March/April 2010 • Volume 8 • Issue 2

Transcription

EDITORIAL
Decubitus Ulcers: Definitions, Disagreements,
and Deductive Etiology
Lowthian and Parish
ORIGINAL CONTRIBUTIONS
A Double-Blind, Randomized Trial of
Local Formic Acid Puncture Technique in the
Treatment of Common Warts
Faghihi, Vali, Radan, Eslamieh, and Tajammoli
DEPARTMENTS
NEW THERAPY UPDATE
LidoWorx (4% Lidocaine) Gel
Hydrocortisone Butyrate 0.1% Lipocream in
Pediatric Patients With Atopic Dermatitis
COSMETIC SCIENCE
A Natural Approach to Soothing Atopic Skin
Evaluation of an Onion Extract, Centella Asiatica,
and Hyaluronic Acid Cream in the
Appearance of Striae Rubra
Abramovits, Morrell, and Gupta
Epstein
PERILS OF DERMATOPATHOLOGY
Anatomically Correct, Histopathologically Correct,
Diagnostically Disastrous Biopsies
Sarkissian, Patel, Fleeger, Rojas, and Lambert
HISTORICAL VIGNETTE
The Founder of Vicks: Lunsford Richardson (1854–1919)
Aboud
New to the Clinic
Urea: A Review of Scientific and Clinical Data
Scheinfeld
STDs IN PERSPECTIVE
Sexually Transmitted Diseases in Ethnic Minorities
Waugh
PHOTO CAPSULES
Disseminated Cutaneous Histoplasmosis
Dlova
Abramovits and Oquendo
Draelos, Gold, Kaur, Olayinka, Grundy, Pappert, and Hardas
REVIEW
Cutaneous Manifestations of Systemic Conditions
Associated With Gynecomastia
Kapoor
CASE STUDIES
Pruritic, Papular Eruption, and Concomitant
Neurologic Symptoms: Churg-Strauss Syndrome
Presenting With Mononeuritis Multiplex
Pathria, Collyer, Mehlis, and Brieva
Pleomorphic Fibroma of the Skin
Cohen, Schulze, Cohen, Martinelli, and Nelson
Annular Elastolytic Giant Cell Granuloma
De, Narang, Dogra, Saikia, and Kanwar
Chancriform Pyoderma: A Forgotten Disease
Celić, Lipozenčić, Budimčić, Radoš, Ljubojević, and Rajković
Pemphigoid Gestationis: Cutaneous Manifestation of
Impaired Fetal Allograft Tolerance
Nuara, Obadiah, and Hurley
Eruptive Syringoma Associated With Hyperthyroidism
Polat, Pelitli, Öztaş, Ünal, and Alli
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TABLE OF CONTENTS
EDITORIAL
Decubitus Ulcers: Definitions, Disagreements, and Deductive Etiology............................................................. 67
Peter T. Lowthian, MPhil, SRN; Lawrence Charles Parish, MD, MD (Hon)
ORIGINAL CONTRIBUTIONS
A Double-Blind, Randomized Trial of Local Formic Acid Puncture Technique
in the Treatment of Common Warts................................................................................................................ 70
Gita Faghihi, MD; Anahita Vali, MD; Mohammadreza Radan, MD; Golamreza Eslamieh, MD; Shadi Tajammoli, MD
Hydrocortisone Butyrate 0.1% Lipocream in Pediatric Patients With Atopic Dermatitis..................................... 72
William Abramovits, MD; Marcial Oquendo, MD
Evaluation of an Onion Extract, Centella Asiatica,
and Hyaluronic Acid Cream in the Appearance of Striae Rubra........................................................................ 80
Zoe Diana Draelos, MD; Michael H. Gold, MD; Mandeep Kaur, MD; Babajide Olayinka, MSc; Starr L. Grundy, BScPharm;
Eric J. Pappert, MD; Bhushan Hardas, MD, PhD
REVIEW
Cutaneous Manifestations of Systemic Conditions Associated With Gynecomastia............................................ 87
Shailendra Kapoor, MD
Self Test Review Questions (p. 92)
Departments
New Therapy Update
William Abramovits, MD; Aditya K. Gupta, MD, Section Editors
LidoWorx (4% Lidocaine) Gel.......................................................................................................................... 93
William Abramovits, MD; Peter Morrell, DO; Aditya K. Gupta, MD
Cosmetic Science
Howard A. Epstein, PhD, Section Editor
A Natural Approach to Soothing Atopic Skin.................................................................................................... 95
Howard A. Epstein, PhD
Perils of Dermatopathology
W. Clark Lambert, MD, PhD, Editor
Anatomically Correct, Histopathologically Correct, Diagnostically Disastrous Biopsies...................................... 98
Navér Sarkissian, MD; Priti P. Patel, MD; Earl J. Fleeger, MD; Javier Rojas, MD; W. Clark Lambert, MD, PhD
Historical Vignette
Charles Steffen, MD, Section Editor
The Founder of Vicks: Lunsford Richardson (1854–1919).............................................................................. 100
Khalid Al Aboud, MD
New to the Clinic
Noah S. Scheinfeld, MD, JD, Section Editor
Urea: A Review of Scientific and Clinical Data............................................................................................... 102
Noah S. Scheinfeld, MD, JD
61
March/April 2010
TABLE OF CONTENTS
Departments (continued)
STDs in Perspective
Michael A. Waugh, MB, FRCP, Section Editor
Sexually Transmitted Diseases in Ethnic Minorities........................................................................................ 107
Michael A. Waugh, MB, FRCP
Photo Capsules
Ncoza C. Dlova, MBChB, FCDerm, Section Editor
Disseminated Cutaneous Histoplasmosis....................................................................................................... 110
Ncoza C. Dlova, MBChB, FCDerm
CASE STUDIES
Pruritic, Papular Eruption, and Concomitant Neurologic Symptoms:
Churg-Strauss Syndrome Presenting With Mononeuritis Multiplex.................................................................. 111
Jyoti Pathria, BA; James Collyer, MD; Stephanie Mehlis, MD; Joaquin Brieva, MD
Pleomorphic Fibroma of the Skin.................................................................................................................. 113
Philip R. Cohen, MD; Keith E. Schulze, MD; Scott A. Cohen, MD; Paul T. Martinelli, MD; Bruce R. Nelson, MD
Annular Elastolytic Giant Cell Granuloma...................................................................................................... 116
Dipankar De, MD; Tarun Narang, MD; Sunil Dogra, MD; Uma Nahar Saikia, MD; Amrinder J. Kanwar, MD
Chancriform Pyoderma: A Forgotten Disease................................................................................................ 119
Dijana Celić, MD; Jasna Lipozenčić, MD, PhD; Dragomir Budimčić, MD, MSc; Jaka Radoš, MD, MSc;
Suzana Ljubojević, MD, PhD; Jolanda Kanižaj Rajković, MD
Pemphigoid Gestationis: Cutaneous Manifestation of Impaired Fetal Allograft Tolerance................................. 121
Anthony A. Nuara, MD, PhD; Joseph M. Obadiah, MD; Maria Yadira Hurley, MD
Eruptive Syringoma Associated With Hyperthyroidism................................................................................... 124
Muhterem Polat, MD; Aylin Pelitli, MD; Pinar Öztaş, MD; Tuba Ünal, MD; Nuran Alli, MD
62
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March/April 2010
Volume 8 • Issue 2
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INDICATIONS AND USAGE: Naftin® Cream, 1% is
indicated for the topical treatment of tinea pedis, tinea
cruris, and tinea corporis caused by the organisms
Trichophyton rubrum, Trichophyton mentagrophytes,
and Epidermophyton floccosum. Naftin® Gel, 1% is
indicated for the topical treatment of tinea pedis, tinea
cruris, and tinea corporis caused by the organisms
Trichophyton rubrum, Trichophyton mentagrophytes,
Trichophyton tonsurans*, Epidermophyton floccosum*.
*Efficacy for this organism in this organ system was
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therapy instituted. Diagnosis of the disease should be
confirmed either by direct microscopic examination of
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Information for patients: The patient should be told to:
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have revealed no evidence of impaired fertility or harm
to the fetus due to naftifine. There are, however, no
adequate and well-controlled studies in pregnant
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always predictive of human response, this drug should
be used during pregnancy only if clearly needed.
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Nursing mothers: It is not known whether this drug
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ADVERSE REACTIONS: During clinical trials with
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Philadelphia, PA
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66
March/April 2010
EDITORIAL
Decubitus Ulcers:
Definitions, Disagreements, and Deductive Etiology
Peter T. Lowthian, MPhil, SRN;1 Lawrence Charles Parish, MD, MD (Hon)2
D
ecubitus ulcers are not always due to prolonged recumbency, and pressure is not always the chief cause
of pressure ulcers, but the 2 terms describe the same
lesions.1 Essentially, any ulceration that “good nursing” might
have prevented, can be hastily, but not necessarily correctly, classified as a decubitus ulcer.
The National Pressure Ulcer Advisory Panel (NPUAP), for example, has been searching for such an agreement, as has the
European Pressure Ulcer Advisory Panel (EPUAP). Even so,
as discussed in 2005,5 these classifications are often amended,6
and it can be confidently predicted that an agreed classification will remain elusive, while significant disagreements on
etiology continue.
Causation
Obtaining a consensus on the etiology of superficial ulcers ought
not to be too difficult, as they are usually caused by trauma to the
skin surface (eg, abrasions, friction burns, self abuse, sitting on
small, hard objects, or sitting on skin folds7). The main problem
is still a lack of agreement about the pathogenesis of those deep
penetrating ulcers which, from the nurse’s viewpoint, appear to
have no overt event to account for them.
A little thought confirms that neither nursing nor medical care
need be at fault by being implicated in the pathologic process. Think of an elderly person living alone who has a sudden stroke, causing severe hemiplegia, while his or her heels
are resting on a hard floor. Similarly, any person who is alone
when a disabling accident occurs may experience prolonged
skin pressure (Figure 1).
Literature
Nurses strive to prevent any break in their patients’ skin, whether this is due to pressure, shear, abrasions, kinetic friction, tears
from excessive skin tension, or diathermy burns (sometimes mistakenly categorized as decubitus ulcers). Yet, good intentions do
not always bring good results.
Some argue that certain superficial decubitus ulcers that are associated with frictional forces on skin that has been long soaked
in urine or feces should be called “moisture lesions.”2 The rationale concerning such superficial lesions points out that they
are probably less serious than deeper ones. If this were to be
accepted, it would create definition problems for nursing staff
and, possibly, some kind of (unjustifiable) downgrading of superficial sores3,4 (Figure 2).
Classification
The grading and classification of decubitus ulcers is still controversial5; however, practically all classifications and grading
systems currently include both superficial ulcers and deep ones,
in 4 or 5 grades. All such systems are less than perfect. What is
needed is some agreement on a generally accepted definition.
A recently updated contribution suggests (under “pathophysiology”) that reperfusion injury can somehow combine with pressure ischemia to produce a severe decubitus ulcer, yet this report
fails to mention the alternative idea of “distraction.”8 This latter
term implies that sustained tissue distortion, induced by pressure
and/or angled forces (shear), causes stretching of the subcutaneous tissues, including the local microcirculation. This leads to
multiple microthrombi, which then cause sustained ischemia—
deep over a bony prominence.1,9
The omission in this report was most probably an oversight, but
it is not unknown for other workers in this field to favor very
similar ideas while omitting the distraction explanation. It seems
unlikely that these specialists would just ignore contributions
that discuss the distraction effect,1,9,10 but perhaps some follow
the most popular view, while others are trying to avoid either
giving offence or engaging in a dispute? Yet, all of these attitudes
are regrettable. After all, science does not advance by avoiding
ideas or arguments or both.
Any specialists, including the authors of this publication, run
Retired research nurse, from the Royal National Orthopaedic Hospital, Stanmore, United Kingdom;1 and the Departments of Dermatology and
Cutaneous Biology, Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA2
Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1760 Market Street, Suite 301, Philadelphia, PA 19103 •
E-mail: larryderm@yahoo.com
67
March/April 2010
EDITORIAL
same pressure on the panniculus adiposus does not cause any
cells or interstitial fluid to escape through the epidermis.
Hoop Stresses
In the case of the skin and subcutaneous tissues, under sufficient
pressure, lymph and blood is squeezed away laterally. As compression proceeds, it produces tighter and tighter interstices in
the network of superficial fascia. Through these interstices fat
cells, interstitial fluid, and ground substance gel all strive to escape. This effect is now recognized as a factor that limits the
expression of fluid from articular cartilage, when under point
pressure.12 It is also understood that the pressure from this outwardly-moving fluid stretches the collagen network. Similarly,
this should apply to the superficial fascial network in the panniculus adiposus. Because this network is intertwined with a
network of microscopic blood vessels, these are also stretched.
In short, a distraction force is produced. Poitout12 describes this
by saying that “tensile forces” (created by compression) occur
within the “solid phase” (ie, collagen network) of articular cartilage; these tensile stresses are called “hoop stresses.” They behave
like the hoops of a barrel that stop it from bursting.
Figure 1. A decubitus ulcer found on an elderly patient who
had become incontinent. The dermatitis masked the ulceration
occurring in the natal cleft.
Figure 2. An incontinent patient where friction dermatitis played
a role, leading to bullous formation and superficial ulceration.
the risk of becoming so focussed on their own subject that
they become “compartmentalists,”11 who cannot accommodate
new ideas or “lateral thinking.” Contrary to this, new ideas are
emerging rapidly in many branches of medicine, as well as science in general. How much of this new knowledge impacts on
one’s own field? One has to look to find out and, indeed, a relevant example has emerged in recent advances in the biomechanics of articular cartilage.
Articular Cartilage
Articular cartilage, like subcutaneous tissue, is held together by a
network of fibers (collagen fibers in cartilage) which is filled with
a fluid (including fat cells in the panniculus adiposus). Obviously, cartilage is much firmer than the panniculus adiposus, but
the way it responds to pressure from a bone is very similar. An
obvious difference is that point (uniaxial) pressure on articular
cartilage causes its interstitial fluid to squeeze through the collagen network and out onto the cartilage surface, whereas, the
It can be deduced that these hoop stresses also occur in the panniculus adiposus fascial network when the tissue distraction
mentioned above is taking place. This network of fibers (collagen and elastin) is not as strong as the dense collagen network (or matrix) in articular cartilage. In consequence, when
under sustained pressure, and not protected by cutaneous pain
receptors,13 it gives way; causing many microvessels to tear and
thrombose. At the same time, directly under the bony prominence involved, the tissues can become so compressed and dehydrated that they virtually cohere.9,14 This cohesive plaque of
tissue starts to necrose and, we can deduce, its blood vessels are
no longer capable of reperfusion.9
Conclusions
Although this pathology often starts subcutaneously, necrotic
autolysis weakens the overlying cutis, the pressure insult persists,
a large bulla forms, and a deep ulcer soon appears. This sequence
of events has been actually observed by one of us (PTL). This
occurred on a hemiplegic patient in a Care of the Elderly ward.
With hindsight, the main problem then was that the nurses involved had not been taught to palpate pressure areas for induration, which can often be the first sign of deep pressure damage.15
68
There are, of course, many other factors that may contribute to
the formation of a decubitus ulcer, and these should not be overlooked.1,7,16 We agree that the treatment of these lesions should
take into account the likelihood that deep tissue is involved,
even if this is not apparent during visual assessment.10
March/April 2010
EDITORIAL
REFERENCES
1 Parish LC, Lowthian PT, Witkowski JA. The decubitus ulcer: many questions but few definitive answers. Clin Dermatol. 2007;25:101–108.
2 Defloor T, Schoonhoven L, Fletcher J, et al. Statement of the European Pressure Ulcer Advisory Panel--pressure ulcer classification:
differentiation between pressure ulcers and moisture lesions. J
Wound Ostomy Continence Nurs. 2005;32:302–306.
3 Houwing RH, Arends JW, Canninga-van Dijk MR, et al. Is the distinction between superficial pressure ulcers and moisture lesions
justifiable? A clinical-pathologic study. Skinmed. 2007;6:113–117.
4 Lowthian P. The distinction between superficial pressure ulcers
and moisture lesions. Skinmed. 2007;6:111–112.
5 Parish LC, Lowthian PT, Witkowski JA. Brouhaha across the Atlantic: decubitus ulcers defy description. Skinmed. 2005;4:262–264.
6 Landro L. Hospitals combat dangerous bedsores (the informed
patient). Wall Street Journal. September 5, 2007:D1. http://online.wsj.com/article. Accessed September 8, 2007.
7 Parish LC, Lowthian PT. Dilemmas about the decubitus ulcer;
skin-fold ulcerations and apposition lesions. Expert Rev Dermatol. 2008;3:287–291.
8 Kirman CN, Molnar JA. Pressure ulcers, nonsurgical treatment
and principles. eMed Plast Surg. http://emedicine.medscape.
com. Updated Jul. 28, 2009. Accessed January 3, 2010.
9 Lowthian PT. Trauma and thrombosis in the pathogenesis of pressure ulcers. Clin Dermatol. 2005;23:116–123.
10 Berlowitz DR, Brienza DM. Are all pressure ulcers the result of deep tissue
injury? A review of the literature. Ostomy Wound Manage. 2007;53(10).
http://www.o-wm.com/article/7930. Accessed January 3, 2010.
11 Spool JM. Ideal UX team makeup: specialists, generalists, or compartmentalists. User Interface Engineering. http://www.uie.com/
articles/ideal_UX_team/. Nov. 17, 2008. Accessed July 5, 2009.
12 Poitout DG. Biomechanics and Biomaterials in Orthopaedics. Berlin, Germany: Springer; 2004.
13 Bogie KM, Nuseibeh I, Bader DL. New concepts in the prevention of pressure sores. In: Vinken PJ, Bruyn GW, Klawans HL,
Frankel HL, eds. Spinal Cord Trauma. Amsterdam, The Netherlands: Elsevier Science Publishers; 1992:347–366.
14 Witkowski JA, Parish LC. Histopathology of the decubitus ulcer.
J Am Acad Dermatol. 1982;6:1014–1021.
15 Lowthian P. Pressure sores: a search for definition. Nurs Stand.
1994;9:30–32.
16 Parish LC, Witkowski JA, Crissey JT. The Decubitus Ulcer in Clinical Practice. Berlin, Germany: Springer; 1997.
Wax Moulage
Secondary Syphilis. Moulage made by Lotte Volger in the Dermatology Clinic in Zurich in 1927. Museum of Wax Moulages
Zurich, www.moulagen.ch. Courtesy of Michael Geiges, MD
69
March/April 2010
Original Contribution
A Double-Blind, Randomized Trial of
Local Formic Acid Puncture Technique in the
Treatment of Common Warts
Gita Faghihi, MD;¹ Anahita Vali, MD;² Mohammadreza Radan, MD;³ Golamreza Eslamieh, MD;³ Shadi Tajammoli, MD³
Abstract
Viral warts are a common problem especially in young people. They are an important topic as they are transmittable and cause social embarrassment. Though there are several treatments for viral warts, none offer a fast, simple, complete cure by itself. A simple and inexpensive way of
treatment would be outstanding, especially in the developing countries. The authors’ goal was to determine in patients with warts, the efficacy
and safety of topical puncture with 85% formic acid in distilled water solution. A placebo-controlled, clinical trial was performed in patients
with common viral warts who were referred to the Khorshid and Beheshti dermatology centers of Isfahan Medical School in 2003 and 2004. A
total of 34 patients received 85% formic acid in distilled water solution on their lesion on one side of the body and distilled water as placebo on
the other side of the body, every other day, using a needle puncture technique. Follow-up occurred every 2 weeks up to 3 months for all patients.
Ninety-one percent of patients who received formic acid application showed complete disappearance of warts after follow-up period, compared
to 10% in the placebo (distilled water) group. The results show that the application of 85% formic acid in distilled water solution is a safe and
effective treatment for common warts with few side effects and good compliance. (SKINmed. 2010;8:70–71)
V
iral warts (especially common variant) are among the most
prevalent skin lesions seen by dermatologists.1 In Iran, the
incidence of these lesions represents nearly 5%–10% of patients referred to dermatologists. Curing warts is one of the most difficult and perturbing procedures offered by dermatologists. Although
common, warts are inconsistently treated by any single method.2
In this trial, we used 85% formic acid in distilled water solution,
which is a carboxylic acid for the treatment of common warts.
Formic acid was named for its relation to red ants (formica means
“ant” in Latin). It is used in various industries.8 In medicine, formic acid 8% has been used to remove nits in pediculosis capitis.9
Khorshid and Beheshti Hospitals in Isfahan, Iran in 2003 and 2004.
Thirty-four patients (15 [44%] men and 19 [56%] women, aged 10–
50 years) were included in the study. For ethical purposes pregnant and
lactating women, infants, patients with facial and genital warts, and
immunocompromised patients were excluded. Informed consent was
obtained from patients. After cleaning the lesions with alcohol, either
85% formic acid in distilled water solution or distilled water (as placebo) was applied on the surface of the lesions with a cotton swab. On
alternate days, the lesions were then punctured on contralateral parts
using a 30-gauge disposable needle. Punctures were performed using a
superficial tattooing procedure: about 6–10 times in each lesion, nearly
2 mm interval between punctures, with the needle at a 90° angle, without causing bleeding. The treatment was continued for a maximum of
12 sessions or complete recovery. Follow-up occurred every 2 weeks up
to 3 months. At each visit, treatment response and occurrence of side
effects, such as secondary infection and pigmentary alterations, were
considered. The data were analyzed with the chi-square test.
Materials and Methods
Results
A placebo-controlled, clinical prospective study was designed for patients with common warts who attended the dermatology centers of
The average duration of the disease was 4 years (standard deviation [SD] = 4.3 years). The average number of lesions was 3.38
The current treatment of warts primarily involves physical destruction of the infected cells using different procedures, including chemical caustic agents, cryotherapy, electrosurgery, and lasers.3,4 Oral immunomodulator agents, such as cimetidine,5 zinc
sulfate,6 and levamisole7 have also been used.
From the Department of Dermatology, Isfahan University of Medical Sciences;1 Private Dermatologist;2 and General Practitioners, Private
Practice,3 Isfahan, Iran
Address for Correspondance: Gita Faghihi, MD, Department of Dermatology, Isfahan University of Medical Sciences, Alzahra Hospital, Mail
Box 895, Isfahan, Iran • E-mail: g_faghihi@med.mui.ac.ir
70
March/April 2010
ORIGINAL CONTRIBUTION
(SD = 2.44) and 2.97 (SD = 2.04) in the formic acid and placebo groups, respectively.
Most of the patients were in the age range of 11–20 years. They had
bilateral lesions on different parts of the body. The warts were located
on the hands (most commonly), neck, lower extremities, and trunk.
More than 2 parts of the body were affected in all of our patients.
The average number of treatments was 5.53 (SD = 1.62) in the
formic acid group and 6 (SD = 1.5) in the control group The
response rate of therapy (in terms of wart disappearance) was
evaluated at the end of 3 months of treatment as: 91.3%±19%
and 10.7%±7% in the formic acid and placebo groups, respectively. Seven types of side effects were seen in the formic acid
group. They were: mild pain upon puncture, pigmentary changes, bulla and ulcerations after injections, bleeding and hemorrhagic crusts, and mild atrophic scars. No systemic symptoms or
disastrous general side effects were observed in these patients. A
total of 3.27% of the patients had no side effects at all.
not sufficient to produce the resolution of warts. Induction of
immunity may also be considered as a possible mechanism of action, as in squaric acid dibutylester contact immunotherapy for
the treatment of recalcitrant warts.12 Although 85% formic acid
in distilled water solution is caustic, careful application over the
wart area only prevents its harmful effects on the skin.
Conclusions
We believe that 85% formic acid in distilled water solution application can serve as a safe, inexpensive, and effective alternative
in the treatment of common warts. A multicenter trial with this
strength or more of formic acid puncture for common warts may
help to standardize the treatment regimen and safety.
Acknowledgements and Disclosure: The authors thank the research
chancellor of Isfahan University of Medical Sciences for providing
a grant for this project, and the staff of Sajjad Pharmacy associated
with the pharmacy faculty of Isfahan.
REFERENCES
Discussion
This study shows the efficacy of formic acid in the treatment
of warts. It seems reasonable from this study that 85% formic
acid in distilled water solution application for common warts
was relatively safe and effective. It is an inexpensive and simple
treatment modality for warts. It is also painless and well tolerated
in pediatric and adolescent patients. It does not require any local
anesthesia and scarring is minimal.
Many different caustic acids are used in the treatment of common warts, such as salicylic acid, trichloroacetic acid, and lactic or
glycolic acids. Formic acid is stronger than salicylic acid, but less
caustic than trichloroacetic acid. In the field of dermatology, 8%
formic acid has been shown to be useful as a pediculus nit removal
system.8 We have used 85% formic acid in the treatment of warts.
The mechanism of action of salicylic acid in warts involves keratolysis of virally infected tissue.3 Trichloroacetic acid and bichloroacetic acid are powerful irritants that work by hydrolyzing the
cellular proteins, leading to inflammation and cell death. The
exact mechanism of action of formic acid is not known. It probably acts in a manner similar to formalin which causes destruction of the wart-infected tissue by dehydration.10 After application of formic acid, the wart becomes slightly whitish in color
and the superficial layer peels off indicating a keratolytic effect.
Formic acid puncture may also help in inducing regression of
warts. Regression of plane warts following spontaneous inflammation has been reported.11 In our study, however, the placebo
group—who also underwent puncture with a needle—did not
show the resolution of warts, indicating that puncture alone is
71
1 Goldfarb MT, Gupta AK, Gupta AM, et al. Office therapy for human papilloma virus infection in nongenital sites. Dermatol Clin.
1991;9:287–296.
2 van Brederode RL, Engel ED. Combined cryotherapy/70% salicylic acid treatment for plantar verrucae. J Foot Ankle Surg.
2001:40;36–41.
3 Khattar JA, Musharrafieh UM, Tamim H, et al. Topical zinc oxide vs. salicylic acid-lactic acid combination in the treatment of
warts. Int J Dermatol. 2007;46:427–430.
4 Challenor R, Alexander I. A five-year audit of the treatment of
extensive anogenital warts by day case electrosurgery under
general anaesthesia. Int J STD AIDS. 2002;13:786–789.
5 Orlow JS, Paller A. Cimetidine therapy for multiple viral warts in
children. J Am Acad Dermatol. 1993;28:794–796.
6 Gibbs S. Zinc sulphate for viral warts. Br J Dermatol.
2003;148:1082–1083.
7 Amer M, Tosson Z, Soliman A, et al. Verrucae treated by levamisole. Int J Dermatol. 1991;30:738–740.
8 Rao DS, Modithaya BS, Gonsalves RA. Carboxylic acids. In:
Rao DS, ed. Chemistry. Mangalore, India: Deepa Publications;
1998:330–350.
9 DeFelice J, Rumsfield J, Bernstein JE, et al. Clinical evaluation
of an after-pediculicide nit removal system. Int J Dermatol.
1989;28:468–470.
10 Formic acid. In: Reynolds JEF, ed. Martindale, the Extra Pharmacopoeia. 31st ed. London, England: Royal Pharmaceutical
Society; 1996:1707.
11 Tagami H, Ogino A, Takigawa M, et al. Regression of plane warts
following spontaneous inflammation. An histopathological study.
Br J Dermatol. 1974;90:147–154.
12 Lee AN, Mallor SB. Contact immunotherapy with squaric acid
dibutylester for the treatment of recalcitrant warts. J Am Acad
Dermatol. 1999;41:595–599.
March/April 2010
Hydrocortisone Butyrate 0.1% Lipocream in
Pediatric Patients With Atopic Dermatitis
William Abramovits, MD;1,2,3 Marcial Oquendo, MD3
Abstract
Only a few corticosteroids for topical use have proven safe and effective in pediatric populations down to 3 months of age. The authors
report the results of a study designed to assess the efficacy and safety of hydrocortisone butyrate (HCB) 0.1% in lipocream (LCr) vehicle in
infants and children. A total of 264 boys and girls 3 months to less than 18 years old, with stable, mild to moderate atopic dermatitis affecting at least 10% body surface area applied HCB 0.1% in LCr or LCr alone twice daily for up to 1 month without occlusion. Primary endpoints included: percent of patients who achieved treatment success based on physician global assessments. Secondary endpoint included:
difference in pruritus and Eczema Area and Severity Index (EASI) at day 29. Treatment was significant (P<0.001) for HCB 0.1% LCr over
vehicle. No serious nor significant adverse events were reported. Results are representative of a short duration treatment for a chronic disease.
HCB 0.1% in LCr is more effective than its vehicle in pediatric populations down to 3 months of age without significant adverse events
when used twice a day for up to 1 month. (SKINmed. 2010;8:72–79)
A
topic dermatitis (AD) is a pruritic disease characterized by
chronic or relapsing eczema in a pattern of distribution that
is linked to the age of the patient as essential features, with
xerosis, atopy (immunoglobulin E reactivity), and early age of onset
as important features, and an array of associated features.1,2
Methods
Trial Design
AD is the most common chronic inflammatory skin condition of
the pediatric population, affecting 2%–20% of infants and children in the United States, drastically impacting quality of life.3
The efficacy and safety of HCB 0.1% lipocream (LCr) for the
treatment of AD was investigated in a phase 3 multicenter, randomized, double blinded vehicle-control study. Patients were enrolled from July 6, 2005 to May 17, 2006. Prior signed consent
was obtained from legal representation, according to national
regulations. The trial was submitted to the Food and Drug Administration as a sponsor-initiated investigation on a new drug
presentation for the pediatric population (Figure 1).
Hydrocortisone butyrate (HCB), the active molecule in the study
drug is a synthetic, nonfluorinated glucocorticosteroid (GC) approved for topical use for the relief of inflammatory and pruritic
manifestations of corticosteroid-responsive dermatoses. The formulation used in this study is the same approved and marketed for
adult use since 1997. It is ranked, in a I to VII potency scale that
utilizes a vasoconstriction assay, as lower mid-strength class V.4,5
Study Population
Corticosteroids for topical use are absorbed and act locally inducing phospholipase A2 inhibitory proteins that control the
biosynthesis of inflammation mediators such as prostaglandins
and leukotrienes. Absorption can be enhanced occlusion, application over extensive areas, or where the skin barrier function
is compromised. With increased absorption the risk of systemic
side effects rises.6–9
Two hundred sixty-four pediatric patients aged 3 months to less
than 18 years were enrolled into the study. Analyses were conducted on the intent-to-treat (ITT) population (all participants
receiving study drug) for efficacy and safety, with supportive efficacy analyses on the per-protocol population.
Demographic and Other Baseline Characteristics
Age averaged 7.08 years across both treatment groups with age
of the HCB 0.1% LCr group averaging 7.37 years and the age of
vehicle-treated participants averaging 6.80 years.
From the Department of Medicine, Baylor University Medical Center;1 the Departments of Dermatology and Family Practice, University of
Texas Southwestern Medical School;2 and the Dermatology Treatment and Research Center,3 Dallas, TX
Address for Correspondence: William Abramovits, MD, Dermatology Treatment and Research Center, 5310 Harvest Hill Road, Suite 160,
Dallas, TX 75230 • E-mail: dra@dermcenter.us
72
March/April 2010
ORIGINAL
CONTRIBUTION
Figure
1 - Trial
Design
Overall, 57% of participants included in the ITT population were
boys (150/264) and 43% were girls (114/264). The distribution
of race was predominantly white in both treatment groups (64%,
168/264) with the majority of non-Hispanic/non-Latino descent
(80%, 212/264). Analyses were conducted to test for differences in
population characteristics between the 2 treatment groups. There was
not a significant difference between treatment groups for the comparison of age (P=0.414), gender (P=0.690), or ethnicity (P=0.114).
Randomization
Treatment duration and patient visits
Multi-center
(15 US sites)
Randomized
(1:1 ratio)
HCB lipocream 0.1% (n=131)
Double blind
Vehicle (n=133)
Parallel group
Days
1
8
Baseline
Visit
Follow-up
Visit
15
22
29
Follow-up
Visit
Final
Visit
Vehicle
controlled
The treatment groups were comparable for the baseline char-Adapted Figure
1. Trial design. HCB indicates hydrocortisone butyrate.
from Abramovits W, Connelly EA, Breneman D, et al. Unpublished data 2007.
Adapted with permission from Abramovits W, Connelly EA,
acteristics of Physician’s Global Assessment (PGA) (P=0.781),
Breneman D, et al., unpublished data, 2007.
pruritus (P=0.421), erythema (P=0.619), induration/papulation
(P=0.659), excoriations (P=0.936), lichenification (P=0.707),
Table I. Physician’s Global Assessment (PGA) Score and
oozing/crusting (P=0.737), scaling (P=0.540), total percent body
Description
surface area (BSA) affected (P=0.920), and Eczema Area and Severity Index (EASI) score (P=0.821). Overall, 39% of participants
Score Category Definition
included in the ITT population (103/264) were assessed as mild
No inflammatory signs of atopic
0
Clear
on the PGA scale and 61% were moderate (161/264). Two perdermatitis
cent of participants (2/264) had no pruritus, 30% had mild pruFaint, barely detectable erythema and/
ritus (79/264), 54% had moderate pruritus (142/264), and 15%
or trace residual induration/papulation
1
Almost clear
had severe pruritus (39/264). The majority of participants had
in limited areas; neither excoriation nor
oozing/crusting are present
mild to moderate erythema (93%, 247/264), mild to moderate
induration/papulation (92%, 243/264), mild to moderate excoLight pink erythema and slightly
riations (77%, 201/264), mild to moderate lichenification (78%,
2
Mild
perceptible induration/papulation;
excoriation, if present, is mild
207/264), none to mild oozing/crusting (81%, 214/264), and
mild to moderate scaling (76%, 203/264). Overall, the mean total
Dull red, clearly distinguishable
erythema and clearly perceptible
percent BSA was 22.58%±13.69% (range: 10%–94%).
3
Moderate
4
Severe 2 - Primary
extensive induration/papulation;
excoriation
Figure
Efficacy Endpoint:
and oozing/crusting
present
Treatment
Success atareDay
29
Clinical Diagnostic Criteria
The 3 major diagnostic criteria for entry into the study included:
1. Participant had a clinical diagnosis of stable, mild to moderate AD defined by the criteria per Hanifin and Rajka.2,10–12
2. Participant’s severity of AD according to the PGA scale was
2 or 3 (Table I).
induration/papulation but not extensive;
excoriation or oozing/crusting, if
present, are mild to moderate
Deep/dark red erythema, and marked and
Dichotomized PGA at Day 29 (ITT)
Day 29 PGA
3. A minimum percent surface area involvement of at least
10% BSA.
Success
Failure
a
HCB 0.1% lipocream
(n=131)
Vehicle cream
(n=133)
82 (63%)
49 (37%)
37 (28%)
96 (72%)
P-valueb
<0.001
* intent to treat
Figure
2. Primary efficacy endpoint: treatment success at
Last observation carried forward was used to impute missing data prior to dichotomization.
The PGA
for each
was dichotomized
“success”
and “failure”
Day 29
day
29.
ITTsubject
indicates
intentto to
treat;
HCB,at hydrocortisone
P-Value from a Cochran-Mantel-Haenszel Test, stratified by analysis center
butyrate; PGA, Physician’s Global Assessment. aLast
Abramovits W, Connelly EZ, Breneman D, et al. Unpublished data 2007.
observation carried forward was used to impute missing data
prior to dichotomization. The PGA for each participant was
dichotomized to “success” and “failure” at day 29. bP value
from a Cochran-Mantel-Haenszel Test, stratified by analysis
center. Reproduced with permission from Abramovits W,
Connelly EA, Breneman D, et al., unpublished data, 2007.
Treatment
a
HCB LCr 0.1% or vehicle was to be applied to the affected areas
twice daily for up to 1 month, without occlusive dressing.
A participant was considered compliant with the dosing regimen
if the participant did not miss more than 4 consecutive doses
and applied at least 75% of the expected number of applications of study medication. If the participant was confirmed clear
at day 21, then the expected number of applications was 42.
If a participant was not confirmed clear at day 21 and was to
continue dosing to the end of the day 29 treatment period, the
expected number of applications was 56.
b
73
Of the ITT participants, those who dosed with HCB LCr 0.1%
applied, on average, 51.4±9.3 doses of study medication. Of
these participants, 123/131 (94%) were compliant with the
Figure 3March/April
- Secondary
Efficacy Endpoints:
2010
Change in Pruritus from baseline to Day 29*
Overall pruritus was assessed and documented at the baseline visit
and each subsequent visit (excluding day 15) using a 4-point numerical scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe.
Pruritus was assessed by the primary caregiver, in discussion with the
participant or legal custodian, and concerned the intensity of overall
pruritus/scratching/discomfort in the 24 hours prior to the visit.
Significant treatment effect favoring HCB 0.1% lipocream (P b <0.001)
Day 29: Change from
Baseline Pruritus Scorea
HCB 0.1% lipocream
(n=131)
Vehicle cream
(n=133)
0 (0%)
0 (0%)
3 (2%)
23 (18%)
0 (0%)
2 (2%)
7 (5%)
52 (39%)
49 (37%)
47 (36%)
9 (7%)
45 (34%)
25 (19%)
2 (2%)
Pruritus worsened
-3
-2
-1
0 (no change)
Pruritus improved
1
2
3
Efficacy Results
The primary efficacy endpoint was the percentage of participants
who achieved treatment success based upon the dichotomized
PGA at the final day 29 visit using the 5-point ordinate PGA
scale. Treatment success was defined as those participants with a
final PGA score of 0 or 1 that had a 2-point or more reduction
from baseline to day 29.
* intent to treat
a
Last observation carried forward was used to impute missing data prior to analysis
The PGA for each subject was dichotomized to “success” and “failure” at Day 29
b
P-Value from a Cochran-Mantel-Haenszel Test, stratified by analysis center
Mean % BSA Affected
Figure 3. Secondary efficacy endpoints: change in pruritus
from baseline to day 29 (intent-to-treat patients). HCB indicates
hydrocortisone butyrate. aLast observation carried forward was
Adapted from Abramovits W, Connelly EA, Breneman D, et al. Unpublished data 2007.
used to impute missing data prior to analysis. bP value from
a Cochran-Mantel-Haenszel Test, stratified by analysis center.
Adapted with permission from Abramovits W, Connelly EA,
Breneman D, et al., unpublished data, 2007.
30
In the HCB 0.1% LCr group, 82/131 participants (63%) were
considered a “success,” compared to 37/133 participants (28%)
in the vehicle group, which resulted in a significant treatment
effect (P<0.001) in favor of HCB 0.1% LCr (Figure 2).
HCB 0.1%
Vehicle
25
The secondary endpoint was the change from baseline in pruritus
score at day 29. In the ITT analysis, the change in pruritus ranged
from –1 to 3 within the HCB 0.1% LCr group and –2 to 3 in the
vehicle group. There was a significant treatment effect (P<0.001)
in favor of HCB 0.1% LCr. In the HCB 0.1% LCr group, pruritus worsened by 1 grade in 2% of participants, showed no change
in 18% of participants, showed a 1-grade improvement in 37% of
participants, a 2-grade improvement in 36% of participants, and a
3-grade improvement in 7% of participants. In the vehicle group,
pruritus worsened by 2 grades in 2% of participants, worsened by
1 grade in 5% of participants, showed no change in 39% of participants, showed a 1-grade improvement in 34% of participants,
a 2-grade improvement in 19% of participants, and a 3-grade improvement in 2% of participants (Figure 3).
20
15
10
5
0
1
8
15
22
29
Day
Figure
4. Body
surface
area
(BSA)
Last observation
carried forward
was used
to impute
missinginvolvement.
data prior to analysis. Mean percent
P-Value and least squares means and standard deviations resulted from
BSA
BSA)with
affected
at each
evaluation
(intent to treat). HCB
analysis(%
of variance
factors of treatment
and analysis
center.
Adapted
from Abramovits
W, Connelly EA, Breneman D, butyrate.
et al. Unpublished data
2007. observation carried
indicates
hydrocortisone
Last
forward was used to impute missing data prior to analysis. P
value and least squares means and standard deviations resulted
from analysis of variance with factors of treatment and analysis
center. Reproduced with permission from Abramovits W,
Connelly EA, Breneman D, et al., unpublished data, 2007.
a
dosing regimen. Participants in the vehicle group applied, on
average, 50.8±12.7 doses of study medication. Of these participants, 124/133 (93%) were dosing compliant.
Assessments of signs/symptoms and area involvement by body region was measured at the baseline visit and each subsequent visit
(excluding day 15), the investigator assessed the severity of the individual signs for the overall body and of each body region (head and
neck, upper limbs, trunk, and lower limbs). The individual signs of
erythema, induration/papulation, lichenification, and excoriation
were rated using a 4-point scale, where 0 = none, 1 = mild, 2 =
moderate, and 3 = severe. Individual signs of oozing/crusting and
scaling for the overall body were rated using the same scale.
Efficacy Grading Scales
In the HCB 0.1% LCr ITT group, percent change in EASI scores
averaged 84.2% compared to the vehicle group, which averaged
45.3%. There was a significant treatment effect (P<0.001) in favor of HCB 0.1% LCr.
Primary: At the baseline visit and each subsequent visit, the investigator assessed the overall disease severity using a 5-point PGA (Table I).
Secondary: Assessments of lesion severity and percent of BSA involvement were made for the overall body and for each body region.
The scores of these assessments were used to calculate the EASI.
74
Figure 4 graphs the mean BSA affected at each evaluation for
the ITT population. Summary statistics are also presented for
March/April 2010
Table II. Summary Statistics for the Signs and Symptoms of Atopic Dermatitis (Intent-to-Treat Participants) (1 of 2)
Baseline
Day 8
Day 22
Day 29
None
1 (1%)
15 (11%)
24 (18%)
67 (51%)
Mild
37 (28%)
79 (60%)
90 (69%)
54 (41%)
Moderate
84 (64%)
35 (27%)
14 (11%)
9 (7%)
Severe
9 (7%)
2 (2%)
3 (2%)
1 (1%)
None
0 (0%)
3 (2%)
11 (8%)
30 (23%)
Mild
35 (26%)
52 (39%)
69 (52%)
50 (38%)
Moderate
91 (68%)
72 (54%)
46 (35%)
44 (33%)
Severe
7 (5%)
6 (5%)
7 (5%)
9 (7%)
None
6 (5%)
27 (21%)
48 (37%)
79 (60%)
Mild
40 (31%)
77 (59%)
75 (57%)
44 (34%)
Moderate
79 (60%)
25 (19%)
5 (4%)
5 (4%)
Severe
6 (5%)
2 (2%)
3 (2%)
3 (2%)
None
4 (3%)
9 (7%)
22 (17%)
41 (31%)
Mild
40 (30%)
64 (48%)
68 (51%)
52 (39%)
Moderate
84 (63%)
58 (44%)
38 (29%)
35 (26%)
Severe
5 (4%)
2 (2%)
5 (4%)
5 (4%)
None
31 (24%)
83 (63%)
104 (79%)
110 (84%)
Mild
52 (40%)
37 (28%)
19 (15%)
16 (12%)
Moderate
44 (34%)
10 (8%)
8 (6%)
5 (4%)
Severe
4 (3%)
1 (1%)
0 (0%)
0 (0%)
None
26 (20%)
45 (34%)
66 (50%)
68 (51%)
Mild
63 (47%)
50 (38%)
41 (31%)
41 (31%)
Moderate
42 (32%)
36 (27%)
22 (17%)
19 (14%)
Severe
2 (2%)
2 (2%)
4 (3%)
5 (4%)
Erythema
Active
(n=131)
Vehicle
(n=133)
Induration/papulation
Active
(n=131)
Vehicle
(n=133)
Excoriations
Active
(n=131)
Vehicle
(n=133)
the percent change from baseline in BSA affected at each postbaseline evaluation. In the HCB 0.1% LCr group, BSA averaged 22.5% at baseline and decreased 82.1% at day 29 to 4.2%.
In the vehicle group, BSA averaged 22.6% at baseline and decreased 43.6% at day 29 to 14.0%.
Safety Results
Table II presents summary statistics for the signs of AD at each
evaluation for the ITT population. Figures 5 and 6 graph the
average scores of signs and symptoms of AD including erythema, induration/papulation, excoriations, lichenification, oozing/
crusting, and scaling for the ITT population at each evaluation.
In the vehicle group, 28/131 participants (21%) reported a
total of 42 adverse events, none of which (0%) was serious.
Thirty-two of 42 events (76%) were of mild severity, 10/42
events (24%) were of moderate severity, and none (0%) was
severe (Table III).
75
In the HCB 0.1% LCr group, 29/131 participants (22%) reported a total of 46 adverse events, none of which (0%) was serious.
Thirty-four of 46 events (74%) were of mild severity, 12/46 (26%)
events were of moderate severity, and none (0%) was severe.
March/April 2010
Table II. Summary Statistics for the Signs and Symptoms of Atopic Dermatitis (Intent-to-Treat Participants) (2 of 2)
Baseline
Day 8
Day 22
Day 29
None
79 (60%)
105 (80%)
119 (91%)
123 (94%)
Mild
25 (19%)
21 (16%)
9 (7%)
6 (5%)
Moderate
26 (20%)
5 (4%)
3 (2%)
2 (2%)
Severe
1 (1%)
0 (0%)
0 (0%)
0 (0%)
None
81 (61%)
91 (68%)
98 (74%)
98 (74%)
Mild
29 (22%)
25 (19%)
20 (15%)
23 (17%)
Moderate
20 (15%)
15 (11%)
12 (9%)
8 (6%)
Severe
3 (2%)
2 (2%)
3 (2%)
4 (3%)
None
20 (15%)
61 (47%)
77 (59%)
97 (74%)
Mild
43 (33%)
50 (38%)
49 (37%)
3I (24%)
Moderate
56 (43%)
19 (15%)
3 (2%)
3 (2%)
Severe
12 (9%)
1 (1%)
2 (2%)
0 (0%)
None
20 (15%)
39 (29%)
62 (47%)
66 (50%)
Mild
48 (36%)
52 (39%)
40 (30%)
39 (29%)
Moderate
56 (42%)
38 (29%)
25 (19%)
23 (17%)
Severe
9 (7%)
4 (3%)
6 (5%)
5 (4%)
None
22 (17%)
55 (42%)
74 (56%)
95 (73%)
Mild
40 (31%)
48 (37%)
45 (34%)
27 (21%)
Moderate
64 (49%)
28 (21%)
10 (8%)
8 (6%)
Severe
5 (4%)
0 (0%)
2 (2%)
1 (1%)
None
22 (17%)
37 (28%)
45 (34%)
53 (40%)
Mild
43 (32%)
50 (38%)
55 (41%)
48 (36%)
Moderate
60 (45%)
45 (34%)
29 (22%)
27 (20%)
Severe
8 (6%)
1 (1%)
4 (3%)
5 (4%)
Oozing/crusting
Active
(n=131)
Vehicle
(n=133)
Scaling
Active
(n=131)
Vehicle
(n=133)
Lichenification
Active
(n=131)
Vehicle
(n=133)
In the HCB 0.1% LCr group, 29/131 participants (22%) reported at least one adverse event compared to 28/133 participants
(21%) in the vehicle group. The difference between treatment
groups was not statistically significant (P=0.319). No serious
adverse events related to study drug were reported. The majority of reports of the severity of adverse events were described as
mild, and none of the adverse events related to study drug were
reported as severe (Table IV).
ficacy and safety of HCB 0.1% LCr in a pediatric population
with mild to moderate AD.
Although hypothalamic-pituitary-adrenal suppression is common
in those AD patients receiving some potent topical GC preparations, it is rarely found in children or adolescents with AD who used
mild or moderately potent topical GC even over many years.13–19
Discussion
The efficacy and safety of topical GC in a pediatric population as
young as 3 months of age has been documented by studies that
withstand the rigors of evidence based medicine, they exist only
for a few preparations.20
This study provides an evidence based approach to assess the ef-
76
March/April 2010
On the other hand, the misuse of high potency topical GCs
in AD to the point of inducing Cushing’s syndrome, has been
repeatedly reported.21–23 The inappropriate use of high potency
topical GC by pediatricians has been a matter of concern.24
cutaneous signs of disease activity which include erythema, scaling,
induration, papulation, lichenification, oozing, crusting, and excoriations in a statistically significant way, but was able to do so without a
significantly increased risk for adverse events in a pediatric population.
Besides the relatively uncommon systemic adverse events reported with their use, topical GCs cause a significant array of application site reactions, these include: skin atrophy, telangiectasias,
striae distentiae, acneiform eruptions, folliculitis, erythema, irritation, contact dermatitis, and dyspigmentation.
Disclosure: The authors certify that there are no real or apparent
conflicts of interest.
References
1 Williams HC, Grindlay DJ. What’s new in atopic eczema? An analysis of systematic reviews published in 2007 and 2008. Part
1. Definitions, causes and consequences of eczema. Clin Exp
Dermatol. 2010;35:12–15. Epub Oct 23, 2009.
The results of this study support the contention that HCB 0.1% LCr
Signs and Symptoms
is not only effective in reducing the pruritus characteristic of AD, the
of Atopic Dermatitis
1.6
1.4
1.2
1.0
1.4
1.2
Day 29
1.2
0.8
0.9
0.6
0.7
0.9
0.6
0.4
0.4
0.2
0
Baseline
1.4
0.4
0.2
Excoriation
0.1% HCB
0.1
Excoriation
Vehicle
Lichenification
0.1% HCB
Lichenification
Vehicle
Oozing/
Crusting
0.1% HCB
Oozing/
Crusting
Vehicle
Figure 5. Signs and symptoms of atopic dermatitis. Based on mean values from physicians assessment scores. HCB indicates
hydrocortisone butyrate.
Signs and Symptoms of Atopic Dermatitis
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
1.8
1.8
1.5
Baseline
1.7
1.6
Day 29
1.4
1.2
1.0
0.8
0.6
0.5
0.3
Erythema
0.1% HCB
Erythema
Vehicle
Scaling
0.1% HCB
Scaling
Vehicle
Induration/
Papulation
0.1% HCB
Induration/
Papulation
Vehicle
Figure 6. Signs and symptoms of atopic dermatitis. Based on mean values from physicians assessment scores. HCB indicates
hydrocortisone butyrate.
77
March/April 2010
Table III. Summary of Participants With Adverse Events
(Intent-to-Treat Subjects) (1 of 3)
Number of events reported
Number of subjects reporting one or
more events
Activea
(n=131)
Vehicle
(n=133)
46
42
29 (22%)
28 (21%)
Serious
Yes
0 (0%)
0 (0%)
No
46 (100%)
42 (100%)
Mild
34 (74%)
32 (76%)
Moderate
12 (26%)
10 (24%)
0 (0%)
0 (0%)
Unassessable
0 (0%)
3 (7%)
Not related
41 (89%)
34 (81%)
Possible
4 (9%)
4 (10%)
Probable
1 (2%)
1 (2%)
14 (11%)
10 (8%)
Nasal congestion
7 (5%)
4 (3%)
Asthma
1 (1%)
2 (2%)
Cough
2 (2%)
1 (1%)
Nasal discomfort
0 (0%)
1 (1%)
Pharyngolaryngeal pain
0 (0%)
1 (1%)
Sinus congestion
2 (2%)
1 (1%)
Rhinorrhea
3 (2%)
0 (0%)
Vocal cord inflammation
1 (1%)
0 (0%)
Gastrointestinal disorders
6 (5%)
5 (4%)
Abdominal pain upper
0 (0%)
2 (2%)
Diarrhea
2 (2%)
2 (2%)
Gastroesophageal reflux disease
1 (1%)
1 (1%)
Vomiting
0 (0%)
1(1%)
Abdominal discomfort
3 (2%)
0 (0%)
General disorders and
administration site conditions
2 (2%)
5 (4%)
Application site dermatitis
0 (0%)
2 (2%)
Pyrexia
1 (1%)
2 (2%)
Severity of event
Severe
Relationship to study drug
System organ classb
Respiratory, thoracic, and
mediastinal disorders
Activea
(n=131)
Vehicle
(n=133)
Application site erythema
0 (0%)
1 (1%)
Application site urticaria
0 (0%)
1 (1%)
Application site irritation
1 (1%)
0 (0%)
Infections and infestations
11 (8%)
5 (4%)
Bacterial infection
0 (0%)
1 (1%)
Ear infection
3 (2%)
1 (1%)
Folliculitis
0 (0%)
1 (1%)
Sinusitis
0 (0%)
1 (1%)
Upper respiratory tract fraction
3 (2%)
1 (1%)
Viral rash
0 (0%)
1 (1%)
Application site folliculitis
1 (1%)
0 (0%)
Gastroenteritis viral
1 (1%)
0 (0%)
Otitis media
1 (1%)
0 (0%)
Pharyngitis streptococcal
1 (1%)
0 (0%)
Respiratory syncytial virus infection
1 (1%)
0 (0%)
Skin and subcutaneous tissue disorders
5 (4%)
4 (3%)
Telangiectasia
0 (0%)
2 (2%)
Ingrowing nail
0 (0%)
1 (1%)
Pruritus
0 (0%)
1 (1%)
Rash
1 (1%)
1 (1%)
Acne
1 (1%)
0 (0%)
Dermatitis diaper
1 (1%)
0 (0%)
Skin atrophy
1 (1%)
0 (0%)
Urticaria
1 (1%)
0 (0%)
0 (0%)
2 (2%)
Depression
0 (0%)
1 (1%)
Insomnia
0 (0%)
1 (1%)
Sleep terror
0 (0%)
1 (1%)
0 (0%)
1 (1%)
0 (0%)
1 (1%)
0 (0%)
1 (1%)
0 (0%)
1 (1%)
0 (0%)
1 (1%)
0 (0%)
1 (1%)
Psychiatric disorders
Ear and labyrinth disorders
Ear pain
Immune system disorders
Hypersensitivity
Injury, poisoning, and procedural
complications
Accident
78
March/April 2010
2 Abramovits W. Atopic dermatitis. J Am Acad Dermatol.
2005;53(1 suppl 1):S86–93.
3 Williams H, Stewart A, von Mutius E, et al. Is eczema really on the
increase worldwide? J Allergy Clin Immunol. 2008;121:947–954.
4 Locoid Lipocream Package Insert. Ferndale Laboratories, Inc.
Ferndale, MI 48220.
Congenital, familial, and genetic
disorders
7 Drake LA, Dinehart SM, Farmer ER. Guidelines of care for
the use of topical glucocorticosteroids. J Am Acad Dermatol.
1996;35:615–619.
Nervous system disorders
10 Hanifin JM, Thurston M, Omoto M, et al. The eczema area and
severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;10:11–18.
11 Brenninkmeijer EE, Schram ME, Leeflang MM, et al. Diagnostic
criteria for atopic dermatitis: a systematic review. Br J Dermatol. 2008;158:754–765. Epub Jan 30, 2008.
14 Eichenflied LF, Basu S, Calvarese B, et al. Effect of desonide
hydrogel 0.05% on the hypothalamic-pituitary-adrenal axis in
pediatric subjects with moderate to severe atopic dermatitis.
Pediatr Dermatol. 2007;24:289–295.
15 Hebert AA, Cook-Bolden FE, Basu S, et al. Safety and efficacy
of desonide hydrogel 0.05% in pediatric subjects with atopic
dermatitis. J Drugs Dermatol. 2007;6:157–181.
16 Hebert AA, Friedlander SF, Allen DB. Topical fluticasone propionate lotion does not cause HPA axis suppression. J Pediatr.
2006;149:378–382.
1 (1%)
0 (0%)
1 (1%)
1 (1%)
0 (0%)
1 (1%)
0 (0%)
2 (2%)
0 (0%)
2 (2%)
0 (0%)
Ichthyosis
Headache
Hydrocortisone butyrate 0.1% lipocream. Counts reflect numbers
of subjects in each treatment group reporting one or more adverse
events that map to the MedDRA system organ classes. At each level of
summarization (system organ class or event), subjects are only counted
once. Percentages of subjects in each treatment group are also given.
a
b
Table IV. Summary of the Number of Participants With
Adverse Events by Relationship (Possible or Probable)
to Study Medication
Activea
(n=131)
Vehicle
(n=133)
Application site folliculitis
1 (1%)
0 (0%)
Application site irritation
1 (1%)
0 (0%)
Application site dermatitis
0 (0%)
1 (1%)
Application site erythema
0 (0%)
1 (1%)
Acne
1 (1%)
0 (0%)
Telangiectasia
0 (0%)
1 (1%)
12 Ricci G, Dondi A, Patrizi A. Useful tools for the management of
atopic dermatitis. Am J Clin Dermatol. 2009;10:287–300.
13 Dohil MA, Alvarez-Connelly E, Eichenfield LF. Fluocinolone acetonide 0.01% in peanut oil: safety and efficacy data in the treatment of childhood atopic dermatitis in infants as young as 3
months of age. Pediatr Dermatol. 2009;26:262–268.
0 (0%)
Nodule on extremity
6 Aksoy MO, Li X, Borenstein M, et al. Effects of topical corticosteroids on inflammatory mediator-induced eicosanoid release by human airway epithelial cells. J Allergy Clin Immunol.
1999;103:1081–1091.
9 Hengge U, Ruzicka T, Schwartz R, et al. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54:1–15.
Vehicle
(n=133)
Musculoskeletal and connective
tissue disorders
5 Fowler JF Jr, Fransway AF, Jackson JM, et al. Hydrocortisone butyrate 0.1% cream in the treatment of chronic dermatitis. Cutis.
2005;75:125–131.
8 Cook D. FDA experience: topical corticosteroids and HPA axis suppression. Pediatric subcommittee of the AIDAC. Oct. 29–30, 2003.
Activea
(n=131)
a
Hydrocortisone butyrate 0.1% lipocream.
atrics. 2000;105(4 pt 1):794–799.
17 Friedlander SF, Hebert AA, Allen DB. Safety of fluticasone propionate cream 0.05% for the treatment of severe and extensive
atopic dermatitis in children as young as 3 months. J Am Acad
Dermatol. 2002;46:387–393.
18 Moshang T. Prednicarbate emollient cream 0.1% in pediatric
patients with atopic dermatitis. Cutis. 2001;68:63–69.
19 Lucky AW, Grote GD, Williams JL, et al. Effect of desonide ointment, 0.05%, on the hypothalamic-pituitary-adrenal axis of children with atopic dermatitis. Cutis. 1997;59:151–153.
20 Ellison JA, Patel L, Ray DW, et al. Hypothalamic-pituitary-adrenal
function and glucocorticoid sensitivity in atopic dermatitis. Pedi-
79
21 Coureau B, Bussieres JF, Tremblay S. Cushing’s syndrome induced
by misuse of moderate- to high-potency topical corticosteroids.
Ann Pharmacother. 2008;42:1903–1907. Epub Nov 18, 2008.
22 Güven A, Gülümser O, Ozgen T. Cushing’s syndrome and adrenocortical insufficiency caused by topical steroids: misuse or
abuse? J Pediatr Endocrinol Metab. 2007;20:1173–1182.
23 Ozon A, Cetinkaya S, Alikasifoglu A, et al. Inappropriate use of
potent topical glucocorticoids in infants. J Pediatr Endocrinol
Metab. 2007;20:219–225.
24 Fleischer AB Jr, Feldman SR. Prescription of high-potency corticosteroid agents and clotrimazole-betamethasone dipropionate
by pediatricians. Clin Ther. 1999;21:1725–1731.
March/April 2010
Evaluation of an Onion Extract,
Centella Asiatica, and Hyaluronic Acid Cream
in the Appearance of Striae Rubra
Zoe Diana Draelos, MD;1 Michael H. Gold, MD;2 Mandeep Kaur, MD;3 Babajide Olayinka, MSc;3
Starr L. Grundy, BScPharm;3 Eric J. Pappert, MD;3 Bhushan Hardas, MD, PhD3
Abstract
This study evaluated the effect of an onion extract cream with Centella asiatica and hyaluronic acid in improving the appearance of striae
rubra (SR). Women participants with bilateral, outer aspect of the thigh SR were randomized to apply a quarter-sized amount of the onion
extract cream twice daily for 12 weeks to the randomized left or right, outer aspect of the thigh. No treatment was administered to the contralateral side. Participants were evaluated at weeks 2, 4, 8, and 12. Primary efficacy endpoints included color, texture, softness, and overall
appearance of SR by the participant and investigator at week 12. The treated thigh demonstrated a statistically significant difference in the
mean change in participant and investigator evaluations in overall appearance, texture, color, and softness compared with the untreated
thigh at week 12. No adverse events occurred during the study. The onion extract cream was well tolerated and significantly improved the
appearance of SR in women. (SKINmed. 2010;8:80–86)
S
tretch marks, also known as striae distensae, are a common concern for post-pubertal men and women patients seeking dermatologic care. They appear as linear thinned skin most often
found on the breasts, abdomen, hips, and thighs.1 Stretch marks may
appear due to the rapid hormonal changes and growth associated with
puberty, during pregnancy, or with medical diseases, such as Cushing
syndrome. Under the microscope, they appear as dermal atrophy accompanied by loss of the rete ridges, a finding similar to scar tissue.2,3
The development of striae distensae has been described as similar to
that of wound healing or scar formation.2,3 Earlier stage or immature striae distensae, also known as striae rubra, appear pink or red in
color and over time become white, flat, and depressed, known as striae
alba.2 There is no clear consensus as to the cause of striae distensae.2
ever, some trials have yielded variable results.9–14 Camouflage is
often selected as the best option for treatment to hide the scars.15
In addition to physician administered stretch mark therapies, a variety of over-the-counter products can be purchased for improving
stretch mark appearance. These products contain cocoa butter, emu
oil, vitamin E, and other oils to apply while massaging the stretch
marks. Many dermatologists recommend massaging the stretch
mark in a circular motion with oil on the finger to reduce friction
and make the skin more pliable, improving appearance—although
no evidence exists for this recommendation. Researchers published
on the lack of evidence for topical ointments and creams in stretch
mark improvement (ie, diminution of the signs for striae).2
The treatment for stretch marks is limited.2 The most invasive
therapies for stretch marks involve physician administered laser
surgery. Improvement in stretch marks (ie, diminution of the signs
for striae) with laser therapy is accomplished by wounding the
scarred skin and hoping that the newly healed skin will have a
more normal, cosmetically acceptable appearance.4 Medical reports of Nd:YAG laser,5 radiofrequency devices,6 and fractional
photothermolysis,7,8 have shown some degree of stretch mark appearance improvement, but not resolution. Topical tretinoin is the
best studied topical stretch mark pharmaceutical product, how-
Red, immature stretch marks are more amenable to treatment than
those that have matured to a silvery white. This is because the reddish stretch marks are still healing and the healing can be modified
by intervention. One botanical ingredient that has been studied in
the treatment of scars is onion extract. Onion extract possesses in vitro antiinflammatory properties due to cepanes, a flavonoid unique
to onions.16 In addition, onion extract contains sulfur in the form
of thiosulfinates accounting for its in vitro antiinfective properties,16
fibrinolytic effects,17 and antimicrobial activity against Gram-positive bacteria.18,19 A proprietary onion extract gel has been shown to
From the Department of Dermatology, Duke University School of Medicine, Durham, NC;1 the Department of Dermatology, Vanderbilt University
School of Medicine, Nashville, TN;2 and Merz Pharmaceuticals, LLC, Greensboro, NC3
Address for Correspondence: Zoe Diana Draelos, MD, 2444 North Main Street, High Point, NC 27262 • E-mail: zdraelos@northstate.net
80
March/April 2010
improve the appearance of post-surgical shave excision scars.20 Another botanical with in vitro and in vivo efficacy in scars21,22 and stretch
marks (data on file, Merz Pharmaceuticals, LLC) is Centella asiatica.
Centella asiatica, also known as Indian pennywort, is a plant found
in Asia, Africa, and North and South America used widely in Indian naturopathic medicine for ulcer healing. It contains asiaticoside,
which is purported to increase the production of collagen I enhancing
wound healing and scar maturation. The leaves are harvested, dried,
and 95% ethanol extracted to obtain the medicinal botanical.
sent, and investigator screening, study participants were randomized
to apply a quarter-sized amount of the onion extract cream twice daily
for 12 weeks to either the assigned right or left thigh. The opposite
thigh received no treatment. Participants returned to the study center
for evaluation at weeks 2, 4, 8, and 12. Participant and investigator assessments were obtained regarding striae rubra softness, texture, color,
and overall appearance. Standardized digital photography (Nikon E3,
Canfield, NJ) by the investigator with a fixed focal length and exposure of the right and left striae rubra was obtained at each visit.
This research evaluated the effect of a formulation containing onion extract and Centella asiatica on newly formed striae rubra on
the proximal aspect of the thighs of women. The botanical extracts are contained in a moisturizing emollient vehicle containing
hyaluronic acid, a potent humectant aiding in the water holding
capacity of the skin and previously studied in wound healing.23
Noninvasive Assessments
MethodS
Skin elasticity was selected as the most appropriate noninvasive
assessment parameter for striae rubra. This evaluation was included to determine if the study product modified the recoil of
the skin. Skin elasticity measurements were obtained via a negative pressure suction device (DermaLab, Hadsund, Denmark).
The device functioned by applying negative pressure to the skin
until distended into a suction cup with a light beam across the
top of the cup. When the skin was adequately distended, the
light beam was interrupted, the negative suction discontinued,
and the skin relaxation evaluated. This cycle was repeated and
recorded to obtain 5 distention and relaxation curves.
Materials
All participants applied the study onion extract cream (Mederma for Stretch Marks, Merz Pharmaceuticals, LLC, Greensboro, NC) to one randomized thigh and no treatment to the
other thigh. No placebo cream was utilized in this study. Adverse
events were captured for the safety analysis.
Clinical Efficacy Parameters
Participant Selection and Study Design
Clinical efficacy was based on the unblinded participant assessments and the blinded investigator assessments comparing the
treated to the untreated striae rubra both visually and tactilely.
The primary efficacy parameter was the participant assessment of
striae rubra softness, texture, color, and overall appearance of the
untreated vs treated striae rubra at 12 weeks using a 5-point ordinal scale: 0 = no improvement, 1 = minimal improvement, 2 =
mild improvement, 3 = moderate improvement, and 4 = marked
improvement. The secondary efficacy outcomes included participant assessment of striae rubra softness, texture, color, and
overall appearance at weeks 2, 4, and 8 using a 5-point ordinal
scale; physician assessment of striae rubra using a 5-point ordinal
scale at all visits; and noninvasive skin elasticity measurements.
This randomized, controlled, investigator-blinded, institutional review board approved study (Concordia Clinical Research, Institutional Review Board, Cedar Knolls, NJ) was conducted at one site
in the United States from November 2008 to March 2009. The
study was performed in accordance with globally accepted standards
of Good Clinical Practice (as defined by the May 1, 1996, International Council on Harmonisation E6 Guidelines for Good Clinical Practice). Women participants between the ages of 18 and 45
years having symmetrical striae rubra on the proximal aspect of the
thighs were enrolled since it was felt that mature striae alba would
not be amenable to improvement. Participants with known allergies
or sensitivities to the study ingredients, history of keloids or hypertrophic scars, excessive sun exposure, pregnancy, breast feeding, and
treatment with an investigational drug or device within a period of
30 days prior to the study were excluded. In addition, participants
with any systemic or dermatologic disorder that, in the opinion of
the investigator, would interfere with the study, body mass index
above 30, prior surgical or prescription topical striae distensae were
excluded. Participants did not apply any products to the areas of
observation for 2 weeks prior to the initiation of therapy.
Statistical Methodology
After successful completion of Health Insurance Portability and Accountability Act authorization, informed consent, photography con-
The safety evaluation set was the subset of randomized participants who received study treatment at least once. The full analysis set was the subset of randomized participants who received
study treatment at least once and for whom at least one postbaseline value of efficacy was available. For all efficacy variables,
descriptive summary statistics and paired two-sided t tests with
confidence intervals were performed for each visit based on the
full analysis set. The post-baseline last observation carried forward method was used to impute missing post-baseline efficacy
variables. Baseline values were not imputed into follow-up visits.
81
March/April 2010
Table I. Summary of Changes From Baseline to Weeks 2, 4, 8, and 12 in Participant Assessment of Striae Rubra (FAS
Population, Last Observation Carried Forward)
Week
Treated
(Onion Extract Cream)
Untreated
Difference
(Treated–Untreated)
Week 2
n=50
n=50
n=50
Overall appearance, mean (SD)
0.56 (0.644)
0.10 (0.364)
0.46 (0.613)
<0.01
Color, mean (SD)
0.28 (0.701)
0.08 (0.566)
0.20 (0.452)
<0.01
Softness, mean (SD)
0.74 (0.922)
0.20 (0.670)
0.54 (0.813)
<0.01
Texture, mean (SD)
0.48 (0.814)
0.14 (0.606)
0.34 (0.626)
<0.01
n=54
n=54
n=54
1.15 (0.878)
0.15 (0.452)
1.00 (0.890)
<0.01
Color, mean (SD)
0.70 (0.882)
0.06 (0.231)
0.65 (0.894)
<0.01
Softness, mean (SD)
1.26 (0.894)
0.20 (0.528)
1.06 (1.054)
<0.01
Texture, mean (SD)
0.89 (0.883)
0.11 (0.317)
0.78 (0.945)
<0.01
n=54
n=54
n=54
0.94 (0.712)
0.20 (0.562)
0.74 (0.935)
<0.01
Color, mean (SD)
0.69 (0.773)
0.11 (0.462)
0.57 (0.924)
<0.01
Softness, mean (SD)
1.17 (0.795)
0.22 (0.538)
0.94 (0.979)
<0.01
Texture, mean (SD)
1.00 (0.777)
0.22 (0.604)
0.78 (0.984)
<0.01
n=54
n=54
n=54
1.13 (0.802)
0.20 (0.562)
0.93 (0.843)
<0.01
Color, mean (SD)
0.70 (0.792)
0.07 (0.328)
0.63 (0.784)
<0.01
Softness, mean (SD)
1.31 (0.865)
0.15 (0.408)
1.17 (0.986)
<0.01
Texture, mean (SD)
1.06 (0.856)
0.19 (0.552)
0.87 (0.848)
<0.01
Week 4
Week 8
Week 12
P Value
Paired t Test
Five-point ordinal scale (0 = no improvement, 1 = minimal improvement, 2 = mild improvement, 3 = moderate improvement, and 4 = marked
improvement). Abbreviations: FAS, full analysis population; SD, standard deviation.
Results
Fifty-five women participants between the ages of 18 and 45 years
were randomized. Fifty-two participants successfully completed the
trial (1 discontinued due to lack of compliance, 2 were lost to follow-up). Fifty-five participants were in the safety evaluation set population and 54 participants were in the full analysis set population.
For all of the participant assessment endpoints (overall appearance,
color, softness, and texture), the difference between the striae rubra
treated with the onion extract cream and the untreated side at week
12 were statistically significant using last observation carried forward
imputed values (Table I). There were statistically significant differences in the mean changes from baseline to weeks 2, 4, 8, and 12 in participant assessments of overall appearance, color, softness, and texture.
The mean change from baseline in the investigator assessments
were statistically significant (P<0.01) at all time points in terms of
overall appearance, softness, and texture on the side treated with
the onion extract cream than on the untreated side (Table II). At
weeks 2 and 4, no significant difference in mean change from
baseline in investigator assessment of color between the treated
and untreated sides was present. Representative photographs of
the treated and untreated sides are presented in the Figure.
A responder analysis was completed in which responders were defined as having at least a one-grade improvement from baseline in
the assessment (Table III). At each visit there were more responders on the side treated with onion extract cream vs the untreated
side as assessed by both the investigator and participant.
The mean baseline skin elasticity was 17.86 pounds per square inch
(psi) for the side treated with the onion extract cream and 16.82 psi
for the untreated side. After 12 weeks of treatment, a trend favoring
the use of the onion extract was observed with mean skin elasticity
82
March/April 2010
Table II. Summary of Changes From Baseline to Weeks 2, 4, 8, and 12 in Investigator Assessment of Striae Rubra
(FAS Population, Last Observation Carried Forward)
Week
Treated
Untreated
Difference
(Treated–Untreated)
Week 2
n=50
n=50
n=50
0.68 (0.741)
0.10 (0.303)
0.58 (0.859)
<0.01
Color, mean (SD)
0.02 (0.247)
0.02 (0.141)
0.00 (0.286)
1.000
Softness, mean (SD)
0.74 (0.723)
0.18 (0.388)
0.56 (0.884)
<0.01
Texture, mean (SD)
0.42 (0.758)
0.04 (0.198)
0.38 (0.805)
<0.01
n=54
n=54
n=54
1.06 (0.738)
0.20 (0.451)
0.85 (0.998)
<0.01
Color, mean (SD)
0.11 (0.420)
0.00 (0.000)
0.11 (0.420)
0.0570
Softness, mean (SD)
1.09 (0.759)
0.22 (0.462)
0.87 (1.047)
<0.01
Texture, mean (SD)
0.96 (0.800)
0.19 (0.438)
0.78 (1.022)
<0.01
n=54
n=54
n=54
1.48 (0.746)
0.17 (0.423)
1.31 (1.006)
<0.01
Color, mean (SD)
0.30 (0.633)
0.0 (0.0)
0.30 (0.633)
<0.01
Softness, mean (SD)
1.61 (0.763)
0.19 (0.438)
1.43 (1.021)
<0.01
Texture, mean (SD)
1.46 (0.818)
0.15 (0.408)
1.31 (1.043)
<0.01
n=54
n=54
n=54
1.72 (0.712)
0.09 (0.351)
1.63 (0.853)
<0.01
Color, mean (SD)
0.61 (0.627)
0.00 (0.00)
0.61 (0.627)
<0.01
Softness, mean (SD)
1.87 (0.825)
0.11 (0.317)
1.76 (0.970)
<0.01
Texture, mean (SD)
1.72 (0.738)
0.07 (0.328)
1.65 (0.872)
<0.01
Week 4
Week 8
Week 12
P Value
Paired t Test
Five-point ordinal scale (0 = no improvement, 1 = minimal improvement, 2 = mild improvement, 3 = moderate improvement, and 4 = marked
improvement). Abbreviations: FAS, full analysis population; SD, standard deviation.
decreasing by 1.40 psi for the treated side vs 0.10 psi for the untreated
side, but statistical significance was not reached (P=0.23).
There were no adverse events reported among the 55 participants
who participated in this trial.
DISCUSSION
In this randomized, controlled, investigator-blinded 12-week
study examining a cream containing onion extract, Centella asiatica, and hyaluronic acid, there was a statistically significant improvement in proximal aspect of the thigh striae rubra in terms
of overall appearance, softness, color, and texture as evaluated by
the participants and the investigator. Using participants with symmetrical striae rubra on the proximal aspect of the thighs allowed
each participant to serve as their own control. Improvement in
skin elasticity was not statistically significant between treated and
untreated sides; however, it is envisaged that perhaps with longer
use and/or an increase in the study sample size, the skin elasticity
measurement might achieve statistical significance.
It is important to recognize that this study demonstrated only improvement (ie, diminution of the signs for striae) in the feel and
appearance of striae rubra, not a reduction in their size or elimination of the scar tissue. Stretch marks are such a common occurrence
that it is hard to classify them as a dermatologic disease, yet they
are designated by an International Classification of Diseases, Ninth
Revision code. They typically occur in women and men at or around
puberty on the proximal, medial aspect of the arms, lateral aspect of
the breasts, lumbar region of the torso, and proximal aspect of the
thighs.24 A second common time for the formation of striae distensae is during pregnancy, again a time of hormonal change characterized by corticosteroid secretion. During pregnancy, striae distensae
83
March/April 2010
Figure. A photographic comparison of the untreated and proprietary onion-extract-cream–treated striae rubra (week 12). Patient
1: (A) right thigh, proprietary onion extract; (B) left thigh, no treatment. Patient 2: (C) right thigh, no treatment; (D) left thigh,
proprietary onion extract.
can occur in the previously mentioned locations, but also commonly on the abdomen. All of the women enrolled in this study had
striae rubra on the proximal aspect of the thighs due to pregnancy.
There are some important limitations of this research. The first
limitation is that the participants were not blinded to treatment,
which could lead to a bias toward the treated side. Since a moisturizing vehicle by itself could induce enhanced moisturization of
the skin and improve the appearance of the striae rubra, it was not
possible to have a true placebo controlled study. The investigator
was blinded, however the study compared some treatment to no
treatment. Some of the improvement noted with the study product might be due to hydration and massage; however, it is not possible to determine if the improvement may have been solely due to
these factors or due to the active ingredients in the study product.
The results are probably due to a combination of all factors.
claims. It is for this reason that it could only be formulated with
botanical ingredients, which contain active plant extracts. This
research methodology and the study cream combining onion
extract, Centella asiatica, and hyaluronic acid demonstrated improvement (ie, diminution of the signs for striae) in striae rubra
appearance in women.
Disclosure: This study was sponsored by Merz Pharmaceuticals, LLC.
This product was designed for use in the over-the-counter market and thus was only evaluated for appearance changes and
Acknowledgements: The authors want to acknowledge Wendy Murray of Merz Pharmaceuticals, LLC, for her project management of
this study and Wendy Jones of Merz Pharmaceuticals, LLC, for her
feedback on study design and regulatory questions.
84
References
1 Salter SA, Kimball AB. Striae gravidarum. Clin Dermatol.
2006;24:97–100.
2 Elsaie ML, Baumann LS, Elsaaiee LT. Striae distensae (stretch
marks) and different modalities of therapy: an update. Dermatol
Surg. 2009;35:563–573.
March/April 2010
Table III. Responder Analysis
Investigator Assessment
Participant Assessment
Week
Treated Side
Number of Responders,a n
Untreated Side
Treated Side
Untreated Side
Number of
Responders,a n
Week 2
n=50
n=50
n=50
n=50
Overall appearance
31
5
24
4
Color
18
2
17
4
Softness
2
1
10
1
Texture
34
9
25
6
n=54
n=54
n=54
n=54
Overall appearance
46
10
43
6
Color
41
9
35
6
Softness
6
0
26
3
Texture
46
11
44
8
n=54
n=54
n=54
n=54
Overall appearance
49
8
39
8
Color
46
7
40
8
Softness
13
0
27
4
Texture
49
9
44
9
n=54
n=54
n=54
n=54
Overall appearance
50
4
43
7
Color
50
3
38
3
Softness
29
0
27
7
Texture
50
6
45
4
Week 4
Week 8
Week 12
A participant that has at least a one-grade improvement from baseline in the assessment.
a
3 Atwal GS, Manku LK, Griffiths CE, et al. Striae gravidarum in
primiparae. Br J Dermatol. 2006;155:965–969.
4 McDaniel DH. Laser therapy of stretch marks. Dermatol Clin.
2002;20:67–76, viii.
5 Goldman A, Rossato F, Prati C. Stretch marks: treatment using
the 1,064-nm Nd:YAG laser. Dermatol Surg. 2008;34:686–691.
6 Manuskiatti W, Boonthaweeyuwat E, Varothai S. Treatment of
striae distensae with a TriPollar radiofrequency device: a pilot
study. J Dermatolog Treat. 2009;1–6 [Epub ahead of print].
7 Bak H, Kim BJ, Lee WJ, et al. Treatment of striae distensae with
fractional photothermolysis. Dermatol Surg. 2009;35:1215–1220.
8 Stotland M, Chapas AM, Brightman L, et al. The safety and efficacy of fractional photothermolysis for the correction of striae
distensae. J Drugs Dermatol. 2008;7:857–861.
9 Rangel O, Arias I, Garcia E, et al. Topical tretinoin 0.1% for
pregnancy-related abdominal striae: an open-label, multicenter,
prospective study. Adv Ther. 2001;18:181–186.
85
10 Ash K, Lord J, Zukowski M, et al. Comparison of topical therapy for
striae alba (20% glycolic acid/0.05% tretinoin versus 20% glycolic
acid/10% L-ascorbic acid). Dermatol Surg. 1998;24:849–856.
11 Kang S. Topical tretinoin therapy for management of early striae. J Am Acad Dermatol. 1998;39:S90–S92.
12 Elson ML. Use of tretinoin in female health practice. Int J Fertil
Womens Med. 1998;43:117–121.
13 Pribanich S, Simpson FG, Held B, et al. Low-dose tretinoin does
not improve striae distensae: a double-blind, placebo-controlled
study. Cutis. 1994;54:121–124.
14 Elson ML. Treatment of striae distensae with topical tretinoin. J
Dermatol Surg Oncol. 1990;16:267–270.
15 Tedeschi A, Dall’Oglio F, Micali G, et al. Corrective camouflage in
pediatric dermatology. Cutis. 2007;79:110–112.
16 Dorsch W, Schneider E, Bayer T, et al. Anti-inflammatory effects
of onions: inhibition of chemotaxis of human polymorphonuclear
leukocytes by thiosulfinates and cepaenes. Int Arch Allergy Appl
March/April 2010
Immunol. 1990;92:39–42.
17 Augusti KT. Therapeutic values of onion (Allium cepa L.) and
garlic (Allium sativum L.). Indian J Exp Biol. 1996;34:634–640.
18 Zohri AN, Abdel-Gawad K, Saber S. Antibacterial, antidermatophytic and antitoxigenic activities of onion (Allium cepa L.) oil.
Microbiol Res. 1995;150:167–172.
19 Dankert J, Tromp TF, de Vries H, et al. Antimicrobial activity
of crude juices of Allium ascalonicum, Allium cepa and Allium
sativum. Zentralbl Bakteriol Orig A. 1979;245:229–239.
20 Draelos ZD. The ability of onion extract gel to improve the cosmetic appearance of postsurgical scars. J Cosmet Dermatol.
2008;7:101–104.
21 Hong SS, Kim JH, Li H, et al. Advanced formulation and pharmacological activity of hydrogel of the titrated extract of C. asiatica. Arch Pharm Res. 2005;28:502–508.
22 Shetty BS, Udupa SL, Udupa AL, et al. Effect of Centella asiatica L (Umbelliferae) on normal and dexamethasone-suppressed
wound healing in Wistar Albino rats. Int J Low Extrem Wounds.
2006;5:137–143.
23 Chrit L, Bastien P, Biatry B, et al. In vitro and in vivo confocal
Raman study of human skin hydration: assessment of a new
moisturizing agent, pMPC. Biopolymers. 2007;85:359–369.
24 Weber FP. Idiopathic stria atrophicae of puberty. Lancet.
1935;226:1347.
HISTORICAL DIAGNOSIS & Treatment
Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of steroptic cards published
in 1910 by The Stereoscopic Skin Clinic, by Dr. S. I. Rainforth.
Synonyms: Rubeola; Measles
DIAGNOSIS: The length of the prodromal period, the catarrhal symptoms, the presence of Koplik’s spots, the swollen, blotchy appearance of the face,
the macular character and crescentic arrangement of the lesions, the prevalence of an epidemic and the nature of the disease from which the contagion
arose, are the points to be considered in a differential diagnosis from other exanthemata, drug rashes or syphilis.
TREATMENT: The patient should be put on a light diet, confined to bed, and isolated in a darkened but well ventilated room. The severe symptoms are
to be mitigated by appropriate symptomatic treatment and the patient is to be guarded against exposure, especially during convalescence.
86
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Cutaneous Manifestations of Systemic Conditions
Associated With Gynecomastia
Shailendra Kapoor, MD
Abstract
Gynecomastia involves enlargement of the male breast secondary to the proliferation of mammary ductules. It is seen in a number of conditions such as cirrhosis, chronic renal failure, Klinefelter syndrome, and leprosy. Recognition of the cutaneous manifestations of these conditions can help in identifying the correct etiology of the gynecomastia. (SKINmed. 2010;8:87–92)
G
ynecomastia is a benign condition that involves enlargement of the male breast secondary to the proliferation of mammary ductules. It is seen in one-third to
two-thirds of men.1 A prevalence rate of 15.2% was reported in
a recent study involving children 6 to 8 years of age who were
clinically followed for a period of 7 years.2
tations of some of these common systemic conditions that cause
secondary gynecomastia are discussed below.
PATHOGENESIS OF GYNECOMASTIA
Cirrhosis and chronic renal failure are the two most significant
causes of gynecomastia.
Ductal breast tissue in men is under the influence of circulating sex hormones especially estrogen and testosterone. These
hormones have opposite effects on ductal breast tissue. Thus,
while testosterone tends to decrease ductal breast tissue proliferation, estrogen tends to stimulate ductal breast tissue proliferation. Any alteration in the serum free levels of these hormones
disturbs the “hormonal milieu intérieur” thus resulting in gynecomastia. For instance, individuals with polyneuropathy,
organomegaly, endocrinopathy, M protein, and skin changes
(POEMS) syndrome usually have hyperestrogenemia resulting
in gynecomastia.3 Gynecomastia has been reported following
the use of medications such as fenofibrate and even natural
plant oils such as lavender tree oil.4,5
CLINICAL DIAGNOSIS OF GYNECOMASTIA
A clinical diagnosis of gynecomastia is made by palpation of the
involved breast. On physical examination the patient has a subareolar disc of firm tissue that should be more than half a centimeter in diameter for making a clinical diagnosis of gynecomastia.1,2
Gynecomastia may occur as a result of a number of systemic conditions such as cirrhosis and Klinefelter syndrome.1 Many of these
systemic conditions also have cutaneous manifestations (Table).
The correct identification of these skin lesions can usually point to
the correct etiology of the gynecomastia. The cutaneous manifes-
SYSTEMIC CONDITIONS ASSOCIATED WITH GYNECOMASTIA AND CUTANEOUS MANIFESTATIONS
Chronic Metabolic Disorders
Cirrhosis
Gynecomastia is a common finding in patients with hepatic diseases, especially cirrhosis. There is a decrease in the hepatic clearance of androstenedione in patients with cirrhosis.1 The excess
androstenedione is converted to estrogen in the peripheral fatty
tissue resulting in the characteristic gynecomastia noted in patients with extensive cirrhosis.
Examination of the skin in patients with cirrhosis may reveal
blanching and spider angiomas (telangiectasia) especially on the
upper chest.6 In a recent study, 33% of the patients with cirrhosis had telangiectasia.7 Another characteristic feature is “paper
money skin” characterized by the appearance of scattered, single,
cutaneous blood vessels.8 In another study involving 235 patients
with cirrhosis and 20 controls, the estradiol:free testosterone ratio was the highest in cirrhotic men with spider angiomas.9 This
hormonal imbalance is the most likely cause of these nevi. Other
researchers have suggested that other pathophysiological mechanisms may be responsible for the appearance of these lesions. For
instance, some researchers believe that substance P may have a
role in the pathogenesis of these cutaneous lesions.10 Interestingly,
the examination of the anterior abdominal wall may reveal “caput
medusae.”11 These are dilated cutaneous blood vessels that result
From the University of Illinois at Chicago, Chicago, IL
Address for Correspondence: Shailendra Kapoor, MD, Knoxville, TN 37923 • E-mail: shailendrakapoor@yahoo.com
87
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Table. Cutaneous Manifestations of Systemic Conditions Associated With Gynecomastia
Systemic Conditions Associated
With Gynecomastia
Pathogenesis of Gynecomastia
Cutaneous Manifestations
Cirrhosis6–8
Decrease in the hepatic clearance of
androstenedione. The excess androstenedione is
converted to estrogens in the peripheral fatty tissue.
Spider angiomas,6,7 paper money skin,8 caput
medusae,11 palmar erythema, Dupuytren’s
contractures,11 pale, brittle nails, clubbing
Chronic renal failure1,15
Decreased production of testosterone by testes
Pruritis,12,13 hyperpigmentation,13 xerosis,14
dermatitis, keratotic pits, uremic frost, halfand-half nails,15 Beau’s lines,15 Mee’s lines,15
scleromyxedema-like skin lesions,16 Kyrle’s disease17
Graves’ disease19,20
Decrease in serum free testosterone levels
Increase in extra gonadal aromatase activity that
results in the increased peripheral conversion of
testosterone to estradiol
Warm, moist skin; pretibial myxedema18;
Plummer’s nails19; thyroid acropathy20
Hypopituitarism
Decreased production of testosterone by testes
Epidermal thinning; decreased pubic, axillary and
facial hair; “parchment like,” cold, hypohidrotic,
and hyperkeratotic skin; β-carotenemia21; loss of
the lateral third of the eyebrows; erythema ab igne
Leprosy22
Testicular atrophy
Hypoesthetic, hypopigmented macules23
Human immunodeficiency virus1,25,26
Decreased testosterone
Seborrheic dermatitis, Kaposi’s sarcoma,25,26 Merkel
cell carcinomas, basal cell carcinomas
Increased secretion of human chorionic
gonadotropin by tumors such as gastric
choriocarcinomas
Cutaneous metastasis,27,28 acanthosis nigricans
Lentiginosis syndromes30
Due to feminizing Sertoli cell tumors
Peutz-Jeghers syndrome: mucocutaneous lentigines
(“peri-orificele”)30; Cowden disease: multiple
hamartomas, hyperkeratotic papules31; Carney
complex: mucocutaneous lentigines, cutaneous blue
nevi, skin myxomas32
Klinefelter syndrome
Decreased testosterone production
Increased extra gonadal aromatase activity
resulting in the increased peripheral conversion
of testosterone to estradiol
Skin ulcers33
Testicular atrophy
Cirrhosis
Seborrheic dermatitis,35 acne rosacea,36 pellagra,37,38
neurodermatitis,39 cutaneous flushing
A. Chronic metabolic disorders
B. Endocrine disorders
C. Systemic infections
D. Malignancies
Gastrointestinal malignancies27
E. Genetic causes
F. Substance abuse
Alcohol abuse1
secondary to the opening of collaterals following the development
of portal hypertension in patients with severe cirrhosis. Examination of the hands in patients with cirrhosis may reveal palmar
erythema, Dupuytren’s contractures, as well as prominent nail abnormalities.11 The clinical spectrum of these nail changes ranges
from pale, brittle nails to severe clubbing.
88
Chronic Renal Failure
Chronic renal failure is another common chronic condition associated with the hyperproliferation of ductal breast tissue. Decreased
production of testosterone by the testicular interstitial cells of Leydig
in patients with chronic renal failure alters the estrogen:testosterone
ratio in the blood, thus resulting in clinical gynecomastia.1
March/April 2010
REVIEW
and the abdomen are other sites where pretibial myxedema may
appear. The typical lesions are violaceous and firm and may have a
“peau d’orange” appearance. Patients with pretibial myxedema almost
always also have ophthalmopathy. Nail involvement in thyrotoxicosis can result in “Plummer’s nails” characterized by the separation of
the nail plates from the nail beds.19 Another rare but unique feature
of thyrotoxicosis is “thyroid acropathy” characterized by pathological
osteogenesis, clubbing, and characteristic swelling of the extremities.
In a recent retrospective study involving 178 patients with thyroid
dermopathy, 23% of the patients also had thyroid acropathy.20
One of the most common dermatologic complaints of patients with
chronic renal failure is pruritis. The pruritis is usually secondary to uremia. In a recent study, 55% of the patients with chronic renal failure
complained of pruritis.12 In another study involving 102 participants
with chronic renal failure, 100% of the patients had some sort of a cutaneous lesion.13 Hyperpigmentation was the most common abnormality noticed in this study. Similar results were reported in another
recent study involving children with chronic renal failure.14 Xerosis
was the most common abnormality noticed in this study. In a more
recent study involving 100 patients with chronic renal failure, 100%
of the patients had some sort of cutaneous abnormality on clinical examination.15 The most common of these was xerosis, which was seen
in 79% of the patients. Other common cutaneous manifestations in
this study included hyperpigmentation and dermatitis. Examination
of the palms and soles in patients with renal failure may reveal keratotic pits. Deposition of urea crystals in the skin may result in uremic
frost. Lindsay’s nails or half-and-half nails was the most common nail
abnormality noticed by researchers in a study of patients with chronic
renal failure.15 In a recent study this lesion was reported in 19% of
renal failure patients who were on dialysis and 40% of those who had
renal transplantation.14 Other common nail abnormalities that may
be seen include Beau’s lines and Mee’s lines.15 An increased incidence
of scleromyxedema-like skin lesions has also been reported in patients
on renal dialysis.16 Kyrle’s disease is another characteristic feature of
chronic renal disease. The lesions appear as follicular or extrafollicular, dome-shaped, umbilicated papules with a central keratotic plug
and surrounding acanthosis.17 Ultraviolet B phototherapy is highly
effective in controlling the symptoms of uremic pruritis, though renal
transplantation remains the treatment of choice.
Hypopituitarism
Patients with hypopituitarism often develop gynecomastia. The gynecomastia results because of the decreased secretion of testicular
testosterone secondary to the decreased secretion of gonadotrophic
hormones by the pituitary.1
The universal prevalence of hypopituitarism is 45.5 per 100,000
population. Causes of hypopituitarism range from trauma to xanthoma disseminatum. Hypopituitarism may result in a wide variety
of cutaneous lesions. The loss of growth hormone may result in epidermal thinning. The loss of follicle stimulating hormone and luteinizing hormone may result in decreased pubic, axillary, and facial
hair. Hypothyroidism secondary to hypopituitarism is often associated with “parchment-like,” cold, hypohidrotic, and hyperkeratotic
skin. Hypothyroidism may also result in β-carotenemia which may
manifest as a yellowish hue of the hands. For instance, researchers
have described the case of a woman who initially presented with
xanthoderma and was ultimately found to have hypothyroidism.21
Hair loss is another common feature of hypothyroidism as is loss
of the lateral third of the eyebrows. “Erythema ab igne” is another
characteristic feature associated with hypothyroidism. Nail changes
such as dry, cracked nails are also common.
Endocrine Disorders
The two main endocrine disorders that result in gynecomastia are thyrotoxicosis and hypopituitarism.
Thyrotoxicosis
Thyrotoxicosis or Basedow’s disease is characterized by a decrease in
serum free testosterone levels. There is a simultaneous increase in extragonadal aromatase activity that results in the increased peripheral
conversion of testosterone to estradiol.1 The resulting decrease in serum free testosterone accounts for the increased incidence of gynecomastia seen in patients with Graves’ disease.
Thyrotoxicosis is associated with a number of characteristic cutaneous
manifestations. For instance, patients with thyrotoxicosis often have
warm, moist skin. Dermal proliferation of fibroblasts and mucin accumulation in the dermis result in the highly characteristic “pretibial
myxedema” which is seen in 4% of all patients with thyrotoxicosis. In
fact, the lesions of pretibial myxedema may be massive. For instance,
investigators recently described the case of a 41 year old with elephantiasic pretibial myxedema and underlying Grave’s disease.18 The neck
Systemic Infections
The two main systemic infections that result in gynecomastia are leprosy and human immunodeficiency virus (HIV).
Leprosy
In a recent study involving 41 patients with lepromatous leprosy,
27% of the patients had gynecomastia.22 Gynecomastia is relatively
less common in patients with tuberculoid leprosy. Cutaneous involvement in leprosy is characterized by the appearance of hypoesthetic, hypopigmented macules.23 While lepromatous leprosy is
usually generalized at the time of presentation, tuberculoid leprosy
is usually localized. Nerves such as the posterior tibial in the lower
extremity and the ulnar in the upper extremity are often affected. In
a recent study of leprosy in children, direct contact was reported in
8.7% of the cases.24 The World Health Organization (WHO) regimen for the treatment of multibacillary leprosy involves the daily
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intake of 100 mg of dapsone and 50 mg of clofazimine along with
the monthly administration of 600 mg of rifampicin and 300 mg of
clofazimine for a minimum period of 12 months. The WHO regimen of treatment of paucibacillary leprosy involves the daily intake
of 100 mg of dapsone along with the monthly administration of
600 mg of rifampicin for a period of 6 months.
HIV Infection
Gynecomastia is often seen in patients with HIV.1 Studies indicate
that the free testosterone index in patients with HIV is markedly decreased resulting in the hyperproliferation of breast ductal tissue.
HIV is associated with a number of cutaneous conditions. One of
the most characteristic cutaneous features of HIV is Kaposi’s sarcoma. This sarcomatous lesion is caused by infection with the human
herpes virus 8. The sarcoma may metastasize to the gastrointestinal
tract or the oral cavity. Rarely, Kaposi’s sarcoma may affect the breast
itself.25 Liposomal doxorubicin and daunorubicin are the first-step
treatments of choice.26 HIV patients also have an increased incidence of Merkel cell carcinomas and basal cell carcinomas.
Malignancies
Gynecomastia may be associated with a number of internal malignancies including those of the testes and the gastrointestinal
system.1 Cutaneous manifestations, however, are relatively more
common with gastrointestinal malignancies, especially those of
the stomach. For instance, gastric choriocarcinomas secrete human chorionic gonadotropin. Human chorionic gonadotropin
results in the increased endogenous production of estrogens thus
resulting in gynecomastia.
Gastrointestinal malignancies may result in a myriad of cutaneous
manifestations. For instance, gastrointestinal malignancies may metastasize to the skin resulting in the formation of nodular cutaneous
lesions. Rarely, these metastatic lesions may appear atypically. For instance, investigators recently described the case of a 60-year-old woman with gastric signet cell carcinoma and cutaneous metastasis that
resembled lesions of contact dermatitis.27 Similarly, other investigators
have described cutaneous metastasis secondary to gastric cancer that
resembled cellulitis-like lesions.28 Acanthosis nigricans is another skin
marker of gastrointestinal malignancies and is characterized by the appearance of hyperpigmented, velvet-like plaques on the skin.
Genetic Causes
The common genetic causes of gynecomastia include the lentiginous
syndromes and Klinefelter syndrome.
Lentiginosis Syndromes
Gynecomastia is associated with a number of congenital lentiginosis
syndromes. These include the Peutz-Jeghers syndrome, Cowden dis-
ease, and the Carney complex.29 Patients may also present with prepubertal gynecomastia secondary to feminizing Sertoli cell tumors.1
Peutz-Jeghers syndrome was first described by Jeghers, McKusick, and
Katz in 1949. It is an autosomal dominant disorder characterized by
the appearance of gastrointestinal hamartomatous polyps. The genetic
locus for Peutz-Jeghers syndrome is located on 19p13. In the context
of dermatology, these patients may display mucocutaneous melanotic
lentigines. These are hyperpigmented lesions on the oro-buccal mucosa and perianal mucosae (“peri-orificele”). For instance, researchers
recently described the case of a 7-year-old boy with gynecomastia and
mucocutaneous lentigines who was ultimately found to have underlying Peutz-Jeghers syndrome.30 The buccal pigmentations usually persist throughout life, though those at other locations may fade with
time. The palmar and plantar aspects of the hand and feet are other
commonly affected sites.
Investigators have described the case of a 64-year-old man presenting with keratotic lesions and gynecomastia who was ultimately
diagnosed with Cowden disease.31 This is another autosomal dominant lentiginosis disorder characterized by the appearance of multiple hamartomas along with gynecomastia and dermatological
changes. Examination of the skin in these patients usually reveals
hyperkeratotic papules.
The genetic locus for Carney complex is located on 2p16. It is another autosomal dominant lentiginosis disorder characterized by the
appearance of testicular Sertoli cell tumors and cardiac myxomas besides gynecomastia and mucocutaneous lentigines.
Cushing syndrome is often seen in these patients. Cutaneous blue nevi
are another common finding. Skin myxomas are also common and
are most often seen on the eyelids and the external auditory canals.32
Klinefelter Syndrome
Patients with Klinefelter syndrome have the XXY karyotype. Gynecomastia is a frequent finding in these patients. The gynecomastia in patients with Klinefelter syndrome usually results because of
decreased testosterone production by the Leydig cells of the testes
combined with increased extragonadal aromatase activity resulting
in the increased peripheral conversion of testosterone to estradiol.1
Klinefelter syndrome is associated with a number of cutaneous
conditions. Skin ulcers are the most common of these cutaneous
manifestations. For instance, the case of a 54-year-old man who initially presented with skin ulcers and was ultimately found to have
Klinefelter syndrome was recently reported.33 Increased activity of
the plasminogen activator inhibitor-1 has been reported in a patient with Klinefelter syndrome.34 This might explain the increased
predisposition to venous thrombosis and subsequent leg ulcers in
patients with Klinefelter syndrome.
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REVIEW
5 Kurtz JL. Prepubertal gynecomastia linked to lavender and tea tree
oils. N Engl J Med. 2007;356:2542–2543; author reply 2543–2544.
Substance Abuse
A number of illicit drugs such as marijuana and alcohol may cause
gynecomastia. However, cutaneous manifestations associated with
gynecomastia are more common in alcohol abusers.
6 Finn SM, Rowland M, Lawlor F, et al. The significance of cutaneous spider naevi in children. Arch Dis Child. 2006;91:604–605.
Alcohol Abuse
Gynecomastia is a common finding in chronic alcoholics. Chronic
alcohol use may directly affect the testes resulting in atrophy and thus
an imbalance in the estrogen:testosterone ratio.1 In addition, chronic
alcohol use may result in cirrhosis which in turn may further aggravate the gynecomastia.7 Both of these factors have a significant role to
play in the pathogenesis of gynecomastia in chronic alcoholics.
Skin conditions such as seborrheic dermatitis are exacerbated by
chronic ethanol consumption.35 An increased prevalence of acne
rosacea has been reported (5.6%).36 The appearance of diarrhea and
dementia in chronic alcoholics with dermatitis should alert the physician to possible pellagra.37 For instance, investigators recently reported
the case of a 66 year old diagnosed with alcoholic pellagra who was
successfully treated with niacin.38 Studies suggest that cutaneous fungal infections such as sporotrichosis and paracoccidioidomycosis are
also relatively more common in alcoholics. About 2.5% of alcoholics
also have neurodermatitis.39 A vast myriad of other nonspecific skin
changes, such as cutaneous flushing, may be seen in alcoholics. In one
study, nearly 43% of all alcohol abusers had some sort of cutaneous
pathology.36 In a more recent study involving 200 participants with
chronic ethanol intake, 91% of the patients had cutaneous or nail
abnormalities.40 Tinea versicolor (14%) was the most common dermatologic abnormality identified in this study.
7 Li CP, Lee FY, Hwang SJ, et al. Spider angiomas in patients with
liver cirrhosis: role of alcoholism and impaired liver function.
Scand J Gastroenterol. 1999;34:520–523.
8 Emerick KM, Whitington PF. Clinical aspects of familial cholestasis (with molecular explanations). Curr Gastroenterol Rep.
1999;1:223–230.
9 Pirovino M, Linder R, Boss C, et al. Cutaneous spider nevi in liver
cirrhosis: capillary microscopical and hormonal investigations.
Klin Wochenschr. 1988;66:298–302.
10 Li CP, Lee FY, Hwang SJ, et al. Role of substance P in the pathogenesis of spider angiomas in patients with nonalcoholic liver
cirrhosis. Am J Gastroenterol. 1999;94:502–507.
11 Denzer U, Arnoldy A, Kanzler S, et al. Prospective randomized
comparison of minilaparoscopy and percutaneous liver biopsy:
diagnosis of cirrhosis and complications. J Clin Gastroenterol.
2007;41:103–110.
12 Murtagh FE, Addington-Hall J, Higginson IJ. The prevalence of
symptoms in end-stage renal disease: a systematic review. Adv
Chronic Kidney Dis. 2007;14:82–99.
13 Pico MR, Lugo-Somolinos A, Sanchez JL, et al. Cutaneous alterations in patients with chronic renal failure. Int J Dermatol.
1992;31:860–863.
14 Silverberg NB, Singh A, Laude TA. Cutaneous manifestations
of chronic renal failure in children of color. Pediatr Dermatol.
2001;18:199–204.
15 Udayakumar P, Balasubramanian S, Ramalingam KS, et al. Cutaneous manifestations in patients with chronic renal failure on hemodialysis. Indian J Dermatol Venereol Leprol. 2006;72:119–125.
CONCLUSIONS
16 Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet.
2000;356:1000–1001.
As is evident from the above examples, most of the systemic conditions associated with gynecomastia affect the skin also. Correct recognition of these lesions can go a long way in identifying the underlying
etiology of the gynecomastia.
18 Bilen H, Atasoy M, Akcay G, et al. Elephantiasic pretibial myxedema and cutis verticis gyrata caused by Graves’ disease. Thyroid. 2006;16:815–816.
17 Shivakumar V, Okade R, Rajkumar V, et al. Familial Kyrle’s disease: a case report. Int J Dermatol. 2007;46:770–771.
Disclosure: The author has no conflicting interests or any financial
interests in this manuscript.
REFERENCES
1 Braunstein GD. Clinical practice. Gynecomastia. N Engl J Med.
2007;357:1229–1237.
2 Kumanov P, Deepinder F, Robeva R, et al. Relationship of adolescent gynecomastia with varicocele and somatometric parameters: a cross-sectional study in 6200 healthy boys. J Adolesc
Health. 2007;41:126–131.
19 McKeown NJ, Tews MC, Gossain VV, et al. Hyperthyroidism.
Emerg Med Clin North Am. 2005;23:669–685, viii.
20 Fatourechi V, Ahmed DD, Schwartz KM. Thyroid acropachy: report of 40 patients treated at a single institution in a 26-year
period. J Clin Endocrinol Metab. 2002;87:5435–5441.
21 al-Jubouri MA, Coombes EJ, Young RM, et al. Xanthoderma:
an unusual presentation of hypothyroidism. J Clin Pathol.
1994;47:850–851.
22 Saporta L, Yuksel A. Androgenic status in patients with lepromatous leprosy. Br J Urol. 1994;74:221–224.
23 Britton WJ, Lockwood DN. Leprosy. Lancet. 2004;363:1209–1219.
3 Gandhi GY, Basu R, Dispenzieri A, et al. Endocrinopathy in POEMS syndrome: the Mayo Clinic experience. Mayo Clin Proc.
2007;82:836–842.
24 Sehgal VN, Sharma V. Reactions in leprosy--a prospective study
of clinical, bacteriological, immunological and histopathological
parameters in thirty-five Indians. J Dermatol. 1988;15:412–419.
4 Gardette V, Vezzosi D, Maiza JC, et al. Gynecomastia associated with fenofibrate. Ann Pharmacother. 2007;41:508–510.
25 Hamed KA, Muller KE, Nawab RA. Kaposi’s sarcoma of the
breast. AIDS Patient Care STDS. 2000;14:85–88.
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REVIEW
26 Di Lorenzo G, Konstantinopoulos PA, Pantanowitz L, et al.
Management of AIDS-related Kaposi’s sarcoma. Lancet Oncol.
2007;8:167–176.
drome presenting with leg ulcers. Skinmed. 2004;3:274–278.
34 Dissemond J, Schultewolter T, Brauns TC, et al. Venous leg
ulcers in a patient with Klinefelter’s syndrome and increased activity of plasminogen activator inhibitor-1. Acta Derm Venereol.
2003;83:149–150.
27 Ahn SJ, Oh SH, Chang SE, et al. Cutaneous metastasis of gastric signet ring cell carcinoma masquerading as allergic contact
dermatitis. J Eur Acad Dermatol Venereol. 2007;21:123–124.
28 Foo KF, Tao M, Tan EH. Gastric carcinoma presenting with cellulitis-like cutaneous metastasis. Singapore Med J. 2002;43:37–38.
35 Jacobi U, Bartoll J, Sterry W, et al. Orally administered ethanol:
transepidermal pathways and effects on the human skin barrier.
Arch Dermatol Res. 2005;296:332–338.
29 Witman PM. More than just a bump: the hamartoma syndromes.
Adv Dermatol. 2006;22:157–180.
36 Rosset M, Oki G. Skin diseases in alcoholics. Q J Stud Alcohol.
1971;32:1017–1024.
30 Winterfield L, Schultz J, Stratakis CA, et al. Gynecomastia and
mucosal lentigines in an 8-year-old boy. J Am Acad Dermatol.
2005;53:660–662.
37 Heath ML, Sidbury R. Cutaneous manifestations of nutritional
deficiency. Curr Opin Pediatr. 2006;18:417–422.
38 Takeru F, Tomotaka S, Masato A, et al. A case of pellagra successfully treated with systemic nicotinic acid in spite of normal serum
level of nicotinic acid. Jpn Clin Dermatol. 2006;60:799–801.
31 Gold BM, Bagla S, Zarrabi MH. Radiologic manifestations of
Cowden disease. AJR Am J Roentgenol. 1980;135:385–387.
32 Chinchurreta-Capote A, Trueba A, Hernandez FJ, et al. Ocular
findings in Carney complex [in Spanish]. Arch Soc Esp Oftalmol.
2006;81:709–711.
39 Parish LC, Fine E. Alcoholism and skin disease. Int J Dermatol.
1985;24:300–301.
40 Rao GS. Cutaneous changes in chronic alcoholics. Indian J Dermatol Venereol Leprol. 2004;70:79–81.
33 De Morentin HM, Dodiuk-Gad RP, Brenner S. Klinefelter’s syn-
SELF TEST REVIEW QUESTIONS
Instructions: For each of the following numbered questions, choose the single most appropriate lettered response.
1) The two main endocrine disorders that result in gynecomastia are
hypopituitarism and:
a. Addison’s disease.
b. Cushing syndrome.
c. hyperaldosteronism.
d. hyperparathyroidism.
e. hypothyroidism.
f. thyrotoxicosis.
4) “Paper money skin,” characterized by the clinical appearance of
scattered, single cutaneous blood vessels, is a sign of:
a. chronic renal failure.
b. cirrhosis.
c. hypopituitarism.
d. stomach cancer.
e. thyrotoxicosis.
5) Which of the following nail changes is (are) associated with renal
failure?
a. Beau’s lines
b. Half-and-half nails
c. Lindsay’s nails
d. Mee’s lines
e. All of the above are correct.
f. None of the above is correct.
2) The two main systemic infections that result in gynecomastia are
human immunodeficiency virus (HIV) infection and:
a. dengue.
b. leprosy.
c. paracoccidioidomycosis.
d. tuberculosis.
e. tularemia.
ANSWERS TO SELF TEST REVIEW QUESTIONS:
1) f, 2) b, 3) a, 4) b, 5) e
3) The most common cutaneous manifestation of Klinefelter
syndrome is:
a. cutaneous ulcers.
b. dry, cracked nails.
c. keratotic pits of the palms and soles.
d. palmar erythema.
e. yellow palms.
From the Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School, Newark, NJ
Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520, Medical Science Building UMDNJ-New Jersey Medical School,
Newark, NJ 07101 • E-mail: lamberwc@umdnj.edu
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NEW THERAPY UPDATE
William Abramovits, MD; Aditya K. Gupta, MD, Section Editors
LidoWorx (4% Lidocaine) Gel
William Abramovits, MD;1,2,3 Peter Morrell, DO;4 Aditya K. Gupta, MD5,6
LidoWorx is a new topical anesthetic designed for local or dermal
analgesia which incorporates a novel drug delivery system trademarked as Small Molecule Solubilization System (SMSS).1 This system is designed to increase the solubility of the active ingredient,
thus allowing the lidocaine to exhibit a rapid onset of action. LidoWorx is a non–oil-based, alcoholic gel containing 4% lidocaine with
skin permeation enhancers (cis-unsaturated fatty acids which fluidize stratum corneum) indicated as a topical analgesic to be used on
normal, intact skin (Baumann LS, et al., unpublished data, 2010).
profile over time of LidoWorx Gel was assessed (Baumann LS, et al.,
unpublished data, 2010). In both studies, subjects received a total of
6 botulinum toxin type A injections in 6 demarcated areas of the lateral periocular regions for “crow’s feet” type wrinkles on the face. The
initial injection being at time zero, in the absence of anesthetic, the
following injections were placed in randomized periocular zones at
regular intervals with the final injection at 45 minutes. Perceived pain
was recorded immediately after each injection on a visual analog scale
(VAS) from 0 to 10. Results indicated that optimum analgesic effects
of LidoWorx were observed 35–40 minutes after application.
CLINICAL PHARMACOLOGY
Safety/Adverse Events
DESCRIPTION
In both of the studies described above, LidoWorx Gel demonstrated itself to be safe and well tolerated. In the safety and efficacy
study (clinical study 2), 14 patients had plasma lidocaine levels
drawn at times 0, 20, 30, 35, 40, and 45 minutes with one last
sample taken at 60 minutes (15 minutes after all LidoWorx Gel
had been removed from the face). Lidocaine plasma levels ranged
between 0 and 16 ng/mL, with the average level being 4 ng/mL—
safely beneath the reported toxicity level of 6.0 µg/mL.
Mechanism of Action
LidoWorx achieves dermal analgesia by the release of lidocaine from
the gel vehicle into the epidermis and dermis. The amide anesthetic,
lidocaine, then reversibly blocks initiation and propagation of nerve
impulses by arresting sodium ion flux through neuronal membranes.
Pharmacokinetics
LidoWorx is designed to deliver lidocaine into the skin, but depending on factors such as duration of use and surface area of application,
systemic absorption may occur. In reference to intravenous infusion
of lidocaine, systemic toxic effects have been observed at plasma lidocaine concentrations of 6–10 µg/mL. In one study of 14 subjects in
which it was applied without occlusion for up to 60 minutes on the
lateral, periocular regions of the face, lidocaine plasma levels were between 0 and 16 ng/mL with a maximum average of 4 ng/mL.
INDICATION, DOSAGE, AND ADMINISTRATION
The safety and efficacy of LidoWorx Gel as a rapid acting topical analgesic for use on normal, intact skin were assessed in 2 prospective
studies on patients 18 years of age and older.
LidoWorx Gel is indicated for rapid, temporary analgesia for penetrating local pain on normal, intact, noninflamed skin in adults and children 2 years of age and older. It is recommended that a moderately
thick layer (approximately 1/8 inch thick) be applied to the area to be
treated. Numbness should develop approximately 15 minutes after
application, with optimum analgesia occurring at 35–40 minutes. LidoWorx Gel should not be applied to large body surface areas, used
under occlusion, or placed on mucous membranes or on inflamed
skin. It is contraindicated in any patient allergic to amide-type local
anesthetics or any component of the product.
Efficacy
SAFETY AND PRECAUTIONS
In both an efficacy study (clinical study 1) and a safety and efficacy
study (clinical study 2), (N=12 and N=14, respectively) the anesthetic
Though generally considered safe medications, topical anesthetics have
been reported to cause rare, but sometimes serious, complications.
CLINICAL STUDIES
From the Department of Medicine, Baylor University Medical Center;1 the Departments of Dermatology & Family Practice, University of Texas Southwestern Medical School;2 and the Dermatology Treatment and Research Center,3 Dallas, TX; the Department of Dermatology, Kirksville College of
Osteopathic Medicine, A.T. Still University, Texas Division, Duncanville, TX;4 and the Division of Dermatology, Department of Medicine, University of
Toronto, Toronto, Canada,5 and Mediprobe Research, London, Ontario, Canada6
Address for Correspondence: William Abramovits, MD, Dermatology Treatment and Research Center, 5310 Harvest Hill Road, Suite 160, Dallas, TX
75230 • E-mail: dra@dermcenter.us
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NEW THERAPY UPDATE
Table. Topical Anesthetics Containing Lidocaine
Active
Ingredients
Delivery Vehicle
Onset of Action
Average Wholesale
Price per Applicationa
2.5% Prilocaine,
2.5% lidocaine
Oil in water
emulsion
60 Minb
$1.80 per 1 gram
4%–5% Lidocaine
Microemulsion gel
30–60 Min
$0.80 per 1 gram
LMX4
(Ferndale Laboratories, Inc)
4% Liposomal
lidocaine
Liposomes
30 Min
$1.58 per 1 gram
LidoWorx
(DermWorx)
4% Lidocaine
SMSS gel
25 Min
$1.30 per 1 gram
70 mg Lidocaine,
70 mg tetracaine
Controlled
heat-activated patch
20–30 Min
$15.36 per patch
Product and Manufacturer
EMLA
(Astra-Zeneca Pharmaceuticals LP)
Topicaine
(ESBA Laboratories)
Synera (S-Caine)c
(Endo Pharmaceuticals)
AWP 2009 Red Book Price. bUnder occlusion, per package insert. cDesigned for use prior to venous canalization.
SMSS indicates Small Molecule Solubilization System.
a
These have included case reports of methemoglobinemia, and even
one report of arrhythmia and cardiovascular collapse2–5 (also Baumann LS, et al., unpublished data, 2010). It is for this reason that
authorities such as the US Food and Drug Administration (FDA)
advise caution, and strongly recommend against using these products
over large surface areas, under occlusion, or on skin whose barrier has
been disrupted.6 Systemic (dose related) reactions usually observed at
plasma lidocaine levels greater than 10,000 ng/mL include: central
nervous system (CNS) excitation and/or depression (light-headedness, nervousness, confusion, dizziness, drowsiness, tinnitus, blurred
vision, vomiting, numbness, convulsions, respiratory depression or
arrest). Similarly, possible cardiovascular complications seen at these
plasma concentrations include bradycardia, hypotension, and cardiovascular collapse and arrest.
LidoWorx Gel falls into pregnancy category B. Lidocaine has shown
no harm to fetal rats (30 mg/kg subcutaneously, 22 times single
dermal administration [SDA]), but no adequate, well controlled
studies on pregnant women exist. Lidocaine hydrochloride has been
tested and found to have no mutagenic effects, but the mutagenicity
and genotoxicity of 2,6-xylidine, a metabolite of lidocaine, is unclear. 2,6-xylidine has, however, been shown to be carcinogenic in
laboratory animals at doses of 900 mg/m2 (60 times SDA). This effect was not observed at daily doses of 300 mg/m2 (20 times SDA).
LidoWorx Gel has been shown in these studies to be both efficacious and safe when used appropriately. The rapid (25 minute)
onset of action, which is achieved without the need for occlusion,
places it competitively among other topical lidocaine anesthetics.
Due to the fact that it is strictly an amide-class anesthetic, there
is no need to worry about the para-aminobenzoic acid metabolite
sensitivity associated with anesthetics belonging to other chemical
classes. Head-to-head studies are needed to fully evaluate relative
efficacy among these anesthetics, but it is clear that LidoWorx Gel
represents a comparatively cost-effective and safe product.
DISCUSSION
Numerous topical anesthetics containing lidocaine as an active
ingredient are commercially available. All make varying claims
of efficacy and cost-effectiveness. A lack of standardized head-tohead trials makes comparison problematic. Nevertheless, we have
adapted and updated a summary of some representative competitors in the lidocaine based topical anesthetic market7–9 (Table).
94
REFERENCES
1 LidoWorx (4% lidocaine) Gel [package insert]. Hallandale, FL:
DermWorx Incorporated; 2009.
2 EMLA Cream [package insert]. Wilmington, DE: AstraZeneca; 2005.
3 Friedman PM, Mafong EA, Friedman ES, et al. Topical anesthetics
update: EMLA and beyond. Dermatol Surg. 2001;27:1019–1026.
4 Smith K, Niamtu J, Carruthers J. Pain control in cosmetic facial
surgery. In: Dover JS, Alam M, Carruthers J, Carruthers A, eds.
Procedures in Cosmetic Dermatology: Soft Tissue Augmentation.
2nd ed. Philadelphia, PA: Saunders Elsevier; 2008:127–141.
5 Khan NA, Kruse JA. Methemoglobinemia induced by topical anesthesia: a case report and review. Am J Med Sci. 1999; 318:415.
6 US Food and Drug Administration. FDA Public Health Advisory:
Life-threatening side effects with the use of skin products containing numbing ingredients for cosmetic procedures. http://www.
fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm054718.
htm. Accessed December 13, 2009.
7 Young KD. What’s new in topical anesthesia. Clin Pediatr Emerg
Med. 2007;8:232–239.
8 Huang W, Vidimos A. Topical anesthetics in dermatology. J Am
Acad Dermatol. 2000;43:286–298.
9 Min-Wei CL. Topical triple anesthetic gel compared with 3 topical
anesthetics. Cosmetic Dermatol. 2003;6:35–38.
March/April 2010
COSMETIC SCIENCE
Howard A. Epstein, PhD, Section Editor
A Natural Approach to Soothing Atopic Skin
Nature’s solutions have been used to combat health problems since antiquity. A 60,000-year-old burial site excavated in Iraq was found to
contain a variety of medicinal plants.1 Use of botanicals to treat diseases of the skin was documented 3000 years ago in the Egyptian papyrus
of Ebers.2 The traditional description for use of medicinal plants, however, is usually not linked to topical application. It is not unusual to
read about the claimed medicinal benefits of a botanical which is lacking appropriate in vitro and in vivo data to support the claims. The
ability to identify new cosmetic uses for botanicals is enhanced when science is able to advance beyond anecdotal information to elucidation
of the mechanism of activity.
B
otanicals are the primary source of medicinal products
in many parts of the globe, particularly less developed
countries. As other industrialized countries achieved a
higher standard of living, synthetic medicinal compounds replaced plant-derived pharmaceutical products. The popularity
of synthetic medicals resulted in a decline of the knowledge
base and use of plant-derived medicinal compounds. Renewed
interest in green chemistry and natural products for skin has
reinvigorated research in understanding how nature provides
solutions for skin care.
MEDICINAL BOTANICALS
Tiliroside
Tiliroside is an example of a single compound found in numerous plants responsible for protecting the plant and also beneficial for human skin. Tiliroside is a flavonoid found in a variety
of medicinal plants including several species of tilia and malva
that grow in Europe and tropical regions of the world. It protects plants from ultraviolet (UV)-induced and other forms of
environmental stress. Tiliroside is found in the hairy protrusions
Redness (Minolta a-Value)
A.
B.
*
*
Figure 1. Effect of tiliroside on the redness of skin. (A) The redness is evaluated by measuring the a-value (Minolta Chromameter
[Konica Minolta, Tokyo, Japan]) after 6, 24, and 48 hours post-induction of erythema (*statistically significant vs placebo: P value
<0.05). (B) The results of all time points are shown as area under the curve (P value = 0.048). UV indicates ultraviolet.
From EMD Chemicals Inc., Gibbstown, NJ
Address for Correspondence: Howard A. Epstein, PhD, EMD Chemicals Inc., 480 South Democrat Road, Gibbstown, NJ 08027 •
E-mail: howard.epstein@emdchemicals.com
95
March/April 2010
COSMETIC SCIENCE
Capillary Flow
A.
B.
*
Figure 2. Antiinflammatory efficacy of tiliroside as a function of time. (A) The capillary blood flow is determined by laser Doppler
flowmetry and the results for each time are presented (*statistically significant vs placebo: P value <0.05). (B) The results of all
time points are shown as area under the curve (P value = 0.002). UV indicates ultraviolet.
and young leaves of plants where environmental protection is
particularly important for plant health.2
reference (negative control and a 1% hydrocortisone cream (positive control). One test area remained untreated (empty field).
Reapplication of the test substances followed the readings after 6
and 24 hours. The study duration was conducted for a period of
3 days. A statistical analysis was conducted on the data obtained
from the study2 (Figure 1, Figure 2, Table).
What Data Are Available?
Tiliroside was tested on 20 healthy, women volunteers with dry,
atopic skin for its influence on erythema (redness and capillary
flow). Following UV irradiation with 1 minimal erythemal dose
on the volar forearm, the test substances were applied after 6, 24,
and 48 hours. Erythema formation and capillary flow were evaluated using a Minolta Chromameter CR 300 (Konica Minolta,
Tokyo, Japan) and a laser-Doppler flow meter, respectively. A
Solar Simulator (SOL3 Honle, Munich, Germany) emitting 1
minimal erythemal dose was used as the UV source. The erythema threshold was determined for each volunteer by using different light intensity. The development of erythema was examined
after the application of the respective test substances at measuring time 6, 24, and 48 hours in comparison with an untreated
FURTHER COMMENTS AND CONCLUSIONS
Oxidative stress is thought to play an important role in initiating
the cellular response following UV irradiation. Increasing levels
of hydrogen peroxides and reactive oxygen species and decreases
in antioxidative enzymes result as skin is exposed to UV irradiation. Plant-derived flavonoids are known to inhibit processes
initiated by oxidative stress. Antioxidant mechanisms include inhibition of enzymes involved in the formation of reactive oxygen
species. Flavonoids also act as chelators of free iron or copper,
which are potential enhancers of free radical formation..3 Skin
Table. Statistical Analysis of In Vivo Results
Rednessa
6 Hours
24 Hours
48 Hours
AUC
Verum vs UV-control
P=0.011
P=0.003
NS
P=0.015
Verum vs placebo
P=0.024
NS
P=0.021
P=0.048
Capillary flowb
6 Hours
24 Hours
48 Hours
AUC
Verum vs UV-control
P=0.007
P=0.001
P=0.002
P<0.001
NS
P=0.009
NS
P=0.002
Verum vs placebo
c
c
c
c
The pre-post difference to baseline at 6, 24, and 48 hours was calculated for redness and capillary flow. The ultraviolet (UV)-control was
only irradiated and not treated with any test product. The analysis of the whole test period was done according to the area under curve (AUC)
procedure. cNot significant (NS), P value >0.05.
a
96
b
March/April 2010
COSMETIC SCIENCE
Figure 3. Chemical structure of tiliroside.
reddening and increased capillary blood flow may be considered
as indicators of UV stress to skin and suitable measurable parameters for inflammation of skin. The findings of this in vivo study
support the conclusion regarding the ability of tiliroside (Figure
3) to function as a potential antiaging agent for skin exposed to
UV irradiation. The study supports in vitro findings conducted
by other investigators that have shown the ability of tiliroside to
down-regulate overproduction of nitric oxide and tumor necrosis factor-α in mononuclear cell culture. Nitric oxide and tumor
necrosis factor-α are markers of inflammation.4,5 The study confirms the ability of the flavonoids, a natural compound known
to protect the plant from environmental stress to also benefit
human skin from similar environmental stress.
REFERENCES
1 Chevallier A. The encyclopedia of medicinal plants. 1st ed. New
York, NY: DK Publishing; 1996.
2 Graf R, Pluecker F, zur Lage J, et al. Nature meets technology - the
natural cosmetic ingredient tiliroside. SOFW J. 2009;135:3–7.
3 Pietta PG. Flavonoids
2000;63(7):1035–1042.
as
antioxidants.
J
Nat
4 Rao YK, Fang SH, Tzeng YH. Inhibitory effects of the flavonoids
isolated from Walthenia indica on the production of NO, TNFalpha and IL-12 in activated macrophages. Biol Pharm Bull.
2005;28:912–915.
5 Matsuda H, Ninomiya K, Shimoda H, et al. Hepatoprotective
principles from the flowers of Tilia argentea (linden): structure
requirements of tiliroside and mechanisms of action. Bioorg
Med Chem. 2002;10:707–712.
Editors Note: Further information regarding the reported study may
be found in the original publication, SOFW J. 2009;135(4): 3–7.
Ozoamblyrosis
Medications known to cause sufficient body odor to lead to diminished to absent sexual interest in a partner
Felbatol
Omega-3-acids
Selenium
Leocarnitine
Provera
Synarel
Lupron
Salagen
Topamax
Adapted from Litt JZ. Curious, Odd, Rare, and Abnormal Reactions to Medications. Fort Lee, NJ: Barricade Books; 2009:155–156.
97
Prod.
March/April 2010
Anatomically Correct, Histopathologically Correct,
Diagnostically Disastrous Biopsies
Navér Sarkissian, MD;1,2 Priti P. Patel, MD;3 Earl J. Fleeger, MD;3 Javier Rojas, MD;4
W. Clark Lambert, MD, PhD1,2
B
iopsies are properly accepted as definitive tests providing
diagnoses and, from them, management and prognostic
guides, but have the critical limitation that not all of the
lesional tissue is actually examined. The physician may choose to
biopsy only part of the lesion, using a destructive mode for the
remainder or even leaving it alone, and the pathologist can never
section everything submitted, since each section is typically only 4
or 5 microns in thickness. Usually this arrangement provides adequate—even excellent—care, but there is always a risk that the
most important tissue is not examined. This risk may be markedly
exacerbated when there is a tissue reaction to the primary lesion that
is more apparent clinically or grossly than the lesion itself. Of the
several tissue reactions that may occur, including fibrosis, calcification, and granulation tissue, the latter is the more likely to cause a
problem. In its full-blown presentation, granulation tissue is known
as a pyogenic granuloma (ie, granuloma pyogenicum [GP]), a lesion
that has plagued medicine in different ways for centuries.
Nomenclature
ing from different directions, they meet within the wound, the
process begins to progress to its later stages, but if they do not
meet they continue growing, projecting upward to form a GP. The
GP undergoes rapid growth, sometimes outstripping the epithelium’s ability to cover it, until it abruptly stops after attaining a
thickness that may exceed 1 centimeter. This process may lead to
spontaneous ulceration or the lesion may ulcerate as a result of
mild trauma. Either process may result in a massive infiltrate of
neutrophils, generating pus on the surface of the lesion. The pus
was once erroneously thought to be responsible for the generation of the GP, supporting the notion—widely held in nineteenth
century medicine—that pus promoted tissue growth and healing
and was, indeed, a highly desirable, if not a necessary, part of the
healing process. When Joseph Lister promoted antiseptic surgery
at the Glasgow Royal Infirmary in the latter part of that century,
he was widely attacked because his approach was not associated
with pus in the patients’ surgical wounds. This delayed acceptance
of Lister’s new surgical methods, and may have discouraged earlier
surgeons from introducing such methods at all.5
Like the Holy Roman Empire, which was not holy, not Roman, and
not an empire,1 GP is not a granuloma and is not pyogenic.2,3 It does
not contain epithelioid cells (which, despite their name, are differentiated macrophages that secrete cytokines) which are required for a
lesion to qualify as a granuloma.4 It is also not generated from pus (ie,
pyogenic). For this reason we prefer the Latin name, GP, to the English term, pyogenic granuloma, since the latter implies that the terms
may be separated and that this is, in fact, a form of granuloma.
Discussion
The stresses created by the presence of a lesion, particularly a neoplasm, may generate granulation tissue. This granulation tissue,
whether or not forming a full blown GP, may be more apparent
than the primary lesional tissue, causing it to be biopsied or selected
for sectioning instead of the underlying lesion.3 It is certainly not
bad medicine to biopsy the most prominent part of a lesion, nor
is it necessarily bad medicine to biopsy only part of the lesion and
proceed with management based on the biopsy results, not necessarily submitting further tissue for pathological analysis. However, this
“anatomically correct” approach, followed by a “histopathologically
correct” diagnosis on the submitted tissue, may nevertheless produce potentially disastrous consequences if the primary lesion is not
sectioned or is not recognized in the sections examined.
When a wound heals by primary intention, capillaries, epithelial cells, fibroblasts, and acute inflammatory cells migrate into it
from adjacent tissue as part of the healing process. When, com-
From the Department of Pathology, Divisions of Dermatopathology1 and Anatomic Pathology;4 the Departments of Dermatology2 and Surgery,
Division of Plastic Surgery,3 UMDNJ-New Jersey Medical School, Newark, NJ
Address for Correspondence: W. Clark Lambert, MD, PhD, Room C520, Medical Science Building UMDNJ-New Jersey Medical School,
Newark, NJ 07101 • E-mail: lamberwc@umdnj.edu
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Two examples illustrate this point: In the first case, a subungual
lesion of a finger produced a GP of the adjacent skin that was far
more apparent than the primary lesion. A biopsy showed only
the GP (Figure 1). Subsequent follow-up resulted in an additional biopsy, revealing that the primary lesion was a squamous
cell carcinoma—which was excised, but only after a delay in diagnosis. In the second case, a postauricular basal cell carcinoma
was excised, followed by a second lesion which on biopsy showed
only acute inflammation and granulation tissue. Deeper levels
on the pathological block showed nests of recurrent basal cell
carcinoma within the lesion (Figure 2).
Conclusions
The risk that a biopsy may show only secondary changes that are
more clinically/grossly prominent than the more serious primary
lesion should be considered in evaluating cutaneous and mucous membrane conditions, especially if only part of the lesional
tissue is biopsied. This is in addition to the risk that a longstanding inflammatory condition may give rise to a secondary
malignancy—as is seen in some chronic ulcers or burns—with a
biopsy showing only the primary, nonmalignant lesion.
REFERENCES
Figure 1. Granuloma pyogenicum associated with subungual
squamous cell carcinoma. The biopsy showed only granuloma
pyogenicum. Hematoxylin and eosin staining (original
magnification ×180).
1 Hartmann PC. Kulturgeschichte des Heiligen Römischen Reiches 1648 bis 1806. Vienna, Austria: Böhlau, Köln; 2001.
2 Gillmore A, Kelsberg G, Safranek S. What’s the best treatment
for pyogenic granuloma? J Fam Pract. 2010;59:40–42.
3 Azzopardi EA, Xuereb CB, Iyer S. Pyogenic granuloma as a surrogate indicator of deep seated foreign bodies: a case report.
Cases J. 2009;2:7354.
4 Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran:
Pathologic Basis of Disease. 8th ed. New York, NY: Saunders;
2010:73.
5 Cartwright FF. Joseph Lister, the Man Who Made Surgery Safe.
London, England: Weidenfeld and Nicholson; 1963.
Figure 2. Basal cell carcinoma, recurrent, within granulation
tissue. The basal cell carcinoma was only seen on deeper
sectioning of the block. Hematoxylin and eosin staining
(original magnification ×180).
99
March/April 2010
Historical Vignette
Charles Steffen, MD, Section Editor
The Founder of Vicks:
Lunsford Richardson (1854–1919)
Khalid Al Aboud, MD
Vicks VapoRub (Procter & Gamble, Cincinnati, OH) is one of the most popular over-the-counter therapies in the world, used to provide
relief from the symptoms of the common cold and non–life-threatening respiratory infections. Even as more advanced products have come
and gone, VapoRub continues to dominate the market almost 9 decades after the death of its formulator, Lunsford Richardson (Figure).
B
orn in 1854 on a plantation near Selma, North Carolina, Richardson was to have lived a genteel life. But his
father drowned when he was 2 years old, and his family’s fortune was destroyed by the invading Union Army during
the Civil War.1 Despite impoverishment, Richardson was determined to receive a college education. He majored in chemistry
and obtained honors in Latin, Greek, and debate.
Although he had intended to become a lawyer, he ran short of
funds and reluctantly accepted a teaching position in a local
school. Although he rose to become principal, his interests still
lay in a different career, one that could combine his mastery of
Latin and knowledge of chemistry.1,2
In 1880 he bought a drug store with his meager savings.2 As
a pharmacist he labored to study his customers’ ailments and
find the drugs that would best alleviate them. He focused on less
serious conditions, which though discomfiting, were not serious
enough for the patient to consult a doctor and pay large fees.
His success allowed him to marry Mary Lynn Smith2 of Greensboro, North Carolina, and open a pharmacy in that city. Richardson continued to devise products that soothed common ailments, some 21 medicines listed in what was then called Vicks
Family Remedies. Most importantly, the products could be
bought directly from the store without a doctor’s prescription.1
Their popularity resulted in the launch of a wholesale company,
which dominated the state’s pharmaceutical distribution.
Later, his son, Henry Smith Richardson, took the reins of the company.3,4 Industrious, and with experience in sales, Henry rightly perceived that the market outside North Carolina had yet to be tapped.
Henry made the crucial decision to concentrate on marketing a sin-
gle product out of the 21, what was then called Vick’s Salve. To emphasize that it was for external use only, it was renamed VapoRub.1,2
This balm had menthol as a distinctive ingredient, which was at
that time a new and little known drug imported from Japan.1 Vicks
VapoRub became a household staple throughout the United States.
Although Vicks VapoRub ointment and cream are used externally on the skin, they are not marketed as a remedy for dermatoses.
However, there are claims that it might be effective as a foot care
product5 and in fungal infections of the nails, since some of the
essential oils, like turpentine, possess antimycotic action.6,7
Richardson was as clever at marketing as he was in compounding remedies. In 1906 he became the first to mail advertisements
to “box holders,” current residents at an address, rather than to
specific names. He is thus, arguably, the father of junk mail.
The company expanded and diversified, and was finally purchased by Procter & Gamble in 1985.1,2
Beyond his success in pharmaceuticals, Lunsford Richardson was
also a man of noble character. He was a staunch supporter of African-American rights, in a time and place where such sympathies
were shocking and even dangerous. A devoted Christian, he taught
Sunday school to African-American children for many years.
Richardson noted that Greensboro’s blacks were woefully underserved medically. There were only 6 hospital beds open to
African Americans in the entire city. He joined in an effort to
build a medical center to serve the black community, a facility
where the best care would be available, and where black doctors
could practice alongside white professionals. The hospital would
also open a nursing school for African Americans. The medical
center was later renamed the L. Richardson Memorial Hospital.
From the Dermatology Department, King Faisal Hospital, Makkah, Saudi Arabia
Address for Correspondence: Khalid Al Aboud, MD, P.O. Box 5440, Makkah, Saudi Arabia • E-mail: amoa65@hotmail.com
100
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HISTORICAL VIGNETTE
It would have pleased him to see that it, and eventually all of
Greensboro’s medical services, would become fully integrated.
During World War II a Liberty ship was christened as the S.S. Lunsford Richardson at the “special request of the leading Negro citizens
of North Carolina, to honor the memory of a white friend.”1,8
Richardson’s life came to an abrupt end during the height of his
success, when he succumbed to pneumonia during an epidemic.
An obituary in the Greensboro Daily News of August 22, 1919
had this to say about Lunsford Richardson’s fine nature: “He
never passed anyone on the street, young or old, black or white,
without a nod and a smile.”
Acknowledgment: Recipient of the Samuel J. Zakon Prize; awarded
at the 35th Annual Meeting of the History of Dermatology Society,
San Antonio, Texas, February 1, 2008.
REFERENCES
1 Hinds-Brown L. The man who helped the world breathe easier.
Tar Heel Junior Historian. 2006;46:6–8.
2 Arthur B. Breathing easier. Our State. 1997;64:12–14.
3 Inventory of the Richardson-Vicks, Inc. Manuscripts Department, University Library of the University of North Carolina at
Chapel Hill, Records; 1885-1995; Collection Number 04468.
http://www.lib.unc.edu/mss/inv/r/Richardson-Vicks,Inc.html.
Accessed February 23, 2010.
4 Office of Archives and History, N.C. Department of Cultural Resources. Lunsford Richardson. Series: North Carolina Inventors.
Copyright 2005 North Carolina Museum of History. http://www.
ncmuseumofhistory.org/collateral/articles/L.Richardson.pdf.
Accessed May 23, 2007.
Figure. Lunsford Richardson (1854–1919). Reproduced with
permission from the Greensboro Historical Museum.
5 Kelechi TJ, Stroud S. The four ‘Vs’ for foot care. Vaseline, vegetable shortening, vinegar and Vicks VapoRub. Adv Nurse Pract.
2004;12:67–70, 84.
7 Vicks VapoRub might help fight toenail fungus. Consum Rep.
2006;71(3):49.
6 Vicks VapoRub to treat nail fungus. Copyright 2005–2006 NailsFungus.com - Get rid of Nail Fungus. http://www.nails-fungus.
com/vicks-vaporub.html. Accessed May 23, 2007.
8 Lunsford Richardson. Wikipedia, the free encyclopedia. http://
en.wikipedia.org/wiki/Lunsford_Richardson. Accessed August
28, 2007.
101
March/April 2010
New to the Clinic
Noah S. Scheinfeld, MD, JD, Section Editor
Urea: A Review of Scientific and Clinical Data
U
rea is one of the natural moisturizing factors (NMFs) of
the stratum corneum (SC). Urea plays an important role
in maintaining the epidermal water level. It possesses
concentration-dependant proteolytic properties and can modify
the structure of amino chains and polypeptides. Urea helps to dissolve amino acids contained in filaggrin (the cornerstone protein
of the epidermis) and to break down protein connections between
corneocytes, which can then can hold more moisture, maintaining the barrier function of the skin. Urea is a humectant, an agent
that attracts water to the skin, in particular from the dermis. Urea
preparations in strengths ranging from 3% to 50% include cream,
lotion, shampoo, gel, gel stick, wipe, emulsion, solution, suspension, spray, ointment, paste, foam, and shower/bath wash. The
10% concentration appears to be provide the best balance of effectiveness and side effects for use on the body skin, although individual patients may benefit from stronger concentrations.
Urea is useful in treating many skin diseases including xerosis;
ungual and cutaneous hyperkeratosis; ichthyosis; keratosis pilaris; keratosis palmaris; keratoderma; clavi; calluses, cracked
heels; psoriasis; hand dermatitis; black hairy tongue; and acne
conglobata. The side effects of urea are mild and include cutaneous eruptions, allergic contact dermatitis, stinging, and irritation. While urea clearly helps to moisturize dry skin, its ability
to restore skin that is inherently lacking in barrier function, as
occurs in the elderly, has yet to be defined. Urea, a substance that
has been in use for over a century in topical preparation, still has
a place in the dermatologic armamentarium.
This review focuses on the role of urea in skin health and disease.
Urea, lactic acid (LA) (as sodium lactate), salts (as ions), sugars, pyrrolidone carboxylic acid (PCA) (as sodium pyrrolidone carboxylate),
and amino acids (ie, filaggrin breakdown products) are the NMFs
in the SC.1–3 Keratinocytes (corneocytes) make urea from proteins.
The NMFs may be up to 10% of the SC weight. The SC forms a
very active part of epidermis, possesses secretory functions, and furnishes urea with a setting in which to work its hydrating functions.4
The water content by weight of the SC is normally about 30%.
Urea plays an important, albeit nonprimary, role in maintaining
this epidermal water level. As stated, NMF are up to 10% of
the weight of the SC, of which urea represents 7%, amino acids
50%, PCA5 12%, lactic acid 12%, and other factors 19%. In
healthy epidermis, there are ≈28 μg of urea per square inch (2.5
cm2). Urea attracts water from the dermis, and binding water
gives the epidermis the capacity to hold moisture and maintain
the barrier integrity of the skin. In xerotic skin, the urea concentration is cut in half, in psoriatic skin it is decreased by 40%, and
in actively atopic skin urea concentration is decreased by 85%.
Topical treatment by urea reduces epidermal hyperproliferation
and induces differentiation in psoriasis.6
Urea possesses concentration-dependant proteolytic properties
and can modify the structure of amino chains and polypeptides;
it also helps to dissolve amino acids contained in filaggrin (the
cornerstone protein of the epidermis) and to break protein connections between corneocytes, which can hold moisture, maintaining the barrier function of the skin. Urea is a humectant,
an agent that attracts water to the skin, in particular from the
dermis. Other humectants include amino acids, LAs, a hydroxy
acids, propylene glycol, and glycerine.
Chemistry
Urea is an organic compound of carbon, nitrogen, oxygen, and
hydrogen, with the formula CON2H4 or (NH2)2CO. Urea is
also known as carbamide, especially in the recommended International Nonproprietary Names in use in Europe (ie, the medicinal compound hydroxyurea [old British approved name] is
now hydroxycarbamide).
Clinical Use
Urea has been a part of natural medicine since biblical times. In
modern times, urea has been used as a therapeutic topical preparation since 1906. The scientific basis for using urea has been underlined in recent years as its role as an NMF has been defined.
The mechanisms of urea’s actions involve its numerous effects on
keratin. Urea preparations include cream, lotion, shampoo, gel, gel
stick, emulsion, solution, suspension, spray, ointment, paste, wipe,
foam, and shower/bath wash and are available from many companies (Table). Strengths of urea preparations range from 3% to 50%.
The most commonly used urea preparation is the over-the-counter
From the Department of Dermatology, Columbia University, School of Medicine, New York, NY
102
March/April 2010
NEW TO THE CLINIC
10% cream. The 10% concentration appears to be the concentration of urea that parallels that of normal skin and is the highest
concentration that is commonly tolerated on the skin.
Urea’s advantages as a moisturizer include the following7:
1. Hydrating effects: Urea is strongly hygroscopic (waterloving) and draws from the dermis and retains water
within the epidermis. Urea causes hard, dry skin cells to
“unpack” and expose their water-binding sites, thus enabling the cell to absorb and retain additional moisture.
Forty percent to 50% urea products are useful agents in the treatment of nail diseases; preparations with this concentration of urea
improve the clinical appearance of toenails by softening nails, decreasing nail thickness, and serving as a debriding agent in such
diseases as onychomycotic nails, psoriatic nails, and ingrown nails.
Products with urea concentrations of 40% to 50% are useful for
treating nail hyperkeratosis induced by repetitive trauma and
friction. When urea is applied to the nails, the surrounding skin
should be covered because urea is a very strong keratinolytic.
Penetration and Chemical Effects
2. Keratolytic effects: Urea softens the SC, facilitating desquamation, a particular advantage on callused or pedal
skin. Urea dissolves the intercellular matrix, facilitating
its keratolytic effects.
Penetration of urea is dependent on the vehicle in which it is contained. Studies indicate that urea alters the physical and chemical properties of keratin so that permeation of monosubstances in
urea-altered keratin is increased. The moisturizing effect of urea
may be enhanced if the urea is applied while the skin is still damp
after washing or bathing. Results have shown that barrier-improving and hydrating abilities of urea are bidirectional and dependent
on both the type of vehicle used for its delivery and the state of
skin.14 It has been shown that the penetration is much deeper in
the layers of the SC (which contains ≈30 layers of flattened cells)
when the urea is applied in appropriate vehicles.
3. Regenerative skin protection: Urea has a direct protective effect against drying influences and, if used regularly, improves
the capacity of the epidermal barriers for regeneration.
4. Barrier function enhancement: Urea prevents water loss
by slowing down evaporation.
5. Anti-irritation/soothing effects: Urea has antipruritic activity based on local anesthetic effects.
6. Moisturizers influence and urea increases the skin barrier
function of normal skin and atopic skin, as measured by
transepidermal water loss and susceptibility to irritants
(eg, sodium lauryl sulfate).8,9
The chemical effects of urea on the skin are complex. The closer the
urea cream is to a pH of 7, the less burning there is with application. Addition of sodium chloride preparations does not increase
the effectiveness of creams with urea.15 Clinical improvement of
xerosis following treatment with a urea-containing cream was not
accompanied by any significant change in the amino acid content
of the SC.16 The damaging effect of oil-inwater emulsions, which
dry the skin, can be reduced by the addition of glycerol and urea.17
7. Penetration-assisting effects: Urea can potentate the effectiveness of antifungal and corticosteroid preparations
by increasing preparation penetration.10
8. Moist skin care with 3% urea lotion delays the occurrence
and reduces the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors.11
Urea is not a panacea for enhancing penetration. Evaluation of
the efficacy of short-incubation, broad-area aminolevulinic acid/
photodynamic therapy for actinic keratoses and diffuse photodamage found no benefits of pretreatment with 40% urea cream
for penetration enhancement.
9. Urea can exert its effect in concentrations as low as 10%.
12
10. Urea also hydrates and dissolves the intercellular matrix
of the nail plate, which can result in the softening and
eventual debridement of the nail plate.
Urea is useful in treating many skin diseases. The most important
for urea as a treatment is for xerotic and hyperkeratotic skin, including such conditions as ichthyosis, keratosis pilaris, keratosis
palmaris, keratoderma, clavi, calluses, and dry and cracked heels.
Topical urea is useful for the debridement and promotion of normal
healing of hyperkeratotic surface lesions, particularly where necrotic
tissue, terra firma, fibrinous debris, purulent debris, or eschar retards
healing. Urea has been used to treat hand dermatitis13 and psoriasis.6 Topical treatment by urea reduces epidermal hyperproliferation
and induces differentiation in psoriasis.6 Urea has also been used in
treating black hairy tongue and acne conglobata and to dissolve and
remove diseased nails in 40% concentration preparations.7
Side Effects. The side effects of urea are mild and include cutaneous eruptions, stinging, and irritation. It should not be applied to
broken skin or the eyes. Urea’s low pH and sensory reactions may
reduce patient acceptance, in particular in the elderly with broken
skin. Strong odor is also present with urea and can reduce acceptance. Urea can cause allergic contact dermatitis. Patch tests with a
cream containing 10% urea were performed on 79 patients with eczematous skin disease; 7 (8.9%) had positive results to urea alone.18
Urea Study Data. A variety of studies have assessed the utility of urea
as a moisturizer.19–26 In a study of 1905 patients,19 the combination of
urea and hydrocortisone was used for acute attacks of neurodermatitis, and urea ointment for chronic therapy. Eight-four percent of the
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March/April 2010
NEW TO THE CLINIC
Table. Productsa With Ureab
Aqua Care, 10%
Keralac 50% cream
Rea-Lo Lotion, 30%
Aquaphilic, 10%
Keralac Nailstik, 50%
Rinnovi nail system 50% solution, cuticle protectant
spray, cuticle cleanser spray
Atrac-Tain Cream (10% urea and 4% alpha
hydroxy acid [lactic acid])
Keralac 50% Ointment
Rosula Sodium Sulfacetamide 10% and Sulfur 4% in
10% Urea Base Clarifying Wash, Aqueous Cleanser
and Gel, NS Medicated Pads
Bianca Rosa 10% Gel
Keralac 50% Gel
U-Kera E Emollient Cream, 40%
BP-K50 (50% suspension)
Keralac 35% Lotion
Ultra Mide 25, 25%
Carmol 10% cream
Keratol Zx 50% solution
Ultralytic 20% foam
Carmol 20% cream
Keratol Plus lotion, 35%
Ultralytic 2 (ammonium lactate and urea foam 20%)
Carmol HC Cream (1% hydrocortisone
acetate and 10% urea)
Keratol plus gel, 50%
Umecta PD Bioadhesive Emulsion (urea 40% sodium hyaluronate 0.3%)
Carmol 40% Cream, Lotion, Gel
Keratol 40% lotion, cream
Umecta 40% Mousse (foam)
Carmol 10% Deep Cleansing Antibacterial
Shampoo
Keratol cream (10% urea and 1%
hydrocortisone)
Umecta 40% Nail Film Pen
Carmol Scalp Treatment Lotion (10%
sulfacetamide sodium in a 10% urea
vehicle)
Kerol 42% cloths
Umecta PD Topical Suspension (urea 40% - sodium
hyaluronate 0.3%)
Cerovel 40% cream
Kerol AD 45% emulsion
Urea-generic/compounded 10%, 20% (solution,
suspension, cream, lotion, ointment) over the counter
Dermatol 10% cream
Lanaphilic Ointment, 10%
Urea-generic/compounded 40%, 50% (solution,
suspension, cream, lotion, ointment) prescription
Epimide 25% lotion
Mectalyte 40% emulsion
Ureacin-10 lotion, 10%
Epimide 50% Topical Paste
Mectalyte 40% suspension
Ureacin-20 Crème, 20% cream
Gord Urea 40% cream
Nutraplus cream/lotion, 10%
Ureacin-40 Crème, 40% cream
Gordons 22% cream
Lanaphilic 10% Ointment with lanolin
Urealac 35% lotion
Gordons 40% cream
Kerol AD 45% emulsion
Urealac 50% gel, cream, ointment, and nail stick
Gormel 10% lotion
RE Urea, 40%
Urix 40% Urea cream
Gormel 20% cream
RE Urea, 50%
Vanamide 40% cream
Hydro 35 foam, 35%
RE Urea 50% Nail Applicator
X Viate 40% cream, gel
Hydro 40 foam, 40%
RE40Gel, 40%
ZoDerm (benzoyl peroxide 6.5%, 8.5%) in 10% urea
base Cream, Gel & Cleanser
Kerafoam 30% emollient foam
RE-U40 foam, 40%
ZoDerm (benzoyl peroxide 6.5%, 8.5%) in 10% urea
base Redi-Pads
Kerafoam, 42%
Rea-Lo cream, 30%
Products are presented as trade names. aNot all products are still available or are available in the United States. bUrea concentration provided as %.
patients showed good to very good results. Local therapy with other
corticosteroids was only reported as necessary in 16% of cases.
A randomized, double-blind, bilateral paired-comparison study
involving 25 patients with moderate to severe xerosis showed
that improvement is achieved quicker with 40% urea cream than
with 12% ammonium lactate lotion, with superior day 14 skin
roughness, fissure reduction, thickness, and dryness measurements.26 Ten percent urea lotion has a strong positive effect on
generalized ichthyotic keratinization disorders.20 In patients with
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March/April 2010
NEW TO THE CLINIC
diabetes, 10% urea and 4% lactic acid vs its emulsion base provided faster and better improvement with significantly less xerosis regression.9 Debridement of necrotic eschar with 40% urea
paste speeds healing of residual limbs and avoids further surgery.
2 Jacobi O. The composition of normal human stratum corneum
and callus. 3. Lactic acid, creatine, creatinine, urea and choline.
Arch Dermatol Forsch. 1970;240:107–118.
In a study of cases with evidence of dry skin according to measurements by noninvasive techniques, 47 patients were enrolled for
a 3-week study with double-blind and randomized treatment of
one forearm; both 3% urea cream and 10% urea cream improved
hydration and reduced scaling. Of interest, the 3% urea cream
turned the skin color golden, while the 10% urea cream improved
the skin’s water barrier function.21
4 Barták P. The epidermal permeability barrier and its function in immune reactions [in Czech]. Cas Lek Cesk. 2001;140:259–261.
A 40% urea product in an emulsion vehicle system (Butyrospermum parkii fruit oil, Helianthus annuus oil, glycine soja sterol,
and stearic acid) significantly accelerated barrier recovery after
tape stripping.22 When used in women aged 56 to 80 years old
who had chronically dry, rough, thick, scaly skin of the legs, this
preparation decreased roughness, pigmentation, and microtopography with no reports of stinging, burning, or itching.23
A foam formulation of 40% urea24 effectively reduced, at 7 and 14
days, the signs and symptoms associated with dry skin. It also improved the visual appearance of the dry skin by physician and patient
assessment based on a sign and symptom rating scale and photodocumentation. Participants preferred the urea foam formulation for the
following attributes: creaminess, lack of oiliness, lack of stickiness, ease
of rub in, and overall feel; this perhaps increased urea acceptance and
patient compliance.25 No differences were noted for odor or odor type.
3 Wellner K, Wohlrab W. Quantitative evaluation of urea in stratum
corneum of human skin. Arch Dermatol Res. 1993;285:239–240.
5 Sodium PCA. MetaGlossary Web site. http://www.metaglossary.com/meanings/1260977/. Accessed December 12, 2007.
6 Hagemann I, Proksch E. Topical treatment by urea reduces epidermal hyperproliferation and induces differentiation in psoriasis. Acta Derm Venereol. 1996;76:353–356.
7 Urea. DermNet NZ Web site. http://dermnetnz.org/treatments/
urea.html. Accessed December 12, 2007.
8 Buraczewska I, Berne B, Lindberg M, et al. Changes in skin barrier function following long-term treatment with moisturizers, a
randomized controlled trial. Br J Dermatol. 2007;156:492–498.
9 Pham HT, Exelbert L, Segal-Owens AC, et al. A prospective, randomized, controlled double-blind study of a moisturizer for xerosis of the feet in patients with diabetes. Ostomy Wound Manage.
2002;48:30–36.
10 Vlahovic T, Mills O. The cumulative effect of urea 40% combined
with essential fatty acids in a bioadhesive delivery system and
ketoconazole cream 2% for the treatment of moccasin tinea pedis in diabetics. J Am Acad Dermatol. 2007;56(2 suppl 2):AB45.
11 Momm F, Weissenberger C, Bartelt S, et al. Moist skin care
can diminish acute radiation-induced skin toxicity. Strahlenther
Onkol. 2003;179:708–712.
12 Serup J. A three-hour test for rapid comparison of effects of
moisturizers and active constituents (urea). Measurement of hydration, scaling and skin surface lipidization by noninvasive techniques. Acta Derm Venereol Suppl (Stockh). 1992;177:29–33.
13 Fredriksson T, Gip L. Urea creams in the treatment of dry skin
and hand dermatitis. Int J Dermatol. 1975;14:442–444.
Conclusions
Urea is a useful moisturizer that is available in a variety of new formulations. It clearly helps to moisturize dry skin; however, its ability to
restore skin that is inherently lacking in barrier function, as occurs in
the elderly, has yet to be defined. Studies have not compared old formulations with new formulations in terms of efficacy. New formulations have been compared, rather, to their bases and have been shown
to be more effective. Patients often cannot tolerate 40% to 50% urea
on their bodies, but they find such concentrations useful and tolerable
on the nails. As is true elsewhere, the literature would benefit from
direct comparisons of urea products in clinical trials performed in specific patient groups and subgroups. Urea is particularly promising as a
treatment for dystrophic toenails whether infected with fungus or not.
It is hoped that clinical study will continue in the area. New vehicles
have been developed by urea to make it more cosmetically acceptable.
These include foams and an essential fatty acid.
References
1 Features–beneficial effects of urea–information supplied by Beiersdorf. Talkeczema Web site. http://www.talkeczema.com/webpages/
features/feature_benefits_urea.htm. Accessed December 12, 2007.
105
14 Savica S, Tamburic S, Savic M, et al. Vehicle-controlled effect of urea on normal and SLS-irritated skin. Int J Pharm.
2004;271:269–280.
15 Kuzmina N, Hagströmer L, Emtestam L. Urea and sodium chloride in moisturisers for skin of the elderly–a comparative, double-blind, randomised study. Skin Pharmacol Appl Skin Physiol.
2002;15:166–174.
16 Horii I, Nakayama Y, Obata M, et al. Stratum corneum hydration and amino acid content in xerotic skin. Br J Dermatol.
1989;121:587–592.
17 Gloor M, Gehring W. Effects of emulsions on the stratum corneum barrier and hydration. Hautarzt. 2003;54:324–330.
18 Cramers M, Thormann J. Skin reactions to a urea-containing
cream. Contact Dermatitis. 1981;7:189–191.
19 Stüttgen G. Results and consequences of long-term urea therapy for clinical practice. Hautarzt. 1992;43(suppl 11):9–12.
20 Küster W, Bohnsack K, Rippke F, et al. Efficacy of urea therapy in children with ichthyosis. A multicenter randomized, placebo-controlled,
double-blind, semilateral study. Dermatology. 1998;196:217–222.
21 Serup J. A double-blind comparison of two creams containing urea as the active ingredient. Assessment of efficacy and
side-effects by non-invasive techniques and a clinical scoring
scheme. Acta Derm Venereol Suppl (Stockh). 1992;177:34–43.
March/April 2010
NEW TO THE CLINIC
22 Rizer R, Elias P, Mills OH. Urea (40%) in an essential fatty acid
(EFA) vehicle improves barrier function in the stratum corneum
(SC). J Am Acad Dermatol. 2006;54(3 suppl 1):602.
23 Kligman A, Stoudemayer S, Yaxian Zhen Y, et al. Improving
chronically dry skin: Clinical, patient, and laboratory evaluations.
J Am Acad Dermatol. 2006;54(3 suppl 1):571.
24 Bikowski J. The treatment of xerosis with a new 40% urea foam.
J Am Acad Dermatol. 2007;56(2 suppl 2):AB40.
25 Gurge R. Evaluation of the aesthetic attributes of topical products containing high concentrations of urea. J Am Acad Dermatol. 2007;56(2 suppl 2):AB45.
26 Ademola J, Frazier C, Kim SJ, et al. Clinical evaluation of 40%
urea and 12% ammonium lactate in the treatment of xerosis. Am
J Clin Dermatol. 2002;3:217–222.
LABEL
Courtesy of Lawrence Charles Parish, MD, MD (Hon)
106
March/April 2010
STDs in Perspective
Michael A. Waugh, MB, FRCP, Section Editor
Sexually Transmitted Diseases in Ethnic Minorities
C
linicians and health workers in Europe and North
America must be able to identify unique symptoms and
signs of sexually transmitted diseases (STDs) in patients
who are not of northern European descent. They must also be
aware of cultural factors, which are crucial to correct investigation, diagnosis, treatment, and follow-up. This sensitivity is also
important for appropriate counselling and contact tracing.
HISTORICAL AND SOCIAL BACKGROUND
Classical descriptions of STDs, especially of syphilis, evolved in
Europe and North America from the studies of 19th-century
teachers in metropolitan centers such as Vienna and Paris. Their
conclusions were based on the observation of the poor of those
cities, whose skin coloring prior to the late 20th century was predominately pale. Until World War II, illustrations in standard
text books were almost all of light-skinned patients. When the
United States entered World War II, its armed forces published
manuals for health workers about venereal diseases which, for
the first time, included photographs of black skin.
Other ethnicities were scarcely represented in the literature. One
exception was “Voordrachten Over Tropische Huidzieten” by J.D.
Kayser1 of the Tropical Diseases Institute of Rotterdam-Leiden,
published in 1929, which included photographs of various stages
of syphilis in Malays, in what was then the Dutch East Indies.
YAWS/SYPHILIS
Early 20th century treatises were greatly concerned about the differences between venereal syphilis and yaws, but with the World
Health Organization’s mass eradication campaigns of the 1950s2
those differences were found to have little practical application.
Hackett and Loewenthal2 state “The skin has a limited number
of reaction patterns so that similar lesions may result from different causes. This concept, so clearly explained by Brocq, may even
apply to all the characters of an eruption, its method of development, its distribution, and subjective symptoms, in addition to
the morphology of its individual components. Only a few lesions are truly diagnostic of yaws and often the repetition of the
same pattern in an endemic area tends to be taken as evidence
of yaws.” They also pointed out that in yaws-endemic areas serologic tests to differentiate the treponematoses are of little value.
SOCIAL BACKGROUND—RACIAL AND
GENETIC THEORIES
We should speak of groups of populations or ethnic groups, and
eliminate the term race, not only because it does not exist on a
biological plane, but because it lacks all scientific foundation.
Although the term “race” is useless on a clinical level,3 it took some
70 years to change ingrained prejudices in the literature. In 1943
Rudolph Kampmeir, practicing in Nashville, Tennessee, wrote
that “Race is a factor which cannot be disregarded with respect to
the reaction between host and invader. Surely the clinician treating syphilis in both the white and Negro races is struck by the
difference in the morphology of the skin reactions in the secondary stage of syphilis. Furthermore, cardiovascular syphilis is much
more common in the colored than in the white patient, and by
contrast it is generally accepted that the reverse is true with respect
to the incidence of central-nervous-system syphilis.”4
In 1977 Robert Morton, writing about population movement
and rising gonorrhoea rates in Sheffield, England, explained that
immigration “has been a feature of the European scene for more
than 20 years. Multiracialism is becoming an established fact,
particularly in France, Holland, and the United Kingdom.”5 He
went on to describe the conditions of immigrants to England
from the West Indies, Pakistan, and Aden. Morton noted objective findings where race played no role in disease, but other
factors did. He cited a 1970 study by Oller and Wood6 of the
incidence of gonorrhea from 1959 to 1968 in Bradford, an industrial city in England. It was found that of 5000 infected men,
80% were immigrants.
In 1976 Verkeij,7 studying gonorrhea in Rotterdam, found the disease 6.7 times more common in immigrants than in Dutch men
(and that the great majority of the immigrants had been infected
by indigenous Dutch women). The reason for the high incidence
From Nuffield Hospital, Leeds, England
Address for Correspondence: Michael A. Waugh, MB, FRCP, Nuffield Hospital, 151 Roker Lane, Pudsley, Leeds LS28 9ND, England •
E-mail: mike@mawpud.fsnet.co.uk
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STDs in Perspective
had nothing to do with “race.” Rather, the young males who were
most likely to immigrate to Europe did so without their families.
TIPS FOR CLINICIANS AND HEALTH WORKERS
The care of STDs is always delicate. However much braggadocio
young adults, especially men, may show when seeking help for STDs,
they are likely to be fearful and seeking compassion. This is even more
so for those of cultural backgrounds where the concept of confidentiality in the medical care of STDs may be little understood.
A calm and welcome atmosphere should be provided by the
treatment clinic as well as the clinician. Staff may need to be
multilingual. They must become familiar with specific community customs and sexual mores.
Among the situations that need to be considered: refugees from
chaotic parts of the world may have endured torture, rape, or
other extremely traumatic events; young people from intolerant
religious backgrounds may be terrified of encountering acquaintances at the clinic; patients from conservative societies may
hesitate to admit sexual activity, even to themselves.
The young men from ethnic minorities who come for help for
STDs after having sex with men (MSM), may need especially
sympathetic care. In some societies, such as Latin America, the
Caribbean, and much of the Islamic world, special opprobrium
is heaped on the passive male.8 Participants in MSM may be
reluctant to identify as homosexual, and may also have female
contacts who will need to be examined and treated.
Women from some ethnic groups have little understanding of
their own sexual rights in a liberal Western society. Havens of safety and confidentiality need to be made for them. It is difficult for
any woman to give a true sexual history if a male or even a female
relative or friend is accompanying her. Privacy must be assured.
With the growth of the international sex trade, the clinician
should be on guard for women who have been forced into prostitution. Health professionals must be able to refer persecuted
women to social agencies that can aid them immediately.
CLINICAL DIFFERENCES IN “ETHNIC” SKINS
There are several easily obtainable atlases of STDs in black skin.
However, many of these are based on studies in Africa. Medical
practice differs in Europe and North America, where physicians
are more accessible, and conditions are generally less advanced
before medical care is sought.
Generally, if an STD is primarily an infection of mucous surfaces, such as gonorrhea, chlamydial infection, trichomoniasis, or
bacterial vaginosis, there is no difference in presentation, whatever the patient’s skin color. However, STDs that affect the skin:
syphilis, chancroid, lymphogranuloma venereum, granuloma
inguinale, herpes genitalis, condylomata acuminata, molluscum
contagiosum, scabies, pediculosis pubis, and human immunodeficiency virus (HIV) skin disease, may present some unique
features. These may be overlooked if the examining physician is
not well trained, makes a cursory examination, or is prejudiced.
A careful, full-skin examination is essential; it may alert the clinician to the secondary rash of syphilis, other dermatoses, or scabies. There may be useful clues in tattoos, tribal scars, piercings,
and needle marks.
A Darkfield examination for Treponema Pallidum from the penis
or vulva may make the diagnosis. However, if the patient has already taken antibiotics or used an antiseptic the test will be useless.
A Darkfield examination from the buccal cavity is not productive,
as it may show commensal spirochetes. It should be remembered
that serologic tests for syphilis, fluorescent treponemal antibody-absorption or rapid plasma reagin, may not be positive before 2 weeks.
Secondary Syphilis
As a general rule, the more pigmented the patient’s skin, the
deeper the color of the lesions. But secondary syphilis may not
always be classical and may only be present for a short time.
Again, examining the patient fully, in good light is paramount.
Whatever its texture, the hair of the scalp and eyebrows must be
examined for alopecia.
It has been said that condyloma lata may be more gross in humid
climates or where hygiene/washing facilities are poor. The rash
may not always look like a textbook example. Palmar and plantar
syphilides may not be obvious in a dark skinned patient.
Skin biopsy should only be done as a last resort in dark-skinned
patients because of the danger of subsequent keloid formation.
Nowadays in the West, tertiary or late congenital syphilis is very rarely
seen, but it may be present in immigrants from third-world countries.
Chancroid
Haemophilus Ducreyi cases are still seen in those who have recently travelled from Africa or the Indian subcontinent.
Donovanosis or Granuloma Inguinale
(Klebsiella Granulomatis)
Donovanosis or Granuloma Inguinale (Klebsiella Granulomatis)
is another condition that is rare in Western practice, but occasionally seen in patients from the tropics, particularly the Indian
subcontinent. The lesion begins as a small erosion or ulcer that
expands on the surface of the penis to become larger with local
spread. It often becomes secondarily infected and malodorous.
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STDs in Perspective
There is no inguinal gland enlargement. Diagnosis is made by
biopsy from the edge of the lesion using Giemsa stain and finding Donovan bodies.
chest, loins, or arms. These may be very widespread. It is a frequent sign of HIV disease in sub-Saharan Africans.
Lymphogranuloma Venereum—L1, L2, L3 Serovars of
Chlamydia Trachomatis
In young, adult men it often presents not only as itching, causing burrows in classical distribution, but also on the penis, scrotum, and buttocks. In impoverished groups living in cramped
and poor housing it may spread to other inhabitants. Public
health services may need to be enlisted in its eradication.
Until recently this had been a rare disease in the West, mostly diagnosed in travellers returning from Asia, Africa, South America,
or the Caribbean. Immigrants from these parts of the world have
increased its incidence in the West. Initially there is a small transient ulcer at the point of inoculation, followed by firm, swollen,
and painful regional lymph nodes, with fever and malaise. Late
stage disease shows results of lymphatic damage, and includes
scarring and fistulae.
Herpes Genitalis
Because herpes simplex infection is often dismissed as nothing
more than an inconvenient minor sore or irritation on the lips,
penis, vulva/vagina, or anal canal, both male and female patients
from less-educated, impoverished groups may hesitate to bring
it to a physician’s attention.
Genital Warts—Condylomata Acuminata—Human
Papilloma Virus
Low risk, rarely associated with invasive cervical cancers—6, 11
and some later HPV genotypes.
High risk types, oncogenic—16, 18 and some later genotypes.
These are caused through direct sexual contact and are occasionally transmitted from mother to child during childbirth. They
warrant close attention in patients from countries where HIV is
widespread among women. Lesions may become quite large and
often pigmented in black patients.
Scabies—Mite Sarcoptes Scabiei
Pediculosis Pubis—Crab Lice
Crab lice may be difficult to see in black patients. On the other
hand, in hirsute ethnic groups, such as Arabs, Turks, Persians,
Afghans, and northern Indians, they may be widespread, occurring on the body, axilla, back, moustache, and eyelash hair. They
are not to be confused with body lice.
HIV Infection
There are numerous skin and genital situations that should make
the observer consider HIV infection, including herpes zoster, severe and chronic seborrhoic eczema, molluscum contagiosum,
papular pruritic eruption, severe herpes simplex, severe human
papilloma infection, scabies, and severe drug eruptions. In evaluating risk factors for HIV, one should be especially sensitive to
cultural sensitivities.
REFERENCES
Molluscum contagiosum, a pox virus, is not uncommon in
ethnic minority patients. There are two main groups. The first
appears in the pubic region of men who, for religious reasons,
shave their pubic hair. The virus settles in small cuts, resulting
in small dome-shaped papules with umbilicated centers, often in
groups of lesions. They are frequently mixed with genital warts,
both becoming pigmented. Lesions occur on the shaft of the
penis and on the scrotum. The second manifestation is a sign of
HIV disease, often in nongenital areas such as the eyelids, face,
109
1 Kayser JD. Voordrachten Over Tropische Huidziekten. Weltevreden, Java: G. Kolff & Co.; 1929.
2 Hackett CJ, Loewenthal LJA. Differential Diagnosis of Yaws. Geneva, Switzerland: World Health Organization; 1960.
3 Morrone A, Hercogova J, Lotti T. Dermatology of Human Mobile
Populations. Bologna, Italy: MNL Science Publishing & Communication; 2004.
4 Kampmeir RH. Essentials of Syphilology. Philadelphia, PA: JB
Lippincott; 1943.
5 Morton RS. Gonorrhoea. London, England: Saunders; 1977.
6 Oller LZ, Wood T. Factors influencing the incidence of gonorrhoea and non-gonococcal urethritis in men in an industrial city.
Br J Vener Dis. 1970;46:96–102.
7 Verkeij H. Gonorrhoea and foreign immigrants at Rotterdam University Hospital. Br J Vener Dis. 1976;52:84–87.
8 Whitaker B. Unspeakable Love: Gay and Lesbian Life in the Middle East. London, England: Saqi Books; 2006.
March/April 2010
PHOTO CAPSULES
Ncoza C. Dlova, MBChB, FCDerm, Section Editor
Disseminated Cutaneous Histoplasmosis
A
25-year-old African woman presented with a 7-month
history of extensive ulceration of the skin and destruction of the nose.
Examination revealed generalized necrotic ulcers involving the
scalp and body, destruction and collapse of the nasal bridge, associated with auto amputation of the finger. Investigations revealed the patient to be positive for human immunodeficiency
virus with a CD4 count of 50/mm3.
Figure 1. Deep necrotic ulcer of the forehead.
Skin biopsy and culture confirmed disseminated cutaneous histoplasmosis caused by histoplasma capsulatum. Bone marrow
aspirate confirmed bone involvement. Chest x-ray was normal.
The patient was officially diagnosed with disseminated cutaneous histoplasmosis with systemic involvement of the bones.
Figure 2. Disseminated punched out necrotic ulcers of the trunk.
Figure 3. Histoplasmosis with spontaneous amputation of the finger.
From the Department of Dermatology, Nelson R. Mandela School of Medicine, Durban, South Africa
110
March/April 2010
CASE STUDY
Pruritic, Papular Eruption, and
Concomitant Neurologic Symptoms:
Churg-Strauss Syndrome Presenting With
Mononeuritis Multiplex
Jyoti Pathria, BA; James Collyer, MD; Stephanie Mehlis, MD; Joaquin Brieva, MD
A 38-year-old man with a medical history of sinusitis, nasal polyps, and asthma presented with a 2-week history of progressive sensory and
motor loss in his right hand and foot. Dermatology was consulted to evaluate mildly pruritic lesions on the elbows and dorsal right hand that
had been recurring for the past year. Since the initial outbreak, the patient had 6 flares of this eruption. Self-medication with oral prednisone
for a few weeks resulted in near-complete resolution of the eruption. The lesions are rarely painful and only mildly tender.
O
n examination of the elbows and right hand, the patient had scattered, 1- to 2-mm erythematous, firm,
nontender papules, some with overlying crust (Figure
1). No purpura or exudates were noted. Laboratory results revealed a perinuclear antineutrophilic cytoplasmic autoantibody
(p-ANCA) of 1:320, peripheral eosinophils of 32%, and elevated
serum IgE, D-dimer, erythrocyte sedimentation rate, and rheumatoid factor. Antinuclear antibody, classic ANCA (c-ANCA),
hepatitis serologies, echocardiography, and cryoglobulin results
were unremarkable. An electromyogram showed a demyelinating process. A biopsy of a papule on the right elbow (Figure 2
and Figure 3) revealed a serohemorrhagic crust and a dense dermal infiltrate on low power. Higher-power examination revealed
inflammation of the blood vessels with hyalinization of the walls
and histiocytes around degenerated collagen. The perivascular
spaces showed an infiltrate composed of histiocytes including
occasional multinucleated giant cells, numerous neutrophils
with karyorrhexis, and many eosinophils. Gram stain results
were negative. A diagnosis of Churg-Strauss syndrome presenting with mononeuritis multiplex was made.
of the right lower extremity and bilateral upper extremities; however, he is not yet able to walk without residual foot drop.
Discussion
In 1951, Churg and Strauss established the precise pathological entity
of this disease. It is a rare multisystem vasculitis that is characterized
by asthma, eosinophilia, and necrotizing vasculitis with extravascular
granulomas. It typically occurs in the third and fourth decades of life.
The patient received intravenous pulse methylprednisolone 1 g for
3 days and was then discharged on oral prednisone 100 mg daily.
The prednisone was tapered within 4 months, and he was switched
to azathioprine 100 mg daily. He was also given 12 weekly doses of
intravenous immunoglobulin (IVIG). He continues to feel better,
with increased strength to his right foot and decreased paresthesias
Figure 1. One- to 2-mm erythematous, firm, nontender
papules, some with overlying crust on the dorsum of the
patient’s hand.
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL
Address for Correspondence: Joaquin Brieva, MD, Northwestern University, Department of Dermatology, 676 North Saint Clair, Suite
1600, Chicago, IL 60611 • E-mail: jbrieva@nmff.org
111
March/April 2010
CASE STUDY
p-ANCA is present in the serum of approximately 70% of patients, whereas c-ANCA is found in only 7% of patients who are
ANCA-positive. ANCA positivity may be positively associated
with other organ system manifestations including purpura and
mononeuritis multiplex.2
Criteria for the classification of Churg-Strauss syndrome were developed by comparing 20 patients who had the diagnosis with 787
control patients with other forms of vasculitis. For the traditional
format classification, 6 criteria were selected: asthma, eosinophilia
>10%, paranasal sinusitis, nonfixed pulmonary infiltrates, histological proof of vasculitis, and mononeuropathy (including multiplex) or polyneuropathy. If a patient met 4 of these 6 criteria,
this traditional format classification had a sensitivity of 85% and a
specificity of 99.7% for the diagnosis of Churg-Strauss syndrome.3
Our patient fulfilled 5 of the 6 criteria.
Figure 2. Low power revealed a sebohemorrhagic crust with
a dense dermal infiltrate.
Peripheral neuropathy is common in patients with Churg-Strauss
syndrome, with mononeuritis multiplex being the most frequent
finding. Peripheral neuropathy is a well-recognized consequence
of systemic vasculitis due to peripheral nerve infarction with
Wallerian degeneration.4 If mononeuritis multiplex is seen in a
patient with asthma and eosinophilia, the diagnosis of ChurgStrauss syndrome is almost certain.5
For vasculitic neuropathy, a long-term regimen of high-dose
prednisone combined with intravenous pulse or oral cyclophosphamide is the standard initial therapy. Other immunosuppressants, such as azathioprine, methotrexate, or IVIG may be helpful if the patient has a contraindication to cyclophosphamide or
is intolerant to it.4
References
Figure 3. Higher power revealed inflammation around blood
vessels with hyalinization of walls and histiocytes around
degenerated collagen. Numerous histiocytes, neutrophils with
karyorrhexis, and eosinophils are visible in perivascular spaces.
1 Davis MD, Daoud MS, McEvoy MT, et al. Cutaneous manifestations of Churg-Strauss syndrome: a clinicopathologic correlation. J Am Acad Dermatol. 1997;37(2 pt 1):199–203.
Characteristic cutaneous lesions occur in 50% to 60% of patients. These lesions consist of petechiae, purpura, and painful
dermal and subcutaneous nodules.
Tissue biopsy specimens reveal an eosinophil-rich inflammatory
infiltrate with granuloma formation in connective tissue and
blood vessel walls. Necrotizing vasculitis with fibrinoid changes
arises in small to medium vessels.1
112
2 Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical
significance of antineutrophil cytoplasmic antibodies in ChurgStrauss syndrome. Arthritis Rheum. 2005;52:2926–2935.
3 Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss
syndrome (allergic granulomatosis and angiitis). Arthritis Rheum.
1990;33:1094–1100.
4 Gorson KC. Vasculitic Neuropathies: an update. Neurologist.
2007;13:12–19.
5 Noth I, Strek ME, Leff AR. Churg-Strauss syndrome. Lancet.
2003;361:593–594.
March/April 2010
CASE STUDY
Pleomorphic Fibroma of the Skin
Philip R. Cohen, MD;1–3 Keith E. Schulze, MD;2,4 Scott A. Cohen, MD;5
Paul T. Martinelli, MD;2,6 Bruce R. Nelson, MD2
A 71-year-old white woman presented with a painless mass at the base of her right great toe of 8 months’ duration. She has chronic myelogenous leukemia, medication-controlled hypertension and hypothyroidism, and mitral valve prolapse. Her leukemia is in partial remission; it
was diagnosed 8 years ago, and she underwent a stem cell transplant 3 years ago. Clinical evaluation revealed a firm, nontender, flesh-colored
1.5×1.0-cm well-circumscribed dermal nodule with a peripheral collarette of scale on the plantar base of her right great toe (Figure 1). A
tangential excision was performed. Microscopic examination demonstrates compact orthokeratosis and a collarette of epithelium overlying
a dermal tumor (Figure 2). The lateral portion of the neoplasm, beneath the collarette, shows an increased number of small telangiectatic
vessels in the upper dermis. Within the fibrous dermis there is a hypocellular tumor predominantly consisting of cells with spindle-shaped
nuclei. Some of the tumor cells are either large and multinucleated with nuclear atypia or mononuclear with pleomorphic nuclei (Figure
3). The pleomorphic tumor cells did not stain with antibody to CD34. The diagnosis of pleomorphic fibroma of the skin was established
based on the correlation of the clinical findings and the pathologic changes. The postoperative defect was allowed to heal by granulation.
P
leomorphic fibroma of the skin is a benign fibrous tumor
initially described by researchers in 1989.1 The dermal tumor is usually solitary, dome-shaped or polypoid, and is
typically located either on the extremities or trunk.1–3 Less common, it may occur on the head.4,5 The peripheral collarette of
scale and the plantar site of our patient’s tumor raised the clinical
possibility of an eccrine poroma.
Microscopic examination of pleomorphic fibroma of the skin
reveals a dermal tumor with sparse cellularity but striking nuclear atypia. The neoplastic cells typically have large pleomorphic and hyperchromatic nuclei with small nucleoli. In addition to these mononuclear cells, the atypical nuclear features
can often also be observed in many of the multinucleated giant
cells that are present.1,2,5
Immunoperoxidase staining of the atypical cells in pleomorphic
fibroma of the skin is always positive for vimentin and negative
for S-100 and cytokeratin. Inconsistent expression of musclespecific actin (or smooth muscle actin), factor XIIIa, and CD34
by the pleomorphic tumor cells has also been observed.1–9
Some pleomorphic fibromas of the skin also have features of
sclerotic fibromas.10 Indeed, some investigators have postulated
that the pleomorphic fibroma of the skin is actually a variant of
the sclerotic fibroma.4,7 Alternatively, other researchers have classified some of these tumors as pleomorphic sclerotic fibromas.6
Neither pleomorphic fibromas nor sclerotic fibromas have been
associated with hematopoietic dysplasias.11 Other benign fibrous
connective tissue tumors, however, such as multiple dermatofibromas, have been reported in patients with either chronic myelogenous leukemia12 or acute myelogenous leukemia.13 The hypothesized pathogenesis for the eruptive onset and proliferation of
dermatofibromas in these oncology patients (malignancy-induced
and/or antineoplastic therapy–associated alteration of their immune status) may be similar to the postulated etiology of multiple
dermatofibromas that have previously been described in individuals receiving immunosuppressive therapy and/or with an acquired
immunodeficiency or an autoimmune disorder or both.14,15
The prominent pleomorphic cells and nuclear atypia observed in
pleomorphic fibromas may initially suggest a malignant dermal neoplasm, such as atypical fibroxanthoma, fibrosarcoma, and malignant
fibrohistiocytoma or benign dermal tumors such as angiofibroma,
desmoplastic or hyalinizing Spitz nevus, fibrous papule of the face,
giant cell fibroblastoma, neurofibromas with atypia, and schwannomas with ancient changes.1,2,5,16 The pathologic differential diagnosis
of pleomorphic fibromas of the skin also includes dermatofibromas
with atypical or monster cells.17,18 In contrast to pleomorphic fibromas of the skin, however, dermatofibromas with atypical or monster
cells: (1) are frequently more cellular, (2) often have areas indistinguishable from typical dermatofibromas, and (3) may have an overlying epidermis that is acanthotic and hyperpigmented.1,2,6
From the University of Houston Health Center, University of Houston, Houston;1 the Dermatological Surgery Center of Houston, Houston;2
the Department of Dermatology, University of Texas-Houston Medical School, Houston;3 the Fort Bend Skin Cancer Center, Sugar Land;4
Private Practice, The Woodlands;5 and Arlington Skin Surgery, Arlington,6 TX
Address for Correspondence: Philip R. Cohen, MD, 805 Anderson Street, Bellaire, TX 77401-2806 • E-mail: mitehead@aol.com
113
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CASE STUDY
Figure 1. Plantar (A) and medial (B) views of a pleomorphic fibroma of the skin, which appears as a nodule with a surrounding
collarette of scale at the base of the right great toe.
Conclusions
Pleomorphic fibroma of the skin is a benign nodular neoplasm
with a fibrous stroma consisting of mononuclear and multinuclear cells with atypical nuclear features. The occurrence of a
plantar pleomorphic fibroma of the skin with a surrounding epidermal collarette prompts us to recommend that pleomorphic
fibroma of the skin be added to the clinical differential diagnosis
of nodules, such as eccrine poromas, pyogenic granulomas, and
keratoacanthomas, that can present morphologically with a peripheral collarette of scale. Conservative treatment of a pleomorphic fibroma of the skin is appropriate once a biopsy-confirmed
diagnosis of the tumor has been established.
References
Figure 2. A pleomorphic fibroma of the skin in the dermis and
a collarette of epithelium with compact orthokeratosis in the
overlying epidermis (hematoxylin-eosin, original magnification ×2).
1 Kamino H, Lee JY, Berke A. Pleomorphic fibroma of the skin:
a benign neoplasm with cytologic atypia. A clinicopathologic
study of eight cases. Am J Surg Pathol. 1989;13:107–113.
Pleomorphic fibroma of the skin does not have a distinctive and
pathognomic clinical presentation; therefore, a biopsy of the
new or persistent dermal nodule is required to establish the diagnosis of this tumor. The clinical behavior of this skin neoplasm is
benign; recurrence is uncommon, even in tumors that have been
incompletely removed. Partial or complete excision of a biopsyconfirmed pleomorphic fibroma of the skin, therefore, is an appropriate and conservative surgical approach to the management
of the tumor.1,4
114
2 Hsieh YJ, Lin YC, Wu YH, et al. Subungual pleomorphic fibroma.
J Cutan Pathol. 2003;30:569–571.
3 Rudolph P, Schubert C, Zelger BG, et al. Differential expression
of CD34 and Ki-M1p in pleomorphic fibroma and dermatofibroma
with monster cells. Am J Dermatopathol. 1999;21:414–419.
4 Garcia-Doval I, Casas L, Toribio J. Pleomorphic fibroma of the
skin, a form of sclerotic fibroma: an immunohistiochemical
study. Clin Exp Dermatol. 1998;23:22–24.
5 Ahn SK, Won JH, Lee SH, et al. Pleomorphic fibroma on the
scalp. Dermatology. 1995;191:245–248.
6 Chen TM, Purohit SK, Wang AR. Pleomorphic sclerotic fibroma: a case report and literature review. Am J Dermatopathol.
March/April 2010
CASE STUDY
Figure 3. The atypical tumor cells (A and B) of a pleomorphic fibroma of the skin: mononuclear cells with large pleomorphic nuclei
and large multinucleated cells with nuclear atypia (hematoxylin-eosin: A, original magnification ×40; B, original magnification ×40).
2002;24:54–58.
7 Mahmood MN, Salama ME, Chaffins M, et al. Solitary sclerotic
fibroma of skin: a possible link with pleomorphic fibroma with immunophenotypic expression for 013 (CD99) and CD34. J Cutan
Pathol. 2003;30:631–636.
8 Ioffreda MD, Kantor GR, Abrams BJ, et al. Cutaneous pleomorphic fibroma [abstract]. J Cutan Pathol. 1997;24:104.
9 Cohen PR, Rapini RP, Farhood AI. Dermatopathology advances
in clinical research: the expression of antibody to CD34 in mucocutaneous lesions. Dermatol Clin. 1997;15:159–176.
13 Chang SE, Choi JH, Sung KJ, et al. Multiple eruptive dermatofibromas occurring in a patient with acute myeloid leukaemia.
[letter]. Br J Dermatol. 2000;142:1062–1063.
14 Cohen PR. Multiple dermatofibromas in patients with autoimmune disorders receiving immunosuppressive therapy. Int J
Dermatol. 1991;30:266–270.
15 Lu I, Cohen PR, Grossman ME. Multiple dermatofibroma in a
woman with HIV infection and systemic lupus erythematosus. J
Am Acad Dermatol. 1995;32:901–903.
10 Cohen PR, Tschen JA, Abaya-Blas R, et al. Recurrent sclerotic
fibroma of the skin. Am J Dermatopathol. 1999;21:571–574.
16 Liu J, Cohen PR, Farhood AI. Hyalinizing Spitz nevus: spindle
and epithelioid cell nevus with paucicellular collagenous stroma.
South Med J. 2004;97:102–106.
11 Mays SR, Cohen PR. Emerging dermatologic issues in the oncology patient. Semin Cutan Med Surg. 2006;25:179–189.
17 Tamada S, Ackerman AB. Dermatofibroma with monster cells.
Am J Dermatopathol. 1987;9:380–387.
12 Alexandrescu DT, Wiernik PH. Multiple eruptive dermatofibromas
occurring in a patient with chronic myelogenous leukemia. Arch
Dermatol. 2005;141:397–398.
18 Setoyama M, Fukumaru S, Kanzaki T. Case of dermatofibroma
with monster cells: a review and an immunohistiochemical
study. Am J Dermatopathol. 1997;19:312–315.
Formulary of Dr. George C. Andrews
Deodorant Powder - C.A.
• Aluminum chloride – 6.00
• Cupric sulphate – 2.00
• Zinc sulphate – 6.00
• Ol. Cinnamon – mx x
• Aq. Camphorae – 300.00
Submitted by Douglas D. Altchek, MD, New York, NY
115
March/April 2010
CASE STUDY
Annular Elastolytic Giant Cell Granuloma
Dipankar De, MD;1 Tarun Narang, MD;1 Sunil Dogra, MD;1 Uma Nahar Saikia, MD;2 Amrinder J. Kanwar, MD1
A 55-year-old woman presented with a minimally itchy, gradually progressive erythematous plaque of 2 months’ duration over the extensor
aspect of her left forearm. There was no history of trauma or any scar at the local site before its onset. She did not have photosensitivity and
denied similar eruptions in the past. She was known to have rheumatoid arthritis and type 2 diabetes mellitus. She has been taking metformin for diabetes mellitus; however, she was not taking any disease-modifying antirheumatic drugs. She complained of exertional dyspnea,
which was later correlated with interstitial lung disease due to rheumatoid arthritis.
O
n cutaneous examination, there was a single, welldefined erythematous to violaceous infiltrated plaque
with an elevated border measuring about 10 × 10 cm
localized over the extensor aspect of the left forearm (Figure 1).
Atrophic scarring was appreciated at places in the center of the
lesion. Diascopy was noncontributory. There was no regional
nerve trunk thickening or sensory impairment in the lesion. No
other abnormality was detected on mucocutaneous examination.
actinic granuloma, atypical annular necrobiosis lipoidica, Miescher’s granuloma of the face, and granuloma multiforme, thus
raising the speculation that they represent the same entity or different clinical expressions in the spectrum of elastolytic disorders.1
O’Brien2 initially described the condition in 1975 as:
Ring-shaped inflammatory lesions [that] sometimes develop in the abnormal ‘elastotic’ connective tissues of skin
damaged by sun and heat. The lesions, which commence as
papules and nodules, enlarge very slowly and may persist for
years. Microscopical sections show that there is an infiltrate
composed mainly of foreign-body giant cells, the cells being
engaged in digesting and absorbing the abnormal elastotic
fibers. The disorder, which occurs on several continents,
should probably be regarded as a phenomenon of repair
within damaged connective tissue.
In the workup to diagnosis, erythrocyte sedimentation rate was
42 mm after the first hour. Otherwise, the complete blood cell
counts and liver and renal function tests were within normal
limits. Rheumatoid factor was strongly positive, C-reactive protein was positive, and antinuclear antibody was mildly positive
with a speckled pattern. Mantoux test result was equivocal. Skiagram of the chest revealed evidence of fibrosis.
A punch biopsy was taken for histopathology study from the
margin of the lesion, which showed a thinned epidermis with
loss of rete ridges (Figure 2 and Figure 3). The dermis showed
palisading histiocytes surrounding mucinous material and degenerated collagen and elastin. Many multinucleated giant cells
were also seen. Elastin van Gieson stain revealed giant cells engulfing degenerated elastin (Figure 4). Thereby, the diagnosis of
annular elastolytic giant cell granuloma (AEGCG) was reached.
Discussion
Some believe that AEGCG and granuloma annulare may be related. Ragaz and Ackerman3 questioned the specificity of actinic
granuloma as a specific connective tissue disorder, as was suggested by Ackerman. They presented the evidence that granulomatous inflammation does not result as a response to degenerated elastotic fibers, but is a consequence of primary pathologic
processes that are unrelated to damaged elastotic material. They
speculated that actinic granuloma and granuloma annulare are
clinically and histologically similar.
AEGCG is a rare granulomatous skin disease characterized by loss
of elastic fibers due to elastophagocytosis of degenerated elastic fibers by multinucleated giant cells. In 1979, Hanke and associates1
first recognized AEGCG as a distinct granulomatous skin disease.
Prior to this, diseases of similar character were termed O’Brien’s
The clinical picture is variable, with lesions varying in size,
number, and shape. Lesions of AEGCG are localized primarily on sun-exposed areas, including the forearms, neck, upper
back, and face, and are less common in covered areas.4 AEGCG
is characterized by annular patches with erythematous borders
From the Department of Dermatology, Venereology and Leprology,1 and the Department of Histopathology,2 Postgraduate Institute of Medical Education and Research, Chandigarh, India
Address for Correspondence: Sunil Dogra, MD, Assistant Professor, Department of Dermatology, Venereology and Leprology,
Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India • E-mail: sundogra@hotmail.com
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CASE STUDY
Figure 1. Well-defined infiltrated plaque over forearm. Atrophic scarring can be appreciated at places.
and hypopigmented centers showing atrophy. It is common in
middle-aged white women. AEGCG usually affects older adults,
although it has been described in an infant aged 8 months.5 The
systemic involvement is rare, although ocular, intestinal, and
lymph node involvement has been reported in a single patient.6
Why elastolysis and elastophagocytosis occur in AEGCG is a matter of conjecture. In granuloma annulare, the closest clinical mimicker of AEGCG, Th1 lymphocytes activate macrophages expressing tumor necrosis factor a and matrix metalloproteinases 2 and
9, which are capable of degradation of both collagen and elastic
fibers. It can be speculated that in AEGCG the macrophages differentially degrade only elastic fibers.7 The capacity for elastolysis
and elastophagocytosis may depend on differentiation status of
macrophages. A patient with AEGCG has been reported in whom
the lesions did not involve burn scars, thus suggesting that immune reaction might be specifically directed against or induced
by intact elastic tissue.8 Other factors that have been hypothesized
to cause AEGCG include UV radiation, heat, or other unknown
factors that can change the antigenicity of elastic fibers and thus
trigger a cellular immune response directed toward them. Moreover, diabetes mellitus–producing structural damage of the elastic
tissue may incite the immune reaction.
AEGCG has been reported in association with systemic sarcoidosis, cutaneous amyloidosis, molluscum contagiosum, chronic
hepatitis C, squamous cell carcinoma of the lung, and cutaneous
T-cell lymphoma.9
The dermatoses that can clinically as well as histopathologically
mimic AEGCG include actinic granuloma, granuloma annulare, necrobiosis lipoidica, sarcoidosis, annular lichen planus,
subacute lupus erythematosus, and type-2 inflammatory middermal elastolysis; the first two entities being the closest mim-
Figure 2. Hematoxylin-eosin stain (original magnification
×550) showing mild hyperkeratosis with deposition of pale
eosinophilic degenerated elastin in the dermis. Note made of
the multinucleated giant cells.
icker.8 The distinctive zone of elastophagocytosis, abundance
and distribution of the giant cells, absence of collagen necrobiosis, and mucin deposition help to differentiate this entity from
granuloma annulare.
The course of the disease is chronic. Rare spontaneous remission
has also been reported.1 Different options have been tried in the
treatment of AEGCG, although none are uniformly effective.8
These include excision of the solitary lesion, cryotherapy, cauterization, intralesional or systemic corticosteroids, psoralen–UV-A
(PUVA), RePUVA (oral retinoids + PUVA), cyclosporine, tranilast, dapsone, clofazimine, chloroquine, methotrexate, topical
pimecrolimus, or a combination of these. In a review by Breuer
and colleagues,10 remission was achieved in 1 of 3 patients
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CASE STUDY
treated with fumaric acid esters. Our patient was initially given
colchicine for 1 month and subsequently hydroxychloroquine
sulfate for 2 months without success.
References
1 Hanke CW, Bailin PL, Roenigk HH Jr. Annular elastolytic giant cell
granuloma: a clinicopathologic study of five cases and a review
of similar entities. J Am Acad Dermatol. 1979;1:413–421.
2 O’Brien JP. Actinic granuloma. An annular connective tissue
disorder affecting sun- and heat-damaged (elastotic) skin. Arch
Dermatol. 1975;111:460–466.
3 Ragaz A, Ackerman AB. Is actinic granuloma a specific condition? Am J Dermatopathol. 1979;1:43–50.
4 Revenga F, Rovira I, Pimentel J, et al. Annular elastolytic giant cell granuloma-actinic granuloma? Clin Exp Dermatol.
1996;21:51–53.
Figure 3. Hematoxylin-eosin stain (original magnification ×550)
showing degenerated elastin and multinucleated giant cells.
5 Lee HW, Lee MW, Choi JH, et al. Annular elastolytic giant cell
granuloma in an infant: improvement after treatment with
oral tranilast and topical pimecrolimus. J Am Acad Dermatol.
2005;53:S244–S246.
6 Kurose N, Nakagawa H, Iozumi K, et al. Systemic elastolytic
granulomatosis with cutaneous, ocular, lymph nodal and intestinal involvement. Spectrum of annular elastolytic giant cell granuloma and sarcoidosis. J Am Acad Dermatol. 1992;26:359–363.
7 Klemke CD, Siebold D, Dippel E, et al. Generalized annular elastolytic giant cell granuloma. Dermatology. 2003;207:420–422.
8 Ozkaya-Bayazit E, Buyukbabani N, Baykal C, et al. Annular elastolytic giant cell granuloma: sparing of a burn scar and successful
treatment with chloroquine. Br J Dermatol. 1999;140:525–530.
9 Doulaveri G, Tsagroni E, Giannadaki M, et al. Annular elastolytic
giant cell granuloma in a 70-year-old woman. Int J Dermatol.
2003;42:290–291.
10 Breuer K, Gutzmer R, Volker B, et al. Therapy of noninfectious
granulomatous skin diseases with fumaric acid esters. Br J Dermatol. 2005;152:1290–1295.
Figure 4. Elastin van Gieson stain showing thinned out
epidermis and extensive elastotic degeneration. Collection of
histiocytes forming granuloma with phagocytosis of elastic
fibers is also seen.
Address for correspondence
118
March/April 2010
CASE STUDY
Chancriform Pyoderma: A Forgotten Disease
Dijana Celić, MD;1 Jasna Lipozenčić, MD, PhD;2 Dragomir Budimčić, MD, MSc;2 Jaka Radoš, MD, MSc;2
Suzana Ljubojević, MD, PhD;2 Jolanda Kanižaj Rajković, MD1
Case 1: A 34-year-old male office worker first observed the appearance of a papular lesion on the right upper eyelid, which subsequently
ulcerated (Figure 1). The ulcer, 5 × 10 mm in size, was well defined with an indurated base and a central eschar that was easily removed to
reveal serous discharge. The edge of the ulcer was smooth and raised with minimal erythema and edema. No regional lymphadenopathy was
detected. The patient had no previous history of any skin condition or serious illness. His physical status was normal, and so was standard
blood and urine biochemistry. Bacteriologic examination was positive for Staphylococcus aureus. The mycologic examination was negative, as
well as treponemal and human immunodeficiency virus (HIV) serology. Leishman-Donovan bodies were not demonstrated in smears taken
from the ulcer and stained with Giemsa. The patient declined biopsy. He was treated with oral cloxacyline for 14 days, oral cephalexine,
and mupirocine ointment for 10 days, with no therapeutic results. Treatment with 0.9% sodium chloride dressings and gentamycinebetamethasone ointment led to rapid improvement. The lesion healed with minimal scar.
Case 2: A 66-year-old male retiree presented with a 5-month history of an ulcer, 15 x 20 mm in size, on his left hand. The ulcer was indurated and covered with tawny eschar (Figure 2). No regional lymphadenopathy was detected. The patient was generally healthy, reporting
only a gastric ulcer operation at age 53, and a colon polyp at age 65. Routine blood and urine biochemistry were normal. Lesion cultures
were negative for fungi and positive for S. aureus. Syphilis and HIV serology were negative, as well as direct examination for LeishmanDonovan bodies. Histopathology showed acanthosis and numerous polymorphonuclear infiltrations around the blood vessels in the upper
dermis. The patient was treated with oral clindamycine for 14 days and local antiseptic dressings, with no therapeutic results. Treatment with
hydrocolloid dressings triggered ulcer epithelialization.
C
hancriform pyoderma is a rare condition of uncertain
etiology, with intense inflammatory response, producing a lesion that resembles syphilitic chancre.1 The lesion can be found on the face, especially around the eyelids, near
and in the mouth, or on the genitalia.1–5 To our knowledge, this
is the first case of chancriform pyoderma located on the hand.
Clinically, papules or pustules appear on the affected skin, rapidly enlarging and progressing to painless ulceration.6 Regional
lymph nodes are enlarged and tender, but it is not a rule.6 The
role of S. aureus is still controversial.2,4,7 An abnormal immune
response of the host tissues has been postulated.7 If left untreated, the ulcer may persist for weeks or months to spontaneously
involute with or without scarring.6
CONCLUSIONS
The diagnosis of chancriform pyoderma is based on detailed disease history, clinical picture, and negative laboratory findings for
Treatment with local and systemic antibiotics is not efficient.7
According to our experience, differential diagnosis is wide and
includes a large group of diseases which contain ulceration in
their evolution (Table). Therefore, case history and recognition of other general and specific findings are important for
correct diagnosis.
Figure 1. The ulcer on the right upper eyelid.
From the Medikol Outpatient Department, Zagreb, Croatia;1 and the Department of Dermatology and Venereology, Zagreb University Hospital
Center, Zagreb, Croatia2
Address for Correspondence: Dijana Celić, MD, Medikol Outpatient Department, Voćarska 106, 10000 Zagreb, Croatia •
E-mail: dijana_celic@yahoo.com
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CASE STUDY
all microbial agents except S. aureus. Exclusion of other dermatoses that present with an ulcer, using direct examination, cultures,
serology, and histopathology is of greatest importance.
REFERENCES
1 Braun-Falco O, Plewig G, Wolff HH, et al. Bacterial diseases. In:
Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC, eds. Dermatology. Heidelberg, New York: Springer-Verlag; 2000:165.
2 Frain-Bell W. Pyodermia chancriformis faciei. Br J Dermatol.
1957;69:19–24.
3 Starzycki Z. Chancriform pyoderma as a clinical problem: observation of 45 patients treated at the Dermatology Clinic, Medical
Academy, in Cracow 1962–1986 [in Polish]. Przegl Dermatol.
1990;77:348–354.
4 Holmes SC, Thomson J. Recurrent chancriform pyoderma: report of a case with tongue lesions. Is Staphylococcus aureus
implicated? Br J Derm. 1995;133:326–327.
Figure 2. The ulcer on the left hand, with tawny eschar on the base.
5 Hegemann B, Helmbold P, Dickert C, et al. Recurrent chancriform mucous membrane ulcer in plasmacytoma with secondary
IgA deficiency. Pyoderma chancriforme of the tongue [in German]. Hautarzt. 2001;52:820–823.
Table. Differential Diagnosis of Chancriform Pyoderma
Disease
Clinical Presentation
Primary lues
Macule/papule/ulcer
Chancroid
Papule/pustule/erosion/ulcer
Donovanosis
Papule/nodule/ulcer
Lymphogranuloma venereum
Papule/erosion/ulcer
Human orf
Papule/vesicle/nodule/ulcer
Milker’s nodule
Papule/vesicle/nodule/ulcer
Primary inoculation tuberculosis
Papule/nodule/ulcer
Swimming pool granuloma
Papule/nodule/plaque/ulcer
Ecthyma
Pustule/ulcer
Cat scratch disease
Papule/pustule/ulcer
Tularemia
Papule/pustule/ulcer
Rickettsialpox
Papule/ulcer
Sporotrichosis
Papule/pustule/nodule/ulcer
Blastomycosis
Plaque/ulcer
Cutaneous leishmaniasis
Papule/nodule/ulcer
Delusion of parasitoses
Erosion/ulcer
Dermatitis artefacta
Erosion/ulcer
Pyoderma gangrenosum
Pustule/nodule/ulcer
Basal cell carcinoma—ulcer type
Ulcer
Squamous cell carcinoma—ulcer type
Ulcer
Lymphomatoid papulosis
Papule/nodule/ulcer
Behçet disease
Ulcer
6 Žmegač Z. Pyodermas. In: Kogoj F. Skin Diseases. Zagreb, Croatia: Yugoslav Academy of Arts of Science and Arts Publishing;
1970:136–137.
7 Hay RJ, Adriaans BM. Dermatoses possibly attributable to bacteria. In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook’s
Textbook of Dermatology. Oxford, England: Blackwell Publishing; 2004:27.79–27.80.
120
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CASE STUDY
Pemphigoid Gestationis: Cutaneous Manifestation of
Impaired Fetal Allograft Tolerance
Anthony A. Nuara, MD, PhD; Joseph M. Obadiah, MD; Maria Yadira Hurley, MD
A 31-year-old prima gravida woman (32 weeks estimated gestational age) was referred by her obstetrician to rule out infection with varicella
zoster virus. She presented with a several week history of multiple pruritic papules that began on her left thigh and were now present across
her body. She had a positive childhood history of primary varicella zoster virus infection. On examination, there were multiple papules and
plaques on the abdomen in a periumbilical distribution (Figure 1A), as well as on the lower extremities and mid-back. There were also small
bullae on the medial and dorsal feet (Figure 1B). No mucosal lesions were observed. Punch biopsy of lesional skin demonstrated areas of focal parakeratosis, focal spongiosis, and a superficial lymphohistiocytic infiltrate with scattered eosinophils (Figure 2A). Direct immunofluorescence examination of nonlesional skin demonstrated linear deposition of C3 along the basement membrane (Figure 2B). Immunoglobulin stains were negative. These findings were consistent with the urticarial phase of pemphigoid gestationis. The patient was treated with
oral prednisone (40 mg/d), diphenhydramine (50 mg every 6 hours as needed), and triamcinolone 0.1% cream topical to the body. There
was improvement of her pruritus, but she experienced multiple flares when the prednisone was tapered. The fetus was delivered without
complication and the patient’s disease resolved approximately 4 weeks after delivery, followed by a successful prednisone taper over 5 weeks.
P
emphigoid gestationis (PG) is a rare autoimmune bullous
dermatosis. It is exclusively a disorder of pregnancy and
the puerperium. The reported incidence of this condition
is variable, but studies with immunofluorescence place the estimates at around 1:50,000 pregnancies.1 PG is predominantly a disease of white women and tends to present in the later
stages of pregnancy, but may occur during the first trimester or
postpartum. PG can initially manifest in prima- or multiparous
women, although the disease almost invariably recurs in subsequent pregnancies and is usually earlier and more severe.2 The
lesions are typically polymorphous consisting of pruritic papules
and plaques, which may evolve into vesicles and bullae. PG was
previously known as herpes gestationis because of the tendency
of the lesions to start periumbilically and “creep” centripetally.1
Lesions tend to be confined to the body and rarely occur on the
face or mucous membranes. The condition is also characterized
by intense pruritus which may precede cutaneous eruption by
days to weeks.1,3,4 Rarely, PG can develop into a protracted illness or evolve into bullous pemphigoid (BP).3
The sera of patients with PG contains complement fixing immunoglobulin G (IgG) antibody directed against a placental antigen, which cross reacts with an antigen in the skin basement
membrane.3 The target antigen is the same as in BP, although the
severity of their clinical presentation varies considerably.1,3 Anti-
bodies in both diseases recognize determinants on the BP 180kd antigen (BP180), a transmembrane glycoprotein integral in
adhesion of basal cells to the basement membrane.2 The antigenic NC16A region of BP180 is in the extracellular domain which
passes through the hemidesmosome and aids in attachment of
the basal cell layer to the basement membrane.5 Deposition of
anti-BP180 antibody along the hemidesmosomes in the basement membrane results in C3 fixation, activation of the classical
complement cascade, and recruitment of leukocytes to the area.
Destruction of the basal keratinocyte hemidesmosomes results
in the formation of a subepidermal blister (Figure 2C).1,3 Animal
models wherein antibodies to the BP180 antigen of mice and
hamsters were passively transferred resulted in bullous disease
further supporting the role of anti-BP180 in the pathogenesis of
these dermatoses.6,7 The detection of anti-BP180 IgG along the
amniotic and chorionic basement membrane support the notion that PG represents a cross reactivity between epidermal and
placental antigens.1
The histological findings of PG are dependent upon the stage of
the lesion biopsied. Early papular lesions demonstrate a perivascular
infiltrate comprised of lymphocytes, histiocytes, and eosinophils.3
This infiltrate is often accompanied by edema of the papillary dermis and spongiosis within the epidermis. Bullous lesions show a
subepidermal blister with eosinophils. Direct immunofluorescence
From the Department of Dermatology, St. Louis University School of Medicine, St. Louis, MO
Address for Correspondence: Anthony A. Nuara, PhD, Department of Dermatology, St. Louis University School of Medicine, 1755 South Grand
Boulevard, St. Louis, MO 63104
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March/April 2010
CASE STUDY
bilically whereas PUPPP tends to develop within the abdominal
striae. Both lesions are intensely pruritic and may progress from
papules to vesicles or bullae, making clinical distinction difficult.
Biopsy for fixed tissue and for direct immunofluorescence is key
for diagnosis.1,3,4 Additionally, enzyme linked immunosorbent
assays and protein immunoelectrophoresis using BP180 as a capture reagent, originally developed for evaluation of BP, have been
used to diagnose and follow patients with PG.5
Figure 1. (A) Characteristic papules and plaques were
observed on the abdomen in a periumbilical distribution. (B)
Multiple small bullae were also noted on the medial aspects of
the patient’s feet. No mucosal lesions were observed.
Early case reports indicated an increase in morbidity and mortality in fetuses of affected mothers, although there are conflicting
reports on the actual risk to the developing fetus.1,3 It is generally
accepted, however, that risk to the fetus is low and may be comprised of signs of placental insufficiency such as low birth weight
and infants who are small for gestational age. Placental insufficiency requiring delivery of the fetus has been reported and the
authors recommended monitoring of end-diastolic umbilical artery velocity to assess placental function in patients with PG.13 PG
associated autoantibodies have been detected in the cord blood
of infants born to affected mothers and may result in transient
erythema and blistering in up to 10% of infants born to affected
mothers, resolving within a few weeks.1,2,4 Additionally, infants
born to mothers treated with systemic glucocorticoids should be
appropriately monitored and managed by a neonatologist.14
An intricate immune regulation system exists to prevent maternal rejection of the invading fetal allograft. Several studies have
suggested a role for controlling this response by regulatory T
cells (CD4+ CD25+), Th3 cells (transforming growth factor-β),
regulatory natural killer cells, as well as the expression of soluble
local mediators such as macrophage migration inhibitory factor
and local degradation of tryptophan by indolamine 2,3 deoxygenase.15,16 While the exact nature of fetal allograft tolerance is
not completely understood, it is likely that PG represents a loss
of tolerance to both fetal and self antigens during pregnancy.
The autoantibodies in PG appear to be related to, or driven by,
an antigenic stimulus that is unique to pregnancy. Although
PG is a rare complication of trophoblastic tumors, it has not
been reported in nongestational hormone producing malignancies, pointing to an essential gestational component.1,3 A major
event in the development of PG is thought to be expression of
major histocompatibility complex (MHC) class II molecules,
particularly paternal alleles, by the placenta and recognition by
the maternal immune system. The connection between these
anti-HLA antibodies and the development of antiplacental basement membrane antibodies is poorly understood. Antibodies
that are actually directed against the paternal MHC molecules
are thought to be a parallel phenomenon, as they are present in
many multiparous women without PG.1 Interestingly, PG may
skip a pregnancy if there is a change in paternity or maternal
fetal match at the HLA-D locus, supporting a role for paternal antigens in the pathophysiology of the disease.3 Like many
other humoral autoimmune conditions, there is an increased incidence of the class II MHC alleles HLA-DR3 and HLA-DR4
in PG affected individuals (54%) as compared to the general
population (3%).1 It seems then, that patients who develop PG
may be genetically predisposed to such autoimmune conditions.
The differential diagnosis of PG includes many other dermatoses
of pregnancy; however, PG is most often confused clinically with
pruritic urticarial papules and plaques of pregnancy (PUPPP).
Early lesions of PG closely resemble and must be distinguished
from PUPPP. Both tend to occur in the second and third trimesters of the pregnancy; however, PUPPP shows a stronger predilection for prima gravida patients whereas PG may first appear
in later pregnancies. Additionally, PG tends to develop perium-
Although a rare complication of gestation, PG represents an interesting manifestation of maternal fetal allograft intolerance. The
mechanisms responsible for maternal tolerance of invading allogeneic cells are complex and remain poorly understood. Even more
remarkable is that these boundaries of immune tolerance do not
fail more often. Indeed, PG represents a case wherein the maternal
immune system fails to ignore antigens within the placenta. Of
interest is that the predicted offending antigens, paternal MHC
studies of lesional and nonlesional skin shows a linear deposition of
C3 and, less consistently, IgG along the epidermal basement membrane.1,3 Indirect immunofluorescence using monoclonal antibodies to IgG1 show anti-BP180 antibodies present in all cases of PG.2,4
Although topical steroids and antihistamines offer relief in mild
cases, the mainstay of PG treatment is systemic corticosteroids
(prednisone 0.5–1mg/kg/d).2 Refractory cases, or those progressing to BP, require more aggressive management including
chemotherapeutic compounds like cyclophosphamide, methotrexate, and cyclosporine.8,9 Plasmapheresis or high dose intravenous immunoglobulin have been reported successful in some
patients recalcitrant to systemic corticosteroids.10–12
122
March/April 2010
CASE STUDY
Figure 2. (A) Patient histology showing areas of focal parakeratosis, spongiosis, and a superficial lymphohistiocytic infiltrate with
scattered eosinophils. (B) Direct immunofluorescence examination of nonlesional skin demonstrated linear deposition of C3 along
the basement membrane. (C) Late stage lesion demonstrating subepidermal blistering with eosinophilic infiltrate.
class II, are not the target antigen in this disease process and antibodies to these molecules can be detected in multiparous women
without PG. The coexistence of an anti-HLA reaction may only
be an indicator of further derangement in the delicate immune
environment of the placenta and not necessarily directly associated
with PG or its clinical manifestations.
REFERENCES
1 McKee PH, Calonje E, Granter SR. Pathology of the Skin With Clinical Correlations. 3rd ed. Philadelphia, PA: Elsevier Mosby; 2005.
2 Cunningham FG, Williams JW. Williams Obstetrics. 22nd ed.
New York, NY: McGraw-Hill; 2005.
antibody and complement in hamster bullous pemphigoid. J Invest Dermatol. 2002;118:485–492.
8 Wallengren J. Prurigo: diagnosis and management. Am J Clin
Dermatol. 2004;5:85–95.
9 Amato L, Mei S, Gallerani I, et al. A case of chronic herpes
gestationis: persistent disease or conversion to bullous pemphigoid? J Am Acad Dermatol. 2003;49:302–307.
10 Kroumpouzos G, Cohen LM. Specific dermatoses of pregnancy:
an evidence-based systematic review. Am J Obstet Gynecol.
2003;188:1083–1092.
11 Hern S, Harman K, Bhogal BS, et al. A severe persistent case of
pemphigoid gestationis treated with intravenous immunoglobulins and cyclosporin. Clin Exp Dermatol. 1998;23:185–188.
3 Weedon D. Skin Pathology. 2nd ed. London: Churchill Livingstone, 2002.
12 Jolles S. A review of high-dose intravenous immunoglobulin (hdIVIg) in the treatment of the autoimmune blistering disorders. Clin
Exp Dermatol. 2001;26:127–131.
4 Freedberg IM, Goldsmith LA, Katz S, et al. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York, NY: McGraw-Hill,
Medical Pub. Division; 2003.
13 Dolkart L, Harter M, Snyder M. Pemphigoid gestationis: report
of a case with umbilical artery Doppler assessment. J Reprod
Med. 2006;51:591–594.
5 Sitaru C, Powell J, Messer G, et al. Immunoblotting and enzymelinked immunosorbent assay for the diagnosis of pemphigoid
gestationis. Obstet Gynecol. 2004;103:757–763.
14 Kasper DL, Harrison TR. Harrison’s Principles of Internal Medicine.
16th ed. New York, NY: McGraw-Hill, Medical Pub. Division; 2005.
6 Liu Z, Diaz LA, Troy JL, et al. A passive transfer model of the
organ-specific autoimmune disease, bullous pemphigoid, using
antibodies generated against the hemidesmosomal antigen,
BP180. J Clin Invest. 1993;92:2480–2488.
7 Yamamoto K, Inoue N, Masuda R, et al. Cloning of hamster type
XVII collagen cDNA, and pathogenesis of anti-type XVII collagen
123
15 Saito S, Shiozaki A, Sasaki Y, et al. Regulatory T cells and regulatory natural killer (NK) cells play important roles in feto-maternal tolerance. Semin Immunopathol. 2007;29:115–122.
16 Vigano P, Cintorino M, Schatz F, et al. The role of macrophage migration inhibitory factor in maintaining the immune
privilege at the fetal-maternal interface. Semin Immunopathol.
2007;29:135–150.
March/April 2010
CASE STUDY
Eruptive Syringoma Associated With Hyperthyroidism
Muhterem Polat, MD;1 Aylin Pelitli, MD;3 Pinar Öztaş, MD;1 Tuba Ünal, MD;2 Nuran Alli, MD1
A 45-year-old woman presented with a 9-year history of eruptions that began as a few papules on the trunk and gradually spread to the
whole trunk and face. The lesions were asymptomatic, and since they first appeared, the patient’s skin had never been completely clear. The
patient’s notable past medical history was hyperthyroidism. She had been on oral antithyroid drug therapy (50 mg/d propylthiouracil) for
10 years. In her previous history, the patient was euthyroid at the onset of the syringoma lesions. No family member had ever had a similar
skin condition, and a review of other systems was noncontributory. Physical examination revealed multiple skin-colored or reddish brown
flat-topped papules 1–3 mm in diameter on the trunk, periorbital region, malar areas and forehead (Figure 1A, Figure1B). The remainder
of the physical examination was unremarkable.
A
punch biopsy specimen from the trunk revealed cystic
ducts lined with a double row of epithelium in the dermis (Figure 1C). A complete blood count and serum
biochemistry were within normal ranges.
DISCUSSION
Syringoma is a benign tumor derived from the intraepidermal
portion of the eccrine duct.
Clinical presentation of syringoma is variable. The lesion may be
solitary or multiple. The distribution may be localized, multifocal, or generalized. They may also appear in eruptive manners.
Classically, syringomas occur in women at puberty or later in
life.1–3 The most frequent clinical variant is location on the infraocular areas in healthy people, but other clinical variants have
been reported, as well as familial cases or an association with
Down syndrome.4–7
Generalized eruptive syringoma is a rare variety, characterized by
multiple lesions that arise in successive crops on the anterior body
surfaces, generally in prepubertal or adolescent individuals.8
Our patient’s lesions began when she was 36 years old. The
higher incidence of syringomas in women and the frequent development of the lesions before or around puberty, as well as
occasional exacerbation of the lesions during pregnancy, may
imply a hormonal role in some cases.9 A strong expression of
progesterone receptors by immunohistochemistry was noted in
2 studies.10,11 Syringoma is also seen with diabetes.12 Aliagaoglu
and colleagues13 reported the first case of unilateral syringoma of
the face associated with hyperthyroidism. Our patient’s lesions
were of an eruptive manner that began 1 year after the diagnosis
of hyperthyroidism. More cases on this association should be
reported—despite the suggested hormonal interactions in the
development of syringomas—before speculating whether hyperthyroidism and syringoma coincidentally occur or hyperthyroidism may have a role in the pathogenesis of syringoma. Although
2 cases of syringoma associated with hyperthyroidism is very
limited to propose a hypothesis that hyperthyroidism may have
a role in the pathogenesis of syringoma, future reported cases
may help to show the relationship of syringoma with decreased
thyroid stimulating hormone level, and increased triiodothyronine and thyroxine levels.
Clinically, syringomas may be mistaken for acne vulgaris, sebaceous hyperplasia, milia, lichen planus, and eruptive xanthoma.14 The definitive diagnosis of syringoma can be made on
histological examination.
Syringomas are benign and usually asymptomatic, so treatment
is offered primarily for cosmetic reasons.8,14,15 Unfortunately,
there is no satisfactory treatment for eruptive syringomas, as in
our patient, because any method of surgical or chemical destruction carries the risk of scarring. Furthermore, there is a high rate
of recurrence. Our patient did not want any treatment.
CONCLUSIONS
In conclusion, eruptive syringoma associated with hyperthyroidism is unusual. Report of more cases on this association is
needed to strengthen the hypothesis about the role of hyperthyroidism in the pathogenesis of syringoma and to show that this
coexistence is not a coincidence.
From the 1st Dermatology Department1 and the Pathology Department,2 Ankara Numune Education and Research Hospital, Ankara, Turkey;
and the Keçiören Education and Research Hospital Dermatology Clinic, Ankara Turkey3
Address for Correspondence: Muhterem Polat, MD, Çukurambar mah. 41. cad. No: 2/8, Ankara, Turkey • E-mail:drmuhterempolat@mynet.com
124
March/April 2010
CASE STUDY
REFERENCES
1 Soler-Carrillo J, Estrach T, Mascaro JM. Eruptive syringoma: 27
new cases and review of the literature. J Eur Acad Dermatol
Venereol. 2001;15:242–246.
2 Miranda JJ, Shahabi S, Salih S, et al. Vulvar syringoma: report of a case and review of the literature. Yale J Biol Med.
2002;75:207–210.
3 Akaraphanth R, Giam YC. Eruptive syringoma in a Chinese boy.
Int J Dermatol. 1993;32:202–203.
4 Metze D, Jurecka W, Gebhart W. Disseminated syringomas of
the upper extremities. Dermatologica. 1990;180:228–235.
5 Pruzan DL, Esterly NB, Prose NS. Eruptive syringoma. Arch Dermatol. 1989;125:1119–1120.
6 Friedman SJ, Butler DF. Syringoma presenting as milia. J Am
Acad Dermatol. 1987;16:310–314.
7 Schepis C, Torre V, Siragusa M, et al. Eruptive syringomas with
calcium deposits in a young woman with Down’s syndrome. Dermatology. 2001;203:345–347.
8 Tatiana SS, Esteban D, Andrés PC, et al. Eruptive pruritic syringomas: treatment with topical atropine. J Am Acad Dermatol.
2001;44:148–149.
9 Turan C, Ugur M, Kutluay L, et al. Vulvar syringoma exacerbated during pregnancy. Eur J Obstet Gynecol Reprod Biol.
1996;64:141–142.
10 Yorganci A, Kale A, Dünder I, et al. Vulvar syringoma showing progesterone receptor positivity. Br J Obstet Gynaecol.
2000;107:292–294.
11 Wallace ML, Smoller BR. Progesterone receptor positivity supports hormonal control of syringomas. J Cutan Pathol.
1995;22:442–445.
12 Timpanidis PC, Lakhani SR, Groves RW. Progesterone receptorpositive eruptive syringoma associated with diabetes. J Am
Acad Dermatol. 2003;48:103–104.
13 Aliagaoglu C, Atasoy M, Yildirim U, et al. Unilateral syringoma of the face associated with hyperthyroidism. J Dermatol.
2004;31:828–830.
14 Supriya G, Martins CR. Multiple syringomas on the abdomen,
thighs, and groin. Cutis. 2000;66:259–262.
15 Gomez MI, Pérez B, Azana JM, et al. Eruptive syringoma: treatment with topical tretinoin. Dermatology. 1994;189:105–106.
Figure 1. (A) Syringomas on the periorbital region, malar
area, and forehead. (B) Multiple syringomas on the anterior
surface of the trunk. (C) Cystic ducts lined with a double row
of epithelium in the dermis (hematoxylin-eosin stain, original
magnification, ×40).
125
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Before
After 12 weeks
Locoid Lipocream® Cream, 0.1%
(hydrocortisone butyrate 0.1% cream)
For Topical Use Only
Rx Only
BRIEF SUMMARY
INDICATIONS AND USAGE
Locoid Lipocream is a topical corticosteroid indicated for: relief of the inflammatory
and pruritic manifestations of corticosteroid-responsive dermatoses in adults and
the treatment of mild to moderate atopic dermatitis in patients 3 months to 18 years
of age.
WARNINGS AND PRECAUTIONS
Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, with
the potential for glucocorticosteroid insufficiency. Consider periodic evaluations for
HPA axis suppression if Locoid Lipocream is applied to large surface areas or used
under occlusion. If HPA axis suppression is noted, reduce the application frequency,
discontinue use, or switch to a lower potency corticosteroid.
Systemic effects of topical corticosteroids may also include manifestations of
Cushing’s syndrome, hyperglycemia, and glucosuria.
Pediatric patients may be more susceptible to systemic toxicity due to their larger
skin surface-to-body-mass ratios.
Initiate appropriate therapy if concomitant skin infections develop.
Discontinue use if irritation develops.
ADVERSE REACTIONS
The most common adverse reactions (>1%) are HPA axis suppression and
application site reactions.
The following additional local adverse reactions have been reported infrequently
with topical corticosteroids, and they may occur more frequently with the use of
occlusive dressings and higher potency corticosteroids. These reactions included:
irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis,
allergic contact dermatitis, secondary infection, skin atrophy, striae, miliaria and
telangiectasia.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. Corticosteroids have been shown to be teratogenic in
laboratory animals when administered systemically at relatively low dosage levels.
Some corticosteroids have been shown to be teratogenic after dermal application
in laboratory animals.There are no adequate and well-controlled studies in
pregnant women. Therefore, Locoid Lipocream should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Please refer to full prescribing information for detailed information regarding
systemic embryofetal development studies.
Nursing Mothers
Systemically administered corticosteroids appear in human milk and could
suppress growth, interfere with endogenous corticosteroid production, or cause
other untoward effects. It is not known whether topical administration of
corticosteroids could result in sufficient systemic absorption to produce detectable
quantities in human milk. Because many drugs are excreted in human milk, caution
should be exercised when Locoid Lipocream is administered to a nursing woman.
Pediatric Use
Safety and efficacy in pediatric patients below 3 months of age have not been
established.
Because of higher skin surface-to-body-mass ratios, pediatric patients are at a
greater risk than adults of HPA axis suppression when they are treated with topical
corticosteroids. They are therefore also at a greater risk of glucocorticosteroid
insufficiency after withdrawal of treatment and of Cushing’s syndrome while on
treatment.
Eighty-six (86) pediatric subjects (5 months to less than 18 years of age) with
moderate to severe atopic dermatitis affecting at least 25% of body surface area
(BSA) treated with Locoid Lipocream three times daily for up to 4 weeks were
assessed for HPA axis suppression. The disease severity (moderate to severe
atopic dermatitis) and the dosing regimen (three times daily) in this HPA axis study
were different from the subject population (mild to moderate atopic dermatitis) and
the dosing regimen (two times daily) for which Locoid Lipocream is indicated.
Five of the 82 evaluable subjects (6.1%) demonstrated laboratory evidence of
suppression, where the sole criterion for defining HPA axis suppression was a
serum cortisol level of less than or equal to 18 micrograms per deciliter after
cosyntropin stimulation. Suppressed subjects ranged in age from 5 months to
16 years and, at the time of enrollment, had 25% to 95% BSA involvement. These
subjects did not develop any other signs or symptoms of HPA axis suppression.
At the first follow up visit, approximately one month after the conclusion of
treatment, cosyntropin stimulation results of all subjects had returned to normal,
with the exception of one subject. This last subject recovered adrenal function by
the second post treatment visit, 65 days post-treatment.
Cushing’s syndrome, linear growth retardation, delayed weight gain, and
intracranial hypertension have also been reported in pediatric patients receiving
topical corticosteroids. Manifestations of adrenal suppression in pediatric patients
include low plasma cortisol levels to an absence of response to ACTH stimulation.
Manifestations of intracranial hypertension include bulging fontanelles, headaches,
and bilateral papilledema.
Geriatric Use
Clinical studies of Locoid Lipocream did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies were conducted to determine the photococarcinogenic or dermal
carcinogenic potential of Locoid Lipocream.
Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic
potential based on the results of two in vitro genotoxicity tests (Ames test and
L5178Y/TK+ mouse lymphoma assay) and one in vivo genotoxicity test (mouse
micronucleus assay).
No evidence of impairment of fertility or effect on mating performance was
observed in a fertility and general reproductive performance study conducted in
male and female rats at subcutaneous doses up to and including 1.8 mg/kg/day
(0.7X maximum topical human dose [MTHD]). Mild effects on maternal animals,
such as reduced food consumption and a subsequent reduction in body weight gain,
were seen at doses ≥0.6 mg/kg/day (0.2X MTHD).
PATIENT COUNSELING INFORMATION
Patients using Locoid Lipocream should receive the following information
and instructions:
Apply a thin layer to the affected skin two or three times daily for corticosteroidresponsive dermatoses in adults. Consult with your physician to determine if
treatment is needed beyond 2 weeks. Apply a thin film to the affected skin areas
two times daily for atopic dermatitis in patients 3 months of age and older.
Safety of Locoid Lipocream in pediatric patients has not been established beyond 4
weeks of use.
Rub in gently.
Avoid contact with the eyes.
Do not bandage, otherwise cover, or wrap the affected skin area so as to be
occlusive unless directed by your physician.
Do not use Locoid Lipocream in the diaper area, as diapers or plastic pants may
constitute occlusive dressings.
Do not use Locoid Lipocream on the face, underarms, or groin areas unless
directed by your physician.
If no improvement is seen within 2 weeks, contact your physician.
Do not use other corticosteroid-containing products while using Locoid Lipocream
without first consulting your physician.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
Room Temperature]. Protect from freezing. Keep out of the reach of children.
Manufactured for: Triax Pharmaceuticals, LLC
Cranford NJ 07016
By: Ferndale Laboratories, Inc.
Ferndale MI 48220
Locoid Lipocream is a registered trademark of
Astellas Pharma Europe BV licensed to
Triax Pharmaceuticals, LLC.
Marketed and Distributed By:
Triax Pharmaceuticals, LLC
Cranford NJ 07016
www.Locoid.com
131B301
Rev 11/09
Now younger eczema
patients have something
to smile about
Now approved for use in children
down to 3 months of age
The power of an ointment with the elegance of a cream
Locoid Lipocream is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses,
including the treatment of mild to moderate atopic dermatitis in patients 3 months of age and older.
Safety and effectiveness in pediatric patients below 3 months of age have not been established.
Reversible HPA axis suppression may occur, with the potential for corticosteroid insufficiency. Consider periodic evaluations for HPA
axis suppression if applied to large surface areas or used under occlusion. Systemic effects of topical corticosteroids may also include
manifestations of Cushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity
due to their large skin surface-to-body-mass ratios. Initiate appropriate therapy if concomitant skin infection develops. Discontinue use
if irritation develops. Please see full Prescribing Information on adjacent page.
Visit us at www.locoid.com
(hydrocortisone butyrate 0.1%) Cream
©2010 Triax Pharmaceuticals, LLC. All rights reserved. Locoid is a registered trademark of Astellas Pharma Europe B.V. licensed to Triax Pharmaceuticals, LLC. LOC-0410-01

March/April 2010 • Volume 8 • Issue 2

Transcription

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