Abstract
Toenail onychomycosis and tinea pedis are common, often
coexisting, fungal infections. The former, in particular, may
be viewed incorrectly as not worthy of treatment. However,
infection is progressive if not addressed and can permanently
damage the nail plate. It can also spread to other individuals.
New topical therapies have been introduced in recent years
for both infections.
Semin Cutan Med Surg 34(supp4):S62-S64
© 2015 published by Frontline Medical Communications
■ Keywords
Onychomycosis, tinea pedis, luliconazole, naftifine, terbinafine,
itraconazole, fluconazole, efinaconazole, tavaborole
O
nychomycosis is a common fungal infection affecting the
nails. It occurs in roughly 10% of the general population,
with higher prevalence in men, older individuals, and in
people with psoriasis, diabetes, or immunosuppressive conditions (eg, HIV).1-4 Dermatophytes are the most frequent cause of
onychomycosis. Of these pathogens, Trichophyton rubrum is the
most common, accounting for 70% of onychomycosis cases.5
Dermatophyte infection of the toenails is usually not a primary
condition but is secondary to tinea pedis, a dermatophyte infection
of the soles of the feet and interdigital spaces.1 T. rubrum is also
a common cause of tinea pedis.6 Prevalence of subclinical dermatophyte infection of the toenail is higher among patients with
tinea pedis but clinically normal toenails (n=35) compared with
individuals without tinea pedis (n=66) (17% vs 1.5%; P=0.0066).7
Patients with either tinea pedis or toenail onychomycosis should
be evaluated for the other infection.
If topical therapy is chosen for toenail onychomycosis, then
separate agents must be prescribed to treat tinea pedis.
constituent of fungal cell membranes.8 According to an animal
study, it was more effectively retained in the stratum corneum than
terbinafine cream.9 Luliconazole 1% cream is also indicated for
tinea cruris and tinea corporis.8 Naftifine 2%, available as a gel
or cream, is also FDA-approved specifically for interdigital tinea
pedis. It interferes with sterol biosynthesis, decreasing the amount
of ergosterol.10,11
A publication of two phase III trials (n=1,174) of naftifine 2%
gel reported efficacy rates separately for interdigital (43.3%) and
moccasin-type tinea pedis (56.7%). Rates of complete clearance,
effective treatment, and mycological cure were similar for patients
with interdigital and moccasin-type tinea pedis at 4 weeks posttreatment (22% vs 20%, 52% vs 51%, and 62% vs 65%, respectively).12
Onychomycosis
Some clinicians incorrectly view onychomycosis as a cosmetic
condition not worthy of treatment. However, this infection is
progressive if untreated. It can disrupt skin integrity, permanently
damage the nail plate, and spread to other individuals and to other
body parts on the infected individual.1,13
The most sensitive diagnostic test for onychomycosis is periodic
acid–Schiff staining (82% sensitivity in one analysis).14 The severity
of onychomycosis can be scored based on the proportion of a nail
affected multiplied by the proximity of the infection to the nail
matrix (Figure 1), with 10 points added if dermatophytoma (longitudinal streak or a patch) or subungual hyperkeratosis (>2 mm) is
present (Figure 2). Mild disease is classified as a score of 5 or less,
moderate as 6 to 15, and severe as 16 to 35. Severe involvement
requires systemic treatment and carries a poorer prognosis. Hostrelated poor prognostic factors include immunosuppression, poor
peripheral circulation, and poorly controlled diabetes.15
Oral Therapies
Address reprint requests to: Roger I. Ceilley, MD, RCI, LLC, 1280 Burr
Oaks Drive, West Des Moines, IA 50266; rceil45@gmail.com.
Systemic agents used to treat onychomycosis include terbinafine,
itraconazole, and fluconazole. A meta-analysis reported a mycological cure rate of 76% ± 3% with terbinafine (n=18 studies,
993 patients), 63% ± 7% with itraconazole pulse therapy (n=6
studies, 318 patients), and 48% ± 5% with fluconazole (n=3 studies,
131 patients).16
A trial of terbinafine (12 or 16 weeks of therapy, 5-year follow-up)
in toenail onychomycosis reported complete cure (ie, mycological
plus clinical cure) in 35% of patients and mycological cure in 46%
of patients.17 The recommended dose for toenail onychomycosis
is 250 mg once daily for 12 weeks.18
A pulse regimen is FDA-approved for fingernail infection but not
toenail infection.19 Among patients receiving itraconazole for toenail
onychomycosis in three double-blind, controlled trials (n=110),
complete cure was reported in 14% of patients and mycological
cure in 54% of patients. Therapy was deemed effective (mycological cure plus clear or minimal nail involvement) in 35% of those
receiving itraconazole. Mean time to effective therapy was about
10 months. The recommended dose of itraconazole for toenail
onychomycosis is 200 mg once daily for 12 consecutive weeks.19
Fluconazole is sometimes used off-label to treat onychomycosis.
When given once weekly for up to 1 year (n=362), it has produced
clinical cure rates of 37% (150 mg/wk), 46% (300 mg/wk), and
S62 Seminars in Cutaneous Medicine and Surgery, Vol. 34, No. 4S, June 2015
© 2015 Frontline Medical Communications 1085-5629/13/$-see front matter
doi:10.12788/j.sder.2015.0153
Tinea Pedis Therapy
Two topical antifungal agents are commonly used to treat tinea
pedis. Luliconazole 1% cream received approval from the US
Food and Drug Administration (FDA) in 2013 for the treatment
of interdigital tinea pedis, but has been available in Japan for
many years. It appears to inhibit the synthesis of ergosterol, a
*Clinical Professor of Dermatology, The University of Iowa,
West Des Moines, Iowa.
Dr Ceilley has received an honorarium for his participation in this activity.
He acknowledges the editorial assistance of Eileen McCaffrey, MA,
medical writer, and Global Academy for Medical Education in the
development of this continuing medical education journal article.
Roger I. Ceilley, MD, Consultant: Ferndale Pharma Group, Inc, DUSA
Pharmaceuticals, Inc., LEO Pharma Inc., Valeant Pharmaceuticals North
America LLC, Xoft Inc.; Speakers Bureau: DUSA and LEO Pharma;
Advisory Board: Ferndale, DUSA, Xoft Inc.
Proximal nail fold
5
Lunula
4
3
5. 76%-100%
4. >3/4
4. 51%-75%
3. >1/2–3/4
3. 26%-50%
2. 1/4–1/2
10 points if
dermatophytoma
or subungual
hyperkeratosis
(>2 mm)
2. 11%-25%
1. <1/4
1. 0-10%
2
1
Distal groove
% of nail involved
Proximity of disease to matrix/
involvement from distal edge
■ FIGURE 2 Onychomycosis Severity Index.
Multiply score (boldface numerals in each bar) for % nail
involved × proximity to matrix, + 10 if dermatophytoma or
subungual hyperkeratosis (>2 mm).
Source: Carney C, et al. Arch Dermatol. 2011;147(11):1277-1282.
Topical Therapies
■ FIGURE 1 Proximity to Matrix Scoring.
The nail is divided transversely into quarters. Involvement of the
distal quarter is given a score of 1 (distal groove in red); if involvement extends to the first half of the nail, it is given a score of 2; the
third quarter, a score of 3; and the proximal quarter, a score of 4.
Involvement of the lunula (aqua) and the proximal nail fold (red)
represents matrix involvement and is given a score of 5.
Source: Courtesy of Roger I. Ceilley, MD.
48% (450 mg/wk) at 6-month post-therapy follow-up. Clinical
cure was defined as a clinically normal target nail with complete
regrowth of healthy tissue. Mean time to clinical success was
6.6, 6.2, and 6.7 months with 150-, 300-, and 450-mg weekly
doses, respectively.20 The risk of myopathy and rhabdomyolysis
increases when fluconazole is coadministered with a statin.21
Consider advising patients on statin therapy to withhold that
agent on the day they take fluconazole. The once-weekly regimen
may improve adherence.
Notably, ketoconazole oral tablets are no longer indicated for
cutaneous fungal infections. The FDA withdrew the indication as
of July 2013 due to the risk of severe liver injury and adrenal gland
problems.22 Topical formulations of ketoconazole are unaffected
by this change.
Consider obtaining a complete blood count and hepatic panel
prior to initiating oral antifungal therapy.4 Fluconazole and terbinafine have rarely been associated with serious hepatic toxicity.18,21
Itraconazole is metabolized primarily in the liver.19 Patients at
elevated risk for hepatic or other adverse events, or receiving
medications that may interact with antifungal therapy, should be
monitored closely.
Systemic therapy does not cure all patients. Reasons for treatment failure include treatment nonadherence, incorrect diagnosis,
a nondermatophyte pathogen, and patient factors (eg, immunocompromised, poorly controlled diabetes, peripheral vascular
disease).4 A certain level of recurrence is associated with systemic
antifungal therapy. A 7-year prospective study (n=73) reported
a 16.4% recurrence at a mean of 3 years following successful
therapy. The recurrence rate was higher following treatment with
itraconazole than with terbinafine (35.7% vs 11.9%, respectively;
P=0.046).23
Mild to moderate onychomycosis may respond to topical antifungal therapy alone. The FDA approved two topical agents in
2014 that were developed specifically for toenail onychomycosis:
efinaconazole 10% solution and tavaborole 5% solution.24-26 Each
agent is indicated for 48 weeks of therapy. Many patients prefer
topical therapy to systemic therapy. Laboratory monitoring is not
required, and the most common side effects are local (application
site vesicles and pain with efinaconazole, application site
exfoliation and erythema with tavaborole, and ingrown toenails
and application site dermatitis with both agents).25,26
Efinaconazole is a non-lacquer alcohol-based triazole antifungal agent characterized by low surface tension (desirable for
application to a dry nail plate surface) and a low (ie, desirable)
level of keratin binding.24,25 Two identically designed phase III
studies in patients with toenail distal lateral subungual onychomycosis (20%-50% clinical involvement) randomized patients
(3:1) to efinaconazole or vehicle once daily for 48 weeks (study
1: n=870; study 2: n=785). Mycological cure rates of 55.2% and
53.4% were reported at 4 weeks post-treatment in the two studies
(P<0.001 vs vehicle).27
Complete cure (0% clinical involvement of target toenail and
negative potassium hydroxide [KOH] examination and fungal
culture) lagged behind mycological cure (17.8% and 15.2% in
the two studies at week 52; P<0.001 vs vehicle).27 Nonetheless,
it is noteworthy that the rate of mycological cure in these studies
appears comparable to the 54% level reported with oral itraconazole.19 An additional advantage of efinaconazole is that its nail
penetration does not appear to be influenced by nail polish.28
Tavaborole, a boron-based molecule, represents a new class of
antifungals.29 It inhibits a fungal aminoacyl-transfer ribonucleic
acid synthetase necessary for protein synthesis.26,29
Two phase III studies including patients with distal subungual onychomycosis affecting 20% to 60% of a great toenail were
randomized (2:1) to tavaborole or vehicle for 48 weeks (study 1:
n=593; study 2: n=601). At 4 weeks post-treatment cessation, mycological cure rates were 31.1% and 35.9% in the two studies. Clear or
almost clear rates were 26.1% and 27.5%. As with efinaconazole,
complete cure (clinical and mycological cure) lagged behind mycological cure (6.5% vs 9.1%; P≤0.001 vs vehicle). Also noteworthy is
■ ❚ ❙ Fungus: New Treatment Options for Toenail Onychomycosis and Tinea Pedis
that fungal cultures were negative at week 52 in 87.0% and 85.4% of
patients treated with tavaborole. Negative fungal culture is distinct
from mycological cure in that the latter was defined as negative
KOH wet mount and negative fungal culture.29
Summary
The current classification system for onychomycosis divides
cases into mild, moderate, and severe disease.15 Severe disease
requires oral therapy. Two recently FDA-approved topical antifungal agents—efinaconazole 10% solution and tavaborole
5% solution—have demonstrated effectiveness in mild to moderate
onychomycosis. Topical luliconazole 1% cream and naftifine
2% cream and gel offer effective options for tinea pedis. Patients with
either toenail onychomycosis or tinea pedis should be evaluated
for the other fungal infection.
References
1. Ameen M, Lear JT, Madan V, Mohd Mustapa MF, Richardson M. British
Association of Dermatologists’ guidelines for the management of onychomycosis
2014. Br J Dermatol. 2014;171(5):937-958.
2. Gupta AK, Jain HC, Lynde CW, Macdonald P, Cooper EA, Summerbell RC.
Prevalence and epidemiology of onychomycosis in patients visiting physicians’
offices: A multicenter Canadian survey of 15,000 patients. J Am Acad Dermatol.
2000;43(2 pt 1):244-248.
3. Saunte DM, Holgersen JB, Haedersdal M, et al. Prevalence of toe nail onychomycosis in diabetic patients. Acta Derm Venereol. 2006;86(5):425-428.
4. Westerberg DP, Voyack MJ. Onychomycosis: Current trends in diagnosis and
treatment. Am Fam Physician. 2013;88(11):762-770.
5. Tosti A. Onychomycosis Clinical Presentation. 2015. http://emedicine.medscape.
com/article /1105828-clinical#a0218. Accessed May 17, 2015.
6. Havlickova B, Czaika VA, Friedrich M. Epidemiological trends in skin mycoses
worldwide. Mycoses. 2008;51(suppl 4):2-15.
7. Walling HW. Subclinical onychomycosis is associated with tinea pedis. Br J
Dermatol. 2009;161(4):746-749.
8. Luzu [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals; 2013.
9. Koga H, Nanjoh Y, Kaneda H, Yamaguchi H, Tsuboi R. Short-term therapy with
luliconazole, a novel topical antifungal imidazole, in guinea pig models of tinea
corporis and tinea pedis. Antimicrob Agents Chemother. 2012;56(6):3138-3143.
10.Naftin gel, 2% [package insert]. Greensboro, NC: Merz Pharmaceuticals, LLC;
2013.
11.Naftin cream, 2% [package insert]. Greensboro, NC: Merz Pharmaceuticals, LLC;
2012.
12.Stein Gold LF, Parish LC, Vlahovic T, et al. Efficacy and safety of naftifine HCl
Gel 2% in the treatment of interdigital and moccasin type tinea pedis: Pooled
results from two multicenter, randomized, double-blind, vehicle-controlled trials.
J Drugs Dermatol. 2013;12(8):911-918.
13.Daniel RC. Onychomycosis: Burden of disease and the role of topical antifungal
treatment. J Drugs Dermatol. 2013;12(11):1263-1266.
14.Wilsmann-Theis D, Sareika F, Bieber T, Schmid-Wendtner MH, Wenzel J. New
reasons for histopathological nail-clipping examination in the diagnosis of onychomycosis. J Eur Acad Dermatol Venereol. 2011;25(2):235-237.
15.Carney C, Tosti A, Daniel R, et al. A new classification system for grading the
severity of onychomycosis: Onychomycosis Severity Index. Arch Dermatol.
2011;147(11):1277-1282.
16.Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic
antifungal agents for the treatment of onychomycosis. Br J Dermatol. 2004;
150(3):537-544.
17. Darkes MJ, Scott LJ, Goa KL. Terbinafine: A review of its use in onychomycosis
in adults. Am J Clin Dermatol. 2003;4(1):39-65.
18.Lamisil [package insert]. East Hanover, NJ: Sandoz Pharmaceuticals Corp; 2015.
19.Sporanox [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.
20.Scher RK, Breneman D, Rich P, et al. Once-weekly fluconazole (150, 300, or
450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am
Acad Dermatol. 1998;38(6 pt 2):S77-86.
21.Diflucan [package insert]. New York, NY: Pfizer Inc.; 2014.
22.FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole)
oral tablets due to potentially fatal liver injury and risk of drug interactions and
adrenal gland problems. http://www.fda.gov/Drugs/DrugSafety/ucm362415.htm.
Accessed May 17, 2015.
23.Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis
caused by dermatophytes after successful treatment with systemic antifungal
agents. J Am Acad Dermatol. 2010;62(3):411-414.
24.Del Rosso JQ. The role of topical antifungal therapy for onychomycosis and the
emergence of newer agents. J Clin Aesthet Dermatol. 2014;7(7):10-18.
25.Jublia [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America
LLC; 2015.
26.Kerydin [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc.; 2014.
27.Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment
of toenail onychomycosis: Two phase III multicenter, randomized, double-blind
studies. J Am Acad Dermatol. 2013;68(4):600-608.
28.Zeichner JA, Gold LS, Korotzer A. Penetration of (14C)-efinaconazole topical solution, 10%, does not appear to be influenced by nail polish. J Clin Aesthet Dermatol.
2014;7(9):34-36.
29.Elewski BE, Aly R, Baldwin SL, et al. Efficacy and safety of tavaborole topical
solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail
onychomycosis: Results from 2 randomized phase-III studies. J Am Acad
Dermatol. 2015;73(1):62-69.
Using the Anti-TNF Agents in Psoriasis
Kristina Callis Duffin, MD, MS*
Address reprint requests to: Kristina Callis Duffin, MD, MS, University
of Utah, 30 North 1900 East 4A330, Salt Lake City, UT 84132;
kristina.duffin@hsc.utah.edu
Etanercept
Unlike the other two anti-TNF-α agents FDA-approved for psoriasis, etanercept is a fusion protein of the TNF receptor rather than
a monoclonal antibody.2,3,6 The recommended dosage is 50 mg twice
weekly for 3 months, followed by 50 mg once weekly thereafter.2
Advantages of etanercept include extensive experience
(FDA-approved 10 years ago for plaque psoriasis), consistent
efficacy across clinical studies (~50% of patients achieving
Psoriasis Area and Severity Index [PASI] 75),7-9 and long-term
safety.9 Nearly half (49%) of participants in a randomized,
placebo-controlled, double-blind, parallel-group, phase III clinical
trial achieved PASI 75 (ie, ≥75% improvement) with etanercept
50 mg twice weekly at week 12. This proportion rose to 59% after
24 weeks on this high dose.7 Response is dose dependent, with
higher efficacy at higher doses. Proportions achieving PASI 90
(≥90% improvement) with high-dose etanercept were 22% and
30% at weeks 12 and 24, respectively.7
Another phase III study of etanercept in plaque psoriasis
produced similar results: At week 12, 49% of patients randomized
to high-dose therapy (50 mg twice weekly) achieved PASI 75 and
21% achieved PASI 90.8 This study reduced the highest dose to
25 mg twice weekly after 12 weeks, yet 54% of those whose dose was
reduced from 50 to 25 mg twice weekly at week 12 achieved PASI 75
at week 24. As in the other phase III trial, response rates rose with
dose: 34% of those initiated at the lower dose (25 mg twice weekly)
achieved PASI 75 at week 12. A long-term extension of a phase
III randomized study (n=591) reported that at 96 weeks, 51.6% of
patients demonstrated PASI 75 and 23.2% attained PASI 90 with
etanercept 50 mg twice weekly.9
Etanercept has the lowest efficacy (measured as PASI 75 at 10
to 16 weeks) of all the anti-TNF agents approved by the FDA for
the treatment of psoriasis, with the caveat that this comparison
does not come from head-to-head studies.7,8,10-13 Anecdotally,
patients and clinicians often observe a reduction in efficacy when
patients decrease the dose from 50 mg twice weekly to weekly at
12 weeks, as recommended in the prescribing information.2 It is
FDA-approved for PsA and has demonstrated long-term safety,
with rates of exposure-adjusted adverse events (other than injection site reactions) and infections over 96 weeks similar to those
of placebo.9 It requires the most frequent injection schedule of
the three anti-TNF inhibitors that are FDA-approved for plaque
psoriasis.2,3,6 Only non-neutralizing antibodies have been observed,
which did not affect efficacy or safety.9 Etanercept syringes or
autoinjectors can be stored at room temperature for up to 14 days
prior to use, which offers convenience for patients who travel.2
Combining etanercept with other agents can increase its efficacy. Adding no more than two courses of clobetasol propionate
foam to etanercept for up to 2 weeks (at weeks 11 and 12, and
weeks 23 and 24) increases the proportion of patients achieving
PASI 75 at week 12 (65.2% with combination [n=295] vs 48.3%
with etanercept alone [n=297]; P<0.001), though not at week 24.14
Adding narrow-band ultraviolet light B therapy to etanercept
(single-arm study, 86 patients) led to 85% of patients achieving
PASI 75 and 58% reaching PASI 90 at 12 weeks.15 Combining
methotrexate (7.5-15 mg/wk; n=239) or placebo (n=239) with
doi:10.12788/j.sder.2015.0154
■ Abstract
The introduction of tumor necrosis factor (TNF) inhibitors
greatly improved the level of care available for patients with
psoriasis. The three anti-TNF medications that have received
approval by the US Food and Drug Administration (FDA) for
use in plaque psoriasis have many similarities and differences
in terms of efficacy, safety, dosage route and frequency,
and effectiveness in comorbid conditions. Familiarity with
their characteristics can inform the choice of therapy for
each patient.This article reviews the major clinical trials of each
agent as well as real-world evidence.
■ Keywords
Psoriasis, tumor necrosis factor inhibitors, efficacy, safety,
psoriatic arthritis
T
umor necrosis factor (TNF) is among the cytokines that
play key roles at multiple points in the pathophysiology of
psoriasis.1 It induces the release of interleukin (IL)-23 from
dendritic cells and contributes to the differentiation of T cells
into the production of IL-17, another important substance in the
psoriasis inflammatory cascade. TNF regulates tissue remodeling
and expression of genes for inflammatory responses. It appears
to act synergistically with IL-17 to induce changes in psoriasisrelated gene expression.1
Five TNF-α inhibitors are available in the United States.
Three of these agents are FDA-approved for both psoriasis
and psoriatic arthritis (PsA)—etanercept, adalimumab, and
infliximab—and two agents are FDA-approved for PsA but
not psoriasis—golimumab and certolizumab.2-6 Certolizumab is
now in phase III trials for use in psoriasis (http://dermira.com/
dermira-and-ucb-announce-start-of-phase-3-program-for-cimziacertolizumab-pegol-in-psoriasis/). The Table on page S66 summarizes some of the characteristics of and differences among the
agents that are currently approved for psoriasis.
*Assistant Professor, Dermatology, University of Utah, Salt Lake City, Utah.
Dr Duffin has received an honorarium for her participation in this activity.
She acknowledges the editorial assistance of Eileen McCaffrey, MA,
Kristina Callis Duffin, MD, MS, Grant/Research: AbbVie Inc., Amgen Inc.,
Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen
Biotech, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Stiefel
Laboratories, Inc., and XenoPort, Inc.; Consultant: AbbVie, Amgen,
Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and XenoPort;
Advisory Board: Eli Lilly and Janssen.
■ ❚ ❙ Using the Anti-TNF Agents in Psoriasis
Infliximab
This monoclonal antibody, delivered by intravenous infusion,
displays a rapid onset of action and the highest efficacy rates of
all three anti-TNF agents approved for the treatment of plaque
psoriasis. Again, this comparison is not based on head-to-head
trials but on proportions of patients achieving PASI 75 at 10 to
16 weeks in landmark trials.7,8,10-13 In two phase III studies, 80%
and 75.5% of patients randomized to infliximab at the recommended dose of 5 mg/kg reached PASI 75 at week 10; 57% and
45.2% reached PASI 90 at week 10.12,13 Infliximab requires an
induction period with infusions at 0, 2, and 6 weeks, followed by
infusions every 8 weeks.6
Efficacy in these studies for patients receiving 5 mg/kg every
8 weeks was sustained at week 24 or 26 (PASI 75 in 82% and 78%,
PASI 90 in 58% and 56%) but declined at week 50 (PASI 75 in 61%
and 54.5%, PASI 90 in 45% and 34.3%).12,13 Giving infliximab as
needed (ie, when PASI response drops below 75) led to a greater
reduction in efficacy.13 It is important for clinicians to explain to
patients the need to obtain the infusion on schedule even if their
skin is clear, as delaying a dose until symptoms recur can lead to
loss of efficacy. Increasing the dose to 7.5 or 10 mg/kg, or reducing
the dose interval (eg, to every 6 weeks) at the first sign of a diminution in efficacy, can forestall further reduction in effectiveness.17
Adding another immunosuppressive agent such as methotrexate
can also increase efficacy (documented in RA 18), decrease the
risk of anti-drug antibodies, and reduce the risk of infusion reactions,19 though it may also increase the risk of serious infections.6
Along with the loss of efficacy, the high risk of infusion reactions is one of the major drawbacks to treatment with infliximab.
Infusion reactions have been reported in 20% of clinical trial
participants, compared with 10% of those randomized to placebo.
Manifestations can range from flu-like symptoms to dyspnea or
anaphylaxis.6 Infusion reactions were two to three times more
common in patients who developed anti-drug antibodies, and
occurred more frequently in those who were re-treated following
a break in therapy.6 A serum sickness-like reaction that can occur
following therapy is also more common among patients who
develop anti-drug antibodies, and in those who stop and then
restart infliximab therapy.6 Anti-drug antibodies were detected in
19% of patients receiving infliximab for psoriasis through week 46
in one study.12 The prescribing information reports rates of 36%
and 51% in patients with psoriasis treated for 1 year.6
etanercept (50 mg twice weekly for 12 weeks followed by 50 mg
once weekly for 12 weeks) was associated with significantly higher
rates of achieving PASI 75 at week 24 (77.3% vs 60.3%; P<0.0001).
Methotrexate was associated with a higher incidence of elevated
hepatic transaminases classified as adverse events (2.9% with
methotrexate, 1.7% with placebo).16
Adalimumab
Two major clinical trials documented the efficacy of adalimumab in plaque psoriasis. Nearly three-quarters (71%) of the
814 patients randomized to adalimumab (40 mg every other
week) in the Randomized controlled EValuation of adalimumab
Every other week dosing in moderate to severe psoriasis TriAL
(REVEAL) attained PASI 75 at week 16,10 substantially more
than the roughly 50% reaching this threshold at week 12 with
etanercept in pivotal studies.7-9 Nearly half (45%) of patients
receiving adalimumab achieved PASI 90 at 16 weeks, and 20% of
patients reached PASI 100.10
In the Comparative Study of Humira vs Methotrexate vs
Placebo in Psoriasis Patients (CHAMPION; n=271), 79.6%
of adalimumab-treated patients achieved PASI 75 at week 16,
compared with 35.5% receiving methotrexate and 18.9% randomized to placebo (P<0.001, adalimumab vs either comparator).
Response with adalimumab was rapid (57% improvement
in mean PASI at week 4), possibly due to the loading dose
(80 mg initial dose).11 The study discontinuation rate was higher
with methotrexate than with adalimumab, primarily because of
hepatic-related adverse events. Methotrexate reduces adalimumab
clearance, though no dose adjustment of either agent is required.3
One of the primary disadvantages of using adalimumab is its
association with the formation of anti-drug antibodies and a
resultant loss of drug efficacy. In REVEAL, 8.8% of patients had
detectable anti-adalimumab antibodies (AAA) at least once over
a 1-year period. Nearly half (43%) of AAA-positive patients and
28% of AAA-negative patients lost an adequate response to the
drug.10 The prescribing information reports an immunogenicity
rate of 20.8% in the subset of patients with psoriasis in which
AAA could be measured. The rate of AAA formation in patients
with rheumatoid arthritis (RA) is lower when methotrexate is
added to adalimumab.3 Clinicians may wish to consider adding
methotrexate to adalimumab, especially in patients with severe
psoriasis and PsA who have failed other therapies.
■ TABLE Characteristics of TNF Inhibitors Approved for Use in Plaque Psoriasis
Etanercept
Adalimumab
Infliximab
Structure
Fusion protein of the
TNF receptor
Human monoclonal antibody
Chimeric monoclonal antibody
Half-life
5-6 days
10-20 days
8-10 days
Dose/frequency
Self-administered, 50 mg
subcutaneous injection,
2x/wk for 3 mo, then weekly
Self-administered, 40 mg;
80 mg on day 1, then 40 mg on
day 8, then every other week
IV infusion, 5 mg/kg;
weeks 0, 2, 6, then every
8 weeks
Efficacy*
49% at week 127,8 and 51.6% at
week 969 with 50 mg 2x/wk
71% and 79.6% at week 1610,11
80% and 75.5% at week 10,
61% and 54.5% at week 50
(5 mg/kg)12,13
PsA
FDA-approved
FDA-approved
FDA-approved
*% reaching PASI 75 at specified time points in phase III clinical trials referenced.
TNF Inhibitors in Children With Psoriasis
No anti-TNF inhibitors are FDA-approved for children with
psoriasis. However, the efficacy of etanercept in children and
adolescents (n=211, ages 4-17 years old) has been documented
in a rigorously conducted randomized controlled trial. A total of
57% of patients receiving etanercept achieved PASI 75 at week
12.20 Long-term follow-up demonstrated continued efficacy (PASI
75 in 61% at week 96) and safety (five serious adverse events,
none of which were treatment-related). 21 Most children and
adolescents regained efficacy after withdrawal and re-treatment;
80% of the 65 patients maintained or regained PASI 75 under
such circumstances.22
Use in Patients With Comorbid Conditions
Roughly 30% of patients with psoriasis also have PsA.23 All three
anti-TNF agents approved by the FDA for psoriasis are also
marketed for use in PsA. Efficacy (measured as a 20% improvement,
or ACR20) is similar for all three agents: 59%, 58%, and 58% for
etanercept, adalimumab, and infliximab at weeks 12, 12, and 14,
respectively.24-26
Obesity affects an estimated 13% to 34% of individuals with
chronic plaque psoriasis.27 Of the three TNF inhibitors approved
for psoriasis, only infliximab offers weight-based dosing.6 This
may be an advantage when treating patients who are obese.
Adalimumab and infliximab are FDA-approved for use in Crohn’s
disease and ulcerative colitis3,6; psoriasis has been associated with
both of these conditions.28
Real-World Evidence
A study including 713 patients from 10 outpatient clinics at a single
point in time reported somewhat lower efficacy with TNF inhibitors than the rates observed in clinical trials (Figure).29 Eligible
patients were those receiving phototherapy or commonly used
systemic therapies. The primary outcome was achieving a score
of clear or almost clear (0-1) on the Physician’s Global Assessment
(PGA) scale. Among the most commonly used treatments, rates
of reaching this threshold were 47.7% for adalimumab, 36.1% for
the non-TNF biologic agent ustekinumab, 34.2% for etanercept,
27.6% for narrow-band UV-B, and 23.8% for methotrexate.29
Other noteworthy findings from this study were that less than
5% of patients were treated with infliximab, and many patients
were treated with higher than recommended doses. Specifically,
30% of patients receiving etanercept were treated with 50 mg twice
weekly despite having passed the 12-week mark. Roughly 11.5%
of patients treated with adalimumab received the agent weekly
rather than every other week as recommended, or injected double
the recommended dose every other week.29
Safety
Considerations with all three TNF inhibitors approved by the
FDA for plaque psoriasis include risk of serious infections (eg,
tuberculosis, bacterial sepsis, invasive fungal infections), onset
or exacerbation of demyelinating diseases (eg, multiple sclerosis,
optic neuritis) or heart failure, risk of lymphoma or leukemia,
or a lupus-like syndrome.2,3,6 An ongoing observational study
(N=12,095) of patients receiving or eligible to receive biologic or
other systemic therapy for psoriasis has reported that exposure to
infliximab (hazard ratio [HR], 3.101, P<0.001) or other biologics
(HR, 1.954, P=0.005) predicted the risk of serious infections. Use
of biologics did not predict the risk of death, malignancy, or major
adverse cardiac events compared with nonbiologic therapy.30
Summary
TNF inhibitors have revolutionized the field of psoriasis management. These agents are now the cornerstone of therapy for psoriasis
and PsA. Their efficacy rates are high, they have been thoroughly
evaluated in controlled clinical studies, and they can be used in
combination with other medications to improve safety and efficacy.
Distinguishing factors among the three anti-TNF agents approved
by the FDA for use in psoriasis and PsA therapy include the following:
• When comparing the proportion of patients who achieve
PASI 75 at 10 to 16 weeks in clinical trials, etanercept offers
the lowest rate of efficacy (~50% at 12 weeks, compared with
71% and 80% at week 16 with adalimumab10,11 and 75.5% and
80% at week 10 with infliximab12,13).
• Infliximab is associated with the loss of efficacy over time.12,13
• Etanercept is not associated with neutralizing anti-drug
antibodies, unlike adalimumab and infliximab.3,6,9
• Etanercept’s efficacy in the pediatric population has been
evaluated in a randomized controlled trial.
• Etanercept requires the most frequent dosing.2,3,6
• Risk of infusion reaction is high with infliximab.6
• Infliximab offers weight-based dosing, which may be helpful
in patients who are obese.6
References
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90
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% of patients
80
70
60
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50
40
30
20
10
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severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol.
2008;58(1):106-115.
23.8%
47.7%
34.2%
36.1%
27.6%
Methotrexate
Adalimumab
Etanercept
Ustekinumab
NB-UVB
11.Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in
patients with psoriasis (CHAMPION). Br J Dermatol. 2008;158(3):558-566.
■ FIGURE The Real World: Cross-Sectional Data.
Primary end point: Clear/minimal on PGA at any time point.
Enrollment started February 2010.
12.Reich K, Nestle FO, Papp K, et al. Infliximab induction and maintenance therapy
for moderate-to-severe psoriasis: A phase III, multicentre, double-blind trial.
Lancet. 2005;366(9494):1367-1374.
0
Current treatment
NB-UVB=narrow-band UV-B; PGA=Physician’s Global Assessment.
Source: Used with permission. Gelfand JM, et al. Arch Dermatol. 2012;148(4):487-494.
13.Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment
of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2007;56(1):31.e1-e15.
■ ❚ ❙ Using the Anti-TNF Agents in Psoriasis
14.Lebwohl MG, Kircik L, Callis Duffin K, et al. A randomized study to evaluate
the efficacy and safety of adding topical therapy to etanercept in patients with
moderate to severe plaque psoriasis. J Am Acad Dermatol. 2013;69(3):385-392.
15.Kircik L, Bagel J, Korman N, et al. Utilization of narrow-band ultraviolet light B
therapy and etanercept for the treatment of psoriasis (UNITE): Efficacy, safety,
and patient-reported outcomes. J Drugs Dermatol. 2008;7(3):245-253.
16.Gottlieb AB, Langley RG, Strober BE, et al. A randomized, double-blind, placebocontrolled study to evaluate the addition of methotrexate to etanercept in patients
with moderate to severe plaque psoriasis. Br J Dermatol. 2012;167(3):649-657.
17. Kalb RE,Gurske J. Infliximab for the treatment of psoriasis: Clinical experience at the State University of New York at Buffalo. J Am Acad Dermatol.
2005;53(4):616-622.
18.Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple
intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody
combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis
Rheum. 1998;41(9):1552-1563.
19.Kapetanovic MC, Larsson L, Truedsson L, Sturfelt G, Saxne T, Geborek P.
Predictors of infusion reactions during infliximab treatment in patients with
arthritis. Arthritis Res Ther. 2006;8(4):R131.
20.Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and
adolescents with plaque psoriasis. N Engl J Med. 2008;358(3):241-251.
21.Paller AS, Siegfried EC, Eichenfield LF, et al. Long-term etanercept in pediatric
patients with plaque psoriasis. J Am Acad Dermatol. 2010;63(5):762-768.
22.Siegfried EC, Eichenfield LF, Paller AS, Pariser D, Creamer K, Kricorian G.
Intermittent etanercept therapy in pediatric patients with psoriasis. J Am Acad
Dermatol. 2010;63(5):769-774.
23.Gladman D, Antoni C, Mease P, Clegg D, Nash P. Psoriatic arthritis: Epidemiology,
clinical features, course, and outcome. Ann Rheum Dis. 2005;64(suppl 2):ii14-ii17.
24.Antoni C, Krueger GG, de Vlam K, et al. Infliximab improves signs and symptoms of psoriatic arthritis: Results of the IMPACT 2 trial. Ann Rheum Dis.
2005;64(8):1150-1157.
25.Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment
of patients with moderately to severely active psoriatic arthritis: Results
of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum.
2005;52(10):3279-3289.
26.Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic
arthritis: Safety, efficacy, and effect on disease progression. Arthritis Rheum.
2004;50(7):2264-2272.
27.Roongpisuthipong W, Pongpudpunth M, Roongpisuthipong C, Rajatanavin N.
The effect of weight loss in obese patients with chronic stable plaque-type psoriasis.
Dermatol Res Pract. 2013;2013:795932.
28.Cohen AD, Dreiher J, Birkenfeld S. Psoriasis associated with ulcerative colitis and
Crohn’s disease. J Eur Acad Dermatol Venereol. 2009;23(5):561-565.
29.Gelfand JM, Wan J, Callis Duffin K, et al. Comparative effectiveness of commonly
used systemic treatments or phototherapy for moderate to severe plaque psoriasis
in the clinical practice setting. Arch Dermatol. 2012;148(4):487-494.
30.Gottlieb AB, Kalb RE, Langley RG, et al. Safety observations in 12095 patients
with psoriasis enrolled in an international registry (PSOLAR): Experience
with infliximab and other systemic and biologic therapies. J Drugs Dermatol.
2014;13(12):1441-1448.
Impact of Psoriasis Therapy
on Comorbid Conditions
Kenneth B. Gordon, MD*
■ Abstract
Several conditions have been associated with psoriasis,
including chronic kidney disease, Crohn’s disease, depression,
and cardiovascular disease. Psoriasis also negatively impacts
patients’ economic health in terms of employment and work
productivity. Clinicians should be aware of these potential
comorbidities and consider them when monitoring patients
and choosing psoriasis therapy. Recent studies have evaluated
if treating psoriasis can alleviate these comorbidities.
■ Keywords
Psoriasis, chronic kidney disease, Crohn’s disease, depression,
cardiovascular disease, economic health, treatment
P
soriasis has been associated with an increased risk of a
variety of concomitant conditions (Table 1). The link
between psoriasis and at least some associated comorbidities
is thought to be T-cell and cytokine (eg, tumor necrosis factor
[TNF]) activation.1,2 Recent studies have evaluated if psoriasis
treatment—especially treatment directed at the underlying
inflammation—affects these comorbidities and if any improvement in comorbidities associated with psoriasis treatment is linked
to psoriasis treatment response (Table 2 on page S71).
Chronic Kidney Disease
A recently published claims data analysis (n=143,883 with psoriasis
and n=689,702 without psoriasis) reported an association between
severe psoriasis and an increased risk of incident chronic kidney
disease (CKD), independent of risk factors (eg, age, sex, hypertension, diabetes, cardiovascular disease [CVD], body mass index,
and use of nonsteroidal anti-inflammatory drugs [NSAIDs]).2
Specifically, individuals with severe psoriasis had nearly twice the
risk of incident CKD compared with controls, after risk factor
adjustment. Severe psoriasis was also associated with a four-fold
increased incident risk of end-stage renal disease (Table 1). Among
those with severe psoriasis, younger age was associated with a
higher relative risk of CKD.2 Further study is needed to evaluate
if psoriasis therapy can alleviate concomitant CKD.
Impact on Choice of Psoriasis Therapy and Patient Monitoring
Of all the conditions associated with psoriasis, CKD probably has
the greatest impact on the choice of psoriasis therapy. Patients
with psoriatic arthritis (PsA) are often prescribed NSAIDs, which
are associated with deterioration of kidney function3 as well as
acute renal failure.4 The dosage of apremilast must be reduced to
30 mg once daily (from twice daily) in patients with severe renal
impairment (creatinine clearance <30 mL/min).5
Methotrexate is eliminated primarily through the kidneys so that
excretion is reduced in patients with impaired renal function. As
reduced kidney function is common in older individuals, consider
using only low doses of methotrexate in these individuals, with
close monitoring for toxicity.6 Consider monitoring renal function
in older adults using creatinine clearance rather than serum creatinine as the latter may overestimate renal function in this population.
Cyclosporin A is associated with nephrotoxicity and should not be
prescribed for patients with impaired renal function.7
Crohn’s Disease
Psoriasis has been linked to a roughly four-fold increased risk
for developing Crohn’s disease (CD) in the Nurses’ Health Study
(Table 1). Risk of CD was even higher among women with psoriasis and PsA (relative risk [RR], 6.43, 95% confidence interval
[CI] 2.04-20.32).8 Psoriasis and CD share autoinflammatory
pathophysiology as well as genetic associations,9 which may explain
the comorbidity. Clinicians should ask patients with psoriasis
about gastrointestinal symptoms. Patients who report persistent
diarrhea should be evaluated for possible CD.
Impact on Choice of Psoriasis Therapy
Patients with both CD and psoriasis may benefit from therapy
with the anti-TNF agents adalimumab or infliximab; these
two agents are approved by the US Food and Drug Administration
(FDA) for both conditions.10,11 Ustekinumab, an interleukin
[IL]-23 and 12 antagonist that has received FDA approval for use
in plaque psoriasis, is under study as a therapy for CD.12,13
■ TABLE 1 Psoriasis and Risk of Comorbidities
Condition
Risk associated with psoriasis*
CKD
Adjusted HR 1.93; 95% CI 1.79–2.08†2
*Professor of Dermatology, Northwestern University Feinberg School
of Medicine, Chicago, Illinois.
ESRD
Adjusted HR 4.15; 95% CI 1.70–10.11†2
Crohn’s disease
Adjusted RR, 4.00; 95% CI 1.72–9.27 (NHS)
3.76; 95% CI 1.82–7.74 (NHS II)8
Depression
Adjusted HR 1.39; 95% CI 1.37–1.4116
MACE
Adjusted HR 1.53; 95% CI 1.26–1.85†24
CV death
Adjusted HR 1.57; 95% CI 1.26–1.96†26
Unemployment
Adjusted OR, 1.78; 95% CI 1.40–2.26
vs mild psoriasis†30
Dr Gordon has received an honorarium for his participation in this activity.
Kenneth B. Gordon, MD, Grant/Research: AbbVie Inc., Amgen Inc.,
Celgene Corporation, Eli Lilly and Company, Novartis Pharmaceuticals
Corporation, and Pfizer Inc.; Consultant: AbbVie, Amgen, Celgene, Eli
Lilly, Novartis, and Pfizer.
Address reprint requests to: Kenneth B. Gordon, MD, 925 Sutton Drive,
Northbrook, IL 60062; Gordon.kenneth@att.net.
doi:10.12788/j.sder.2015.0155
*Compared with controls without psoriasis unless otherwise noted; †Severe psoriasis;
CI=confidence interval; CKD=chronic kidney disease; CV=cardiovascular; ESRD=
end-stage renal disease; HR=hazard ratio; MACE=major adverse cardiovascular
events; NHS=Nurses’ Health Study (1996–2008); NHS II=Nurses’ Health Study II
(1991–2007); OR=odds ratio; RR=relative risk.
■ ❚ ❙ Impact of Psoriasis Therapy on Comorbid Conditions
Secukinumab, an IL-17A antagonist approved by the FDA for
use in plaque psoriasis and PsA, has exacerbated CD in studies
evaluating active CD.14 A proof-of-concept study evaluating
secukinumab as a treatment for CD (n=59) reported superior results
with placebo, along with an increased rate of serious adverse events
(14 events in 10 patients [7 receiving secukinumab, 3 randomized
to placebo]).15 Consider avoiding use of this secukinumab in
patients with active CD.
Depression
Risk of depression, anxiety, and suicidality is 39%, 31%, and
44% higher, respectively, in people with psoriasis (n=146,042
with mild psoriasis, n=3,956 with severe psoriasis) compared
with controls (n=766,950), according to an analysis of electronic
medical records from the UK-based General Practice Research
Database (GPRD). Severe psoriasis was associated with a higher
risk of depression than mild psoriasis (72% and 38%, respectively;
hazard ratio [HR] 1.72, 95% CI 1.57-1.88; and HR 1.38, 95% CI
1.35-1.40, respectively). Risk of depression was higher in younger
patients than in older patients with mild psoriasis.16
A case-control study using information from an outpatient database in Germany reported similar findings (3,147 with psoriasis
matched to 3,147 without psoriasis). The adjusted risk of depression associated with psoriasis was 49% higher with psoriasis (odds
ratio [OR] 1.49; 95% CI 1.20-1.86).17
Effect of Psoriasis Therapy on Depression
Evidence suggests that treating psoriasis does alleviate symptoms of depression. Patients randomized to receive etanercept for
moderate to severe psoriasis (n=311) were more likely than those
receiving placebo (n=306) to show at least a 50% improvement
in depression symptoms (Hamilton Rating Scale for Depression
[HAM-D] or the Beck Depression Inventory [BDI]) in one study.
Roughly one-third of the participants had mild or moderate to
severe depression at baseline, based on BDI scores.18
Ustekinumab (45 or 90 mg) therapy has also been associated with improvements in depression and anxiety symptoms
compared with placebo (n=1,230 with moderate to severe psoriasis).19 Specifically, depression and anxiety scores improved by
29.3% and 13.9% (Hospital Anxiety and Depression Scale–
Depression [HADS-D] and Hospital Anxiety and Depression
Scale–Anxiety [HADS-A], respectively) at 12 weeks in patients
randomized to treatment with ustekinumab compared with those
receiving placebo (P<0.001). Improvement in Psoriasis Area and
Severity Index (PASI) scores at week 12 was significantly though
modestly correlated with easing of depression and anxiety
symptoms (r=0.32 and r=0.24, respectively; P<0.0001 for each
correlation).19 The proportion of patients with mild to severe
anxiety or depression symptoms fell from baseline to week 12
by 34% and 55%, respectively, in the ustekinumab groups, but
increased by 1.4% and 10.2%, respectively, in those randomized
to placebo (P<0.001 vs placebo for each value).
These changes occurred in a population in which about onefourth (26.7%) of participants displayed depression and two-fifths
(40.3%) showed anxiety symptoms at baseline (HADS-D or
HADS-A scores ≥8), with roughly one-tenth (11%) and one-fifth
(20%) meeting the criteria for moderate to severe depression or
anxiety (HADS-D or HADS-A scores ≥11). Impact of disease on
quality of life was high at baseline, with 54.6% of study participants reporting Dermatology Life Quality Index [DLQI] scores
>10. Those assigned to ustekinumab saw DLQI scores improve by
76.2% at week 12 compared with placebo (P<0.001).19
Another investigation found that improvement in depression
symptoms (measured by the Zung Self-rating Depression Scale
[ZDS]) among patients with moderate to severe psoriasis (n=96)
randomized to receive adalimumab was significantly correlated with
improvement in PASI (r=0.5; P<0.0001) and in the DLQI (r=0.5;
P<0.0001). Depression symptoms were significantly more likely
to improve in adalimumab responders (≥PASI 75 at week 12 or
termination of therapy) than in nonresponders (Table 2). Baseline
levels of depression were similar for both adalimumab and placebo
groups as measured by mean ZDS scores, proportions with ZDS
score ≥50, and proportion reporting a history of depression.20
Nonbiological therapy also has been associated with improvement in depression and anxiety. The proportions of patients with
definite depression or anxiety (measured on the HADS-D and
HADS-A, respectively) decreased significantly from pre- to posttreatment with 1 month of the modified Goeckerman regimen
(diluted topical tar treatment followed by phototherapy; n=48).21
Specifically, rates of definite depression fell from 20% to 3%, and
rates of definite anxiety decreased from 24% to 5%.21
Cardiovascular Disease
Similar to psoriasis, atherosclerosis, CVD, and myocardial
infarction (MI) have been linked to immunological abnormalities and markers of system inflammation.22 Psoriasis has been
associated with an increased risk of MI,23 major adverse cardiovascular events (MACE),24,25 and CV mortality26 in analyses of
data from the UK GPRD.
The risk of MI in patients with psoriasis was higher among
younger patients and those with severe psoriasis compared with
older patients and those with less severe psoriasis.23 Adjusted RR of
MI was 1.08 (95% CI 1.03-1.13) for a 60-year-old with mild psoriasis, 1.29 (95% CI 1.14-1.46) for a 30-year-old with mild psoriasis,
1.36 (95% CI 1.13-1.64) for a 60-year-old with severe psoriasis, and
3.10 (95% CI 1.98-4.86) for a 30-year-old with severe psoriasis.
After adjustment for CV risk factors, severe psoriasis was
associated with a 53% increased risk for MACE (Table 1) as
well as a 6.2% attributable risk of MACE over 10 years. 24 It
has also been linked to an increased risk of CV death (Table
1); the risk was higher among younger patients, with a nearly
2.7-fold increased risk for a 40-year-old with severe psoriasis and
a 1.9-fold increased risk for a 60-year-old with severe psoriasis
(RR 2.69; 95% CI 1.45-4.99, and RR 1.92; 95% CI 1.41-2.62,
respectively).26
A meta-analysis confirmed these findings, reporting a 39%
increased risk of CV death and a 70% increased risk of MI
with severe psoriasis, and a 29% increased risk of MI with mild
psoriasis (RR 1.39; 95% CI 1.11-1.74; RR 1.70; 95% CI 1.322.18; RR 1.29; 95% CI 1.02-1.63). These investigators attributed
1,269 excess CV deaths and 6,479 excess MIs per year in the
United States to psoriasis.25
Effect of Psoriasis Therapy on Risk of Cardiovascular Disease
Data indicate that methotrexate reduces CV risk, and that antiTNF therapy leads to a greater degree of risk reduction than
methotrexate.27,28 A meta-analysis reported that methotrexate
therapy was associated with a 21% lower risk of CVD (n=10
studies, 95% CI 0.73-0.87, P<0.001), and an 18% lower risk of MI
(n=5, 95% CI 0.71-0.96, P=0.01). Most studies (9 of 10) included
evaluated patients treated for rheumatoid arthritis, with one study
focused on psoriasis and one study focused on polyarthritis.27
Analysis of a US claims database (2000-2011) focused on individuals with psoriasis and compared CVD risk in those prescribed
either methotrexate (n=8,581) or a TNF inhibitor (n=9,148). At
12 months, use of an anti-TNF agent rather than methotrexate was
associated with significantly lower incidence of a major CV event
(1.87% vs 5.52%; P<0.01). Each incremental 6 months of cumulative TNF inhibitor exposure was associated with a 12% reduction in
risk of a major CV event over a median of 23 months.28
Still unanswered is the question of whether the difference in CV
risk reduction results from anti-TNF agents reducing inflammation more effectively or of some other effect of the medications.
Economic Health
Multiple studies of data from National Psoriasis Foundation
surveys indicate that psoriasis, especially severe disease, negatively affects income and ability to work. Among individuals
working full time, the probability of low income (<$30,000)
was significantly higher among individuals with severe psoriasis
compared with mild psoriasis (21% vs 13%, P=0.0002) based on
2003-2005 survey data (n=601). Compared to individuals with
mild disease, those with severe psoriasis were less likely to work
full time (56.1% vs 62.0%; P=NS) and more likely to cite their
disease as the reason for not working (17% vs 6%; P=0.01).29
A subsequent analysis (2003-2011; n=5,604) reported that
12% of patients with psoriasis were unemployed, and 92% of
those cited psoriasis alone or along with PsA as the sole reason
for not working. Less than half (48%) worked full time, 11%
worked part time, and 22% were retired. As in the earlier study,
psoriasis severity was linked to unemployment. Individuals with
severe psoriasis were nearly twice as likely to be unemployed as
those with mild disease, after adjustment for age and sex (Table 2).
Disease-related absenteeism is common among individuals with
psoriasis. Nearly half (49%) of the employed individuals reported
regularly missing work due to psoriasis.30
Impact of Psoriasis Therapy on Work Productivity
Does psoriasis therapy improve income, ability to work, or work
productivity? A study of 246 patients receiving etanercept for
moderate to severe psoriasis reported significant reductions in
degree of work impairment as measured by the Work Productivity
and Activity Impairment questionnaire. Over the first 3 months of
treatment, mean degree of impairment while working decreased
from 22.7% to 6.6% (P<0.0001). Mean activity impairment
outside of work also decreased from 31.4% to 12.9% (P<0.0001).
These improvements were sustained at 12 months.31
Adalimumab therapy has also been associated with improved work
productivity and reduced total activity impairment when compared
with placebo, according to an analysis of data from the Randomized
controlled EValuation of adalimumab Every other week dosing
in moderate to severe psoriasis TriAL (REVEAL).32 Only adalimumab responders (ie, ≥PASI 75 at week 16) demonstrated significant
improvement compared with baseline in total work productivity
impairment, total activity impairment, absenteeism, and presenteeism (ie, present but less effective at work).32
■ TABLE 2 Unemployment and Psoriasis Severity
Mild psoriasis
Moderate psoriasis
Severe psoriasis
Unadjusted
Odds Ratio
95% Confidence
Interval
1
–
0.99
0.77–1.26
1.75
1.38–2.21
Adjusted
Odds Ratio
95% Confidence
Interval
1
–
Moderate psoriasis
0.99
0.77–1.28
Severe psoriasis
1.78
1.40–2.26
Age
1.03
1.02–1.04
Sex
Male
Female
1
2.33
–
1.93–2.83
Mild psoriasis
Source: Armstrong AW, et al. PLoS One. 2012;7(12):e52935.
Summary
Patients with psoriasis, especially severe disease, face a higher
risk of developing renal, gastrointestinal, CV, and psychiatric
comorbidities as well as a higher likelihood of unemployment
and low income.2,8,16,24,26,30 Therapy for psoriasis has been linked
to improvements in depression, CV risk, and work productivity.20,27,28,31,32 Clinicians managing patients with psoriasis should
screen and monitor patients for these concomitant conditions and
consider them in their choice of therapy.
References
1. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet.
2007;370(9583):263-271.
2. Wan J, Wang S, Haynes K, Denburg MR, Shin DB, Gelfand JM. Risk of moderate
to advanced kidney disease in patients with psoriasis: Population based cohort study.
BMJ. 2013;347:f5961.
3. Gooch K, Culleton BF, Manns BJ, et al. NSAID use and progression of chronic
kidney disease. Am J Med. 2007;120(3):280.e1-7.
4. Huerta C, Castellsague J, Varas-Lorenzo C, Garcia Rodriguez LA. Nonsteroidal
antiinflammatory drugs and risk of ARF in the general population. Am J Kidney
Dis. 2005;45(3):531-539.
5. Otezla [package insert]. Summit, NJ: Celgene Corp; revised December 2014.
6. Methotrexate tablets [package insert]. Fort Lee, NJ: Dava Pharmaceuticals; revised
September 2010.
7. Neoral [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015.
8. Li WQ, Han JL, Chan AT, Qureshi AA. Psoriasis, psoriatic arthritis and increased
risk of incident Crohn’s disease in US women. Ann Rheum Dis. 2013;72(7):1200-1205.
9. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more
than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955-962.
10.Humira [package insert]. North Chicago IL: AbbVie Inc; revised December 2014.
11.Remicade [package insert]. Horsham, PA: Janssen Biotech Inc; revised January 2015.
12.Tuskey A, Behm BW. Profile of ustekinumab and its potential in patients with
moderate-to-severe Crohn’s disease. Clin Exp Gastroenterol. 2014;7:173-179.
13.Sandborn WJ, Gasink C, Gao L-L, et al. Ustekinumab induction and maintenance
therapy in refractory Crohn’s disease. N Engl J Med. 2012;367(16):1519-1528.
14.Cosentyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp;
January 2015.
15. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: Unexpected results of a
randomised, double-blind placebo-controlled trial. Gut. 2012;61(12):1693-1700.
16. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety
and suicidality in patients with psoriasis: A population-based cohort study. Arch
Dermatol. 2010;146(8):891-895.
17. Schmitt J, Ford DE. Psoriasis is independently associated with psychiatric morbidity
and adverse cardiovascular risk factors, but not with cardiovascular events in a population-based sample. J Eur Acad Dermatol Venereol. 2010;24(8):885-892.
18. Tyring S, Gottlieb A, Papp K, et al. Etanercept and clinical outcomes, fatigue, and
depression in psoriasis: double-blind placebo-controlled randomised phase III trial.
Lancet. 2006;367(9504):29-35.
19. Langley RG, Feldman SR, Han C, et al. Ustekinumab significantly improves
symptoms of anxiety, depression, and skin-related quality of life in patients with
moderate-to-severe psoriasis: Results from a randomized, double-blind, placebocontrolled phase III trial. J Am Acad Dermatol. 2010;63(3):457-465.
20. Menter A, Augustin M, Signorovitch J, et al. The effect of adalimumab on reducing
depression symptoms in patients with moderate to severe psoriasis: A randomized
clinical trial. J Am Acad Dermatol. 2010;62(5):812-818.
21. Chern E, Yau D, Ho JC, et al. Positive effect of modified Goeckerman regimen on
quality of life and psychosocial distress in moderate and severe psoriasis. Acta Derm
Venereol. 2011;91(4):447-451.
22. Kolliker Frers RA, Bisoendial RJ, Montoya SF, et al. Psoriasis and cardiovascular
risk: Immune-mediated crosstalk between metabolic, vascular and autoimmune
inflammation. IJC Metab Endocr. 2015;6:43-54.
23. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of
myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-1741.
24. Mehta NN, Yu Y, Pinnelas R, et al. Attributable risk estimate of severe psoriasis on
major cardiovascular events. Am J Med. 2011;124(8):775.e1-6.
25. Armstrong EJ, Harskamp CT, Armstrong AW. Psoriasis and major adverse cardiovascular events: A systematic review and meta-analysis of observational studies. J
Am Heart Assoc. 2013;2(2):e000062.
26. Mehta NN, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Patients
with severe psoriasis are at increased risk of cardiovascular mortality: Cohort study
using the General Practice Research Database. Eur Heart J. 2010;31(8):1000-1006.
27. Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and metaanalysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol.
2011;108(9):1362-1370.
28. Wu JJ, Poon KT, Channual JC, Shen A. Association between tumor necrosis factor
inhibitor therapy and myocardial infarction risk in patients with psoriasis. Arch
Dermatol. 2012;148(11):1244-1250.
29. Horn EJ, Fox KM, Patel V, Chiou CF, Dann F, Lebwohl M. Association of patientreported psoriasis severity with income and employment. J Am Acad Dermatol.
2007;57(6):963-971.
30. Armstrong AW, Schupp C, Wu J, Bebo B. Quality of life and work productivity
impairment among psoriasis patients: Findings from the National Psoriasis
Foundation survey data 2003-2011. PLoS One. 2012;7(12):e52935.
31. Vender R, Lynde C, Ho V, Chau D, Poulin-Costello M. Work productivity and
healthcare resource utilization outcomes for patients on etanercept for moderateto-severe plaque psoriasis: Results from a 1-year, multicentre, open-label, single-arm
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32. Kimball AB, Yu AP, Signorovitch J, et al. The effects of adalimumab treatment
and psoriasis severity on self-reported work productivity and activity impairment for patients with moderate to severe psoriasis. J Am Acad Dermatol.
2012;66(2):e67-e76.
What’s New in Acne
Linda F. Stein Gold, MD*
■ Abstract
Recent studies about the treatment of acne address
antibiotic dosing, maintenance therapy, topical antibiotics
and benzoyl peroxide in facial and trunkal acne, the link
between antibiotics and risk of inflammatory bowel disease,
and the role of diet in acne.
■ Keywords
Acne, antibiotic dosing, minocycline, doxycycline, benzoyl
peroxide, isotretinoin, diet, lauric acid, probiotics
S
ystemic and topical antibiotics form the cornerstone of acne
therapy. Studies have examined if increasing the dose of oral
antibiotics improves efficacy. Minocycline (extended release)
has demonstrated similar efficacy compared with placebo at daily
doses of 1, 2, and 3 mg/kg in patients with moderate to severe
facial acne treated for 12 weeks (n=233, a randomized, doubleblind study). Each dose reduced the number of inflammatory acne
lesions by roughly 50% from baseline. However, higher doses were
associated with increased incidence of side effects (acute vestibular and central nervous system adverse events).1
In contrast, higher doses of doxycycline calcium do lead to
improved efficacy. A randomized, double-blind phase II study
evaluating 3 doses (0.6, 1.2, and 2.4 mg/kg daily, or placebo for
12 weeks in patients with moderate to severe inflammatory acne)
found that only the highest dose yielded results superior to those
of placebo. Efficacy was measured as change in inflammatory
lesion count and Investigator’s Global Assessment (IGA) score.
Incidence of gastrointestinal adverse events also rose with dose.2
Maintenance Therapy
Once acne is under control, can treatment be stopped or stepped
down? Two studies found that topical therapy was sufficient to
maintain efficacy achieved with systemic antibiotic plus topical treatment. Patients with severe acne were randomized to an induction
regimen of doxycycline plus either vehicle or adapalene 0.1% –
benzoyl peroxide 2.5% for 12 weeks. Those who achieved at least
50% global improvement then received maintenance therapy with
either the topical regimen or vehicle for 24 weeks. Starting with
systemic plus topical therapy and continuing with topical maintenance therapy yielded the best results: 50.0% of participants
assigned to these regimens were rated “clear” or “almost clear”
and total lesion count fell by 76% at week 36. Comparable figures
for those started with combination therapy but maintained on
vehicle were 26.2% and 51%, respectively. Initiating therapy with
both topical and systemic treatment led to faster onset of action
compared with systemic therapy alone (P<0.05 at week 2).3
A similar study with oral minocycline (100 mg twice daily) and
topical tazarotene (0.1%) as induction therapy found that maintenance results were similar with systemic therapy only, topical
therapy only, or both treatments.4 Patients with moderately severe
to severe acne who achieved at least 75% global improvement after
a 12-week initiation phase were randomized (n=90) to continue
both therapies or to continue one of the treatments plus a placebo
for another 12 weeks. More than 80% of patients in each group
maintained at least a 50% global improvement from baseline, and
more than half retained at least a 75% global improvement at the
end of the maintenance phase. Topical tazarotene was sufficient to
maintain the benefit induced with systemic plus topical treatment.4
Topical Antibiotic Therapy
Benzoyl Peroxide
Address reprint requests to: Linda F. Stein Gold, MD, 2360 Heronwood
Drive, Bloomfield Hills, MI 48302; lstein1@hfhs.org.
Benzoyl peroxide cleanser (6%) applied to the face once
daily for 3 weeks reduced counts of antibiotic-resistant facial
Propionibacterium acnes. Participants (n=30) were acne free but
had high counts of organisms resistant to erythromycin (30/30),
clindamycin (25/25), tetracycline (29/30), doxycycline (25/30), and/
or minocycline (19/30). Total P. acnes counts and counts of each
resistant strain decreased by at least 2log after 3 weeks of treatment.5
Benzoyl peroxide efficacy for acne on the back varied with
formulation. Two weeks of once-daily therapy with a topical
emollient “leave-on” foam benzoyl peroxide (5.3%) significantly
reduced counts of P. acnes on the back (n=20 adults). P. acnes
colonies were reduced by 1.9log at week 1 and by 2.1log at week 2.
In contrast, 2 weeks of therapy with a benzoyl peroxide wash (8%)
had little or no effect on P. acnes counts.6
Another study evaluated a higher-concentration (9.8%) benzoyl
peroxide emollient foam to be left on the back for 2 minutes. It
was compared with a 5.3% emollient foam (used once daily for
2 weeks). Efficacy as measured by reduction of P. acnes organisms
on the back was similar with the two products.7 Patients with acne
on the trunk of the body therefore appear to benefit from a “leaveon” or short-contact product rather than a wash. Patients should
be informed that benzoyl peroxide typically bleaches towels and
other fabrics, so that white towels may be a good choice while
using these treatments.
doi:10.12788/j.sder.2015.0156
*Director of Dermatology Research, Henry Ford Health System,
Detroit, Michigan.
Dr Stein Gold has received an honorarium for her participation in this
activity. She acknowledges the editorial assistance of Eileen McCaffrey, MA,
Linda F. Stein Gold, MD, Consultant: Allergan, Inc., Anacor
Pharmaceuticals, Inc., Celgene Corporation, Eli Lilly and Company,
Galderma Laboratories, L.P., LEO Pharma Inc., Novartis
Pharmaceuticals Corporation, and Valeant Pharmaceuticals North
America LLC; Speakers Bureau: Celgene, Galderma, LEO Pharma,
Novartis, Taro, and Valeant; Advisory Board: Allergan, Anacor
Pharmaceuticals, Celgene, Eli Lilly, Galderma, LEO Pharma, Novartis,
Promius Pharma, LLC, and Valeant; Medical Legal Advisor: HoffmannLa Roche Inc.
■ TABLE Risk of IBD Associated With Tetracycline Class Antibiotics8
Hazard Ratios (95% Confidence Interval)
IBD
UC
CD
Doxycycline
1.63 (1.05–2.52)
1.06 (0.53–2.13)
2.25 (1.27–4.00)
Minocycline
1.19 (0.79–1.79)
1.10 (0.76–1.82)
1.28 (0.72–2.30)
Tetracycline/oxytetracycline
1.43 (1.02–2.02)
1.27 (0.78–2.07)
1.61 (0.995–2.63)
CD=Crohn’s disease; IBD=inflammatory bowel disease; UC=ulcerative colitis.
Acne Medication and Inflammatory Bowel Disease:
Antibiotics?
A retrospective cohort study using a UK database (n=94,487 with
acne) found that tetracycline antibiotics, especially doxycycline, may
be associated with an increased risk of inflammatory bowel disease
(IBD) and especially of Crohn’s disease (CD) (Table). Individuals
exposed to a tetracycline class antibiotic had a 39% increased risk
of developing IBD (hazard ratio [HR] 1.39; 95% CI 1.02-1.90).8
Analysis of data from the University of Manitoba IBD
Epidemiologic Database (2001-2008; n=2,234 with IBD and
22,346 controls) and the Manitoba Drug Program Information
Network also reported an association of IBD with a history of
receiving at least three courses of oral antibiotics. A total of 12%
of those with IBD received at least three antibiotic prescriptions
2 years before their first IBD diagnosis date, compared with 7%
of controls.9
Diet and Acne
Acne is ubiquitous in Western societies but absent in at least two
non-Westernized populations (Kitavan people on the Trobriand
Islands near Papua New Guinea and the Aché hunter-gatherers
of Paraguay). Genetic influences may contribute to this finding.
However, diet may also be a factor. The Kitavan people, in
particular, consume a diet with a low glycemic index, consisting
of tubers, fruit, fish, and coconut.10 Foods with a high glycemic
index, such as those commonly consumed in a Western diet,
lead to increased levels of insulin in the blood. Insulin and
insulin growth factor 1 (IGF-1) stimulate androgen synthesis.
Androgens, in turn, stimulate the production of sebum, required
for acne development.10
Compared with a high-glycemic-load diet, eating low-glycemicload foods for 12 weeks reduced lesion count and free androgen
index in 43 males with acne. Patients eating the low-glycemic-load
diet also lost weight, a confounding factor.11
Milk consumption has been associated with acne. A prospective
cohort study of boys (mean age, 11.75 years at baseline; n=4,273)
found that higher consumption of skim milk (>2 servings/day)
was associated with higher prevalence of acne (multivariate prevalence ratio, 1.19, 95% CI 1.01-1.40; P=0.02 for trend).12 Milk may
affect acne formation, as it contains androgens. Additionally, milk
consumption has been associated with higher levels of IGF-1,
which stimulates androgen synthesis.10,12 Whey protein supplementation (eg, used to gain weight and/or build muscle) has also
been temporally associated with acne development in case reports.
Acne did not respond to oral antibiotics, topical retinoids, and
benzoyl peroxide but resolved in four of five patients upon discontinuation of whey protein supplementation.13
Coconut Oil, Probiotics
Lauric acid, a main ingredient in coconut oil, has demonstrated
greater antimicrobial effectiveness against P. acnes than benzoyl
peroxide. The minimal inhibitory concentration for lauric acid
against P. acnes in vitro was 15 times lower than that of benzoyl
peroxide. Lauric acid also reduced inflammation without cytotoxicity to sebocytes in an animal model, and retained its killing
effectiveness in this model when delivered intradermally and
epicutaneously.14 Lauric acid is poorly soluble in water but
retained its anti-P. acnes effectiveness when incorporated into a
liposome formulation in an experimental study.15
Bowe and Logan have reviewed small studies in non-English
language journals of oral probiotic supplements in acne.
Adding 250 mg of freeze-dried Lactobacillus acidophilus and
Bifidobacterium bifidum to standard care improved clinical
outcomes compared with standard care only. Probiotics were
also associated with better tolerance and adherence to antibiotic therapy. Another study reported shortened time to clinical
improvement after adding probiotics. A third publication indicated that consuming a Lactobacillus-fermented dairy beverage
was associated with significantly reduced total lesion counts and
reduced sebum production.16
New Topical Antibiotic
A topical clindamycin phosphate 1.2% and benzoyl peroxide
3.75% (clindamycin-BP 3.75%) aqueous gel received approval by
the US Food and Drug Administration (FDA) for acne in patients
ages 12 years and older as of November 2014.17 Compared with
vehicle, clindamycin-BP 3.75% reduced inflammatory and noninflammatory lesions as well as acne severity at 12 weeks in a
double-blind controlled study (n=498). The agent was well tolerated, with no withdrawals due to adverse events.18
Summary
Antibiotics, both topical and systemic, remain the key to acne
therapy. Oral doxycycline is characterized by a dose-response
curve, while oral minocycline effectiveness does not increase with
dose.1,2 Once systemic plus topical therapy has led to at least a
50% global improvement in acne, topical therapy is sufficient to
maintain efficacy.3,4 Benzoyl peroxide topical wash is effective on
the face but not on the back; a leave-on, short-contact preparation is superior for trunkal acne.5-7 Systemic antibiotic therapy
should be used for the shortest possible time, as antibiotic use has
been associated with an increased risk for IBD.8,9 Consumption of
skim milk and whey protein supplements has been associated with
acne in an observational study and case reports, respectively.12,13 A
small study has reported a link between a low-glycemic-load diet
and improvement in acne lesion count, though weight loss may
confound results.11 Clindamycin-BP 3.75% gel, which received
FDA approval for use in acne as of November 2014, offers another
option for treatment.17
■ ❚ ❙ What’s New in Acne
References
1. Stewart DM, Torok HM, Weiss JS, Plott RT. Dose-ranging efficacy of new oncedaily extended-release minocycline for acne vulgaris. Cutis. 2006;78(4 suppl):11-20.
2. Leyden JJ, Bruce S, Lee CS, et al. A randomized, phase 2, dose-ranging study in
the treatment of moderate to severe inflammatory facial acne vulgaris with doxycycline calcium. J Drugs Dermatol. 2013;12(6):658-663.
3. Tan J, Stein Gold L, Schlessinger J, et al. Short-term combination therapy and
long-term relapse prevention in the treatment of severe acne vulgaris. J Drugs
Dermatol. 2012;11(2):174-180.
4. Leyden J, Thiboutot DM, Shalita AR, et al. Comparison of tazarotene and
minocycline maintenance therapies in acne vulgaris: A multicenter, double-blind,
randomized, parallel-group study. Arch Dermatol. 2006;142(5):605-612.
5. Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium
acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis. 2008;82(6):417-421.
6. Leyden JJ. Efficacy of benzoyl peroxide (5.3%) emollient foam and benzoyl
peroxide (8%) wash in reducing Propionibacterium acnes on the back. J Drugs
Dermatol. 2010;9(6):622-625.
7. Leyden JJ, Del Rosso JQ. The effect of benzoyl peroxide 9.8% emollient foam on
reduction of Propionibacterium acnes on the back using a short contact therapy
approach. J Drugs Dermatol. 2012;11(7):830-833.
8. Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association between the
oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel
disease. Am J Gastroenterol. 2010;105(12):2610-2616.
9. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics
and new diagnoses of Crohn’s disease and ulcerative colitis. Am J Gastroenterol.
2011;106(12):2133-2142.
10.Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne
vulgaris: A disease of Western civilization. Arch Dermatol. 2002;138(12):1584-1590.
11.Smith RN, Mann NJ, Braue A, Makelainen H, Varigos GA. The effect of a highprotein, low glycemic-load diet versus a conventional, high glycemic-load diet on
biochemical parameters associated with acne vulgaris: A randomized, investigatormasked, controlled trial. J Am Acad Dermatol. 2007;57(2):247-256.
12.Adebamowo CA, Spiegelman D, Berkey CS, et al. Milk consumption and acne in
teenaged boys. J Am Acad Dermatol. 2008;58(5):787-793.
13.Silverberg NB. Whey protein precipitating moderate to severe acne flares in 5 teenaged athletes. Cutis. 2012;90(2):70-72.
14.Nakatsuji T, Kao MC, Fang JY, et al. Antimicrobial property of lauric acid against
Propionibacterium acnes: Its therapeutic potential for inflammatory acne vulgaris.
J Invest Dermatol. 2009;129(10):2480-2488.
15.Yang D, Pornpattananangkul D, Nakatsuji T, et al. The antimicrobial activity
of liposomal lauric acids against Propionibacterium acnes. Biomaterials.
2009;30(30):6035-6040.
16.Bowe WP, Logan AC. Acne vulgaris, probiotics and the gut-brain-skin axis – Back
to the future? Gut Pathog. 2011;3:1.
17.Valeant Pharmaceuticals announces FDA approval of ONEXTON™ Gel for the
treatment of acne vulgaris [press release]. http://ir.valeant.com/investor-relations/
news-releases/news-release-details/2014/Valeant-Pharmaceuticals-AnnouncesFDA-Approval-Of-ONEXTON-Gel-For-The-Treatment-Of-Acne-Vulgaris/
default.aspx. Accessed May 4, 2015.
18.Pariser DM, Rich P, Cook-Bolden FE, Korotzer A. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 3.75% for the
once-daily treatment of moderate to severe acne vulgaris. J Drugs Dermatol.
2014;13(9):1083-1089.
Rosacea: Pathogenesis and Therapy
Jerry K. L. Tan, MD, FRCPC*
■ Abstract
Recent studies have illuminated the pathophysiology of
rosacea. Evidence supports the hypothesis that rosacea
is caused by dysregulation of the innate immune system,
resulting in vasoactive and neuroinflammatory consequences.
New treatments have been approved by the US Food and
Drug Administration (FDA) in recent years, and studies have
further documented the benefit of other therapies.
■ Keywords
Rosacea, inflammation, innate immunity, cathelicidins,
brimonidine, ivermectin
R
osacea is diagnosed based on the presence of one or more
primary features: transient erythema (flushing), nontransient erythema (most common sign of rosacea), papules
and pustules, and/or telangiectasia (small blood vessel lines).
Patients may also display one or more secondary features: burning
or stinging, plaque, dry appearance, edema, ocular manifestations, phymatous changes, and peripheral (ie, nonfacial) location
of manifestations.1 Rosacea is divided into three cutaneous and
one ocular subtype, plus one variant (granulomatous: characterized by hard, brown, yellow, or red cutaneous papules or nodules
of uniform size, generally less inflammatory than papules and
pustules). Some evidence suggests that rosacea may evolve from
one subtype to another; patients may also progress from mild to
severe disease.1
Reported figures for incidence and prevalence vary, with the
highest prevalence rates in people of northern European or Celtic
ancestry (2.7%-10%).2 Rosacea is more common among women
than men, and in individuals with fair skin. Incidence peaks between
the ages of 30 and 50 years old.3 An estimated 16 million Americans
have rosacea, according to the National Rosacea Society.4
*Adjunct Professor, Department of Medicine, University of Western
Ontario, London, Ontario, Canada.
Dr Tan has received an honorarium for his participation in this activity.
Jerry K.L. Tan, MD, FRCPC, Grant/Research: Allergan, Inc., Bayer,
Cipher Pharmaceuticals Inc, Dermira, Galderma Laboratories, L.P.,
and Valeant Pharmaceuticals North America LLC; Consultant: Cipher
Pharmaceuticals, Galderma, GlaxoSmithKline Pharmaceutical Company,
Hoffmann-La Roche, Stiefel Laboratories, Inc., and Valeant; Speakers
Bureau: Cipher Pharmaceuticals, Galderma, Pierre-Fabre, and Valeant.
Pathogenesis
A growing body of evidence has accumulated in recent years
supporting the hypothesis that rosacea develops because of a
disordered innate immune system. 5 Individuals with rosacea
express abnormally high levels of cathelicidin in facial skin,
compared with matched control.6 A form of cathelicidin found
in rosacea (LL-37) is typically present in neutrophils that are
recruited to infected or injured skin. In patients with rosacea, this
cathelicidin appears to result from abnormal activity of serine
protease kallikrein 5 (KLK5; also known as stratum corneum
tryptic enzyme). Injecting cathelicidin-producing peptides into
murine skin produced skin inflammation resembling rosacea-like
changes.5,6 Cathelicidins can cause both vasoactive and inflammatory changes, consistent with those observed in rosacea.5
Mast cells, found in increased numbers in the dermis of individuals with rosacea, are among the primary sources of the
cathelicidin peptide (LL-37) demonstrated to induce rosacea in
murine skin. Mast cells have also been shown to mediate skin
inflammation induced by cathelicidin.7
The skin of people with rosacea also expresses toll-like receptor
2 (TLR2) highly compared with healthy individuals. Increased
TLR2 leads to increased production of cathelicidin. Recent experimental findings suggest that high levels of TLR2 in skin increases
susceptibility to microbial and environmental stimuli, increasing
cathelicidin and KLK5 expression.5
Reverse transcriptase polymerase chain reaction and gene
array analysis support the concept of rosacea as an inflammatory
disease. Proinflammatory genes involved in vasoregulation and
neurogenic inflammation are upregulated in early rosacea, before
clinical signs such as papules, nodules, or pustules have emerged.
Different genes are upregulated in each subtype.3
A wide range of stimuli can trigger symptom exacerbations,
including emotional stress, spicy food, hot beverages, alcohol
consumption, high environmental temperatures, sun exposure,
menopause, and microbes (Figure).5 Many of these same triggers activate the transient receptor potential vanilloid receptor
1 (TRPV1), a cell surface receptor nerve fiber. The density of
TRPV1+ nerve fibers is increased in erythematotelangiectatic
rosacea compared with healthy skin. In individuals with healthy
skin, TRPV1 activation produces brief periods of flushing and
burning pain. It has been suggested that patients with rosacea
experience hyperactive or dysregulated TRPV1, with sustained
flushing and neurogenic inflammation.3
Treatment
It is important to set patients’ expectations appropriately regarding
the benefits of therapy. Rosacea cannot be cured but treatment can
control the disease’s signs and symptoms. Avoiding triggers, the use
of gentle skin cleansers, and frequent moisturizing can help heal
and minimize further skin damage. In the last few years, new treatments have been FDA-approved for some rosacea subtypes, and
studies have documented the benefit of other treatments (Table).
Erythematotelangiectatic Rosacea
Address reprint requests to: Jerry K. L. Tan, MD, FRCPC, 2224 Walker
Road, Suite 300, Windsor, Ontario, NBW 5L7 Canada; jerrytan@bellnet.ca.
Intense pulsed light has been used to treat rosacea for many years
and is clinically accepted despite the absence of high-quality
evidence supporting its value.8 A small (n=34) study reported
doi:10.12788/j.sder.2015.0157
■ ❚ ❙ Rosacea: Pathogenesis and Therapy
Papulopustular Rosacea
Isotretinoin has been used for decades to treat rosacea despite
the lack of evidence-based support. A double-blind, randomized,
12-week study conducted in 35 centers in Germany (n=573 with
papulopustular or phymatous rosacea) compared oral isotretinoin
(0.1, 0.3, or 0.5 mg per kg body weight) to doxycycline (100 mg
daily for 14 days, then 50 mg daily) and placebo. The 0.3 mg/kg
dose proved to be the most effective, demonstrating significant
superiority to placebo and noninferiority compared with doxycycline. Lesions were reduced by 90% with isotretinoin 0.3 mg/kg
and by 83% with doxycycline. Investigators determined that
isotretinoin led to complete remission in 24% of patients and
marked improvement in another 57% of patients. Comparable
figures for doxycycline were 14% and 55%, respectively. The safety
profile of isotretinoin 0.3 mg/kg was similar to that observed when
it is used in the treatment of acne.13
Ivermectin 1% cream received FDA approval for inflammatory
rosacea lesions as of December 2014.14 Roughly 40% of patients
with papulopustular rosacea randomized to ivermectin were rated
“clear” or “almost clear” on the Investigator’s Global Assessment
(IGA) in two 12-week phase III trials (38.4% and 40.1%, respectively; P<0.001 vs vehicle). Ivermectin reduced lesion count by
76% and 75% in the 2 trials. Fewer subjects reported dermatologic
adverse events with ivermectin than with vehicle, and more subjects
experienced no skin drying or itching as compared with vehicle.15
Once-daily ivermectin 1% also demonstrated superiority
compared with an active control (twice-daily metronidazole cream
0.75%) for 16 weeks (n=962). Inflammatory lesions were reduced
from baseline by 83% with ivermectin and by 73.7% with metronidazole (P<0.001). The proportion of subjects attaining “clear”
or “almost clear” (IGA rating) was also superior with ivermectin
(84.9% and 75.4%, respectively; P<0.001). Ivermectin demonstrated better local tolerability than the comparator.16
A low-dose formulation of oral minocycline (45 mg extended
release, once daily) demonstrated efficacy in papulopustular
rosacea, alone or when used with once-daily 15% azelaic acid.
Participants in a double-blind study (n=60) were randomized
to receive one of these regimens for 12 weeks. Both treatments
significantly reduced lesion count and improved IGA and Clinical
Erythema Assessment compared with baseline, with no significant
difference in efficacy or safety between the two regimens. Benefits
were maintained 4 weeks after therapy discontinuation.17
Stress
Sun
Temperature
Food
ROSACEA
Emotion
Alcohol
Demodex
Infection
■ FIGURE Multiple and Diverse Triggers.
Source: Yamasaki K, Gallo RL. J Investig Dermatol Symp Proc. 2011;15(1):12-15.
significant improvements in erythema (46%) and telangiectasia by
55% from baseline after four treatments administered at 3-week
intervals. Benefits were sustained at 6 months, with minimal and
self-limiting side effects.9
Brimonidine gel 0.33%, a selective alpha2-adrenergic receptor
agonist with vasoconstrictive activity, received FDA approval
for persistent facial erythema of rosacea in August 2013.10,11
When studied at a concentration of 0.5%, it significantly reduced
erythema severity compared with vehicle when applied once daily
for 4 weeks in phase III studies. Benefit was observed within as
little as 30 minutes of application. No tachyphylaxis or rebound
was reported after treatment cessation.10 Efficacy was maintained
over 1 year (n=345). Some patients experience exacerbation of
rosacea signs and symptoms (flushing 10%, erythema 8%, rosacea
5%, and skin burning sensation 4%).12
■ TABLE Rosacea Treatments and Mechanisms of Action
Mechanism of Action
Retinoids
Metronidazole
Topical
Azelaic Acid
Topical
Demodex
TLR2 activation
Ivermectin
Topical
Brimonidine Cyclosporine Doxycycline
Topical
Topical
po
+
+
Serine protease activity
+
+
Th1 adaptive profile
+
Vasodilation
+
Reactive O2 & NO
Sebaceous hyperplasia
+
+ (po)
Source: Courtesy of Jerry K. L. Tan, MD, FRCPC.
+
+
+
Ocular Rosacea
The diagnosis of ocular rosacea is often missed, as symptoms are
nonspecific and there is no specific test to confirm diagnosis.18 Most
but not all patients also have cutaneous signs and symptoms of
rosacea. Manifestations include watery or bloodshot eyes, sensation of a foreign body, burning or stinging, dryness, itching, light
sensitivity, and blurred vision. Ocular rosacea should be considered in patients with corneal damage, a history of blepharitis,
recurrent conjunctivitis, iritis, keratitis or styes (chalazion, hordeolum), and meibomian gland dysfunction. Periocular erythema,
or telangiectases at the eyelid margins or lid, may be present.
Ocular rosacea can lead to vision loss; treating cutaneous rosacea
without addressing the ocular component may be insufficient to
prevent this consequence.1
Treatment with cyclosporine ophthalmic emulsion 0.05% was
associated with an increase in Schirmer test scores (a measure of
tear production), compared with a decrease (worsening) with artificial tears. Patients with rosacea-associated eyelid and corneal
changes (ie, lid margin telangiectasia, meibomian gland inspissation, and/or fullness of the lid margin; n=37) were randomized
to receive topical cyclosporine or artificial tears for 3 months.
Quality-of-life scores also improved with therapy.19
14.Galderma receives FDA approval of novel treatment option for rosacea patients
[press release]. December 24, 2014. http://www.galderma.com/News/articleType/
ArticleView/articleId/75/Galderma-Receives-FDA-Approval-of-Novel-TreatmentOption-for-Rosacea-Patients. Accessed July 21, 2015.
15.Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in
treatment of papulopustular rosacea: Results of two randomized, double-blind,
vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13(3):316-323.
16.Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream
over metronidazole 0.75% cream in treating inflammatory lesions of rosacea:
A randomized, investigator-blinded trial. Br J Dermatol. 2015;172(4):1103-1110.
17.Jackson JM, Kircik LH, Lorenz DJ. Efficacy of extended-release 45 mg oral minocycline and extended-release 45 mg oral minocycline plus 15% azelaic acid in the
treatment of acne rosacea. J Drugs Dermatol. 2013;12(3):292-298.
18.Vieira AC, Mannis MJ. Ocular rosacea: Common and commonly missed. J Am
Acad Dermatol. 2013;69(6):S36-S41.
19.Schechter BA, Katz RS, Friedman LS. Efficacy of topical cyclosporine for the
treatment of ocular rosacea. Adv Ther. 2009;26(6):651-659.
Summary
An increasing body of pathophysiologic evidence supports the
hypothesis that rosacea results from disordered innate immunity,
which leads to neuroinflammation and vasoactive changes.3,5-7 The
introduction of brimonidine gel 0.33% for erythematotelangiectatic rosacea and ivermectin 1% cream for papulopustular rosacea
offers new options for managing this common condition. A large
(n=573), double-blind randomized trial has documented efficacy of oral isotretinoin (0.3 mg/kg) in papulopustular rosacea.13
Low-dose (45-mg), extended-release oral minocycline has demonstrated efficacy in papulopustular rosacea, alone or when used in
conjunction with once-daily 15% azelaic acid.17 Topical cyclosporine 0.05% has demonstrated efficacy in ocular rosacea.19
References
1. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of
the National Rosacea Society Expert Committee on the Classification and Staging
of Rosacea. J Am Acad Dermatol. 2002;46(4):584-587.
2. Abram K, Silm H, Oona M. Prevalence of rosacea in an Estonian working population using a standard classification. Acta Derm Venereol. 2010;90(3):269-273.
3. Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects
in the pathophysiology of rosacea. J Investig Dermatol Symp Proc. 2011;15(1):2-11.
4. Society NR. If you have rosacea, you’re not alone. http://www.rosacea.org/patients/
index.php. Accessed May 11, 2015.
5. Yamasaki K, Gallo RL. Rosacea as a disease of cathelicidins and skin innate
immunity. J Investig Dermatol Symp Proc. 2011;15(1):12-15.
6. Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and
cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975-980.
7. Muto Y, Wang Z, Vanderberghe M, Two A, Gallo RL, Di Nardo A. Mast cells
are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest
Dermatol. 2014;134(11):2728-2736.
8. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L.
Interventions for rosacea. Cochrane Database Syst Rev.. 2015;(4):CD003262.
9. Papageorgiou P, Clayton W, Norwood S, Chopra S, Rustin M. Treatment of
rosacea with intense pulsed light: Significant improvement and long-lasting results.
Br J Dermatol. 2008;159(3):628-632.
10.Fowler J Jr, Jackson M, Moore A, et al. Efficacy and safety of once-daily topical
brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial
erythema of rosacea: Results of two randomized, double-blind, and vehiclecontrolled pivotal studies. J Drugs Dermatol. 2013;12(6):650-656.
11.Galderma. Galderma receives FDA approval of Mirvaso® [press release]. 2013.
http://www.galderma.com/Media/Press-releases/articleType/ArticleView/articleId/41/Galderma-Receives-FDA-Approval-of-Mirvaso. Accessed May 7, 2015.
12.Mirvaso [package insert]. Fort Worth, TX: Galderma Laboratories; revised
August 2013.
13.Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea – doxycycline- and placebo-controlled, randomized clinical study.
J Dtsch Dermatol Ges. 2010;8(7):505-515.
Tattoo Treatment: Current State of the Art
Christopher B. Zachary, MBBS, FRCP*
■ Abstract
Lasers can remove tattoos effectively but many treatments
can be required for effective fading. New techniques have
been shown to improve the speed and practicality of
therapy, and new lasers may improve fading of recalcitrant
or multicolored tattoos.
■ Keywords
Tattoo removal, Q-switched lasers, perfluorodecalin, picosecond laser, R20, R0
Q
uality-switched (Q-switched) lasers are the instrument of
choice for tattoo removal. As many as 15 or 20 treatments
can be required to remove professional tattoos.1 One of
the limiting factors in any one treatment session is the whitening
that immediately follows Q-switched laser treatment. This reaction
results from the formation of gas bubbles in the dermis. The
bubbles lead to optical scattering, limiting laser penetration for
the roughly 20 minutes required for the reaction to subside.2
R20 Method
In an effort to shorten the number of sessions required for
tattoo removal, Kossida and colleagues evaluated a method in
which patients are treated in four consecutive passes separated
by 20-minute intervals (the “R20 method”). Treatments were
performed with a Q-switched alexandrite laser. Eighteen tattoos
on 12 adults were divided in half, with half receiving the R20
treatment and half receiving a single pass from a laser. Reviewers
blinded to treatment assignment evaluated tattoos 3 months later.2
Compared with results from a single pass, tattoo lightening was
significantly more effective with the R20 method (P<0.01 for all
tattoos). The majority (61%) of the tattoo sites treated with the
R20 method cleared completely, compared with no tattoo sites
with the single-pass method. No scarring or textural changes
occurred, and no infection or postinflammatory hyperpigmentation was observed. One patient experienced transient mild
hypopigmentation, which had resolved completely at 6 months
post-therapy. Investigators noted that less whitening developed
immediately following each subsequent laser pass with the R20
method, potentially facilitating deeper optical penetration.2
R0 Method
The R20 procedure is effective but the time required (≥1 hour)
renders it impractical for the office setting. Applying topical
perfluorodecalin (PFD) after a laser treatment resolves the immediate whitening reaction quickly, within a mean of 5 seconds
(range 3-10 seconds).3 PFD works by absorbing the gas released
in the dermis.4
Tattoos receiving three passes with PFD to remove the frosting
after each pass (the “R0 method”) demonstrated fading equal to
that observed with the R20 method, and superior to that seen
following a single pass. Total treatment time with the R0 method
in this study averaged 5 minutes,3 making it feasible for clinical
practice. Figure below illustrates the impact of PFD on treatment results.
Laser Type, Pulse Width, and Duration
The tattoo color should be considered when choosing the type of
laser. Any of the three types of Q-switched lasers (ruby [694 nm],
alexandrite [755 nm], and Nd:YAG [only the 1064 nm]) can treat
black or dark blue tattoos. Both the QS ruby and alexandrite
lasers may cause hypopigmentation in darker skinned individuals,
though these are preferred for removal of green pigment. Red or
orange ink requires the Nd:YAG 532 nm laser.5
The particle size of tattoo pigments generally falls between 30
to 300 nm, with a thermal relaxation time (TRT) of approximately
A.
B.
*Professor and Chair, Department of Dermatology, University of
California, Irvine, Irvine, California.
Dr Zachary has received an honorarium for his participation in this
activity. He acknowledges the editorial assistance of Eileen McCaffrey, MA,
Christopher B. Zachary, MBBS, FRCP, Consultant: Cutera, Inc. and
ZELTIQ Aesthetics, Inc.; Speakers Bureau: Cynosure, Inc. and Solta
Medical, a division of Valeant; Advisory Board: ZELTIQ.
Address reprint requests to: Christopher B. Zachary, MBBS, FRCP,
Dermatology, UC Irvine Health, 118 Med Surge I, Irvine, CA 92697;
czachary@uci.edu.
■ FIGURE Results Following Three Passes and
Topical Perfluorodecalin.
A. Blue and black tattoo
B. Significant fading 1 month post-single treatment with three passes
QSRL with topical PFD. Total treatment time 4 minutes pre-treatment.
PFD=perfluorodecalin; QSRL=quality-switched ruby laser.
Source: Photos courtesy of Roy Geronemus, MD.
doi:10.12788/j.sder.2015.0158
10 nanoseconds or shorter. Lasers for treating tattoos should
therefore have a pulse duration that matches these TRTs,
in the nanosecond range (10−9 sec) or shorter. While the Qswitched lasers do provide the upper range of pulse durations,
newer picosecond lasers offer pulse times measured in picoseconds (10−12 sec), which often improve tattoo removal.1
One study evaluated tattoo removal results with a picosecond
laser in 12 green and/or blue pigment tattoos on 10 patients. Two
of the tattoos had clinically apparent pigment after at least 10
prior treatments with traditional Q-switched lasers (designated
recalcitrant tattoos); the remainder (n=10) were multicolored.6
Investigators used an alexandrite laser (755 nm) with variable
pulse duration of 750 to 900 picoseconds, repetition rate of
5 Hz, and spot sizes from 3.0 to 3.6 nm. At 1-month follow-up
after one treatment, 11 of the 12 tattoos demonstrated at least
75% clearance of the blue and/or green pigment. The remaining
tattoo required two treatments to achieve >75% clearance. Patients
reported average pain scores of 1.08 on a 10-point scale (1=no
pain, 10=worst pain). One individual reported blistering.
Summary
The traditional Q-switched lasers historically have provided variable outcomes. While some tattoos can be removed easily with
these nanosecond devices, the multicolored tattoos, and others
recalcitrant for various reasons, have often required numerous
treatments and still had modest outcomes. The new treatments
utilizing topical PFD between treatments can more efficiently
fade tattoos. However, the biggest development has been the
newer picosecond lasers because of their highly effective ability
to remove blue and/or green tattoos more easily than the black
or dark blue colors.
References
1. Sardana K, Ranjan R, Ghunawat S. Optimising laser tattoo removal. J Cutan
Aesthet Surg. 2015;8(1):16-24.
2. Kossida T, Rigopoulos D, Katsambas A, Anderson RR. Optimal tattoo removal
in a single laser session based on the method of repeated exposures. J Am Acad
Dermatol. 2012;66(2):271-277.
3. Reddy KK, Brauer JA, Anolik R, et al. Topical perfluorodecalin resolves immediate whitening reactions and allows rapid effective multiple pass treatment of
tattoos. Lasers Surg Med. 2013;45(2):76-80.
4. Shah SD, Aurangabadkar SJ. Newer trends in laser tattoo removal. J Cutan Aesthet
Surg. 2015;8(1):25-29.
5. Ho SG, Goh CL. Laser tattoo removal: A clinical update. J Cutan Aesthet Surg.
2015;8(1):9-15.
6. Brauer JA, Reddy KK, Anolik R, et al. Successful and rapid treatment of
blue and green tattoo pigment with a novel picosecond laser. Arch Dermatol.
2012;148(7):820-823.
Highlights of Skin Disease Education Foundation’s 39th Annual Hawaii Dermatology Seminar Post-Test and Evaluation Form
Original Release Date: June 2015 • Most Recent Review Date: June 2015 • Expiration Date: June 30, 2016 • Estimated Time to Complete Activity: 2.0 hours
FOR NOTES PURPOSES ONLY.
MUST BE COMPLETED ONLINE.
To get instant CME/CE credits online, go to http://tinyurl.com/39HawaiiSupp. Upon successful completion of the online test and evaluation form, you will be directed to a Web page that will allow you to receive your certificate of
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POST-TEST CME/CE QUESTIONS
1. Of the TNF inhibitors approved for the treatment of psoriasis, which
has the highest efficacy rates (ie, proportions of patients achieving
PASI 75 at 10 to 16 weeks) in landmark clinical trials for psoriasis?
A. Etanercept
B. Adalimumab
C. Infliximab
D. Golimumab
5. Which of the following agents used to treat psoriasis has been shown
to exacerbate Crohn’s disease in some cases?
A. Adalimumab
B. Infliximab
C. Secukinumab
D. Ustekinumab
8. Which of the following treatments approved for rosacea has
demonstrated superiority compared with metronidazole?
A. Brimonidine
B. Ivermectin
C. Isotretinoin
D. Azelaic acid
2. Nearly half of those who develop anti-drug antibodies to which
of the anti-TNF agents approved for the treatment of psoriasis
experience a loss of adequate drug response?
A. Etanercept
B. Adalimumab
C. Infliximab
D. Golimumab
3. Which of the following agents represents a new, boron-based
class of antifungals approved to treat toenail onychomycosis?
A. Tavaborole
B. Luliconazole
C. Efinaconazole
D. Naftifine
6. Which of the following statements most accurately describes the
relationship of psoriasis therapy to CVD risk?
A. Psoriasis therapy does not affect CVD risk, regardless of specific
therapy used
B. Compared with methotrexate, anti-TNF therapy for psoriasis was
associated with significantly reduced risk of a major CV event
C. Compared with no therapy, methotrexate and anti-TNF therapy
each significantly reduced risk of CVD, and risk reduction is
similar regardless of type of psoriasis therapy
D. Evidence demonstrates that reduced inflammation is
responsible for the decreased risk of major CV events
observed with anti-TNF therapy
9. Which of the following statements accurately describes the R20
and R0 methods of tattoo removal?
A. Both involve multiple treatments in a single session
B. R20 involves the use of topical perfluorodecalin to increase the
amount of tattoo ink removed at each treatment
C. R0 involves the use of topical perfluorodecalin to speed
resolution of the immediate whitening reaction and facilitate
delivery of multiple treatments within a brief single session
D. A and C
4. Clinical trials of which one of the following topical antifungal
agents have demonstrated a mycological cure rate in toenail
onychomycosis comparable to that of oral itraconazole?
A. Tavaborole
B. Luliconazole
C. Naftifine
D. Efinaconazole
7. The preponderance of evidence about rosacea pathophysiology
indicates that rosacea results from:
A. A disordered innate immune system
B. A disordered adaptive immune system
C. Something other than a disorder of the immune system
D. Little is known about rosacea pathophysiology
ACTIVITY EVALUATION FORM
Please indicate your profession/background:
MD/DO MSN/BSN/RN PA APN/NP PharmD/RPh Resident/Fellow Researcher Administrator LEARNING OBJECTIVES: Having completed this activity, you are better able to:
10. Once acne has been controlled with 12 weeks of induction therapy
with oral plus topical antibiotic therapy, which of the following best
describes clinical trial findings regarding maintenance therapy?
A. Continued therapy is unnecessary to maintain efficacy
B. Continued therapy with either oral or topical therapy alone
is sufficient to maintain efficacy
C. Oral therapy is required to maintain efficacy after successful
induction therapy
D. Both oral and topical therapy must be continued to
maintain efficacy
Student Strongly Agree
Other; specify _______________________________________
Agree
Somewhat Agree
Disagree
Strongly Disagree
Differentiate the characteristics of the tumor necrosis factor (TNF) inhibitors approved for use in treating psoriasis and apply that
information to clinical practice.
5
4
3
2
1
Demonstrate familiarity with the impact of comorbid conditions on patients with psoriasis and incorporate the effect of psoriasis therapy
on those comorbidities into patient management.
5
4
3
2
1
Integrate new therapies for rosacea into practice and describe current theories about rosacea pathophysiology.
5
4
3
2
1
Explain the use of new treatments for tinea pedis and toenail onychomycosis.
5
4
3
2
1
Apply current knowledge about anti-acne antibiotic dosing, maintenance therapy, topical therapy, and diet to clinical practice.
5
4
3
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1
Identify current and updated techniques to improve tattoo removal.
5
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2
1
If you do not feel confident that you can achieve the above objectives to some extent,
please describe why not.
_____________________________________________________________________________
_____________________________________________________________________________
Based on the content of this activity, what will you do differently in the care of your
patients/regarding your professional responsibilities? (check one)
Implement a change in my practice/workplace.
Seek additional information on this topic.
Do nothing differently. Current practice/job responsibilities reflect activity
recommendations.
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OVERALL EVALUATION
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to do so.
_____________________________________________________________________________
_____________________________________________________________________________
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Yes. E-mail address: ___________________________________________________________
No.
I don’t plan to make a change.
If you are not able to effectively implement what you learned in this activity, please tell us
what the system barriers are (eg, institutional systems, lack of resources, etc)?
_____________________________________________________________________________
_____________________________________________________________________________
Strongly Agree
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Strongly Disagree
The information presented increased my awareness/understanding of the subject.
5
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5
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Supplement to Seminars in Cutaneous Medicine and Surgery

Transcription

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