Journal of Drugs in Dermatology

Contents | Zoom in | Zoom out
*44/
For navigation instructions please click here
Search Issue | Next Page
+VOFt7PMVNFt*TTVF
JDD
+6/&*446&
Do Not Copy,
Penalties Apply
44 Years in Dermatologic Surgery: A Retrospective
Treatment of Poikiloderma of Civatte With Ablative Fractionated Laser Resurfacing:
Prospective Study and Review of the Literature
Treatment of Pruritus in Mild-to-Moderate Atopic Dermatitis With a Topical Non-Steroidal Agent
2009-Journal of Drugs in Dermatology. All Rights Reserved.
This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
Anti-TNF Agents for the Treatment of Psoriasis
No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
If you feel you have obtained this copy illegally, please contact JDD immediately.
Photodynamic Therapy With Low-Strength ALA, Repeated Applications and Short Contact
Periods (40-60 Minutes) in Acne, Photoaging and Vitiligo
Are Ointments Better Than Other Vehicles for Corticosteroid Treatment of Psoriasis?
/FXT 7JFXT BOE3FWJFXT

1JQFMJOF1SFWJFXT $MJOJDBM5SJBM3FWJFX
Contents | Zoom in | Zoom out
For navigation instructions please click here
Search Issue | Next Page
Previous Page | Contents | Zoom in | Zoom out | Front Cover | Search Issue | Next Page
BEMaGS
F
Proudly
Supported by
Introducing the rst and only once-daily combination

acne treatment with adapalene and benzoyl peroxide
Do Not Copy,
Penalties Apply
NEW Epiduo Gelenhanced efcacy and convenience
for your mild to moderate acne patients1,2
* At week 12, statistically more Epiduo Gel patients were rated as (IGA)
clear or almost clear in comparison to the monotherapy arms1,2
* Significant clearing of both inflammatory
(67%) and noninflammatory
2009-Journal of Drugs in Dermatology.
All Rights Reserved.
lesions (59%) at week 121
* Easy-to-use
application
No reproduction or use of any portion
of the contentsonce-daily
of these materials
may be made without the express written consent of JDD.
Prescribe NEW Epiduo Gel for your mild to moderate acne patients
Important Safety Information
Epiduo Gel is a retinoid and antimicrobial combination product indicated for the topical treatment of acne vulgaris in patients 12 years
and older. The most common adverse events associated with use of Epiduo Gel are erythema, scaling, dryness, stinging and burning.
In addition, in clinical trials, adverse events reported in greater than 1% of patients treated with the Gel included contact dermatitis and
skin irritation. Excessive exposure to sunlight and sunlamps should be avoided during treatment, and use of sunscreen products and
protective clothing is recommended. Concomitant use of irritating topical products (like products containing resorcinol, salicylic acid or
sulfur) should be avoided. Epiduo Gel has not been tested in pregnant or nursing women, or with the elderly. Pregnancy Category C.
Please see brief summary of Prescribing Information on next page.

THE ADVANTAGE IS CLEAR
BEMaGS
F
BEMaGS
8)'9 8)9 ')9 &/3&/! 08)? ;)8 ?)8 &/ /!2)

! % # #&# $ ?)A 02

B)< 02 # : ( & ) # %!
!
" #
& & ##! #
$
%
&%&'"( (
%)* #
% . $)

* & % . $
$+,!$- ,$ -,
! .# '9(91 ! " & 0='8 #
! "
! " 2 . !) $
# $%& '( !
"% ! ';A 02 (89 02 & !
& )
"/3&) ! % # $ (B<8
# : ) % . ! .# (91
+$!,$+,!$ ! " & 9= .3 . !
*)
.# '91 ! " & # ( ! %!
.,$$- ,$ +,!$ ! .# 91 ! " &
$ +&# $ "%,
$ "% %&#
. !)
%) - % .# % "% $)
5# ! " % # . #
!# & ! &&/%& ! % .# %
$ ) :.$ # & # & #%
)
%3.)
,/- ,+!$ #&! %! % .# 91 ! "
$ $ .# .
& C% % . $
!# & ! && %&) # !
# ! <8 .3)
$ $ 0'12 .# . !
* #&! % . % .# ) :.$
3 %&
% #$ #. %& 3 .# # %
3 )
#&! %& 0)&) 2 .# " C
# ! %&#)
#%&# # & #
$!,+!$& #% #% $ $
" % %& & %%
"% # %&# %)
! $ % .#
"# %& &" 0

#&# # & .# )
4# # $! ! % !# 5D !2
4 % % .# & !&
0% %% 2)
) .# %)
%&! ! 0
2 .# ! " # $
*"
" % %& . $ . %
&! 4&! 4) 5# . &
7! $&) ! " # #. %
. .# )
% % #$
& *
3 #% # # %
% .# # & ! ") %#
# % *
3 # #% #
%# % .! $ #% 6 #
% # "#&
#% % %& &! ! #
4# # $! ) % (8 & /3&/!
7% # 3 # %)
0'(8 &/(/!6 ?A # : &/(/! 2
* & . $ .# 8)'9

# %$ ! 8
(
9)8 & /3&/! % (9 0&/ /!2 # "%
&.# $ %$ % ' &)
#% 0 : 2 ( & ) :.$
* ! % . % .# ! ")
& #& . $ .# .#
,!$! +$-3$ $ 1,!$
(9 & /3&/! & '(; (<= :
E
$ # .#
$!) & % ## #
6 !)
! # ! $& # !
3 6 % # "##
%% )
3! 3 )
E
$ % # # %
&! % % 8)==)8 &
(
! # ! # . % % % !
/3&/! >(99? 0&/ 2 # : @ "# "!
)
! %%! # !
E ! % %# !# & !
)
&& %&)
$0#* 1
%&#
E
$ "% %&# %& %)
3. .## ! " " #%
# % % % $ 0)&)
3 .& % ) % ! %& " #%
#2 .# "% $)
3 % #% " .#
E ! # # )
%& .)
%" #
This document
contains
proprietary
information,
images
and marks of Journal of Drugs in Dermatology (JDD).
! $

% # &

'( #$
#)
3
!,
No reproduction
or use of any portion of the contents of these materials
may !,
be made without the express written consent of JDD.
3
%" #

+
+

5
+

5 +))
+))

+
If
you
feel
you
have
obtained
this
copy
illegally,
please
contact JDD immediately.
4 % % % % %7
-#
-# 5"
5" B='BB
B='BB

& =9 $ .## #! ! !%&
%% !,
!,
%%
%7)
%
% 4
4 )
)

+"
*##( 10%*##( ''%
2 %%
FG
FG H4
H4 :?I
:?I ;<
;< 4
4

* &! #&! &"! ! % .

4)
4)

% .# )

+
&
& 3)
3)

+

4&! % .# #$ %
$,
(88A
(88A
$,
8)< '); <)8 &/3&/! 0')( ;)? '( &/(/!2
9';9=8
9';9=8

Do Not Copy,
Penalties Apply
References: 1. Data on le. Galderma Laboratories, L.P. Phase 3 data. 2. Thiboutot DM, Weiss J, Bucko A, et al; Adapalene-BPO
Study Group. Adapalene-benzoyl peroxide, a xed-dose combination for the treatment of acne vulgaris: results of a multicenter,
randomized double-blind, controlled study. J Am Acad Dermatol. 2007;57(5):791-799.
Epiduo is a trademark, and Galderma is a
registered trademark of Galderma Laboratories, L.P.
2009 Galderma Laboratories, L.P.
Galderma Laboratories, L.P.
14501 N. Freeway
BEMaGS
F
BEMaGS
F
508
JUNE 2009
VOLUME 8 t ISSUE 6
EDITORIAL STAFF
PUBLISHER
-BXSFODF&3PCJOT
EDITOR
+BNFT+(PSNMFZ
ASSISTANT EDITOR
4IFMMFZ/5BOOFS
EDITORIAL ASSISTANT
+BNJF5SBQQ
NATIONAL SALES & ADVERTISING MANAGER
3JTB(PMENBO
Journal of Drugs in Dermatology (JDD)

is published monthly by the
Journal of Drugs in Dermatology
377 Park Avenue South, 6th Floor, New York, NY 10016
telephone: 212-213-5434 ~ fax: 212-213-5435
www.JDDonline.com
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in
electrical or other forms or by any means without prior written permission from the Journal of
Drugs in Dermatology (JDD). This publication has been registered with the Library of Congress
(ISSN: 1545 9616). The publisher and the organizations appearing herein assume no responsibility
for any injury and/or damage to persons or property as a matter of product liability, negligence,
or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein. No suggested test or procedure should be carried out unless, in
the readers judgment, its risk is justied. Because of the rapid advances in the medical sciences,
we recommend that independent verication of diagnoses and drug dosages should be made.
Discussions, views, and recommendations as to medical procedures, choice of drugs, and drug
dosages are the responsibility of the authors. Statements and opinions expressed in the articles
and communications herein are those of the author(s) and not necessarily those of the editors,
publisher, or staff. The editors, publisher, and staff disclaim any responsibility for such material
and do not guarantee, warrant, or endorse any product or service advertised in this publication
nor do they guarantee any claim made by the manufacturer of such product or service.
Do Not Copy,
Penalties Apply
PRODUCTION EDITOR
&MJ[BCFUI#PSHFT
SALES ASSOCIATE
"NBOEB)FBSUZ
DESIGN
4UFWFO-BXSFODF
Although all advertising material is expected to conform to ethical and medical standards, inclusion in this publication does not constitute a guarantee or endorsement by the Journal or its staff
of the quality or value of such products or of the claims of any manufacturer. The paper used in
this publication meets the minimum requirements of the American National Standard for Information Sciences Permanence of Paper for Printed Library Materials, ANSI Z39.48-1992.
2009 Journal of Drugs in Dermatology
PERMISSIONS: Contact James J. Gormley at 646-736-4328;

e-mail: james.gormley@JDDonline.com
_________________
REPRINTS & ADVERTISING: Contact Risa Goldman at 617-840-7472;
e-mail: risa.goldman@JDDonline.com
________________
SUBSCRIPTIONS:
log on to www.JDDonline.com
This document contains proprietary
information, images and marks of Journal of Drugs in Dermatology (JDD).
or call 212-213-5434
Journal of Drugs in Dermatology (JDD) (ISSN 1545-9616) is published monthly for
$150 per year (US subscriptions)/$300 per year (International subscriptions) by
the Journal of Drugs in Dermatology, 377 Park Avenue South, 6th Floor, New York,
NY 10016. Application to mail Periodicals postage rates is pending at New York,
NY and additional ofces. POSTMASTER: Send address changes to the Journal
of Drugs in Dermatology, 377 Park Avenue South, 6th Floor, New York, NY 10016.

International Society for

Dermatologic Surgery

BEMaGS
F
BEMaGS
F
509
JUNE 2009
INTERNATIONAL EDITORIAL BOARD
VOLUME 8 t ISSUE 6
Gerhard Sattler MD
Darmstadt, Germany
Elizabeth Hale MD
New York, NY
MEDICAL
EDITORIAL STAFF
Alan R. Shalita MD
Brooklyn, NY
Sherry H. Hsiung MD
New York, NY
Kendra G. Bergstrom MD
Jerome l. Shupack MD
New York, NY
Leon Kircik MD
Louisville, KY
Marissa Heller MD
Susan Weinkle MD
Bradenton, FL
Flor Mayoral MD
Miami, FL
Brian Zelickson MD
Minneapolis, MN
Mark S. Nestor MD
Aventura, FL
New York, NY
Joseph B. Bikowski MD
Pittsburgh, PA
SENIOR ASSOCIATE
EDITORS
Jeffrey Orringer MD
Ann Arbor, MI
Boca Raton, FL
Dee Anna Glaser MD

St. Louis, MO
Macrene AlexiadesArmenakas MD PhD

New York, NY
Maritza Perez MD
Danbury, CT
New York, NY
Kevin Pinski MD
Chicago, IL
EDITOR OF CASE
REPORTS
Maurizio Podda MD PhD

Frankfurt, Germany
Joel L. Cohen MD
EDITOR-IN-CHIEF
Perry Robins MD
New York, NY
CO-EDITOR-IN-CHIEF
James M. Spencer MD
St. Petersburg, FL
SENIOR EDITORS
Robert Baran MD
Cannes, France
C. William Hanke MD
Indianapolis, IN
William Levis MD
New York, NY
Henry W. Lim MD
Detroit, MI
Ronald L. Moy MD
Los Angeles, CA
Keyvan Nouri MD
Miami, FL
Neil S. Sadick MD
New York, NY
Deborah S. Sarnoff MD
New York, NY
Martin Braun MD
Vancouver, British Columbia
Isaac Brownell MD PhD
New York, NY
Patricia Farris MD
Metairie, LA
Michael H. Gold MD
Nashville, TN
Luigi Rusciani Scorza MD

Rome, Italy
New York, NY
Boston, MA
Hillary Johnson-Jahangir MD
Robert Johr MD
Jonathan Zippin MD PhD
Englewood, CO
PAST EDITORS
Ritu Saini MD
New York, NY
Keyvan Nouri MD
Noah S. Scheinfeld MD
New York, NY
Susan Weinkle MD
Miami, FL
Do Not Copy,
Penalties Apply
Mitchel P. Goldman MD
La Jolla, CA
Aditya K. Gupta MD PhD

London, Ontario
Bradenton, FL
Amy Taub MD
Lincolnshire, IL
Danny Vleggaar MD
Geneva, Switzerland
Calvin Day MD
Kishwer S. Nehal MD
Europe
Doris Day MD FAAD
Jorge J. Ocampo Candiani MD
Francisco M. CamachoJames Q. Del Rosso DO
Philip Orbuch MD
Martinez MD
Zoe
Diana
Draelos
MD
Anna
C.
Pavlick
MD
Alejandro
Camps
North America
Madeleine
D.
Duvic
MD
Sheldon
V.
Pollack
MD
FRCPC
Fresnada
MD
William Abramovits MD
Lawrence
F
.
Eicheneld
MD
Fitzgeraldo
A.
Julian
S.
Conejo-Mir
MD
Rex A. Amonette MD
Joseph
C.
English
III
MD
Sanchez-Negron
MD
Alina
A.
Fratila
MD
Martha P. Arroyo MD
Michael J. Franzblau MD
Julie Schaffer MD
John Hawk MD
Robin Ashinoff
MD
This
document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
Dore
Gilbert
MD
Daniel
Mark
Siegel
MD
Martino Neumann MD
Marc R. Avram MD
No reproduction or use of any portion
ofJ.the
contentsMD
of these materials
mayJ.be
madeMD
without the express written consent of JDD.
David
Goldberg
Arthur
Sober
Christopher R. Payne MD
David E. Bank MD
If you feel
you have
obtained this
copy illegally,
pleaseA.contact
JDD immediately.Antonio Picoto MD
Leonard
H.
Goldberg
MD
Nicholas
Soter
MD
Jay G. Barnett MD FAAD
Gloria F. Graham MD
Ella L. Toombs MD
Lidia Rudnicka MD
Kenneth Beer MD
Michael
P
.
Heffernan
MD
Ken
Washenik
MD
PhD
Miguel Sanchez-Viera MD
Richard G. Bennett MD FAAD
N.
Patrick
Hennessey
MD
Jeffrey
Weinberg
MD
Diane S. Berson MD
Alysa R. Herman MD
Robert A. Weiss MD
Asia and the
Gary Brauner MD
George
J.
Hruza
MD
FAAD
W.
Phillip
Werschler
MD
Middle East
Jean-Claude Bystryn MD
Shasa
Hu
MD
Ronald
G.
Wheeland
MD
Rana Anadolu Brasie MD
Jeffrey Phillip Callen MD
Bruce
E.
Katz
MD
John
Zic
MD
Poong Myung Kim MD
Marian Cantisano-Zilkha MD
Amor
Khachemoune
MD
John
A.
Zitelli
MD
FAAD
Jai Il Youn MD
Jean Carruthers MD
Mary
P
.
Lupo
MD
Isaac Zilinsky MD
Roger I. Ceilley MD
Warwick
L.
Morison
MD
South
America
Clay J. Cockerell MD
Rhoda S. Narins MD
Cleire Paniago-Pereira MD
David E. Cohen MD
Mark Naylor MD
Fernando Stengel MD
ASSOCIATE
EDITORS
BEMaGS
F
BEMaGS
F
Do Not Copy,
Penalties Apply
_______________
BEMaGS
F
BEMaGS
JUNE 2009
VOLUME 8
ISSUE 6
ORIGINAL ARTICLES


Perry Robins MD

Treatment of Poikiloderma of Civatte With Ablative

Fractional Laser Resurfacing:
Emily P. Tierney MD and C. William Hanke MD MPH

FIGURE 1. Left to right: Theodore

Tromovitch, Perry Robins, R. Raymond
Allington, Frederic Mohs, George
Vavruska, William R. Buckley, Richard
Moraites (page 519).
Treatment of Pruritus in Mild-to-Moderate Atopic

Dermatitis With a Topical Non-Steroidal Agent
Do Not Copy,
Penalties Apply
Stefano Veraldi MD PhD, Paolo De Micheli MSc,

Rossana Schianchi MD, Luisa Lunardon MD


Leon H. Kircik MD and James Q. Del Rosso DO

Photodynamic Therapy With Low-Strength ALA,

Repeated Applications and Short Contact Periods
(40-60 Minutes) in Acne, Photoaging and Vitiligo
Gabriel Serrano MD, Matilde
Lorente
MD,in Madga
Reyes
MD,Reserved.
2009-Journal
of Drugs
Dermatology.
All Rights
This document
proprietary
information,
images andMelendez,
marks of Journal of Drugs in Dermatology (JDD).
Fernando
Millncontains
MD, Adrin
Lloret
MD, Joaqun
No reproduction
or use of Miguel
any portion
of the contents
Maria Navarro,
Navarro
MD of these materials may be made without the express written consent of JDD.

Are Ointments Better Than Other Vehicles for

Corticosteroid Treatment of Psoriasis?
Anna H. Zivkovich and Steven R. Feldman MD, PhD
FIGURE 1. High-intensity light source

emitting in the yellow and orange spectrum (page 562).
(SBDFXBZ1IBSNBDFVUJDBMT UIFNBLFSPG"MEBSB JTQSPVEUP

TQPOTPSDPNQMJNFOUBSZTVCTDSJQUJPOTUPUIFJournal of Drugs
in DermatologyGPSBMM64CBTFEEFSNBUPMPHZSFTJEFOUT
BEMaGS
F
BEMaGS
JUNE 2009
VOLUME 8
CASE REPORTS

Localized Dyskeratotic Plaque With

Milia Associated With Sorafenib
Jeaneen A. Chappell MD,
Nicole M. Burkemper MD,
Natalie Semchyshyn MD

ISSUE 6
New
Supplement
Coming Soon
Painful Parotid Hypertrophy With

Bulimia: A Report of Medical
Management
A SUPPLEME
Kelly K. Park MD, Rebecca C. Tung MD,

Arlene Ruiz de Luzuriaga MD MPH

Do Not Copy, J DD
Penalties Apply
NT TO
Intramuscular Triamcinolone: A
Safe, Effective and Underutilized
Dermatologic Therapy
Genomics of
Skin Aging:
Practical Ap
plications
Sympos
Douglas N. Robins MD
American Soc ium Proceedings,

iety for Derm
ato
2008 Annua
l Meeting, No logic Surger y
vember 9, 200
8
*44/: 1545 9616
+VMZt
VPMVNFt
July
*TTVF supp
lement)
2009 Supplement
Genomics of Skin Aging:

Practical
Applications
If you feel you have obtained this copy illegally, please contact
JDD immediately.
Symposium Proceedings,
American Society for Dermatologic Surgery
2008 Annual Meeting, November 9, 2008
Look for this supplement with

your July issue of JDD or eJDD.
This supplement to the Journal of Drugs in Dermatology is sponsored by P&G Beauty & Grooming
FIGURE 2. Focal acantholytic dyskeratosis of the epidermis (Hemotoxylin-eosin stain; original magnication: X100) (page 573).
BEMaGS
F
BEMaGS
F
Hig
P
h S ublish
ati ed P.
sfa U.M
cti .P. d
on ata
.* L con
ow firms
Irr
ita
tio
n.
2
Start with
satisfaction in mind
LIFY DOSIN
MP
G1
SI
ENT OVERU
EV
SE
PR
L TRETI
NO
TRO
IN
ON
Do Not Copy,
Penalties Apply
___________
This document contains proprietary information, images and marks of Journal of Drugs in Dermatology
(JDD).
RETIN-A MICRO (tretinoin gel) microsphere, 0.04% and 0.1% are indicated for topical application in the treatment of acne vulgaris.
RETIN-A MICRO 0.04% and 0.1% showed a visible reduction in total mean lesion count in as little as 2 weeks with full benefit of therapy
seen after 7 weeks.
The most common adverse reactions to RETIN-A MICRO 0.04% and 0.1% were limited to mild or moderate irritation of the skin. 1.3% of
patients using RETIN-A MICRO 0.04% and 6% of patients using RETIN-A MICRO 0.1% discontinued due to irritation.
Please see brief summary of prescribing information on the next page.
*Reported at the end of the 12-week P.U.M.P. Study.
Data based on a consumer preference study designed to evaluate preference of Pump versus tube delivery. 104 male and female acne sufferers between the ages of 13 and 36
completed the study.3
References: 1. RETIN-A MICRO 0.04%/0.1% [prescribing information]. Los Angeles, Calif: OrthoNeutrogena; May 2006. 2. Eichenfield LF, Nighland M, Rossi AB, et al; PUMP Study
Group. Phase 4 study to assess tretinoin pump for the treatment of facial acne. J Drugs Dermatol. 2008;7(12):1129-1136. 3. Data on file, Ortho Dermatologics. 4. Embil K, Nacht S.
The Microsponge Delivery System (MDS): a topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives. J Microencapsul.
1996;13(5):575-588.
RETIN-A MICRO is a trademark of Ortho Dermatologics. 2009 Ortho Dermatologics 09DD0052 Printed in USA
BEMaGS
F
BEMaGS
F
New Zealand white rabbits were treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%,
,? /:>0> :1

,9/
82 62 /,D ,/8494>?0=0/ ?:;4.,77D 1:= 3:@=> , /,D B3470
B0,=49274E,-0?3,9.:77,=>?:;=0A09?4920>?4:9:1?30/=@2&30=0,;;0,=0/?:-049.=0,>0/
incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid49/@.0/10?,78,71:=8,?4:9>49?34>>;0.40>,?
,9/
82 62 /,D%4847,=8,71:=8,?4:9>
B0=09:?:->0=A0/,?
82 62 /,D ?480>?308,C48@83@8,9>D>?084./:>0:1?=0?49:49
after topical administration of Retin-A Micro ?=0?49:49 207 84.=:>;30=0
9:=8,74E0/
1:=?:?,7-:/D>@=1,.0,=0,9,=0;0,?>?@/D:1?3034230>??:;4.,7/:>0
82 62 /,D49
FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE.
pregnant
rabbits, these effects were not seen, but a few alterations that may be associated
Brief Summary
B4?3?=0?49:490C;:>@=0B0=0>009"?30=;=029,9?=,--4?>0C;:>0/?:;4.,77D1:=>4C3:@=>?:
Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04% is a formulation containing 0.1%
:=
82 62 /,D?=0?49:49B3470=0>?=,490/49>?:.6>?:;=0A09?4920>?4:9/4/9:?>3:B
or 0.04%, by weight, tretinoin for topical treatment of acne vulgaris. This formulation uses
teratogenic effects at doses up to 17 t480>
82 62 /,D?308,C48@83@8,9>D>?084.
patented methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres any
dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, adjusted for
(MICROSPONGE System) to enable inclusion of the active ingredient, tretinoin, in an aqueous
?:?,7-:/D>@=1,.0,=0,-@?10?,7=0>:=;?4:9>B0=049.=0,>0/,?
82 629,//4?4:9?:;4.,7
gel.
tretinoin in non Retin-A Micro (tretinoin gel) microsphere formulations was not teratogenic in
IMPORTANT NOTE: This information is a BRIEF SUMMARY of the complete prescribing =,?>,9/=,--4?>B30924A0949/:>0>:1,9/?480>?308,C48@83@8,9>D>?084./:>0
information provided with the product and therefore should not be used as the basis
after topical administration of Retin-A Micro (?=0?49:4920784.=:>;30=0
9:=8,74E0/1:=?:?,7
for prescribing the product. This summary has been prepared by deleting information
body surface area, respectively, (assuming ,
62,/@7?,;;740/,/,47D/:>0:1
2:1

from the complete prescribing information such as certain text, tables, and references. gel topically). At these topical doses, however, delayed ossification of several bones occurred
The physician should be thoroughly familiar with the complete prescribing information
in rabbits. In rats, a dose-dependent increase of supernumerary ribs was observed.
before prescribing the product.
Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuINDICATIONS AND USAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is
8,9;=48,?0>&=0?49:49B,>?0=,?:2094.49)4>?,==,?>B30924A09:=,77D:=?:;4.,77D49/:>0>
indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the
2=0,?0=?3,982 62 /,D?480>?308,C48@83@8,9>D>?084./:>09:=8,74E0/1:=?:?,7
use of this product in the treatment of other disorders have not been established.
body surface area). However, variations in teratogenic doses among various strains of rats have
CONTRAINDICATIONS: This drug is contraindicated in individuals with a history of sensitivity
-009=0;:=?0/9?30.D9:8:72@>8:960DB34.380?,-:74.,77D4>8:=0>4847,=?:3@8,9>?3,9
reactions to any of its components. It should be discontinued if hypersensitivity to any of its other species in its handling of tretinoin, fetal malformations were reported for doses of 10
ingredients is noted.
82 62 /,D:=2=0,?0=-@?9:90B0=0:->0=A0/,?82 62 /,D ?480>?308,C48@83@8,9
PRECAUTIONS:
>D>?084./:>09:=8,74E0/1:=?:?,7-:/D>@=1,.0,=0,,7?3:@2349.=0,>0/>6070?,7A,=4,?4:9>
General:
were observed at all doses. Dose-related increases in embryolethality and abortion also were
F&30>649:1.0=?,4949/4A4/@,7>8,D-0.:800C.0>>4A07D/=D=0/>B:7709:=-74>?0=0/1?30 reported. Similar results have also been reported in pigtail macaques.
degree of irritation warrants, patients should be directed to temporarily reduce the amount
Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence
or frequency of application of the medication, discontinue use temporarily, or discontinue
1:=?0=,?:2094.4?D>3:=?090/:=64960/?,47:1?:;4.,7?=0?49:4949)4>?,==,?>,?/:>0>2=0,?0=
use all together. Efficacy at reduced frequencies of application has not been established. ?3,982 62 /,D?480>?308,C48@83@8,9>D>?084./:>09:=8,74E0/1:=?:?,7-:/D>@=1,.0
If a reaction suggesting sensitivity occurs, use of the medication should be discontinued. ,=0,9:8,740>3@80=@>>3:=? -09?:>;,=40?,749.:8;70?07D:>>4140/3,A0
C.0>>4A0 >649 /=D90>> 8,D ,7>: -0 0C;0=409.0/ 41 >: @>0 :1 ,9 ,;;=:;=4,?0 08:77409? ,7>:-009=0;:=?0/B309
82 62 /,DB,>?:;4.,77D,;;740/%@;0=9@80=,=D=4->3,A0-009
during the day may be helpful.
a consistent finding in rats when dams were treated topically or orally with retinoids.
F'9;=:?0.?0/0C;:>@=0?:>@97423?49.7@/492>@97,8;>>3:@7/-0849484E0//@=492?30@>0:1 There are no adequate and well-controlled studies in pregnant women. Retin-A Micro should be
Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, and patients with sunburn should @>0//@=492;=029,9.D:97D41?30;:?09?4,7-09014?5@>?4140>?30;:?09?4,7=4>6?:?3010?@>
be advised not to use the product until fully recovered because of heightened susceptibility to
)4?3B4/0>;=0,/@>0:1,9D/=@2,>8,779@8-0=:1-4=?3/010.?=0;:=?>,>>:.4,?0/?08;:=,77D
sunlight as a result of the use of tretinoin. Patients who may be required to have considerable
>@90C;:>@=0/@0?::..@;,?4:9,9/?3:>0B4?34930=09?>09>4?4A4?D?:?30>@9>3:@7/0C0=.4>0 B4?3 ?30 ,/8494>?=,?4:9 :1 ?30 /=@2 B:@7/ -0 0C;0.?0/ -D .3,9.0 ,7:90&34=?D 3@8,9 .,>0>
of
temporally associated congenital malformations have been reported during two decades of
;,=?4.@7,=.,@?4:9'>0:1>@9>.=009;=:/@.?>%#,9/;=:?0.?4A0.7:?3492:A0=?=0,?0/
clinical use of Retin-A. Although no definite pattern of teratogenicity and no causal association
,=0,>,=0=0.:8809/0/B3090C;:>@=0.,99:?-0,A:4/0/
F)0,?30=0C?=080>>@.3,>B49/:=.:7/,7>:8,D-04==4?,?492?:;,?409?>@9/0=?=0,?809? has been established from these cases, five of the reports describe the rare birth defect category
holoprosencephaly (defects associated with incomplete midline development of the forebrain). The
with tretinoin.
>429414.,9.0:1?30>0>;:9?,90:@>=0;:=?>49?0=8>:1=4>6?:?3010?@>4>9:?69:B9
F$0?49 4.=:?=0?49:4920784.=:>;30=0
,9/

>3:@7/-060;?,B,D1=:8?30
Non-Teratogenic Effects: &:;4.,7 ?=0?49:49 3,> -009 >3:B9 ?: -0 10?:?:C4. 49 =,--4?> B309
eyes, the mouth, paranasal creases of the nose, and mucous membranes.
F&=0?49:493,>-009=0;:=?0/?:.,@>0>0A0=04==4?,?4:9:90.E08,?:@>>649,9/>3:@7/-0@>0/ ,/8494>?0=0/
82 62 /,D?480>?308,C48@83@8,9>D>?084./:>0,;;740/?:;4.,77D,9/
9:=8,74E0/1:=?:?,7-:/D>@=1,.0,=0,=0>@7?4924910?,7=0>:=;?4:9>,9/A,=4,?4:9>49:>>414.,
with utmost caution in patients with this condition.
tion. Oral tretinoin has -009>3:B9?:-010?:?:C4.=0>@7?49249>6070?,7A,=4,?4:9>,9/49.=0,>0/
Information for Patients: A Patient Information Leaflet has been prepared and is included with 49?=,@?0=490/0,?349=,?>B309,/8494>?0=0/82 62 /,D?480>?308,C48@83@8,9
0,.3;,.6,20:1$0?49 4.=:?=0?49:4920784.=:>;30=0
,9/

>D>?084./:>0,;;740/?:;4.,77D,9/9:=8,74E0/1:=?:?,7-:/D>@=1,.0,=0,
Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, There are, however no adequate and well-controlled studies in pregnant women.
products that have a strong drying effect, products with high concentrations of alcohol, astringents,
or spices should be used with caution because of possible interaction with tretinoin. Avoid contact Animal Toxicity Studies: In male mice treated topically with Retin-A Micro (tretinoin gel)
B4?3?30;007:17480>#,=?4.@7,=.,@?4:9>3:@7/-00C0=.4>0/B4?3?30.:9.:84?,9?@>0:1?:;4.,7 84.=:>;30=0
,?

:=
82 62 /,D ?=0?49:49 := ?480> ?30 8,C48@8
:A0=?30.:@9?0=,.90;=0;,=,?4:9>.:9?,49492-09E:D7;0=:C4/0>@71@==0>:=.49:7:=>,74.D74.,.4/ human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere,
9:=8,74E0/1:=?:?,7-:/D>@=1,.0,=0,1:=
/,D>,=0/@.?4:949?0>?4.@7,=B0423?-@?
with Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. It also is advisable to allow the
effects of such preparations to subside before use of Retin-A Micro (tretinoin gel) microsphere, with no pathological changes were observed at the two highest doses. Similarly, in female mice
there was a reduction in ovarian weights, but without any underlying pathological changes, at
0.1% and 0.04%, is begun.
Carcinogenesis, Mutagenesis, Impairment of Fertility:9,B006/0=8,7>?@/D49B34.3
82 62 /,D?480>?308,C48@83@8,9/:>09?34>>?@/D?30=0B,>,/:>0=07,?0/
49.=0,>049?30;7,>8,.:9.09?=,?4:9:1?=0?49:493:@=>,1?0=?3014=>?/:>0>0;,=,?0?:C4
84.0B0=0,/8494>?0=0/

,9/

1:=8@7,?4:9>:1?=0?49:49.@?,90:@>><@,
.:6490?4.>?@/D4984.049/4.,?0>?3,?>D>?084.0C;:>@=04>2=0,?0=,1?0=?:;4.,7,;;74.,?4:9?:
mous cell carcinomas and papillomas in the treatment area were observed in some female
@9=0>?=,490/,948,7>?3,9?:=0>?=,490/,948,7>>@220>?492?3,??30>D>?084.?:C4.4?D:->0=A0/
mice. These concentrations are near the tretinoin concentration of these clinical formulations
is probably related to ingestion. Male and female dogs treated with Retin-A Micro (tretinoin gel)
(0.04% and 0.1%). A dose-related incidence of liver tumors in male mice was observed at
?3:>0>,80/:>0>&308,C48@8>D>?084./:>0>,>>:.4,?0/B4?3?30,/8494>?0=0/

84.=:>;30=0
,?

:=
82 62 /,D?=0?49:49:=?480>?308,C48@8
,9/

1:=8@7,?4:9>,=0
,9/
82 62 /,D=0>;0.?4A07D&30>0/:>0>,=0?B:,9/ human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere,
1:@=?480>?308,C48@83@8,9>D>?084./:>0,;;740/?:;4.,77DB3099:=8,74E0/1:=?:?,7
9:=8,74E0/1:=?:?,7-:/D>@=1,.0,=0,=0>;0.?4A07D1:=
/,D>>3:B0/9:0A4/09.0:1
reduced testicular or ovarian weights or pathological changes.
body surface area. The biological significance of these findings is not clear because they
:..@==0/,?/:>0>?3,?0C.00/0/?30/0=8,78,C48,77D?:70=,?0//:>0 &:1?=0?49:49,9/ Nursing Mothers:?4>9:?69:B9B30?30=?34>/=@24>0C.=0?0/493@8,984760.,@>08,9D
-0.,@>0 ?30D B0=0 B4?349 ?30 -,.62=:@9/ 9,?@=,7 :..@==09.0 =,?0 1:= ?30>0 ?@8:=> 49 ?34> /=@2>,=00C.=0?0/493@8,98476.,@?4:9>3:@7/-00C0=.4>0/B309$0?49 4.=:?=0?49:49
strain of mice. There was 9: 0A4/09.0 :1 .,=.49:2094. ;:?09?4,7 B309

82 62 /,D :1 gel) microsphere, 0.1% or 0.04%, is administered to a nursing woman.
?=0?49:49B,>,/8494>?0=0/?:;4.,77D?:84.0
?480>?308,C48@83@8,9>D>?084./:>0
9:=8,74E0/1:=?:?,7-:/D>@=1,.0,=0,:=;@=;:>0>:1.:8;,=4>:9>:1?30,948,70C;:>@=0 Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established.
?:>D>?084.3@8,90C;:>@=0?308,C48@83@8,9>D>?084./:>0,;;740/?:;4.,77D4>/01490/ Geriatric Use: Safety and effectiveness in a geriatric population have not been established.
,>2=,8:1$0?49 4.=:?=0?49:4920784.=:>;30=0
,;;740//,47D?:,
62;0=>:9 7494.,7>?@/40>:1$0?49 4.=:/4/9:?49.7@/0>@114.409?9@8-0=>:1>@-50.?>,20/,9/
over to determine whether they respond differently from younger subjects.

82?=0?49:49 62-:/DB0423?
Dermal carcinogenicity testing has not been performed with Retin-A Micro (tretinoin gel)
ADVERSE REACTIONS:
microsphere, 0.04% or 0.1%.
&30>649:1.0=?,49>09>4?4A049/4A4/@,7>8,D-0.:800C.0>>4A07D=0/0/08,?:@>-74>?0=0/:=
2009-Journal
of
Drugs
in
Dermatology.
%?@/40>493,4=70>>,7-49:84.0>@220>??3,?.:9.@==09?0C;:>@=0?:?=0?49:498,D093,9.0?30 crusted. If these effects occur, the medication should either be discontinued until the integrity
?@8:=42094.;:?09?4,7:1.,=.49:2094./:>0>:1'(,9/'(7423?1=:8,>:7,=>48@7,?:=&34>
:1?30>6494>=0>?:=0/:=?3080/4.,?4:9>3:@7/-0,/5@>?0/?:,70A07?30;,?409?.,9?:70=,?0
This document contains proprietary information, images and
0110.?3,>-009.:914=80/49,7,?0=>?@/D49;42809?0/84.0,9//,=6;42809?,?4:9/4/9:? However, efficacy has not been established for lower dosing frequencies.
:A0=.:80?30093,9.0809?:1;3:?:
True contact
to topical
tretinointhe
is rarely
encountered.
Temporary
hyperhypopigNo reproduction or use.,=.49:2090>4>-D

?=0?49:497?3:@23?30>429414.,9.0
of any portion of the contents of these materials
mayallergy
be made
without
express
written
consent
oforJDD.
:1?30>0>?@/40>?:3@8,9>4>9:?.70,=;,?409?>>3:@7/849484E00C;:>@=0?:>@97423?:=,=?414.4,7 mentation has been reported with repeated application of tretinoin. Some individuals have been
ultraviolet irradiation sources.
If you feel you have obtained this copy illegally,
contactsusceptibility
JDD immediately.
reportedplease
to have heightened
to sunlight while under treatment with tretinoin.
The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse
OVERDOSAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is intended for topical
micronucleus assay, both of which were negative.
@>0:97D180/4.,?4:94>,;;740/0C.0>>4A07D9:8:=0=,;4/:=-0??0==0>@7?>B477-0:-?,490/,9/
&30.:8;:909?>:1?3084.=:>;30=0>3,A0>3:B9;:?09?4,71:=2090?4.?:C4.4?D,9/?0=,?:2090>4> 8,=60/=0/90>>;007492:=/4>.:81:=?8,D:..@="=,74920>?4:9:17,=20,8:@9?>:1?30/=@2
,.:8;:909?:1?300C.4;409?,.=D7,?0>.:;:7D80=B,>;:>4?4A01:=49/@.?4:9:1>?=@.?@=,7 8,D70,/?:?30>,80>4/00110.?>,>?3:>0,>>:.4,?0/B4?30C.0>>4A0:=,749?,60:1(4?,849
chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in
Rx only.
?30,->09.0:180?,-:74.,.?4A,?4:9,9/902,?4A01:=2090?4.?:C4.4?D49?3080>,>>,D?30
#,?09?!:>

HGPRT forward mutation assay, and the mouse micronucleus assay.
Do Not Copy,
Penalties Apply
In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statisti.,77D>429414.,9?/0.=0,>0>49>;0=8.:@9?,9/8:?474?DB0=0>009,?
82 62 /,D?480>
?308,C48@83@8,9>D>?084./:>0,;;740/?:;4.,77D,9/9:=8,74E0/1:=?:?,7-:/D>@=1,.0
area), and slight (not statistically significant) increases in the number and percent of nonviable
08-=D:>49108,70>?=0,?0/B4?3
82 62 /,D?480>?308,C48@83@8,9>D>?084./:>0
,;;740/?:;4.,77D,9/9:=8,74E0/1:=?:?,7-:/D>@=1,.0,=0,,9/,-:A0B0=0:->0=A0/9:=,7
Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and
2=:B?3=0?,=/,?4:9B0=0:->0=A0/,?/:>0>490C.0>>:182 62 /,D?480>?303@8,9
?:;4.,7/:>09:=8,74E0/1:=?:?,7-:/D>@=1,.0,=0,
Dermal fertility and perinatal development studies with Retin-A Micro (tretinoin gel) microsphere,
0.1% or 0.04%, have not been performed in any species.
Pregnancy: Teratogenic Effects: Pregnancy Category C.
In a study of pregnant rats treated with topical application of Retin-A Micro (tretinoin gel)
84.=:>;30=0
,? /:>0> :1
?: 82 62 /,D :9 20>?,?4:9 /,D> ?:
?480> ?30 8,C48@8 3@8,9 >D>?084. /:>0 :1 ?=0?49:49 9:=8,74E0/ 1:= ?:?,7 -:/D >@=
face area after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%)
some alterations were seen in vertebrae and ribs of offspring. In another study, pregnant
Distributed by: OrthoNeutrogena

(%"!""$&" !#$ '&!
:>92070>

H" #

RETIN-A MICRO4>,=024>?0=0/?=,/08,=6:1"=?3: .!047#3,=8,.0@?4.,79.
MICROSPONGE 4>,=024>?0=0/?=,/08,=6:1,=/49,70,7?39.@-749"
BEMaGS
F
BEMaGS
F
#1 Dermatologist
Recommended
Baby Sunblock
Do Not Copy,
Penalties Apply
Theres no such thing as
over
protective
when it comes to babys skin.

advanced
photostable
technology
No
or use
of any portion of
the contents of these materials may be made without the express written consent of JDD.
+ reproduction
scientically shown
maintain
levels
of broad
If youto
feel
you have high
obtained
this copy
illegally, please contact JDD immediately.
spectrum protection against UVA and UVB rays
+ fragrance free, natural colloidal oatmeal

formula is as gentle to babys skin as water
thats the beauty of
nature+science
Johnson & Johnson Consumer Companies, Inc. 2009
BEMaGS
F
BEMaGS
F
IN THE MANAGEMENT OF ATOPIC DERMATITIS
Do Not Copy,
Penalties
Apply
BREAKS THE ITCH
SCRATCH CYCLEFAST
G Itch relief significantly better than vehicle
as early as day 3 and at all time points
1
measured during 43-day study (P<.0001)
G Controls recurring flares
1,2
G Supports healthy skin-barrier function
3,4
Rx Onlyinformation, images and marks of Journal of Drugs in Dermatology (JDD).

100g tube
www.atopiclairUS.com
For external use only; avoid contact with eyes.

Please see adjacent Prescribing Information.
Under the supervision of a healthcare professional, Atopiclair nonsteroidal cream is indicated to manage and relieve the itching, burning, and pain experienced with
various types of dermatoses, including atopic dermatitis and allergic contact dermatitis. Atopiclair nonsteroidal cream helps to relieve dry, waxy skin by maintaining
a moist skin environment, which is beneficial to the healing process.
Atopiclair nonsteroidal cream does not contain milk, wheat, peanut or animal derivatives. Atopiclair nonsteroidal cream does contain shea butter (Butyrospermum
parkii), a derivative of shea nut oil (not peanut oil). Patients with a known allergy to nuts or nut oils should consult their physician before using this topical preparation.
Frequently reported adverse events in Atopiclair-treated and vehicle-treated groups were burning (6.9% vs 7.1%) and stinging (8.3% vs 2.8%).
References: 1. Boguniewicz M, Zeichner JA, Eichenfield LF, et al. MAS063DP is effective monotherapy for mild to moderate atopic dermatitis in infants and children: a multicenter, randomized, vehicle-controlled study.
J Pediatr. 2008;152(6):854-859. 2. Abramovits W, Boguniewicz M. A multicenter, randomized, vehicle-controlled clinical study to examine the efficacy and safety of MAS063DP (Atopiclair) in the management of mild
to moderate atopic dermatitis in adults. J Drugs Dermatol. 2006;5(3):236-244. 3. Data on file. Graceway Pharmaceuticals, LLC. 4. Atopiclair Nonsteroidal Cream, Prescribing Information.
2009 Graceway Pharmaceuticals, LLC, Bristol, TN
ATP080807
www.gracewaypharma.com
BEMaGS
F
JUNE 2009
VOLUME 8
BEMaGS
F
ISSUE 6
DEPARTMENTS

News, Views and Reviews

Pipeline Previews

Clinical Trial Review
READER SERVICES
9
FIGURE 3. Treatment with maintenance pilocarpine resulting in reduction of parotid gland size (page 578).
JDD Buyers Resource
Do Not Copy,
Penalties Apply
a
ATOPICLAIR
Rx Only
NONSTEROIDAL CREAM
FOR TOPICAL DERMATOLOGICAL AND
EXTERNAL USE ONLY.
AVOID CONTACT WITH EYES.
Indications for Use: Under the supervision of a healthcare professional, Atopiclair

nonsteroidal cream is indicated to manage and relieve the itching, burning, and pain
experienced with various types of dermatoses, including atopic dermatitis and allergic
contact dermatitis. Atopiclair nonsteroidal cream helps to relieve dry, waxy skin by
maintaining a moist skin environment, which is beneficial to the healing process.
Directions for Use: Apply Atopiclair nonsteroidal cream to the affected skin areas 2 to 3
times a day (or as needed), and massage gently into the skin. If the skin is broken, cover
Atopiclair nonsteroidal cream with a dressing of choice.
Ingredients: Atopiclair is an off-white, nonsteroidal cream comprised of Deionized water,
Ethylhexyl palmitate, Pentylene glycol, Butyrospermum parkii, Capryloyl glycine, Glyceryl
2009-Journal
of Drugs
in Dermatology. All Rights Reserved.
stearate, PEG-100 stearate, Arachidyl glucoside,
Behenyl
alcohol, Arachidyl
alcohol, Bisabolol,
Tocopheryl acetate
Glycyrrhetinic
Carbomer, Ethylhexylglycerin,
Piroctone and marks of Journal of Drugs in Dermatology (JDD).
This(anti-oxidant),
document
containsacid,
proprietary
information, images
olamine, Sodium hydroxide, Allantoin, DMDM hydantoin, Vitis vinifera, Disodium EDTA, Ascorbyl
No reproduction
use of any
of the contents
of glycol.
these materials may be made without the express written consent of JDD.
tetraisopalmitate,
Sodiumorhyaluronate,
Propylportion
gallate, Telmesteine,
and Butylene
Cautions: The use of Atopiclair nonsteroidal
cream
is contraindicated
in anythis
patient
withillegally,
a
If you feel
you
have obtained
copy
please contact JDD immediately.
known history of hypersensitivity to any of the ingredients. Atopiclair nonsteroidal cream does
not contain milk, wheat, peanut or animal derivatives. Atopiclair nonsteroidal cream does
contain shea butter (Butyrospermum parkii), a derivative of shea nut oil (not peanut oil).
Patients with a known allergy to nuts or nut oils should consult their physician before using this
topical preparation.
Other Patient Information: The formulation contains no dyes or fragrances and is well
FIGURE 1. Localized neurodermatitis. FTN: The patient had a
tolerated and safe for patients of all ages.
two-year history of severe pruritus involving her eyelids and
How Supplied: 100g tube.
periorbital areas of her face, and she had developed tissue
Precautions: Do not use the product if the packaging is damaged or after expiration date.
hypertrophy and lichenication secondary to rubbing a).
Store at room temperature up to 25C (77F). Do not freeze.
Manufactured under license from

Sinclair Pharmaceuticals Ltd.
Godalming Surrey UK, GU7 2AB
Distributed by Graceway Pharmaceuticals, LLC
Bristol, TN 37620
A101 0207
PATENT PENDING
Several courses or oral corticosteroids had given temporary relief only, and numerous topical medications had been
ineffective. Eight weeks after one triamcinolone injection b),
she still has residual pigmentation, but the tissue hypertrophy and lichenication have gone and the pruritus has not
recurred. (page 582).
BEMaGS
F
BEMaGS
Ive got
a secret
its about
the DOT!
Do Not Copy,
Penalties Apply
$/44HERAPYTMISTHELATESTINNOVATIONFORSKINRESURFACING
$/44HERAPYISPERFORMEDUSINGTHE3MART8IDE$/4#/2LASERSYSTEM
FEATURINGTHEUNIQUE$/43CANNERWITHInnite Delivery OptionsFOR
ABLATIVESKINRESURFACINGWITHRAPIDHEALING
If you feel you have
obtained this copy illegally, please contact JDD immediately.
$/44HERAPYISIDEALFORTREATMENTOFPIGMENT
SKINLAXITYTEXTUREWRINKLESANDACNESCARS
)TSABOUTCHOICE)TSABOUTCONTROL)TSABOUTTHE$/4
3INGLE4REATMENT s -INIMAL$OWNTIME s /UTSTANDING2ESULTS
Before
After
#OURTESYOF$EBORAH33ARNOFF-$
Manufactured by
Distributed by
ECLIPSEMED,TD s TOLLFREE s ________________

WWWECLIPSEMEDCOM s ________________
WWWDOTTHERAPYCOM
BEMaGS
F
BEMaGS
F
JUNE 2009
519
70-6.&t*446&
COPYRIGHT 2009
ORIGINAL ARTICLES
JOURNAL OF DRUGS IN DERMATOLOGY

1FSSZ3PCJOT.%
INTRODUCTION
From todays perspective, one cannot imagine how different
the eld of dermatology was in 1965. Chemosurgery was a
word that very few dermatologists had heard, and one practically unknown to all other physicians in the medical community,
with the exception of a few surgeons who had heard Dr. Frederic Mohs speak at a conference.
Development of Mohs Surgery

It was then, at the start of my practice at New York University
(NYU) Medical Center, when I was to take my the next intentional
step in a young medical career, and, thus, what would be an unintentional step toward a life-long career in skin cancer education.
It all began when a colleague of mine mentioned a general surgeon, named Frederic Mohs, who spoke at a conference for plastic surgeons on a new surgical technique that showed promise
for successfully treating skin cancers, which intrigued me.
FIGURE 1. Left to right: Theodore Tromovitch, Perry Robins,

R. Raymond Allington, Frederic Mohs, George Vavruska,
William R. Buckley, Richard Moraites.
Dermatology (AAD) in Chicago (Figure 1). There were only 20
of us at that meeting who were at that time performing this
technique in North America. In my rst year (1966), we treated
70 patients with the numbers increasing to 1,300 patients per
year by the late 1980s. As a consequence of the growing success and popularity of the technique, dermatologists logically
gravitated to Mohs surgery. As a result, my role as a student
began to evolve into that of an educator.
Do Not Copy,
Penalties Apply
Dr. Mohs lectured on chemosurgery, (now known as Mohs micrographic surgery), a technique for the staged removal of skin
cancers using the in situ xation of cutaneous tissue. Chemosurgery was so named because of the xative used, an application of a paste made with zinc chloride on cutaneous skin
cancers, followed by excision and histologic examination of
the layers. I made arrangements to observe Dr. Mohs as a visiting physician in Madison, Wisconsin, where he was performing
chemosurgery daily. After ve weeks, I purchased a how-to
kit, a jar of zinc chloride paste and Dr. Mohs textbook, and then
returned to New York to put what I had learned into practice.
Dr. Alfred Kopf predicted 25 years ago there would be a Mohs

surgeon in all of the leading medical centers in the country. Not
only has this prediction come true, but many centers may even
have multiple Mohs surgeons on staff.
To my dismay, many of my colleagues were upset because they

In October 1970 in Las Vegas, at the annual meeting of the Americonsidered chemosurgery to be black magic and and the
can Academy of Ophthalmology and Otolaryngology (AAOO) in
2009-Journal
zinc paste to be painful. A few attempts
were made of
to Drugs
have in
meDermatology.
Las Vegasnow
two organizations, the American Academy of
stopped, removed
from
the faculty
at NYU
and expelled
fromimages
the and
Ophthalmology
(incorporated
in 1979) and
the American AcadeThis
document
contains
proprietary
information,
marks of Journal
of Drugs in Dermatology
(JDD).
American
of or
Dermatology
(AAD).
belief was
thatmaterials
my may
of OtolaryngologyHead
and Neck
Surgery
of 1981)we
NoAcademy
reproduction
use of any portion
ofTheir
the contents
of these
be made without the express
written
consent(as
of JDD.
dermatologists are not surgeons.
Conventional
that illegally,
presented
a number
cases of tumors on or around the eyelids
If you
feel you havewisdom
obtainedwas
this copy
please contact
JDDofimmediately.
if I had wanted to practice surgery I should have become a plastic
which were treated using serial excisions of fresh tissue. The zinc
surgeon. Slowly the merits of the technique became apparent, and
chloride paste was not employed for fear of damaging the globe.
it was clear that, with additional training, dermatologists could beFollowing the surgical removal of eyelid cancers in this fashion,
come competent in performing the procedure. My vision was that
wounds healed spontaneously and uneventfully.1
dermatologists, as physicians trained to recognize skin cancers,
In the early days, it was called chemosurgery. Without the
are the best equipped to treat them, preferably by a method that
chemical, it was referred to as the fresh tissue technique. In
provided the highest cure rate. Nevertheless, chemosurgery was
later years, the name was changed to Mohs micrographic surnot yet a part of the medical lexicon, and the concept of a dermagery, and recently shortened to Mohs surgery.
tologist performing surgery was, as noted, unheard of.
In 1965 a group of doctors who were performing Mohs surgery
gathered at the annual meeting of the American Academy of
In December, 1970 at the annual Mohs Conference, Drs. Ted

Tromovitch and Sam Stegman presented 104 cases of surgery
BEMaGS
F
BEMaGS
F
520
+6/&t70-6.&t*446&
without using zinc chloride chemical xative (a technique they

called chemosurgery fresh tissue technique). They reported
four recurrences.2
In 1972, I began a study on the efcacy of this new fresh tissue technique. By 1974, I found it unnecessary to use the zinc
chloride paste, except in cases of extensive, poorly-dened
squamous cell carcinomas. The cure rate with the fresh tissue
technique was equal to that of the paste. The technique was far
more advantageous: less pain and swelling; less postoperative
bleeding; several stages could be done within a day; if necessary, repairs could be carried out done immediately; and many
patients could be treated in one day.3
Between 1965 and 1980, the cases that were referred to my
practice for treatment were not random. Most were very difcult and extensive, both primary and recurrent. The borders
were poorly demarcated and morphea-like, or sclerosing basal
cell carcinomas (BCCs) involving areas known to have high recurrence rates, namely the nasolabial fold, ears, and inner canthus. Some tumors had been operated on as many as 10 times.
13PCJOT
later with software, and found a series of statistically interesting trends among our patients.4
A compendium of some notable data is provided.5 We continued to develop and publish studies illustrating the effectiveness
of the Mohs technique, and what we found to be successful
treatments for a variety of common and rare tumors (Figures
24).
a.
b.
Do Not Copy,
Penalties Apply
A number of patients were referred to me with cancers on

their ngers, and were scheduled for amputation because
physicians at that time were unaware that, through the Mohs
technique, ngers and other extremities they could possibly
be saved. Fortunately, most of the cancers were not extensive
and the digits were saved. Not infrequently, patients were referred with lesions on the penis, both the shaft and glans penis.
These patients were also scheduled for amputation. Fortunately,
however, the organs were saved. Mohs surgery was superior in
terms of saving vital organs which previously would have been
deemed unsalvageable and widely excised to a point of lost
function or fully amputated.
c.
FIGURE 2. Basal cell carcinoma (of the ear) with a history of three recurrences. a) Upon presentation. b) Extent of lesion following Mohs
surgery. c) Healing by second intention, three months post-op.
Early in my practice, my colleagues and I made great efforts

a.
to record and study the medical history and habits of patients,
b.
2009-Journal of
Drugs
including the timing of patients self-identication
and
reporting of lesions. With
assistance
of Dr.
Darrell information,
Rigel, we comThisthe
document
contains
proprietary
images and marks of Journal of Drugs in Dermatology (JDD).
puterized
of our
with
andmaterials may be made without the express written consent of JDD.
Norecords
reproduction
or patients,
use of anyinitially
portion of
the punch
contentscards
of these
Tumors Treated With Mohs
Basal cell carcinoma
Sebaceous carcinoma
Squamous cell carcinoma
Angiosarcoma
Dermatobrosarcoma
protuberans
Cylindroma
Merkels cell carcinoma
Atypical broxanthoma
Microcystic adnexal carcinoma
Keratoacanthoma
Malignant brous histiocytoma

(MFH)
Melanoma
c.
FIGURE 3. Recurrence of basal cell carcinoma (of the cheek)
following multiple excisions and grafts. a) Upon presentation.
b) Extent of lesion following Mohs surgery. c) Post-Mohs with
full-thickness graft.
BEMaGS
F
BEMaGS
F
521
+6/&t70-6.&t*446&
13PCJOT
Pearls Of Wisdom
1. Never Promise No Scar
The object of all surgery is to make the scar as least noticeable
as possible. Assure your patient that you will make every effort
to minimize the size and visibility of the scar . If the patient is
expecting a scar and you produce an inconspicuous one, youre
a hero.
a.
2. Do the Simplest Procedure
b.
c.
FIGURE 4. 21-year-old college student with a squamous cell carcinoma on the bridge of the nose. a) Upon presentation. b) Extent of
lesion following chemosurgery. c) Post reconstructive surgery after
one year.
The First Mohs Fellowships

Under the direction of Dr. Alfred Kopf, we established the rst
ever one-year fellowship training program in Mohs surgery.
The program included instruction in dermatopathology, surgery,
wound care, reconstructive surgery, anesthetics, anatomy, oncology, and prosthetics. Dr. Henry Bud Menn, from Geissinger
Medical Center, was our rst fellow (for the year 1968/69). Upon
completion of his fellowship, he was not happy that he had to
devote a full year to training since, at that time, nobody wanted
a Mohs surgeon nor would they have known what value the
technique represented. However, this lack of general awareness
did not stop Drs. Victor Witten and Harvey Blank from requesting funding from the Miami Dermatology Society to establish a
chemosurgery unit at the University of Miami in 1969.
Many physicians, to exercise their skills and ability, will

sometimes take what could be a simple repair and convert it
into a complex procedure. My philosophy is to attempt to do the
simplest procedure rst, as a more extensive procedure could
run into complications and produce a larger scar. I recommend
wide undermining and a simple closure when possible.
3. A Two-Stage Procedure
Tell the patients in advance that wound repair requires two
stages, the rst stage to be completed now, the second stage
to be done to ne-tune the repair in three to six weeks. In
the event that the second stage is necessary, you inform the
patient that they were told this in the beginning, so the patient
will not ask, Doctor, what did you do wrong? Most often, a
second stage will not be necessary. The patient may ask, Why
not? To this, you can answer that they have such healthy skin
that it was not necessary.
Do Not Copy,
Penalties Apply
4. Three Keys to a Good Result
It is important to remind the patient that there are three

componentns to achieving a good result.
t(PPEEPDUPS*MJLFUPJOTUJMMDPOmEFODFJOUIFQBUJFOUPG
the ability of the physician, to tell them that this is textbook
quality work, classic repairs, techniques that are established,
predictable, reproduceable, and tried-and-true.
t(PPEQBUJFOU*UJTJNQPSUBOUUPJOTUSVDUUIFQBUJFOUUPCF
compliant: follow written instructions, use discretion, limit
activities and sun exposure post-surgery. Also, the patient
should avoid alcohol and aspirin.
Interest in Mohs surgery grew very slowly. In the rst 10 years,

rarely did I have more than two applicants for the fellowship.
t(PPEMVDLo4VSHFSZJTBIFBMJOHBSU*UJTOPUBQFSGFDUTDJFODF
2009-Journal
of Drugs
in Dermatology.
With the development of the fresh
tissue
technique
in 1975,
Even under the best of circumstances, things can go wrong. With
interest grew exponentially.
there
are about
70 training
This documentToday
contains
proprietary
information,
a good doctor, a good patient, and good luck, the patient will get
programs
that offer aorone-year
fellowship,
with
each of
training
No reproduction
use of any
portion of the
contents
these materials
mayresults.
be made without the express written consent of JDD.
good
center receiving 20 to 30 applications
annually.
Doctors
If you feel you
have obtained
this also
copy illegally, please contact JDD immediately.
5. Minimize Revisions
came to me from abroad for training in Mohs surgery and subsequently established units in their own respective countries.
Your goal as a surgeon should be to do the minimum amount
One of the earliest trainees was Dr. Gunther Burg, who estabof correction in the maximum amount of time. Try to convince
the patient to wait six months or longer before you agree to
lished the rst European unit in Munich, Germany. I also had
reoperate. In many instances, waiting longer will shift the
the opportunity to train a plastic surgeon from Israel, Dr. Isaac
patients focus. You will often discover that the imperfection
Zilinsky; with his expertise in repairs, we went on to teach rethat bothered the patient is fully resolved at six months. Wound
constructive surgery.
Publicizing Mohs Surgery

In the early 1970s, despite the building interest in Mohs, it was
impossible to get an article on Mohs surgery published. When approached with an article on the subject, a leading dermatology
healing in the third stage starts at six months and continues for
a period of up to two years, when the broblasts are realigned.
When it comes to revisions, the longer you can wait, the better. A
revision may not be necessary.
BEMaGS
F
BEMaGS
F
522
+6/&t70-6.&t*446&
13PCJOT
Early Observations in Mohs

Sex of Patients
Men have more skin cancers than do women, in one study 3,743 men (53.8%) versus 3,211 women (46.2%). Perhaps this is because, at least historically men have been employed outdoors more than have women (as construction workers, shermen, utility workers, postal carriers, etc.resulting in more exposure to the sun.
One of my early studies showed that men had more lesions on the left side of the face and women had more
lesions on the right. This was attributed to the fact that, historically, men were usually in the drivers seat and
women in the passenger seat of an automobile. However, 15 years later, a newer further study revealed that both
men and women both had lesions more frequently on the left side of the face than the right.
Age of Patients
My youngest skin cancer patient was 10 years old and my oldest was 101. I believe we are seeing an increase in
the number of younger patients for a variety of reasons. People are spending more time in the sun, are aware of
skin cancers and come to see physicians sooner.
Size of Lesions
Almost half of the lesions were between 2 and 2.9 cm. Almost 10% (8.82%) were greater than 5 cm. Today it is rare
to see lesions as large as 2-3 cm. Patients are more aware of growths on their face and body. Men had signicantly larger lesions than did females; probably, for aesthetic reasons, female patients would seek medical attention
sooner.
Duration of Lesions
The average duration is 2 to 5 years. Twent-ve percent of patients said they had the lesion(s) for less than one
year. Men claimed they had them a shorter time; women felt their lesions were present longer. This difference
could, perhaps, be due to less frequent self-examination by men.
Cases Referred for

Mohs
For the rst 20 years of my practice, 50.4% of cases were primary lesions and 49.6% were recurrent. A two-year
study during this period, recording 1,170 cases showed that 199 were primary in females and 337 were recurrent.
Two hundred seventy-one males had primary lesions and 363 of the lesions were recurrent. Today I would estimate that less than 3% are recurrent lesions.
Metastasis of BCC
Of my rst 3,863 patients, we noted that four patients developed metastases. In the past 20 years I have seen
none.
Recurrence Related
to Sex of Patient
Recurrence was higher in men (3.2%) than women (1.8%). In men, the lesions were larger and present for a longer
period of time.
5-Year Cure Rate

Related to Size
Under 1 cm - 99.6%
BCC in Bone
I have found BCCs involving the periostium, but rarely do they invade bone. One of the signs of carcinoma in the
bone is pitting of the outer table. One sees tumor in the bone when radiation has been unsuccessful in eradicating
a skin cancer. In the early days, radiation was used as the last resort when other methods had proved unsuccessful.
BCC in Cartilage
It is extremely rare to see BCC involving cartilage. In the March 1980 issue of the Journal of the American
Academy of Dermatology, Dr. June Robinson, Dr. Sheldon Pollack and I published two cases involving basal cell
carcinomas invading cartilage.7
Do Not Copy,
Penalties Apply
Over 5 cm - 92.2%
I have seen photos

where considerable
deformities
hadReserved.
been caused by removal of cartilage from noses
2009-Journal
of Drugs incosmetic
Dermatology.
All Rights
and ears. Tumor glides along the perichrondium and extends laterally further than it appears clinically.
Exophytic
Lesions
theofearly
days, patients
with large
exophytic
neoplasms
however,
I soon
learned
No reproduction
orIn
use
any portion
of the contents
of these
materials
may be were
madehospitalized;
without the express
written
consent
of that
JDD.they
extended
only
short
distance
in depth
andillegally,
that hospitalization
was
notimmediately.
necessary.
If you
feelayou
have
obtained
this copy
please contact
JDD
Recurrence in Young
Women
In a two-year study of 19 patients between the ages of 21 and 30 who were referred for Mohs surgery for basal cell
carcinomas, 17 patients (each of whom had one lesion each) were female (3 lesions being primary and 14 recurrent), and two patients were men, one with a primary lesion and the other with a recurrent lesion. It is possible
that women had originally been treated less aggressively for fear of scars or disgurement. 8
Mohs surgery and

Antibiotics
There are two sites for which I strongly recommend the use of antibiotics prophylactically;
Ear the antibiotic can reduce the chance of pseudomonas. If you ever had a patient with a pseudomonal infection, you would never want to see another since the infection becomes increasingly difcult to treat. Also, the
antibiotic can possibly reduce swelling which causes the pain in the ear.
Hand all lesions are treated post-operatively with oral antibiotics because, should an infection occur, the swelling and pain in the hand is likely to be more severe than in another part of the body.
BEMaGS
F
BEMaGS
F
523
+6/&t70-6.&t*446&
Recurrences by location following Mohs
P. Robins
In a 1981 article in Head & Neck Surgery, I reported that the highest recurrences, 14%, occurred in the retroauricular area (50 cases, 7 recurrences).
An oft-neglected factor that may explain the high recurrence in auricular neoplasms has recently been reported
by Dr. Bailin et al.9 The ear is composed of different embryonic fusion planes and it has been determined that malignant neoplasm often follow these planes. The patterns of growth and spread of cutaneous carcinomas of the
auricular and post- and pre-auricular regions are probably related to the embryonic development of the auricle.
Keratoacanthoma
In the late 1960s, keratoacanthomas (KA) were considered benign conditions that were not always treated aggressively. In one interesting case, there was a patient with a KA of the right cheek who had been treated three times.
The patient was referred for Mohs surgery, the tumor was quite large in depth and periphery. It was removed by
Mohs surgery. A very short time later, a mass in the right neck was diagnosed as metastatic SCC. From that point
on, all KAs were treated as SCCs, since it is difcult to distinguish between the two, clinically and histologically.
Granulation
Early on, I had been taught not to leave large wound areas uncovered, but the following case caused me to reconsider my thinking on the subject. A young man with a defect about 6 in diameter on the scalp involving the periosteum (but not involving bone) was referred to me for Mohs surgery. Because of the size of the surgical effect,
the patient was referred to the plastic surgery clinic at NYU Medical Center for repair, where he was warned that it
could be dangerous to leave this wound to heal by granulation because of the risk of bone necrosis and imminent
infection. The type of proposed repair frightened the young patient to such an extent that he was lost to follow-up
for 18 months. He then returned to my ofce concerned about a possible new lesion. Upon examination of the
scalp, the wound had completely granulated in, and was cosmetically acceptable.
I recently lectured on the subject of wounds left to granulate, and prior to the presentation, reviewed over 100 of
such cases (of the 6,000 cases I had had in my career). I had forgotten how many achieved had good cosmetic
results. John Zitelli published an excellent article highlighting this topic and indicated how to predict which type of
wound would produce good results, with concave surfaces yielding the best results.
Do Not Copy,
Penalties Apply
journal, at that time, rejected it based on the reasoning that a similar article was published a year previously and that there would
not be any interest. I co-authored a paper with Dr. Thomas Reese,
one of the foremost plastic surgeons of the time, which he submitted to a plastic surgery journal. It was summarily rejected on
the grounds that it was inconceivable that dermatologists could
practice surgery. Other dermatological journals had no interest.
No channels existed for the advances we were discovering daily,
which I saw as a crucial contribution to medical literature; as none
existed, I saw no other option but to create one.
After losing money for 20 years, the journal was acquired by Elsevier and then, recently, by the American Society of Dermatologic Surgery (ASDS). There is no doubt that the establishment
of the journal was the turning point in the acceptance of dermatologic surgery worldwide. This acceptance and acknowledgement of its merits would have been delayed for many years
without it. Today, the journal is highly referenced and one of the
leading journals in dermatology.
The interest in dermatologic surgery exploded in the early

1980s. With an educational grant, I had produced 24 video
In 1975, with the support of Dr. George Popkin, I launched the
tapes on all aspects of dermatologic surgery. Schering-Plough
2009-Journal
of Drugs in Dermatology.
Allmany
Rightsof
Reserved.
Journal of Dermatologic Surgery (Figure
5), a peer-reviewed
showed
these tapes at their booth at the AAD annual
journal, and established
it ascontains
a 501 (c)
(3) nonprot
organizaThis document
proprietary
information,
tion. The
year, myorcolleagues
and I of
published
four
Norst
reproduction
use of any portion
the contents
of issues
FIGURE 5. Journal of
and the journal was listed in Ifthe
Medicus,
which this
wascopy
an illegally, please contact JDD immediately.
youIndex
feel you
have obtained
Dermatologic Surgery
extraordinary feat in those days. The second year, the journal
grew to ve issues and, by the fourth year, publication was
monthly. I arranged sponsorships with leading pharmaceutical
companies to provide a complimentary subscription for every
dermatology resident in the U.S. (the rst time this had been
done). With the support of the Schering-Plough Corporation, for
many years we had the journal translated and distributed in Europe and South America. Looking back, many today would be
surprised to know that the American Society for Dermatologic
Surgery was originally not happy with the idea of my establishing the Journal of Dermatologic Surgery.
BEMaGS
F
BEMaGS
F
524
+6/&t70-6.&t*446&
meetings to groups of 50-100 dermatologists; watching these

tapes in their entirety was not uncommon. These videos were
also on loan by Schering-Plough, without charge, to all practicing dermatologists.
The Skin Cancer Foundation

Thirty years ago, my patients complained that no
one had ever told them the sun was harmful to
their health. Many patients were older and had
grown up with the belief that sun exposure was
healthy, using mineral oil and iodine to enhance
a suntan, desiring that healthy look.
These beliefs hailed back to the late nineteenth and early twentieth centuries, when the suns ultraviolet radiation (UVR) was
suggested as a medical treatment for many ailments. Sunlight
was the accepted therapy for rickets, a then-common childhood
disease caused by Vitamin D deciency. Certain forms of tuberculosis were also treated with sunlight exposure. In addition,
the fashionable view of sun tanning was originally popularized
when, in the 1920s, Gabrielle (Coco) Chanel returned from
a vacation in the French Riviera with a tan; soon tans were erroneously, albeit popularly, associated with a carefree lifestyle
and upper crust social status.
P. Robins
dations newly instituted Seal of Recommendation, a program

designed to help consumers recognize and select safe and effective sun-protection products. The committee veries the claims
of the products submitted by conrming test results on SPF levels, phototoxicity and contact irritancy, and claims of water- or
sweat-resistance. The Seal of Recommendation is granted to
such products as sunglasses and window glass lm, awnings
and umbrellas, sun-protective clothing, and laundry products
that provide UV protection for fabrics, and is now carried on
more than 570 sun-protection products. It has been featured as
a useful guide to sun protection products on such programs as
Good Morning America and in the Washington Post, Los Angeles Times and Readers Digest.
SCFInternational Outreach, Research & Campaigns

The rst World Congress on Cancers of the Skin (which the
SCF co-sponsors with organizations from the host nation) took
place in 1983, and has been held on a biennial basis ever since.
In May of this year, over 500 physicians attended a conference
of the World Congress of Cancers of the Skin in Tel Aviv. At the
World Congress meetings, doctors from all over the world
share the most recent information on skin cancer. Local press
coverage of this event is important in raising skin cancer awareness among the population, so the foundation presents its
newest materials on skin cancer to journalists in addition to the
local government and professionals, including pharmaceutical
employees, nurses and educators. International outreach and
advocacy came to the forefront with the establishment of the
International Advisory Council. Members are involved in public
education and work to make skin cancer education a priority
around the world. There are 23 countries represented on the
Council, including Australia, Brazil, Ireland, Israel, Portugal, the
Philippines and Sweden, and we have translated the literature
into French, Spanish, German and Italian.
Do Not Copy,
Penalties Apply
In 1979, I founded The Skin Cancer Foundation (SCF), another

501 (c) (3) nonprot organization, designed to educate the public and the medical profession about preventing, detecting, and
treating skin cancer. At the time, many of the members of the
dermatology community were skeptical, as they foresaw that
the SCF would compete with the Dermatology Foundation for
funds. This has not been the case. As a matter of fact, most of
the SCFs funding has come from appreciative patients (including two patients who donated total of $1.5 million). To this day,
the SCF is the only foundation that is solely dedicated to the
Since 1981, The Skin Cancer Foundation has also funded nearly
ght against skin cancer. As an independent organization, and
100 pilot research and clinical studies. The SCF Fellowship proas a core organizational member of the National Council on
2009-Journal
of Drugs
in Dermatology.
gram, instituted
in 1987, has awarded hundreds of thousands of
Skin Cancer Prevention, the SCF raises
the awareness
of skin
dollars
research
or advanced
cancer and promotes
sun-safecontains
behavior
around information,
the world. images and
This document
proprietary
marksto
of doctors
Journal offor
Drugs
in Dermatology
(JDD).training. Over the
years
weve
supported
number
scientic
studies
relating to
No reproduction or use of any portion of the contents of these materials
may
be made
without a
the
expressof
written
consent
of JDD.
cancers
ofcontact
the skin.
In 1979, the highest available SPF
infeel
sunyou
screens
12.The
If you
have was
obtained
this Skin
copy illegally,
please
JDD immediately.
Cancer Foundation was the rst organization to recommend and
The Childrens Sun Protection Program was another effort we
promote the use of a sun screen with an SPF number of 15. That
began early on to reach this vulnerable population. With the
same year, the foundation assembled a photobiology committee,
illustrated book, Play it Safe in the Sun and the tabloid Sun
the members of which whose members were authorities on the
Day News, we were the rst organization to provide sun safety
effects of ultraviolet radiation on the skin. Madhukar Pathak, MB,
messages and educational activities to elementary schools and
PhD, an expert in SPF based at Harvard University, served as
camps nationwide. Our childrens programs have been expandthe committees chair from its inception until his death in 2005.
ed to include an online program for 20,000 middle schools.
Thanks to the efforts of Dr. Pathak and the photobiology committee, SPF 15 became the minimum acceptable standard for
CONCLUSION
sun protection among the medical and scientic communities,
Looking back, I do not regret all the walls I had to tear down
and that standard has led to corporate promotion of sun-safe
to prove that Mohs surgery is the most effective technique for
products. An SPF of at least 15 was required to obtain the foun-
BEMaGS
F
BEMaGS
F
525
+6/&t70-6.&t*446&
P. Robins
the treatment of skin cancers, and to show that dermatologists,

with their knowledge and training, are best equipped to perform that function. My intention in presenting this paper is to
encourage any of you to continue to pursue your objectives
even in the face of lack of support or outright rejection.
5.
If your goals have merit, in time you will prevail.
7.
ACKNOWLEDGEMENTS
8.
Deep appreciation is extended to the following physicians for

their unending support and encouragement, which helped make
these projects come to fruition: Dr. Alfred Kopf, Dr. Daniel Baker,
the late Dr. George Popkin and the late Dr. Philip Casson.
I have been very fortunate that in my years practicing Mohs
surgery many patients with skin cancers have been cured. I am
also happy to say that, my staff, my nurses, my secretaries, my
technicians have shared in this feeling of achievement. I am
also pleased that doctors I have trained have gone on to train
others. All the training programs, workshops, videos, lms,
congresses, journals, organizations that I have contributed to
and been responsible for have helped not only patients, but the
lay public, my colleagues and doctors in other specialties.
6.
9.
cinomas treated by microscopically controlled excision: A recurrence

index score. J Dermatol Surg Oncol. 1981;7(10):807-810.
Robins P, Day CL Jr, Lew R. A multivariate analysis of factors affecting
wound-healing time. J Dermatol Surg Oncol. 1984;10(3):219-221.
Robins P. Chemosurgery: My 15 years of experience. J Dermatol Surg
Oncol. 1981;7(10):779-89.
Robinson JK, Pollack SV, Robins P. Invasion of cartilage by basal cell
carcinoma. J Am Acad Dermatol.1980;2(6):499-505.
Robins P and Albom M. Recurrent basal cell carcinomas in young
women. J Dermatol Surg Oncol. 1975;1(1):49-51.
Bailin PL, Levine HL, Wood BG, Tucker HM. Cutaneous carcinoma of the auricular and periauricular region. Arch Otolaryngol.
1980;106(11):692-696.
ADDRESS FOR CORRESPONDENCE

Perry Robins, MD
345 East 37th Street, Suite 209
New York, NY 10016
Phone: ................................................................... (212) 263-7222
Fax: ........................................................................ (212) 686-5842
E-mail:................................................... Doctorrobins@yahoo.com
_______________
Do Not Copy,
Penalties Apply
Editorial note:
Dr. Robins holds (or has held) the following positions:
professor Emeritus of Dermatology, New York Universitys
School of Medicine; founder and president, The Skin Cancer
Foundation; co-founder and past president, International
Society of Dermatologic Surgery; founder and past president,
American College of Mohs Micrographic Surgery (now
American College of Mohs Surgery); past president, American
Society of Dermatologic Surgery; chairman, past World
Congresses on Cancers of the Skin; and honorary member,
the American Academy of Dermatology.
To date, Dr. Robins has been conferred honorary memberships

2009-Journal
of has
Drugs
in the dermatologic societies of over 14
countries; he
had
the opportunity to
lecture
in over
34 countries
four different
This
document
contains
proprietaryininformation,
languages.
He counts as
his of
greatest
accolade
honorary
No reproduction
or use
any portion
of the contents
of memthese materials may be made without the express written consent of JDD.
bership in the Spanish Academy
offeel
Medicine.
If you
you haveHistorically,
obtained thisthis
honor has been given to few Americans. Prior recipients have
included Dr. Alexander Fleming (the inventor of penicillin).
REFERENCES
1.
2.
3.
4.
Robins P, Henkind P, Menn H. Chemosurgery for the treatment of

periorbital malignancy. Trans Am Acad Ophthalmol Otolaryngol.
1971;75(6):1228-1235.
Tromovitch TA and Stegman SJ. Microscopically controlled excision of
skin tumors. Arch Dermatol. 1974;110(2):231-232.
Robins P and Albom MJ. Mohs surgery fresh tissue technique. J
Dermatol Surg Oncol. 1975;1(2):37-41.
Rigel DS, Robins P, Friedman RJ. Predicting recurrence of basal-cell car-
BEMaGS
F
BEMaGS
F
Rapid relief and restoration...

without a visible trace
Do Not Copy,
Penalties Apply
The mid-potency cream with the highest concentration of barrier-enhancing lipids
Locoid Lipocream (hydrocortisone butyrate 0.1%) Cream is indicated for the relief of the inflammatory and pruritic manifestations
of corticosteroid-responsive dermatoses. Contraindicated in those patients with a history of hypersensitivity to any of the components
of the preparation. Prolonged use may produce reversible HPA axis suppression. May cause local adverse reactions, including itching,
irritation, and dryness.
For Dermatological Use Only
BRIEF SUMMARYPlease see full Prescribing Information for complete product information
CONTRAINDICATIONS: Topical corticosteroids are contraindicated in thosepatients
with a history of hypersensitivity
of the components of the
General: Systemic absorption of topical corticosteroids has produced reversible
2009-Journal
of Drugs toinanyDermatology.
Allpreparation.
RightsPRECAUTIONS
Reserved.
HPA axis suppression, manifestations of Cushings syndrome, hyperglycemia, and glucosuria in some patients. Conditions which increase the risk of systemic toxicity include the application of more potent steroids, use over large surface areas, prolonged use,
and the addition of occlusive dressings. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity. (See PRECAUTIONS - PEDIATRIC USE.) If irritation develops, topical corticosteroids should
This instituted.
document
contains
proprietary
information,
images
marks
Journal
ofIf aDrugs
in Dermatology
(JDD).
be discontinued and appropriate therapy
In the presence
of dermatological
infections, the
use of an appropriate
antifungal orand
antibacterial
agent of
should
be instituted.
favorable response
does not occur promptly,
the corticosteroid should be discontinued
until the infection has been adequately controlled. Information for the Patient: Patients using topical corticosteroids should receive the following information and instructions: 1. This medication is to be used as directed by the physician. It is for external use
No
reproduction
or
use
of
any
portion
of
the
contents
of
these
materials
may
be
made
without
the
express
written
consent
only. Avoid contact with the eyes. 2. Patients should be advised not to use this medication for any disorder other than for which it was prescribed. 3. The treated skin area should not be bandaged or otherwise covered
or wrapped of
as toJDD.
be occlusive. 4. Patients
should report any signs of local adverse reactions. 5. Parents of pediatric patients should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments may constitute occlusive dressings. Laboratory
If
you
feel
you
have
obtained
this
copy
illegally,
please
contact
JDD
immediately.
Tests: The following tests may be helpful in evaluating the HPA axis suppression: Urinary free cortisol test, ACTH stimulation test. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term animal studies have not been performed to evaluate the
carcinogenic potential or the effect on fertility of topical corticosteroids. Studies to determine mutagenicity in Salmonella ryphimurium strains TA98, TA100, and TA92 with prednisolone and hydrocortisone have revealed negative results. Pregnancy: Teratogenic
Effects: Pregnancy Category C: Corticosteroids are generally 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. In teratogenicity studies, topical administration of 1% or 10% hydrocortisone butyrate in an ointment to pregnant Wistar rats (gestational days 6-15) or New Zealand white rabbits (gestational days 6-18) resulted in no teratogenic findings. However, a
dose-dependent increase in fetal resorptions was reported in rabbits, and fetal resorptions were observed in rats treated with 10% hydrocortisone butyrate. The doses given to rats are approximately 8 to 80 times the human topical dose based on a body surface
area comparison (assuming 100% absorption). For rabbits, the doses given were approximately 0.2 and 2 times the human topical dose. Increased resorptions were also noted in Wistar rats given subcutaneous administrations of hydrocortisone butyrate (9
mg/kg/day; 3 times the human topical dose) on gestational days 9 through 15. In CS mice given subcutaneous administrations of 1 mg/kg/day (0.2 times the human topical dose), an increased number of cervical ribs and one fetus with clubbed legs was reported.
There are no adequate and well-controlled studies in pregnant women on teratogenic effects from topically applied corticosteroids. Therefore, topical corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus. Locoid Lipocream (hydrocortisone butyrate 0.1%) Cream should not be used extensively on pregnant patients, in large amounts, or for longer than two weeks. Nursing Mothers: It is not known whether topical administration of corticosteroids could
result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids are secreted into breast milk in quantities not likely to have a deleterious effect on the infant. Nevertheless, caution should be
exercised when topical corticosteroids are administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Pediatric patients may demonstrate greater susceptibility to topical corticosteroid-induced
HPA axis suppression and Cushings syndrome than mature patients because of a larger skin surface area to body weight ratio. HPA axis suppression, Cushings syndrome, and intracranial hypertension have been reported in children receiving topical
corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles,
headaches, and bilateral papilledema. Chronic corticosteroid therapy may interfere with the growth and development of children. ADVERSE REACTIONS: The following local adverse reactions are reported infrequently with topical corticosteroids but may occur
more frequently with the use of occlusive dressings. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic
contact dermatitis, maceration of the skin, secondary infection, skin atrophy, striae and miliaria. OVERDOSAGE: Topically applied corticosteroids can be absorbed in sufficient amounts to produce systemic effects. (See PRECAUTIONS.)
Rx only
Locoid Lipocream is a registered trademark of Astellas Pharma Europe B.V. licensed to Triax Pharmaceuticals, LLC.
Manufactured for
Triax Pharmaceuticals, LLC
Cranford, NJ 07016
By Ferndale Laboratories, Inc.
Ferndale, MI 48220
Marketed and Distributed by

Triax Pharmaceuticals, LLC
Cranford, NJ 07016
Protected under U.S. Patent
LC-1008-02
131 B100
Rev 09/07
BEMaGS
F
BEMaGS
F
JUNE 2009
527
70-6.&t*446&
COPYRIGHT 2009
ORIGINAL ARTICLES
Treatment of Poikiloderma of Civatte With

Ablative Fractional Laser Resurfacing:
&NJMZ15JFSOFZ.%BOE$8JMMJBN)BOLF.%.1)
-BTFSBOE4LJO4VSHFSZ$FOUFSPG*OEJBOB $BSNFM */
ABSTRACT
Background: Previous laser treatments for Poikiloderma of Civatte (PC) (i.e., Pulsed dye, Intense Pulsed Light, KTP and Argon) are
limited by side effect proles and/or efcacy. Given the high degree of safety and efcacy of ablative fractional photothermolysis
(AFP) for photoaging, we set out to assess the efcacy of PC with AFP.
Design: A prospective pilot study for PC in 10 subjects with a series of 13 treatment sessions. Treatment sessions were administered at 68 week intervals with blinded physician photographic analysis of improvement at 2 months post-treatment. Evaluation was
performed of ve clinical indicators, erythema/telangiecatasia, dyschromia, skin texture, skin laxity and cosmetic outcome.
Results: The number of treatments required for improvement of PC ranged from 1 to 3, with an average of 1.4. For erythema/telangiecatasia, the mean score improved 65.0% (95% CI: 60.7%, 69.3%) dyschromia, 66.7% (95% CI: 61.8%, 71.6%), skin texture,
51.7% (95% CI: 48.3%, 55.1%) and skin laxity, 52.5% (95% CI: 49.6%, 55.4%). For cosmetic outcome, the mean score improved
66.7% (95% CI: 62.6%, 70.8%) at 2 months post treatment.
Conclusion: In this prospective study, AFP was both safe and effective for the treatment of the vascular, pigmentary and textural
components of PC. The degree of improvement observed in wrinkling, creping and laxity after AFP has not been reported with prior
laser treatments for PC.
INTRODUCTION
Background
Do Not Copy,
Penalties Apply
oikiloderma of Civatte (PC) is a common benign condition with symmetric involvement of the neck, lateral
cheeks, and upper chest, associated with concomitant
sparing of the photoprotected submental area.1-4 The condition
occurs most frequently in fair-skinned middle aged men and
women, and oftentimes produces signicant dyschromia and
skin texture abnormalities.1-4
phic changes of the skin.1-5 While the lesions are most typically
asymptomatic, there are case reports of associated symptoms,
including itching, burning and ushing.1-5
The pathogenesis of PC remains unknown, however, the distribution of lesions on sun-exposed skin suggests a central
pathogenesis mechanism for damage induced by ultraviolet radiation.6 Other factors which have been implicated in the pathogenesis of the disease include genetic predisposition, hormonal
changes related to menopause and phototoxic or photoallergic
reactions to chemicals in fragrances or cosmetics.7-8
In clinical and epidemiologic studies of PC, the estimated prevaof Drugs

lence of the condition was estimated
to2009-Journal
be 1.4% among
dermaThe
mean age
at diagnosis
signicantly
A recent
study
evaluating
role of contact
sensitivity and photologic patients.1-5
This
document
contains
proprietarywas
information,
images and
marks of
Journal
of Drugs the
in Dermatology
(JDD).
1-5
The
majorlower inNo
females
(47.8 years)
years).
tosensitivity
in the
conditions
pathogenesis
demonstrated
that
reproduction
or use than
of anymales
portion(61.7
of the
contents
of these
materials
may be made
without
the express
written consent
of JDD.
1
The most
ity of patients (8090%) had skin
phototypes
I or II.
there
was contact
a signicantly
greater frequency of positive reactions
If you
feel you have
obtained
this comcopy illegally,
please
JDD immediately.
mon pattern of distribution is the v and sides of the neck as well
to fragrances in the PC group relative to the control group (chi2
as the upper chest.1The face (preauricular and parotid gland) were
value = 3.91, p<0.05).8 Specically, 25% of patients with PC had
also involved in 38% of patients.1 The most common variant of
positive reactions to fragrance mix and/or Balsam of Peru.8 In
PC present was the erythemato-telangiectatic clinical type (58%),
the photopatch testing group, none of the patients with PC had
followed by the mixed type (22%) and the pigmented type (20%).1
a positive photopatch test for any of the allergens tested.8 It has
Nearly half of patients (46%) were symptomatic, with symptoms
been theorized that the reticular pigmentation observed may reincluding itching, burning and ushing.1 The mean duration from
sult from a delayed hypersensitivity reaction to perfume and/or
onset to diagnosis was 6.2 years.1 The disease course was slowly
cosmetic ingredients. Thus, patch testing with a standard series,
progressive (82%) and irreversible.1
including fragrance mixes, may be of value in PC. 8
PC is characterized clinically by a reddish-brown reticulate pattern of pigmentation, associated with telangiectasias and atro-
PC is characterized by distinct histologic and ultrastructural features, further supporting the theory that it represents a distinct
BEMaGS
F
BEMaGS
F
528
+6/&t70-6.&t*446&
&5JFSOFZ $)BOLF
and unique entity. A histologic study analyzing the characteristic feature of PC in 50 patients revealed consistency in features
of an atrophic (62%), attened (84%) epidermis with hyperkeratosis (92%) and occasional follicular plugging (34%).9 The most
consistent and prominent feature across all specimens (100%)
was the presence of diffuse solar elastosis in the papillary dermis.9 The blood vessels were also invariably dilated in the majority of specimens (96%).9 The most constant ndings were
swelling and disruption of the collagen bers as well as focal
degeneration of the collagen bundles.9 The overall consistent
changes in the dermal connective tissue, including prominent
solar elastosis and degeneration of collagen bundles, provide
morphologic evidence for the primary role of ultraviolet radiation in the pathogenesis of PC.9
can be selected as targets. The most likely target for absorption

with the 1550 nm NAFP device, in the treatment of PC, is the
dermal blood vessels.16 Through targeting dermal blood vessels,
NAFP may lead to microvascular destruction with clinical benets of improved erythema and skin texture.16 In addition, the microthermal zones of injury in the dermis produced by the NAFP
also likely result in random hits to dermal vasculature.16 Support
for this hypothesis comes from a recent study by Laubach et al,17
in which the authors demonstrated histopathologic evidence of
damage to dermal vasculature in patients undergoing NAFP. It is
likely that both of these hypotheses of chromophore targeting
of dermal vasculature and microthermal zones of heating resulting in random hits to dermal vasculture play a signicant role in
reducing telangiectasias after treatment with FP.
To date, there has been no single effective treatment modality

for PC. In the past, attempts to treat this condition by using electrosurgery, cryotherapy, argon laser and potassium titanyl phosphate (KTP) laser have yielded largely unsatisfactory effects.10-11
NAFP technology demonstrated signicant improvement in the

treatment of diverse facets of the cutaneous signs of photoaging, including the dyschromia, telangiectasias and skin texture
abnormalities which characterize PC and the skin signs of photoaging.17-18
Recent studies utilizing Pulsed dye laser (PDL) at 585 nm wavelength with uences of 6-7 J/cm2 with a 5-mm spot size have
shown signicant efcacy.12-14 However, adverse effects of PDL
treatment of PC include purpura, a mottled appearance, severe
pigmentation and scarring.12-14 In addition, as PDL targets primarily the vascular component of PC, no signicant change is typically
observed in the pigmented component of the condition.12-14
While NAFP demonstrated modest improvements in conditions,

such as photoaging17-18,23 and PC,16 patients required multiple treatments to achieve signicant results and even with multiple treatments, patients with signicant textural and pigmentary abnormalities were only minimally improved with non-ablative energies.
Do Not Copy,
Penalties Apply
Most recently in 2007, Hantash et al29 described the rst use

One of the most successful treatment modalities to date for PC
of a novel ablative CO2 fractional resurfacing device (AFP)
has been intense pulsed light (IPL), given its versatility in targetwhich produces an array of microthermal zones of a customizing supercial pigmentation, telangiectasias and surface texture
able density and depth but which results in a conuent array of
abnormalities.15,22,30 IPL is noncoherent light, in a broad waveablation and coagulation which extends through the stratum
length spectrum of 515 to 1,200 nm.15 The treatment parameters,
corneum, epidermis and dermis.29 In the initial in vivo studies
including pulse duration, mode, delay between pulses and udemonstrating the histologic and clinical effects of this protoence can all be varied to heat-specic targets and varying skin
type ablative fractionated CO2 device, Hantash et al. conrmed
with immunohistochemistry that persistent collagen remodeldepth, including epidermal and dermal pigmentation and blood
ing occurred for at least three months post-treatment.29 With
vessels in the papillary and reticular dermis.15 In several studies,
2009-Journal
of Drugsand
in Dermatology.
All Rights
Reserved.
clearance rates of greater than 75% ofboth
telangiectasias
the greater
degree
of injury with fractionated CO2 and a greater
and
prolonged
effect
on in
collagen
remodeling,
hyperpigmentation
beencontains
observed;
however,
signicant
Thishave
document
proprietary
information,
images and
marks
of Journal
of Drugs
Dermatology
(JDD). several recent
studies
have
demonstrated
greater
clinical
improvement
side effects
have beenorreported
IPLoffor
including
perNo reproduction
use of anywith
portion
thePC,
contents
of these
materials
may be
made
without the express
written
consent
of JDD. in the
cutaneous
signs of
photoaging
(rhytids, dyschromia and laxity)
manent hypo- and hyperpigmentation
well
asobtained
changesthis
in skin
If you feelas
you
have
copy illegally,
please contact
JDD
immediately.
relative to NAFP. 26-29
texure, including mottling and scarring.15,22,30
The latest advance in laser technology reported to have signicant improvements in the clinical appearance of PC is nonablative fractional photothermolysis (NAFP, Fraxel SR, Reliant
Technologies, Mountain View CA) as reported by Behroozan et
al.16 The authors reported that two weeks after a single treatment
with non-ablative fractionated photothermolysis (NAFP), signicant improvement was effected in degree of erythema, dyschromia and overall skin texture of the neck.16 The authors postulated
that with NAFP, different tissue compartments (i.e., blood vessels,
dermal melanin and sebaceous glands) at various skin depths
Given the greater efcacy in the literature in the cutaneous

signs of photoaging after AFP, 26-29 we postulated that greater
improvement in PC would be achieved with AFP relative to that
previously reported with NAFP.16 Herein, we present the rst
prospective study of AFP for PC.
PATIENTS AND METHODS

The study protocol conformed to the guidelines of the 1975
Declaration of Helsinki and was approved by the St. Vincent
Hospital Institutional Review Board and Ethics Committee, Car-
BEMaGS
F
BEMaGS
F
529
+6/&t70-6.&t*446&
mel, Indiana. Written informed consent was obtained from all

patients prior to enrollment. All patients were required to be
available for longitudinal study over the course of the threeto-nine month study treatment and post-treatment evaluation.
This period involved a pre-operative evaluation, a one-week
post-operative visit and a two-month post-treatment visit.
&5JFSOFZ $)BOLF
The paired t-test was utilized to test the change in each clinical
indicator score (erythema, dyschromia, skin texture, skin laxity
and overall cosmetic outcome) from baseline to month 2 posttreatment. P-values less than 0.05 were considered statistically
signicant.
RESULTS
The trial was a prospective pilot study for the treatment in 10
patients presenting to our ofce for desired treatment of PC
between July 2008-November 2008. Patients were excluded
from the study if they had active infections, current pregnancy,
a history of isotretinoin use in the year prior to laser treatment,
a history of keloid scarring, known allergy to topical lidocaine
anesthetic or any cosmetic procedure in the area(s) of treatment in the 12 months prior to the study.
The treatment area was thoroughly cleansed before the procedure with a gentle skin cleanser. A bupivicane/lidocaine/tetracane topical local anesthetic mix was applied 30 minutes before
treatment. Treatment was administered to the neck and upper
chest with the Dermal Optical Thermolysis (DOT) Laser (Eclipse
Med, Dallas TX), an ablative fractionated CO2 laser (10,600 nm) at
settings of 20 Watts, 500 pitch, 500 milliseconds. Forced cold air
was administered during treatment for anesthesia utilizing the
Zimmer Cooler device (LaserMed, Shelton, CT) at a setting of 5 at
a distance of 34 inches from the skin surface. Patients received
a series of 13 treatment sessions, given at six-to-eight-week intervals. The number of treatment sessions was determined by
the degree of clinical improvement with treatment.
A total of 10 patients with PC were treated with an ablative

fractional photothermolysis device, Dermal Optical Thermolysis (DOT) Laser (Eclipse Med, Dallas TX). Patients were seen for
evaluation at one week and at two months after the procedure.
Incidence of side effects of erythema, edema and pruritus were
assessed at one week.
During treatment, patients reported minimal pain, which was
alleviated with the use of the topical and cold air anesthesia.
Minimal post-operative erythema and edema were noted by
patients, which resolved within 48-72 hours post-treatment.
Only one patient experienced prolonged erythema and pruritus which persisted at the one week post-treatment visit which
resolved completely by one month post-treatment.
Do Not Copy,
Penalties Apply
Cosmetic outcome of improvement in the features of PC was assessed by a blinded physician on photography at the 2 month posttreatment visit. A quartile scale was utilized where 1 signied no
signs of skin change associated with PC and 4 signied signicant
change in skin associated with PC.The distribution, proportion, and
descriptive statistics of all outcomes were considered.
The number of treatment sessions required for signicant imAt two months after the nal treatment, blinded physician evaluprovement of PC ranged from 1 to 3, with an average of 1.4 sesation of photographs was utilized to assess the degree of imsions (Table 1). For erythema/telangiecatasia, the mean score
provement in ve clinical indicators: erythema, dyschromia, skin
decreased from 3.6 pre-treatment to a mean of 1.2 at 2 months
texture, skin laxity and overall cosmetic outcome. A quartile scale
post-treatment (p<0.05) for a 65.0% mean improvement (95% CI:
was utilized where 1 signied no signs of skin change associat60.7%, 69.3%) (Table 1). For dyschromia, the mean score decreased
ed with PC and 4 signied signicant change in skin associated
from 3.7 pre-treatment to 1.2 at 2 months post treatment (p<0.05),
with PC. In addition, the degree of improvement was calculated
66.7% mean improvement (95% CI: 61.8%, 71.6%) (Table 1). For
2009-Journal
Drugs in Dermatology.
All Rights
as the percentage improvement between
the initialoftreatment
skin texture,
theReserved.
mean score decreased from 3.4 pre-treatment to
and the nal visitThis
at two
months
after the
nal treatment.
1.6marks
at 2 months
postoftreatment
(p<0.05), 51.7%
mean improvement
document
contains
proprietary
information, images and
of Journal
Drugs in Dermatology
(JDD).
(95%
CI:be
48.3%,55.1%)
1). For
skin consent
laxity, the
mean score
may
made without (Table
the express
written
of JDD.
Statistical Analysis
decreased
from 3.4
pre-treatment
please contact
JDD
immediately. to 1.6 at 2 months post treatFor each patient, the pre-treatment and post-treatment scores
ment (p<0.05), 52.5% mean improvement (95% CI: 49.6%,55.4%)
for each category were recorded, as were treatment number
(Table 1). For overall cosmetic outcome, mean score decreased
and nal date of follow-up. Pre-treatment scores were recorded
from 3.7 pre-treatment 1.2 at 2 months post treatment (p<0.05),
at baseline on the date of the rst treatment. Post-treatment
66.7% mean improvement (95% CI: 62.6%,70.8%) (Table 1).
scores were recorded the date of nal follow-up.
Clinical images of patients demonstrating improvement in PC
The percent change in score was calculated as the score differare shown in Figures 1a-1b, Figures 2a-2b, Figures 3a-3b, Figence divided by the baseline score. For each category (erytheures 4a-4b and Figures 5a-5b.
ma, dyschromia, skin texture, skin laxity and overall cosmetic
DISCUSSION
outcome) the absolute score change, raw percentage change,
Patients with PC usually seek treatment for cosmetic reasons to
mean percentage change and 95% condence intervals (CI)
improve the erythematous, pigmented and nely wrinkled apwere calculated.
BEMaGS
F
BEMaGS
F
530
+6/&t70-6.&t*446&
&5JFSOFZ $)BOLF
TABLE 1.
Treatment of Poikiloderma of Civatte with Ablative Fractional Photothermolysis
Age/Gender
Patient #1
Erythema/
Telangiectasia
Dyschromia
Texture
Skin Laxity
Overall
Cosmetic
Outcome
54 y/o Caucasian Female
pre treatment
2 months post-treatment
% improvement
75%
75%
75%
75%
75%
# treatment sessions
Patient #2
pre treatment
% improvement
75%
75%
75%
75%
75%
Patient #3
pre treatment
Do Not Copy,
Penalties Apply
4
75%
75%
50%
50%
75%
% improvement
33.3%
50%
0%
0%
33.3%
% improvement
Patient #4
pre treatment
Patient #5
pre treatment
2009-Journal1 of Drugs in Dermatology.

All Rights 1Reserved.
1
% improvement
75%
75%
75%
75%
75%
1
Patient #6
pre treatment
% improvement
33%
33%
25%
25%
50%
BEMaGS
F
BEMaGS
F
531
+6/&t70-6.&t*446&
Patient #7
&5JFSOFZ $)BOLF
pre treatment
% improvement
66.7%
66.7%
50.0%
50.0%
66.7%
Patient #8
pre treatment
% improvement
66.7%
66.7%
50.0%
33.3%
66.7%
Patient #9
pre treatment
% improvement
75%
75%
50%
75%
75%
Patient #10
pre treatment
Do Not Copy,
Penalties Apply
4
75%
75%
66.7%
66.7%
75%
Average #
Sessions
Erythema/
Telangiectasia
Dyschromia
Texture
Skin Laxity
Overall
Cosmetic
Outcome
1.4
3.6
3.7
3.4
3.4
3.7
Mean post-treatment score
1.2
1.2
1.6
1.6
1.2
p value: pre vs post-treatment

score
p<.05
p<.05
p<.05
p<.05
p<.05
Mean % Improvement
65.0%
66.7%
51.7%
52.5%
66.7%
49.6%,55.4%
62.6%,70.8%
% improvement
Mean pre-treatment score
95% CI:
69.3%
61.8%, 71.6%
2009-Journal60.7%,
of Drugs
in Dermatology.
All Rights 48.3%,55.1%
Reserved.
pearance that occurs in visibleIfareas

on you
the have
neck obtained
and upper
rstplease
treatment
modalities
studied for PC was pulsed dye laser
you feel
thischest.
copy illegally,
contact
JDD immediately.
Most importantly, the physician attempts to match the normal
(PDL) with a 585 nm wavelength.11-14 With the small diameter
of ectatic blood vessels in PC (0.1 mm) which are primarily in
pigmentation of the submental region with the hyperpigmented
the papillary dermis and short thermal relaxation times of 0.110
skin of the adjacent neck. Given the cosmetically sensitive losec, the optimal settings for PDL treatment of PC were with a
cation of the condition, it is critical that an effective treatment
spot size of 5 mm, uences of 5-7J/cm2 and short pulse durations
be relatively risk free, with minimal risks of scarring and dyspigof 450 sec.11-14 While the PDL can result in photothermal coagumentation, and that results are obtained in a limited number of
lation of small and supercial vessels characterizing PC, vessel
treatment sessions to minimize discomfort and cost.
rupture characterized by thermal absorption of oxyhemoglobin,
leads to the clinically undesirable side effect of purpura.11-14
For optimal improvement of PC, both pigmentary and vascular
10-16
With selective
components of the condition must be affected.
For PDL treatment of PC, Geronemus20 reported resolution of
photothermolysis, visible laser irradiation is the wavelength of
95% of the redness associated with PC following four treatments
choice as it targets both hemoglobin and melanin. One of the
BEMaGS
F
BEMaGS
F
532
+6/&t70-6.&t*446&
&5JFSOFZ $)BOLF
Intense pulsed light (IPL) has also been widely reported for PC
with the advantages of the broad spectrum of visible and infrared light affecting both hemoglobin and melanin, the two
endogenous chromophores affected in the condition.15,22,30
FIGURE 1a-1b. Pre (left) and Post (right) treatment of Poikiloderma of

Civatte in a 54-year old Caucasian female at 2 months after 3 treatment sessions with Ablative Fractional Photothermolysis (DOT Laser,
Eclipse Med, Dallas, TX).
In the largest patient series to date, Rusciani et al. reported the

treatment of 175 patients with PC with IPL.30 Each patient received three treatments at 3-week intervals.30 Treatment uences
ranged between 32-36 J/cm2. Energy was delivered in double or
triple-pulse trains of 2.5 to 3.5 sec with a pulse delay of 10 to
20 sec.30 A marked 75-100% reduction in poikiloderma lesions
was observed in 142 of 175 patients (81.0%).30 Of the remaining
patients, 14% presented with a clearance of 50-74% and 5% presented with a slight improvement from 25-49%.30 In terms of side
effect prole, the primary side effect observed included erythema and swelling immediately after treatment, which lasted from
24 to 48 hours.30 Mild purpura was noted in 32 of 175 patients,
usually resolving within three to four days.30 Only three patients
experienced blister formation which gradually resolved in seven
days without pigmentary disturbance or scarring.30
Similarly, Weiss et al.22 reported ve-year experience with treatment of the vascular and pigmentary changes of poikiloderma
of Civatte with IPL. They observed a signicant improvement of
more than 75% in the telangiectasias and hyperpigmentation in
the majority of patients (82%). Similarly, the cutoff lter parameters utilized initially were a 515-nm lter and a pulse duration
of 2 to 4 sec, in order to simultaneously treat the pigmented
and vascular component of poikiloderma.22 The overall results
for patients were grade 3.82 (scale 0-5) improvement after an
average of 2.78 treatments (range 1-5).22 A signicant proportion of the overall treatment effect was seen after the initial
treatment, with 16 of 125 patients demonstrating 75% improvement after just a single treatment.22 In total, a signicant reduction of 75-100% in the hyperpigmentation and telangiectasias
associated with PC, were seen in 111 out of 135 patients (82%)
after an average of three treatments.22
Do Not Copy,
Penalties Apply
with 6-7 J/cm2 and a 450 sec pulse. However, treatment side
2009-Journal
of Drugs
in Dermatology.
effects included a post treatment burning
sensation and
purpura
While signicant
improvement in PC can be achieved with PDL
12
reported
persisted for 7-10
days.
Wheeland
and
Applebaum
and
IPL, of
review
literature
demonstrates
This
document
contains
proprietary
information,
images and
marks
Journalofofthe
Drugs
in Dermatology
(JDD). signicant comPDL treatment
of PC with
improvement
vascularity
andmaterials
plications
associated
both of
theseconsent
technologies,
No reproduction
or use
of any portioninofboth
the contents
of these
may be made
withoutwith
the express
written
of JDD. includirregular pigmentation after treatment
withhave
a 585
nm PDL
ing please
transient
prolonged
purpura and permanent depigmentaIf you feel you
obtained
this with
copy illegally,
contact
JDD immediately.
settings of 5-6J/cm2 and overlapping pulses of 360 sec.
tion associated with PDL and transient erythema, swelling and
crusting as well as more modest improvements in skin colorGoldman and Fitzpatrick11 reported variable success rates with
ation and texture with IPL.15,22,30
PDL treatment of PC, where vascular ectasias responded to
treatment; however, epidermal atrophy and hypermelanosis
Given the limitations of these previous laser- and light-based
failed to respond. In addition, signicant adverse events were
modalities for PC, the introduction of FP with its ability to target
noted, including a post-treatment mottled response and hypervasculature, pigmentation as well as to effect improvements in
trophic scarring in one of four patients. Similarly, adverse efskin texture and tightening, may represent an ideal treatment
fects of severe depigmentation were noted in six out of eight
approach. In a case report, Behroozan et al.16 demonstrated signicant improvement in PC after a single treatment with nonpatients treated with PDL for PC in a study in the Netherlands,
ablative fractionated photothermolysis (NAFP). Herein, utilizing
where higher uences (5-7J/cm2) were noted to correlate the
increasing risk of depigmentation.21
ablative fractionated CO2 laser technology (DOT Laser, Eclipse
BEMaGS
F
BEMaGS
F
533
+6/&t70-6.&t*446&

&5JFSOFZ $)BOLF
Most recently, ablative fractional photothermolysis has been

demonstrated to achieve greater improvements in dyschormia
and rhytids associated with photoaging relative to the original
generation of non-ablative fractional devices.26,27,29 Utilizing human forearm skin in vivo, Hantash et al.29 demonstrated that with
AFP, a controlled microthermal zone of injury could be induced
with stimulation of the wound healing response by adjacent intact skin. With the greater degree of injury with AFP technology,
Hantash et al. predicted a greater and prolonged effect on induction of new collagen and remodeling of dermal collagen resulting in greater improvements in skin laxity and texture.29
Given the histologically documented effects of FP on dermal
vasculature and collagen remodeling,23-29 the rapid improvement in PC after treatment with this technology further underscores the versatility and potential for novel applications of
this unique technology. Similar to reports of rapid response
to treatment with Intense Pulsed Light, an average of only 1.4
treatment sessions was needed to achieve 67% improvement
in cosmetic outcome with ablative fractional photothermolysis.
In addition, relative to the previous case report of NAFP, our
prospective study of AFP reported the additional benets of
signicant improvement in skin texture and laxity. Given the
historical reports of purpura, crusting, scarring and permanent
hyperpigmentation on the neck after treatment with other laser- and light-based modalities for PC, the safety prole of AFP
on the neck makes this new technology particularly promising.
However, given the limited scope of our study, additional validation is needed with this and other ablative fractionated devices to better elucidate the safety and efcacy of AFP for the
treatment of PC.
Do Not Copy,
Penalties Apply

Civatte in a 53-year old Caucasian female at 2 months after 1 treatment session with Ablative Fractional Photothermolysis (DOT Laser,
DISCLOSURES
The authors have no relevant disclosures or conicts of interest.
REFERENCES

1.
Civatte A. Poikilodermie reticule pigmentaire du visage et du cou. Ann
Civatte in a 53-year old Caucasian female at 2 months after 1 treat 2009-Journal(DOT
of Drugs
in Dermatology.
All Rights
Reserved.
ment session with Ablative Fractional Photothermolysis
Laser,
Dermatol
Syphilol.
1923;6:605-620.
Eclipse Med, Dallas,
TX).
2. marks
Katoulis
AC, Stavrianeas
Georgala S, et(JDD).
al. Poikiloderma of Civatte:
This
document contains proprietary information, images and
of Journal
of DrugsNG,
in Dermatology
A clinical
and without
epidemiological
study.
J Eurconsent
Acad Dermatol
No reproduction or use of any portion of the contents of these materials may
be made
the express
written
of JDD. Venereol.
Med, Dallas, TX), we have achieved

improvements
in illegally, please
2005;19(4):444-448.
If you feelsimilar
you have
obtained this copy
3. Graham-Little EG. Poikilodermie-Civatte. Br J Dermatol. 1928; 40:231surface pigmentation and vasculature,16 with added benets of
241.
improvement in skin texture and skin tightening. Specically,
4. Graham R. What is poikiloderma of Civatte? Practitioner. 1989;
after AFP the majority (7 out of 10) of our patients had 50-75%
233:1210.
improvement in skin laxity and 9 out of 10 patients had 50-75%
5. Prez-Bernal A, Muoz-Prez MA, Camacho F. Management of facial
improvement in skin texture. The degree of improvement obhyperpigmentation. Am J Clin Dermatol. 2000;1(5):261-268.
served in skin wrinkling, creping and laxity after AFP has not
6. Katoulis AC, Sboukis D, Stavrianeas NG. Poikiloderma of Civatte. Hell
been reported with prior laser based modalities for PC. The
Dermatol Venerol Rev. 1995;6:165-173.
mechanism of action of fractionated laser resurfacing in PC is
7.
Katoulis AC, Stavrianeas NG, Georgala S. Familial cases of poikilopurely speculative, but may include microvascular destruction
derma of Civatte. Genetic implications in its pathogenesis? Clin Exp
at varying skin depths leading to improvement in skin erytheDermal 1999;24:385-7038.
ma and texture in addition to simulation of collagen remodeling and neo-collagenesis.
BEMaGS
F
BEMaGS
F
534
+6/&t70-6.&t*446&
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
&5JFSOFZ $)BOLF
Katoulis AC, Stavrianeas NG, Katsarou A, et al. Evaluation of the role of

can Society for Laser Medicine and Surgery Conference, April 2008,
contact sensitization and photosensitivity in the pathogenesis of poikiKissimee, FL.
loderma of Civatte. Br J Dermatol. 2002;147(3):493-497.
27. Lomeo G, Cassuto D, Scrimali L, Sirago P. Er:YAG versus CO2 ablative
Katoulis AC, Stavrianeas NG, Panayiotides JG, et al. Poikiloderma of
fractional resurfacing: A split face study. Abstract presented at AmeriCivatte: A histopathological and ultrastructural study. Dermatology.
can Society for Laser Medicine and Surgery Conference, April 2008,
2007;214(2):177-182.
Kissimee, FL.
Batta K, Hindson C, Cotterill JA, Foulds IS. Treatment of poikiloderma of
28. Ross V, Swann M, Barnette D. Use of a micro-fractional 2940 nm laser
Civatte with the potassium titanyl phosphate (KTP) laser. Br J Dermain the treatment of wrinkles and dyspigmentation. Abstract presented
tol.1999;140(6):1191-1192.
at American Society for Laser Medicine and Surgery Conference, April
Goldman MP, Fitzpatrick RE. Laser treatment of vascular lesions. In:
2008, Kissimee, FL.
Goldman MP, Fitzpatrick RE, editors. Cutaneous Laser Surgery. St.
29. Hantash BM, Bedi VP, Kapadia B, et al. In vivo histological evaluation
Louis: Mosby; 1999:19-178.
of a novel ablative fractional resurfacing device. Lasers Surg Med.
Wheeland RG, Applebaum J. Flashlamp-pumped pulsed dye laser ther2007;39(2):96-107.
apy for poikiloderma of Civatte. J Dermatol Surg Oncol. 1990;16(1):1230. Rusciani A, Motta A, Fino P, Menichini G. Treatment of poikiloderma of
16.
Civatte using intense pulsed light source: Seven years of experience.
Haywood RM, Monk BE. Treatment of poikiloderma of Civatte with
Dermatol Surg. 2008;34(3):314-319.
the pulsed dye laser: A series of seven cases. J Cutan Laser Ther.
1999;1(1):45-48.
Clark RE, Jimenez-Acosta F. Poikiloderma of Civatte. Resolution after
treatment with the pulsed dye laser. N C Med J. 1994;55(6):234-5
Raulin C, Greve B, Grema H. IPL techology: A review. Lasers Surg Med.
C. William Hanke, MD, MPH
2003;32(2):78-87.
13400 N. Meridian Street, Suite 290
Behroozan DS, Goldberg LH, Glaich AS, et al. Fractional phototherCarmel, IN 46032
molysis for treatment of poikiloderma of civatte. Dermatol Surg.
Phone: ................................................................... (317) 660-4900
2006;32(2):298-301.
Fax: ........................................................................ (317) 660-4901
Laubach H, Chan HH, Rius F, et al. Skin responses to fractional photoEmail:................................................... cwmhanke@sbcglobal.net
_______________
thermolysis. Lasers Surg Med. 2006;38(2):142-149.
Manstein D, Herron GS, Sink RK, et al. Fractional photothermolysis: A
new concept for cutaneous remodeling using microscopic patterns of
thermal injury. Lasers Surg Med. 2004;34(5):426-438.
Wanner M, Tanzi EL, Alster TS. Fractional photothermolysis: Treatment
of facial and nonfacial cutaneous photodamage with a 1,550-nm erbium-doped ber laser. Dermatol Surg. 2007;33(1):23-28.
Geronemus R. Poikiloderma of Civatte. Arch Dermatol. 1990;126:547548.
Meijs MM, Blok FA, de Rie MA.Treatment of poikiloderma of Civatte
with the pulsed dye laser: A series of patients with severe depigmen 2009-Journal of Drugs in Dermatology. All Rights Reserved.
tation. J Eur Acad Dermatol Venereol. 2006;20(10):1248-1251.
Do Not Copy,
Penalties Apply
22. Weiss RA, Goldman

MP, Weiss
MA.proprietary
Treatmentinformation,
of poikiloderma
This document
contains
of No
Civatte
with an or
intense
lightofsource.
Dermatol
Surg.
reproduction
use of pulsed
any portion
the contents
of these
materials may be made without the express written consent of JDD.
2000;26(9):823-827.
23. Lapidoth M, Yagima Odo ME, Odo LM. Novel use of erbium:YAG
(2,940-nm) laser for fractional ablative photothermolysis in the treatment of photodamaged facial skin: A pilot study. Dermatol Surg.
2008;34(8):1048-1053.
24. Glaich AS, Goldberg LH, Dai T, Friedman PM. Fractional photothermolysis for the treatment of telangiectatic matting: A case report. J Cosmet
Laser Ther. 2007;9(2):101-103.
25. Blankenship TM, Alster TS. Fractional photothermolysis of residual hemangioma. Dermatol Surg. 2008;34(8):1112-1114.
26. Weiss R, Weiss M, Beasley K. Prospective split-face trial of a xed
spacing array computed scanned fractional CO2 laser versus hand
scanned 1550nm fractional for rhytids. Abstract presented at Ameri-
BEMaGS
F
BEMaGS
Proudly
Supported by
Differin Gel, 0.3% at work:
POWERFUL EFFICACY FOR MORE CHALLENGING ACNE1
BASELINE 2*
Do Not Copy,
Penalties Apply
WEEK 12
Patient 116
Highly effective for noninammatory, inammatory, and total lesions1, 2

This document
contains
information,
images
Results
seen
asproprietary
early as
week
12 and marks of Journal of Drugs in Dermatology (JDD).
2 obtained this copy illegally, please contact JDD immediately.
Proven tolerability
*A phase 3b, 12-week, noninferiority, multicenter, investigator-blinded, controlled clinical study

of patients 12 to 35 years of age with acne vulgaris (N=172).
Of the patients who experienced cutaneous irritation (erythema, scaling,

dryness, and/or stinging/burning) during the clinical trial, the majority of cases
were mild to moderate in severity, occurred early in treatment, and decreased
thereafter. Adverse events that occurred in greater than 1% of the subjects
included dry skin (14.0%), skin discomfort (5.8%), and desquamation (1.6%).
Please see brief summary of Prescribing Information on adjacent page.
www.differin.com
BEMaGS
F
+ #!

# $& #)
"$ &"# '% "!* "& "$ "#& "$ "$ !&$(! '%
) "!*
BEMaGS
F
8
7 =1. 6>5=2,.7=.; ,87=;855.- ,5272,*5 =;2*5 <207< *7- <B69=86< 8/ 58,*5 ,>=*7.8>< 2;;2=*=287
@.;. 6872=8;.- 27 *,7. 9*=2.7=< @18 ><.- #! .5
87,. -*25B /8; @..4< G/ =1. 9*=2.7=< @18
.A9.;2.7,.- ,>=*7.8>< 2;;2=*=287 .;B=1.6* <,*5270 -;B7.<< *7- 8; +>;7270 <=270270 =1. 6*38;2=B 8/ ,*<.< @.;.
625- =8 68-.;*=. 27 <.?.;2=B 8,,>;;.- .*;5B 27 =;.*=6.7= *7- -.,;.*<.- =1.;.*/=.; %1. 27,2-.7,. 8/ 58,*5 ,>=*7.8><
2;;2=*=287 @2=1 #! .5
/;86 =1. ,87=;855.- ,5272,*5 <=>-B 2< 9;8?2-.- 27 =1. /8558@270 =*+5.
%*+5. "1B<2,2*7 *<<.<<.- 58,*5 ,>=*7.8>< 2;;2=*=287 @2=1 #! .5

#! .5
2< 27-2,*=.- /8; =1. =892,*5 =;.*=6.7= 8/ *,7. ?>50*;2< 27 9*=2.7=<
B.*;< 8/ *0. *7- 85-.;

#! .5
<18>5- 78= +. *-6272<=.;.- =8 27-2?2->*5< @18 *;. 1B9.;<.7<2=2?. =8
!! " 6"
'&!"'% $$&&"! 9& + $"
"!&$"
! &'*
*-*9*5.7. 8; *7B 8/ =1. ,86987.7=< 27 =1. 0.5 ?.12,5.
3/1,

7) ' ($&* "$% 5$ ! 4%!

.;=*27 ,>=*7.8>< <207< *7- <B69=86< 8/ =;.*=6.7= <>,1 *< .;B=1.6* <,*5270 -;B7.<< *77
7"$&
($
<=270270 +>;7270 6*B +. .A9.;2.7,.- @2=1 ><. 8/ #! .5
%1.<. *;. 68<= 524.5B =8 8,,>; ->;270 =1.
/2;<= /8>; @..4< 8/ =;.*=6.7= *;. 68<=5B 625- =8 68-.;*=. 27 27=.7<2=B *7- ><>*55B 5.<<.7 @2=1 ,87=27>.- ><. 8/ =1.
$*&

6.-2,*=287 .9.7-270 >987 =1. <.?.;2=B 8/ =1.<. <2-. .//.,=< 9*=2.7=< <18>5- +. 27<=;>,=.- =8 .2=1.; ><. * 682<
!

=>;2C.; ;.->,. =1. /;.:>.7,B 8/ *9952,*=287 8/ #! .5
8; -2<,87=27>. ><.
$*!%%

/ * ;.*,=287 <>00.<=270 <.7<2=2?2=B 8; ,1.62,*5 2;;2=*=287 8,,>;< ><. 8/ =1. 6.-2,*=287 <18>5- +. -2<,87=27>.-
4'$!!-&!!

A98<>;. =8 <>75201= 27,5>-270 <>75*69< <18>5- +. 627262C.- ->;270 ><. 8/ *-*9*5.7. "*=2.7=< @18 78;6*55B
.A9.;2.7,. 1201 5.?.5< 8/ <>7 .A98<>;. *7- =18<. @2=1 271.;.7= <.7<2=2?2=B =8 <>7 <18>5- +. @*;7.- =8 .A.;,2<. ,*>
F %8=*5 7>6+.; 8/ <>+3.,=< @2=1 58,*5 ,>=*7.8>< -*=* /8; *= 5.*<= 87. 98<=*<.527. .?*5>*=287
=287 &<. 8/ <>7<,;..7 9;8->,=< *7- 9;8=.,=2?. ,58=1270 8?.; =;.*=.- *;.*< 2< ;.,866.7-.- @1.7 .A98<>;. ,*778=
%*+5. "*=2.7= ;.98;=.- 58,*5 ,>=*7.8>< *-?.;<. .?.7=< @2=1 #! .5
+. *?82-.- (.*=1.; .A=;.6.< <>,1 *< @27- 8; ,85- *5<8 6*B +. 2;;2=*=270 =8 9*=2.7=< >7-.; =;.*=6.7= @2=1
*-*9*5.7.
+ #!
8
?82- ,87=*,= @2=1 =1. .B.< 529< *705.< 8/ =1. 78<. *7- 6>,8>< 6.6+;*7.< %1. 9;8->,= <18>5- 78= +. *9952.3/12
3.0
=8 ,>=< *+;*<287< .,C.6*=8>< 8; <>7+>;7.- <427 < @2=1 8=1.; ;.=2782-< ><. 8/ D@*A270E *< * -.925*=8;B 6.=18<18>5- +. *?82-.- 87 <427 =;.*=.- @2=1 *-*9*5.7.
#.5*=.-F -?.;<. ?.7=<

"*=2.7=< ><270 #! .5
<18>5- ;.,.2?. =1. /8558@270 27/8;6*=287 *7- 27<=;>,
;B $427

=287<
$427 2<,86/8;=

%12< 6.-2,*=287 2< =8 +. ><.- 875B *< -2;.,=.- +B =1. 91B<2,2*7
.<:>*6*=287

= 2< /8; .A=.;7*5 ><. 875B
F $.5.,=.- *-?.;<. .?.7=< -./27.- +B 27?.<=20*=8; *< "8<<2+5B ";8+*+5B 8; ./272=.5B #.5*=. ?82- ,87=*,= @2=1 =1. .B.< 529< *705.< 8/ =1. 78<. *7- 6>,8>< 6.6+;*7.<
#.5*=.- *-?.;<. .?.7=< /;86 =1. ,87=;855.- ,5272,*5 =;2*5 =1*= 8,,>;;.- 27 0;.*=.; =1*7 8/ 9*=2.7=< @18 ><. 5.*7<. *//.,=.- *;.* @2=1 * 625- 8; <8*95.<< ,5.*7<.; +./8;. *995B270 =12< 6.-2,*=287
#! .5
87,. -*25B 27,5>-.- -;B <427
<427 -2<,86/8;= 9;>;2=>< -.<:>*6*=287
82<=>;2C.;< 6*B +. ><.- 2/ 7.,.<<*;B 18@.?.; 9;8->,=< ,87=*27270 *591* 1B-;8AB 8; 05B,852, *,2-< <18>5 *7- <>7+>;7 %1. /8558@270 <.5.,=.- *-?.;<. .?.7=< 8,,>;;.- 27 5.<< =1*7 8/ 9*=2.7=< *,7. /5*;.
+. *?82-.-
,87=*,= -.;6*=2=2< .B.52- .-.6* ,873>7,=2?2=2< .;B=1.6* 9;>;2=>< <427 -2<,858;*=287 ;*<1 *7- .,C.6*
A98<>;. 8/ =1. .B. =8 =12< 6.-2,*=287 6*B ;.<>5= 27 ;.*,=287< <>,1 *< <@.55270 ,873>7,=2?2=2< *7- .B.
7 * 87.B.*; 89.75*+.5 <*/.=B <=>-B 8/ 9*=2.7=< @2=1 *,7. @18 ;.,.2?.- #! .5
=1. 9*==.;7 8/
2;;2=*=287
*-?.;<. .?.7=< @*< <2625*; =8 =1. @..4 ,87=;855.- <=>-B
%12< 6.-2,*=287 <18>5- 78= +. *9952.- =8 ,>=< *+;*<287< .,C.6*=8>< 8; <>7+>;7.- <427
8 #! .5
2< 27=.7-.- /8; =892,*5 ><. 875B / =1. 6.-2,*=287 2< *9952.- .A,.<<2?.5B 78
(*A .925*=287 <18>5- 78= +. 9.;/8;6.- 87 =;.*=.- <427 ->. =8 =1. 98=.7=2*5 /8; <427 .;8<287<
68;. ;*92- 8; +.==.; ;.<>5=< @255 +. 8+=*27.- *7- 6*;4.- ;.-7.<< <,*5270 8; <427 -2<,86/8;= 6*B 8,,>; 1;872,
>;270 =1. .*;5B @..4< 8/ =1.;*9B *7 *99*;.7= .A*,.;+*=287 8/ *,7. 6*B 8,,>; %12< 6*B +. ->. =8 =1.
270.<=287 8/ =1. -;>0 6*B 5.*- =8 =1. <*6. <2-. .//.,=< *< =18<. *<<8,2*=.- @2=1 .A,.<<2?. 8;*5 27=*4. 8/ ?2=*627
*,=287 8/ =1. 6.-2,*=287 87 9;.?28><5B >7<..7 5.<287< *7- <18>5- 78= +. ,87<2-.;.- * ;.*<87 =8 -2<,87=27>.
=1.;*9B

< #! .5
1*< =1. 98=.7=2*5 =8 27->,. 58,*5 2;;2=*=287 27 <86. 9*=2.7=< ,87,862
=*7= ><. 8/ 8=1.; 98=.7=2*55B 2;;2=*=270 =892,*5 9;8->,=< 6.-2,*=.- 8; *+;*<2?. <8*9< *7- ,5.*7<.;< <8*9< *7- ,8<
6.=2,< =1*= 1*?. * <=;870 -;B270 .//.,= *7- 9;8->,=< @2=1 1201 ,87,.7=;*=287< 8/ *5,8185 *<=;270.7=< <92,.< 8;
526. <18>5- +. *99;8*,1.- @2=1 ,*>=287 "*;=2,>5*; ,*>=287 <18>5- +. .A.;,2<.- 27 ><270 9;.9*;*=287< ,87=*27270
Marketed by:
<>5/>; ;.<8;,2785 8; <*52,B52, *,2- 27 ,86+27*=287 @2=1 #! .5
/ =1.<. 9;.9*;*=287< 1*?. +..7 ><.-
GALDERMA LABORATORIES, L.P.
Fort Worth, Texas 76177 USA
2= 2< *-?2<*+5. 78= =8 <=*;= =1.;*9B @2=1 #! .5
>7=25 =1. .//.,=< 8/ <>,1 9;.9*;*=287< 1*?. <>+<2-.-
Manufactured by:

*;,2780.72,2=B <=>-2.< @2=1 *-*9*5.7. 1*?. +..7 ,87
DPT Laboratories, Ltd.
->,=.- 27 62,. *= =892,*5 -8<.< 8/
*7-
60 40 -*B *7- 27 ;*=< *= 8;*5 -8<.< 8/

*7-
San Antonio, Texas 78215 USA
60 40 -*B %1.<. -8<.< *;. >9 =8 =26.< 62,. *7- =26.< ;*=< 27 =.;6< 8/ 60 6 -*B =1. 98=.7=2*5 .A98<>;.
GALDERMA is a registered trademark.

*= =1. 6*A26>6 ;.,866.7-.- 1>6*7 -8<. # *<<>6.- =8 +. 0;*6< #! .5
7 =1. 8;*5
Revised: June 2007 325089-0607
<=>-B 27,;.*<.- 27,2-.7,. 8/ +.7207 *7- 6*5207*7= 91.8,1;868,B=86*< 27 =1. *-;.7*5 6.->55*< 8/ 6*5. ;*=< @*<
8+<.;?.-
!8 918=8,*;,2780.72,2=B <=>-2.< @.;. ,87->,=.- 726*5 <=>-2.< 1*?. <18@7 *7 27,;.*<.- ;2<4 8/ <427 7.895*<6<
@2=1 =1. ><. 8/ 91*;6*,85802,*55B <2625*; -;>0< .0 ;.=2782-< @1.7 .A98<.- =8 &' 2;;*-2*=287 27 =1. 5*+8;*=8;B 8;
=8 <>75201= 5=18>01 =1. <2072/2,*7,. 8/ =1.<. <=>-2.< =8 1>6*7 ><. 2< 78= ,5.*; 9*=2.7=< <18>5- +. *-?2<.- =8 *?828; 627262C. .A98<>;. =8 .2=1.; <>75201= 8; *;=2/2,2*5 &' 2;;*-2*=287 <8>;,.<
-*9*5.7. -2- 78= .A12+2= 6>=*0.72, 8; 0.78=8A2, .//.,=< in vitro 6.< =.<= 127.<. 1*6<=.; 8?*;B ,.55 *<<*B
68><. 5B69186* % *<<*B *7- in vivo 68><. 62,;87>,5.>< =.<=
#.9;8->,=2?. />7,=287 *7- /.;=252=B <=>-2.< @.;. ,87->,=.- 27 ;*=< *-6272<=.;.- 8;*5 -8<.< 8/ *-*9*5.7. 27 *68>7=<
>9 =8
60 40 -*B >9 =8 =26.< =1. # +*<.- 87 60 6 ,869*;2<87< !8 .//.,=< 8/ *-*9*5.7. @.;. /8>787 =1. ;.9;8->,=2?. 9.;/8;6*7,. 8; /.;=252=B 8/ =1.
6*5.< 8; /.6*5.< %1.;. @.;. *5<8 78 -.=.,=*+5. .//.,=< 87 =1.
0;8@=1 -.?.5896.7= *7- <>+<.:>.7= ;.9;8->,=2?. />7,=287 8/ =1. 8//<9;270

$&"! &% $!!*
&"$*
#.=2782-< 6*B ,*><. /.=*5 1*;6 @1.7 *-6272<=.;.- =8
9;.07*7= @86.7 -*9*5.7. 1*< +..7 <18@7 =8 +. =.;*=80.72, 27 ;*=< *7- ;*++2=< @1.7 *-6272<=.;.- 8;*55B <.. 726*5
*=* +.58@ %1.;. *;. 78 *-.:>*=. *7- @.55,87=;855.- <=>-2.< 27 9;.07*7= @86.7 #! .5
<18>5- +.
><.- ->;270 9;.07*7,B 875B 2/ =1. 98=.7=2*5 +.7./2= 3><=2/2.< =1. 98=.7=2*5 ;2<4 =8 =1. /.=>< %1. <*/.=B *7- .//2,*,B 8/
#! .5
27 9;.07*7,B 1*< 78= +..7 .<=*+52<1.-
>6*7 *=*
7 ,5272,*5 =;2*5< 27?85?270 #! .5
27 =1. =;.*=6.7= 8/ *,7. ?>50*;2< @86.7 8/ ,125-+.*;270 98=.7=2*5
272=2*=.- =;.*=6.7= 875B */=.; 1*?270 1*- * 7.0*=2?. 9;.07*7,B =.<= *7- ><.- .//.,=2?. +2;=1 ,87=;85 6.*<>;.< ->;270
=1.;*9B 8@.?.; @86.7 =;.*=.- @2=1 #! .5
+.,*6. 9;.07*7= G7. 9*=2.7= .5.,=.- =8 =.;627*=.
=1. 9;.07*7,B =@8 9*=2.7=< -.52?.;.- 1.*5=1B +*+2.< +B 78;6*5 -.52?.;B =@8 9*=2.7=< -.52?.;.- 9;.6*=>;.5B *7- =1.
+*+2.< ;.6*27.- 27 27=.7<2?. ,*;. >7=25 ;.*,1270 * 1.*5=1B <=*=. *7- 87. 9*=2.7= @*< 58<= =8 /8558@>9
726*5 *=*
H !8 =.;*=80.72, .//.,=< @.;. <..7 27 ;*=< *= 8;*5 -8<.< 8/
=8
60 40 -*B *-*9*5.7. ;.9;.<.7=270 >9 Reference: 1. Thiboutot D, Pariser DM, Egan N, et al; Adapalene Study Group. Adapalene gel 0.3% for the
This
document
contains
proprietary
images
=8 =26.< =1. 6*A26>6 ;.,866.7-.- 1>6*7 -8<. #
+*<.- 87 60 6information,
,869*;2<87< -*9*5.7.
1*< and
treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial. J Am Acad
Dermatol. 2006;54:242-250.
+..7
=8 +. =.;*=80.72, or
27 ;*=<
*7- of
;*++2=<
@1.7
*-6272<=.;.-8<.< 60 40
;.9;.<.7=270
No<18@7
reproduction
use
any
portion
of 8;*55B
the *=contents
of these
materials
may be made without the express written consent of JDD.
*7- =26.< ;.<9.,=2?.5B =1. # +*<.- 87 60 6 ,869*;2<87< 27-270< 27,5>-.- ,5./= 9*5*=.
Marketed
by: 1. Data on le. Galderma Laboratories, L.P. A phase 2, 12-week, multicenter, controlled
References:
62,;891=1*562* .7,.91*58,.5. *7- <4.5.=*5 If*+78;6*52=2.<
=1. ;*=have
*7- >6+252,*5
1.;72* .A891=1*568<
you feel27 you
obtained
this copy*7-illegally,
please
contact
JDD
immediately.
GALDERMA
L.P.40
clinical studyLABORATORIES,
of patients 12 to
years of age with acne vulgaris (N=214). 2. Thiboutot D, Arsonnaud S,
42-7.B *7- <4.5.=*5 *+78;6*52=2.< 27 =1. ;*++2=
Fort
Worth,
Texasand
76177
USA of adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment
Soto
P.
Efcacy
tolerability
H >=*7.8>< =.;*=8580B <=>-2.< 27 ;*=< *7- ;*++2=< *= -8<.< 8/

*7-
60 40 -*B .A12+2=.- 78 /.=8 Manufactured by:
of acne vulgaris. J Drugs Dermatol. 2008;7(suppl 6):S3-S10.
=8A2,2=B *7- 875B 62726*5 27,;.*<.< 27 <>9.;7>6.;*;B ;2+< 27 +8=1 <9.,2.< *7- -.5*B.- 8<<2/2,*=287 27 ;*++2=< DPT Laboratories, Ltd.
$B<=.62, .A98<>;. &
1 =8 *-*9*5.7.
0.5 *= =892,*5 -8<.< 8/
60 40 -*B 27 ;*=< *7- ;*++2=< San Antonio, Texas 78215 USA
GALDERMA
is a registered trademark.
;.9;.<.7=.- *7- =26.< ;.<9.,=2?.5B =1. .A98<>;. 27 *,7. 9*=2.7=< =;.*=.- @2=1 *-*9*5.7.
0.5
Revised:
Junethe
2007
325089-0607
Experience
Power,
Differin,
*9952.- =8 =1. /*,. ,1.<= *7- +*,4 0;*6< *9952.- =8
,6 8/ *,7. 27?85?.- <427

and Galderma are registered trademarks
= 2< 78= 478@7 @1.=1.; =12< -;>0 2< .A,;.=.- 27 1>6*7 6254 .,*><. 6*7B -;>0< *;. .A,;.=.- Differin and Galderma are registered trademarks.
www.differin.com
of
Galderma
Laboratories,
L.P.
2007 Galderma Laboratories, L.P.
27 1>6*7 6254 ,*>=287 <18>5- +. .A.;,2<.- @1.7 #! .5
2< *-6272<=.;.- =8 * 7>;<270 @86*7
2009 Galderma
Laboratories,
L.P.
Galderma
Laboratories,
L.P.

$*/.=B *7- .//.,=2?.7.<< 27 9.-2*=;2, 9*=2.7=< +.58@ =1. *0. 8/ 1*?. 78= +..7 .<=*+52<1.-
Galderma
Laboratories, L.P.
N. Freeway

5272,*5 <=>-2.< 8/ #! .5
-2- 78= 27,5>-. <>+3.,=< B.*;< 8/ *0. *7- 85-.; =8 -.=.; 14501
14501
N. Freeway
Fort
Worth,
TX 76177
627. @1.=1.; =1.B ;.<987- -2//.;.7=5B =1*7 B8>70.; <>+3.,=< $*/.=B *7- .//.,=2?.7.<< 27 0.;2*=;2, 9*=2.7=< *0.
Fort Worth, TX 76177
DIFF-039 Printed05/09
*7- *+8?. 1*?. 78= +..7 .<=*+52<1.-
DIF-888
in USA 11/07
Do Not Copy,
Penalties Apply
BEMaGS
F
BEMaGS
F
JUNE 2009
537
70-6.&t*446&
COPYRIGHT 2009
ORIGINAL ARTICLES
Treatment of Pruritus in Mild-to-Moderate Atopic

Dermatitis With a Topical Non-Steroidal Agent
4UFGBOP7FSBMEJ.%1I%B 1BPMP%F.JDIFMJ.4DC
3PTTBOB4DIJBODIJ.%C -VJTB-VOBSEPO.%B
B
*OTUJUVUFPG%FSNBUPMPHJDBM4DJFODFT 6OJWFSTJUZPG.JMBO *3$$4'PVOEBUJPO

0TQFEBMF.BHHJPSF1PMJDMJOJDP .BOHJBHBMMJBOE3FHJOB&MFOB .JMBO *UBMZ
C
&VSPQFBO*OTUJUVUFPG%FSNBUPMPHZ .JMBO *UBMZ
ABSTRACT
Atopiclair (Zarzenda) is a topical non-steroidal anti-inammatory agent for the treatment of allergic diseases of the skin. Three main
ingredients are contained in this product: glycyrrhetinic acid, telmesteine and Vitis vinifera extracts. Other ingredients include: allantoin, _bisabolol, capryloyl glycine, hyaluronic acid, shea butter and tocopheryl acetate. Two previous randomized, double-blind,
vehicle-controlled clinical studies provided evidence that Atopiclair is effective in the treatment of atopic dermatitis. This article
presents an open, multicenter, sponsor-free, study on the anti-pruritic activity of this product in adult patients with mild-to-moderate
atopic dermatitis. The Median Visual Analogue Scale (VAS) values were: at the start of the study (T0), median VAS was 48.5 mm;
three weeks later (T1), median VAS was 34.1 mm (14.4 mm from baseline); six weeks later (T2), median VAS was 24.6 mm (23.9
mm from baseline). Statistical analysis revealed that differences between T0 versus T1, T0 versus T2 and T1 versus T2 were highly
signicant (p<0.001). Side effects (local burning) were relatively common, although mild in severity. On the basis of the results of this
study, Atopiclair showed efcacy in relief of pruritus in adult patients with mild-to-moderate atopic dermatitis.
INTRODUCTION
Do Not Copy,
Penalties Apply
MEAN SCORE
topiclair is a topical non-steroidal anti-inammatory

agent for the treatment of allergic diseases of the skin,
such as irritant/allergic contact dermatitis and atopic
dermatitis (AD). The three main ingredients contained in this
product are glycyrrhetinic acid, telmesteine and Vitis vinifera
extracts, for which it was also named GRA/Tel/Vv. Other ingredients are allantoin, _bisabolol, capryloyl glycine, hyaluronic
acid, shea butter and tocopheryl acetate. The product contains
no parabens, peanut oil, perfumes or proteins.
Literature data for the agent are, so far, limited.16 However,

two randomized, double-blind, vehicle-controlled clinical studies clearly indicated that the product has efcacy in the treatment of AD.2,4,5 This article presents the results of an open,
multicenter, sponsor-free, study on the anti-pruritic effect of
Atopiclair in adult patients with mild-to-moderate AD.
METHODS
Diagnosis and severity of AD was based on criteria proposed

by Hanin and Rajka, and Rajka and Langeland in 1980 and
1989, respectively.7,8 Informed written consent was provided
by each patient. Atopiclair (marketed in the U.S. by Graceway
50
Pharmaceuticals; sold as Zarzenda in Europe via Intendis) was
Rightstimes
Reserved.
appliedAllthree
daily for six weeks. Neither other topical
40
products
phototherapy/sunlight
exposure
were allowed.
marks ofnor
Journal
(JDD).
30 reproduction or use of any portion of the contents of these materials
No may
systemic
medications
were used
and
only aof cleanser
was
No
be made
without the express
written
consent
JDD.
suggested.
20
10
0
VAS Pre-study
VAS 3 Weeks
Later
VAS 6 Weeks
Later
VARIABLE
FIGURE 1. Change in VAS at the beginning of the study, three weeks

later and six weeks later.
Patients were examined after three (T1) and six weeks of treatment (T2). Primary objective of the study was the evaluation of
pruritus after three and six weeks of treatment. Pruritus severity was evaluated by means of a 0-100 mm Visual Analogue
Scale (VAS).9
RESULTS
Eighty-nine Caucasian patients with mild-to-moderate AD were
enrolled: 38 males (42.7%) and 51 females (57.3%), with an age
ranging from 18 to 42 years (average age: 19.9 years).
BEMaGS
F
BEMaGS
F
538
+6/&t70-6.&t*446&
50
47FSBMEJ 1%F.JDIFMJ 34DIJBODIJ --VOBSEPO
48.540
48.540
50
40
MEAN
MEAN SCORE
40
34.143
30
34.143
30
20
24.603
10
VAS 6 Weeks
Later
20
VAS Pre-study
VAS 3 Weeks
Later
VAS Pre-study
(T0)
VARIABLE
PAIRED VARIABLES
FIGURE 2. Repeated ANOVA measures.
MEAN SCORE
40
30
20
10
FIGURE 3. Paired t-test of VAS pre-study (T0) and 3 weeks later (T1).
48.540
34.143
35
30
Do Not Copy,
Penalties Apply
24.603
MEAN SCORE
50
VAS 3 Weeks Later

(T1)
24.603
25
20
15
10
0
VAS Pre-study
(T0)
VAS 6 Weeks Later

(T2)
VAS 3 Weeks Later

(T1)
PAIRED VARIABLES
PAIRED VARIABLES
FIGURE 4. Paired t-test of VAS pre-study (T0) and 6 weeks later (T2).
VAS 6 Weeks Later

(T2)
FIGURE 5. Paired t-test of VAS 3 weeks (T1) and 6 weeks (T2) later.
Sixty-three patients
(70.8%) contains
concluded
the study
and were
Burning
atJournal
the sites
of application
of the(JDD).
product was reported
This document
proprietary
information,
images and
marks of
of Drugs
in Dermatology
considered
evaluable.or
Twenty-six
stopped
thematerials
by 13
Sixexpress
(6.7%) written
of these
13 patients
No reproduction
use of any patients
portion of(29.2%)
the contents
of these
maypatients
be made(14.6%).
without the
consent
of JDD. stopped
study: 12 patients (13.5%) because
of you
lowhave
efcacy
of the
the treatment.
In all
ofimmediately.
these patients it was possible to perform
If you feel
obtained
thisprodcopy illegally,
please contact
JDD
uct, eight patients (9%) because of low adhesion to the protocol
patch tests with the agent, which were negative.
and six patients (6.7%) because of side effects.
DISCUSSION
In the group of evaluable patients, median VAS at the start of
the study (T0) was 48.5 mm (range: 34-64 mm); three weeks
later (T1), median VAS was 34.1 mm (range: 12-76 mm) (14.4
mm from baseline); six weeks later (T2), median VAS was 24.6
mm (range: 12-58 mm) (23.9 mm from baseline).
Statistical analysis revealed that differences between T0 versus T1, T0 versus T2 and T1 versus T2 were highly signicant
(p<0.001) (Figures 1-5).
Despite the methodological characteristics of this study (open,

although sponsor-free, multicenter and based on a large group
of evaluable patients), Atopiclair was effective in the treatment
of pruritus in adult patients with mild-to-moderate AD.
In fact, median VAS decreased from 48.5 mm (baseline) to 34.1
mm (three weeks later) to 24.6 mm (six weeks later) (p<0.001).
These results are notable in consideration of the fact that Atopiclair is not a topical corticosteroid.
BEMaGS
F
BEMaGS
F
539
+6/&t70-6.&t*446&
This study conrms the results of other clinical studies recently

reported in the literature.1,2,4,5 In particular, two randomized, double-blind, vehicle-controlled studies indicated that this agent
achieves signicant activity against pruritus.2,4,5 In a study by
Belloni et al.2, itch severity (VAS score) decreased from 2.7 to
1.3 (p=0.001). In research by Abramovits et al.4,5, the active product induced, after 50 days of treatment, a median reduction of
VAS of 58 mm, in comparison to 21 mm of the vehicle.
The anti-pruritic effect of Atopiclair may be due to the presence
of several compounds, such as Vitis vinifera extracts, glycyrrhetinic acid, _-bisabolol, allantoin or hyaluronic acid.
However, the presence of these compounds in numerous topical agents that actually possess a low effectiveness against
pruritus would support the hypothesis that the anti-pruritic effect of this agent is due to telmesteine. This is an N-carboxy4-thiazolidine carboxylic acid which inhibits metalloproteases
MMP2 and MMP9,10 which are well-known chemical mediators
of pruritus11 and are over-expressed in AD.6 Furthermore, it was
demonstrated that this agent inhibits the release of leukocyte
collagenases and elastases, which lead to the increased proliferation of keratinocytes as well as the synthesis and release of
pro-inammatory and pruritogenic cytokines.6
47FSBMEJ 1%F.JDIFMJ 34DIJBODIJ --VOBSEPO
controlled clinical study to examine the safety and efcacy of MAS063DP in the management of mild to moderate atopic dermatitis in
adults. J Drugs Dermatol. 2006;5(3):236-244.
6. Abramovits W, Perlmutter A. Atopiclair. Its position within a topical
paradigm for the treatment of atopic dermatitis. Expert Rev Dermatol.
2007; 2:115-119.
7.
Hanin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta
Derm Venereol. 1980;92(Suppl):44-47.
8. Rajka G, Langeland T. Grading of the severity of atopic dermatitis. Acta
Derm Venereol. 1989;144(Suppl):13-14.
9. Aitken RC. Measurement of feeling using visual analogue scales. Proc
R Soc Med. 1969;62(10):989-993.
10. Grassi L, Moretti M, Bisetti A. Un nuovo farmaco mucoattivo con attivit anti-proteasica: La telmesteina. Riv Ital Biol Med. 1992;12:67-74.
11. Lerner EA. Chemical mediators of itching. In: Bernhard JD, ed. Itch.
Mechanisms and management of pruritus. New York: McGraw-Hill,
1994:23-35.

Stefano Veraldi, MD, PhD
Institute of Dermatological Sciences
University of Milan
Via Pace 9
20122 Milan, Italy
Phone: ...............................................................+39/02/55035109
Fax: ....................................................................+39/02/50320779
E-mail:...................................................... ______________
stefano.veraldi@unimi.it
Do Not Copy,
Penalties Apply
As previously mentioned, side effects were limited

burning. The latter was rather common (13 out of 89
= 14.6%), although mild in severity: in fact, only six
stopped treatment. Patch tests demonstrated that the
not a sensitizer.
to local
patients
patients
agent is
Further studies are necessary to conrm our results and to understand the anti-pruritic effect of Atopiclair in AD.
DISCLOSURES
None of the authors have any conicts of interest to disclose.
REFERENCES
1.
2.
3.
4.
5.
Zhai H, Villarama
CD,document
Hafeez ZH,
Maibachproprietary
HI. Efcacyinformation,
of a topical agent,
This
contains
MAS063D
(Atopiclairor
),use
in the
treatment
laurylofsulphateNo reproduction
of any
portion of
of sodium
the contents
induced irritant contact dermatitis.
A double-blind,
vehicle-controlled
If you feel
you have obtained
this copy illegally, please contact JDD immediately.
study. Exogenous Dermatol. 2003;2:301-305.
Belloni G, Pinelli S, Veraldi S. A randomised, double-blind, vehiclecontrolled study to evaluate the efcacy and safety of of MAS063D
(Atopiclair), in the treatment of mild to moderate atopic dermatitis.
Eur J Dermatol. 2005;15(1):31-36.
Abramovits W, Gover M, Gupta A. Atopiclair nonsteroidal cream.
Skinmed. 2005;4(6):369.
Abramovits W, Hebert A, Boguniewicz M. A multicenter randomized,
vehicle-controlled, double-blind clinical study to examine the safety
and efcacy of MAS063DP in the management of AD. J Am Acad
Dermatol. 2006; 54(Suppl):AB84.
Abramovits W, Boguniewicz M. A multicenter, randomized, vehicle-
BEMaGS
F
BEMaGS
Dene the Future

of Dermatology
Limited-Time
Offer2009 and
1st,
Register by July
cess Pass
receive the All Ac
r a special
to ODAC 2010 fo
$699 with code
reduced rate of
99 value!
JDDJN a $1,5
ODAC 2010
January 15-18, 2010

The Peabody Orlando
Orlando, FL
Do Not Copy,
Penalties Apply
Now in its 7th year,
the Orlando
Dermatology
&AllClinical
2009-Journal
of Drugs inAesthetic
Dermatology.
Rights Reserved.
This document
contains proprietary
information,
images
and marks
of Journal of Drugs in Dermatology (JDD).
Conference provides
expert guidance
to help you
succeed
in todays
constantly
Noand
reproduction
or use of
any portion of the
contents
these materials
mayafford
be made
changing
competitive
environment.
This
is anof event
you cant
towithout the express written consent of JDD.
If
you
feel
you
have
obtained
this
copy
illegally,
please
contact
miss packed with interactive workshops, live demos and presentations from JDD immediately.
the nations top thought leaders.
CONFERENCE CHAIRMAN:
VISIT US ONLINE AT:
www.OrlandoDerm.org
ADVISORY BOARD:
Perry Robins, MD
Professor Emeritus of Dermatology
New York University Medical Center
New York, NY
Joseph B. Bikowski, MD
Founder, Bikowski Skin Care Center
Sewickley, PA
Deborah S. Sarnoff, MD,

FAAD, FACP
Director of Dermatology
Cosmetique Dermatology
Laser & Plastic Surgery LLP
Greenvale, NY
Alan Shalita, MD
James Spencer, MD, MS
Susan H. Weinkle, MD
Professor and Chairman of Dermatology

SUNY Downstate Medical Center
Brooklyn, NY
Director, Spencer Dermatology

& Skin Surgery Center
St. Petersburg, FL
Bay Area Medical Center

Assistant Clinical Professor
University of South Florida
Bradenton, FL
BEMaGS
F
BEMaGS
F
IMPORTANT SAFETY INFORMATION

RISK OF SERIOUS INFECTIONS
Patients treated with ENBREL are at increased risk
for developing serious infections that may lead
to hospitalization or death. Most patients who
developed these infections were taking concomitant
immunosuppressants such as methotrexate or
corticosteroids or were predisposed to infection
because of their underlying disease. ENBREL should
not be initiated in the presence of sepsis, active
infections or allergy to ENBREL or its components.
ENBREL should be discontinued if a patient develops
a serious infection or sepsis. Reported infections
include: 1) Active tuberculosis, including reactivation
of latent tuberculosis. Patients with tuberculosis
have frequently presented with disseminated or
extrapulmonary disease. Patients should be tested
for latent tuberculosis before ENBREL use and
periodically during therapy. Treatment for latent
infection should be initiated prior to ENBREL use.
2) Invasive fungal infections, including histoplasmosis,
coccidioidomycosis, candidiasis, aspergillosis,
blastomycosis, and pneumocystosis. Patients with
histoplasmosis or other invasive fungal infections
may present with disseminated, rather than localized,
disease. Antigen and antibody testing for
histoplasmosis may be negative in some patients
with active infection. Empiric anti-fungal therapy
should be considered in patients at risk for invasive
fungal infections who develop severe systemic
illness, and 3) Bacterial, viral and other infections
due to opportunistic pathogens, such as listeriosis.
demyelinating disorders (some presenting with mental

status changes and some associated with permanent
disability). Transverse myelitis, optic neuritis, multiple
sclerosis, and cases of new onset or exacerbation
of seizure disorders have been observed in association
with ENBREL therapy. A causal relationship to ENBREL
therapy remains unclear. Exercise caution when
considering ENBREL for patients with these disorders.
Hematologic Events
Rare cases of pancytopenia, including aplastic anemia,
some fatal, have been reported. A causal relationship
to ENBREL therapy remains unclear. Exercise caution
in patients who have a previous history of significant
hematologic abnormalities. Advise patients to seek
immediate medical attention if they develop signs or
symptoms of blood dyscrasias or infection. Consider
discontinuing ENBREL if significant hematologic
abnormalities are confirmed.
Malignancies
In clinical trials of all TNF inhibitors, more cases of
lymphoma were seen compared to control patients.
The risk of lymphoma may be up to several-fold higher
in RA and psoriasis patients. The role of TNF inhibitors
in the development of malignancies is unknown.
Do Not Copy,
Penalties Apply
Hepatitis B Reactivation
TNF inhibitors, including ENBREL, have been associated
with reactivation of hepatitis B virus (HBV) in
chronic carriers of this virus. The majority of these
reports occurred in patients on concomitant
immunosuppressive agents, which may also contribute
to HBV reactivation. Prescribers should exercise
caution in prescribing TNF blockers for patients
identified as carriers of HBV.
The risks and benefits of treatment with ENBREL

should be carefully considered prior to initiating
therapy in patients 1) with chronic or recurrent
infection, 2) who have been exposed to tuberculosis,
3) who have resided or traveled in areas of endemic
Adverse Events
tuberculosis or endemic mycoses or 4) with underlying
The most commonly reported adverse events in RA
conditions that may predispose them to infections
clinical trials were injection site reaction, infection,
such as advanced or poorly controlled diabetes.
and headache.
clinical trials of all other adult
All RightsIn
Reserved.
Patients should be closely monitored for the
indications,
adverse
events
were similar
to those
This document contains proprietary information, images and marks of Journal of Drugs
in Dermatology
(JDD).
development of
signs and symptoms of infection
reported
in
RA
clinical
trials.
reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
during No
and
after treatment with ENBREL, including
feel you have obtained this copy illegally,
please
JDD immediately.
Please
see contact
accompanying
Brief Summary of full
the possible development Ifofyou
tuberculosis
in patients
Prescribing Information on following pages.
who tested negative for latent tuberculosis prior
to initiating therapy.
Neurologic Events
TNF inhibitors, including ENBREL, have been associated
with rare cases of new onset or exacerbation of CNS
References: 1. Scallon B, Cai A, Solowski N, et al. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002;301:418-426.
2. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244-279.
3. Goffe B, Cather JC. Etanercept: an overview. J Am Acad Dermatol. 2003;49:S105-S111. 4. Enbrel (etanercept) Prescribing Information, Immunex Corporation, Thousand Oaks,
Calif. 5. Remicade (infliximab) Prescribing Information, Centocor, Inc, Malvern, Pa. 6. Humira (adalimumab) Prescribing Information, Abbott Laboratories, Abbott Park, Ill.
7. Furst DE, Wallis R, Broder M, Beenhouwer DO. Tumor necrosis factor antagonists: different kinetics and/or mechanisms of action may explain differences in the risk for developing
granulomatous infection. Semin Arthritis Rheum. 2006;36:159-167. 8. Dinarello CA. Differences between anti-tumor necrosis factor- monoclonal antibodies and soluble TNF
receptors in host defense impairment. J Rheumatol. 2005;32(suppl 74):40-47. 9. Enbrel (etanercept) Medication Guide, Immunex Corporation, Thousand Oaks, Calif.
BEMaGS
F
BEMaGS
F
ENBREL
Do Not Copy,
Penalties Apply
ENBREL

When bound to TNF,

ENBREL inhibits TNF activity 3,4
When released, TNF continues its

normal function in the immune system1,8
BEMaGS
F
BEMaGS
F
Enbrel (etanercept)
binds reversibly to TNF
ENBREL continuously binds and unbinds to TNF
1,2
TNF plays a prominent role in the

inflammatory process of plaque
psoriasis and is recognized as an
important target in its treatment.3
Anti-TNF therapies currently approved
for psoriatic diseases* can be divided
into two fundamentally different
protein structures that help define
their binding attributes: soluble
TNF receptor fusion protein and
monoclonal antibody.4-6
mimicking the activity of naturally

occurring soluble TNF receptors.1-4,7
When ENBREL is in the body, there is
a dynamic and relative exchange of
bound and unbound TNF to ENBREL.1
When bound to TNF, ENBREL reduces
inflammation and the signs and
symptoms of moderate to severe
plaque psoriasis.3,4 When released,
TNF is biologically active and is able
to perform its normal functions.1,8
ENBREL, the only soluble form of a

fully human TNF receptor, binds to
TNF trimers in a 1 to 1 relationship,
Because ENBREL suppresses the

immune system, it may increase
the risk of infections.4,9
Do Not Copy,
Penalties Apply
The clinical significance of binding attributes is unknown.

ENBREL is indicated
for the treatment of adult patients (18 years or older) with
chronic moderate to severe plaque psoriasis who are candidates for systemic
therapy or phototherapy.
ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of
structural damage of active arthritis, and improving physical function in patients
with psoriatic arthritis. ENBREL can be used in combination with methotrexate in
patients who do not respond adequately to methotrexate alone.
Please see Important Safety

Information and Brief Summary
of Prescribing Information
on adjacent pages.
*Psoriatic diseases are comprised of plaque psoriasis
and psoriatic arthritis.
BEMaGS
F

!"" #
$ $!

!"#$%

&

'

(

!)* %

'

%
5+J K, +5K=+ 5,3#5K+
/

(

0
! %

$, %
"

(

1
L .

/

'

/

#

L 5

/

0 .

-

(

L

# (

/

(

5
8*

9

&:);<
!):;<;
%
=
+
3

(

#, (

,

.

(

.

>

(

(

(

5
&9-(

(

!:?%

!@?% #

(

.3

! ""!$
&(&
$, - (&% 3

(

((+0 &
#

#,

3

0

#

>

#,

:* /

-

! $, %
3
((+0 &

#

.
(

.
(

!

%

4

#

(

!.3 ) )@<A% >

BEMaGS
F
"
)& 0 +&

-

-
+3(
- #

+3(

! %

*&
(("
5

'

! !
% E/

5

=F
% #

'
#
B
B

/

'

.
-

5

'

&/ .3

#

(

.

(

! $, -
&/ .3

% #
- (

!3C,%

(

#

3C,

3C,

(

+

6@ /

(&&&(
.
-#,

#,

5
9<
.

-

#

A

! %-#
+
&1$, (&1
#
+
&% #

4
(&
"

-

#

(

/

! ! -(&&&(%
5
G5.

0

0

/

D H 5
7

Do Not Copy,
Penalties Apply
$

(

#
+
&
5

#,-(

#, (

4

8
96@< -

@
&@9@

!

8 &9
% 5

-

<

6:&8
))&@)
- #
8-

>

( ! %

#,-(

(

! $, -#
+
&%)))&
(
#

!
%
$, - (
(*&%

&'((& (&
-(

! $, &
&(()*%
+
*0&
( (
( ( (
(& ( &%
+

5

-(

#,-(

.

5

0 -
)*@
>
B

/

!

$+
(&
'

0

%

+

(

-

C (

! $, -#
+
&% #

#

#
5

. &9 (

0

# (

>
B

(
:?

1

#

2
2

!@?% ! %% #

(

!.3 I ) )@<A%
2
3
&,&
0
(

5

>
B

= #, (

! !
$,

!

%
!CD%

- (&%

-

#
5

CD

#,

3

(
#
2009-Journal
of Drugs in Dermatology. All Rights Reserved.
! %-#
+
&
$, -#
+
&%

4

/

0

CD
/

information,
images
and
marks
of
Journal
of
Drugs
in Dermatology
(JDD).

(

( CD

CD

#,-(

#, ( /
No reproduction or use of any portion of the

contents
of
these
materials
may
be
made
without
the
express
written
consent of JDD.

- (

0

#

(

#, (

#, (

/

CD .'

(+&&1#
+&&1
*
(
(

If
you
feel
you
have
obtained
this
copy
illegally,
please
contact
JDD
immediately.

CD
-

-

#, (
CD
/

"

CD
'

#

#,-(

CD

(

5

5

6
(

CD

+

+(

-

4

#
CD

3 -7
!37%

;@- )@@-

(

# (

.
-

#

'

!

(

3

#

.

/

&?
5

-

)-*::-8))-*<:&

(&&&.(*& (+(&**
&/.(*0(
/

&+#( .&
(*+"
1&

&/.(.
00(&
3
1 #

+3(
5
(

(
(
0* (( &/ .
.+.0
( (&&1

! %

(/.(.
0.
*(&(
/ .
&(/ .
0 (&&2

(

/

(
((
&

/
E"

#

!&
7F

( '

. 9*@ .

*< '
;6

# (
'

(
/

.

(

BEMaGS
F

& "

-

&
,

!1)
0 $"2
()&," $" "
+ *2

&
#

'

(
&," $" & "+ *-"$ * "-#$" '

$& "-$3"$ " "

)88&
.
*?

):;
&8

&&&

(

)?

)&:)

' )6
5

-

8>

#

&6 +3 (
5
' &6 +3

( &6 +3 (
6? +3 (
4 $ $"
5

79>

5

' )8>

7

.

!

@

%

5

'

'
#

7 6 +

'

5
(

$"
5

.

(

'

! "#$ .

% #

&?>

-
-

.
.+

)&>
-

'
7

5
-

.
(

'

! )>
-
- %
5

.

1

#

-

-

-

+

- (

+
(

"

!

%

! !% 4

.

;
5

(
&8 (

9> #

!8 %
!8 % D

5
- (

0
5

5

'

-

1

5

&??9?
!&*7?*
- %

??)>
5
)687*

!&76&8
- %

<+

3

???9>

#

-

! !%
#,

:>

.
(

'
#

-
0

C5.

.

#
-

(

#

5+.

.

,

$ $& "
/
.

5
. + 5
55

!..%
.. ! )18?%

!))>%

-

!6>% #

-
4.

!)6>
8> -

%

!7>

-
% #

-
5
+ 555

"#$

#
-

(

@ .

-(

*&," $"
# )? 0

7>

. !

%

+ 555 5
-
'

!:8>%

!)66>%
+ 5
55 D

6? (

&6 ( 5
+ 5

B

<

-

<

(
.

(

'
.

BEMaGS
F
B @ 1

"( 1
1

! !)
$$' ,"%
1

+(
1

<
1

(

5

0

6)
.
6? (
&6
&6 (

6? (
1

0

(

&6
&," $" "+ *2
5

'

! !

(% 4

+

:; C5.
8 )9

! ) 0 $"%

@

@
. ( # )

-

,- :; !:&>%
C5.

! )
- %

'

6*

)&

-

#

C5.

# C5.

'
#

:; C5.

7
78; .

-
#
!);>
)9

- %
!;> )?

- %

!);>
?98

- %

!)7> ?98

- %
5

-

C5.

& 8

5
- (

1

0

! !%

# '

(

"+ */
#
0 -

3B, 5

&6 (
&6 ( 5

&6
( &6 (

.

(

! ) "+ */ %
Do Not Copy,
Penalties Apply
7:)
$ "
$ '&,","
$$& ">
$
$$&
,$$&
<&=
$
"
$
"
&," $$ $$

$$"
$"
.

-

/

"#$

0
'

! H )6&% ! H 78;% ! H &)9% ! H 8)6%

5

)?
79
9
78
.

1
5

! %GG
7&
76
9&
:8
1

-

0

!

-<5%GG
7&
7*
:?
6)
3 1

!
%
<
-

!<5%GG
):
&;
7;
7)
! ) "+ */
B
)7
)9
&9
&8
%

)?
;
&;
)6
41

*
)&
)8
):

400

6
9
))
*
B @ 1

/

6
9
;
:
(

3
7
:
:
6

! !%
.

7
6
)&
))
B 1

.

7
6
)?
)?
"( 1

-(

7
6
&7
)8

/
7
&
8
*

)
6
.
.
1
( 0

' "

4
)
8
)?
))

/


+

&
7
7
6
.
88:&

I

F
7
*
6

&9
!
)????
- %
This document
contains proprietary information, images and marks of Journal of Drugs in Dermatology
(JDD).

! !%
; ??; )??
-
"
)
&
)8
:

# 7-

any

.
)materials
) may )&
: withoutD 1
No
reproduction
or
use
of
portion
of
the
contents
of
these
be
made
the
express
written
consent of JDD.

+

1

/

4 )? .

!J"#$
L%
F illegally,
F please
& contact
? JDD immediately.
If
you
feel
you
have
obtained
this
copy

G5
:-

)))& ! !)
+(
1

"#$
' "% + -

+
-C

D

K#

-

)? .

:

GG5

! %
-

-<5
<5

-

%.* " " ""&$
" ' $ $
5
-

* ;77

,. 56)7898::;

! H ))? H &)7%
) 8)8
.
)&:)

&)

5
3
5

.

!)?:&
- %
#
D ( 3. ;)7&?-)9;;

'
6>
-

&&

&7

2 ;

<+
))7&

5

'

)&
)7

-
(

'
)6>
-
" ( .

= /
!* 6 ' %
)

-B(
A .

7

.

.
E
);;* F &??* 5

3
.
-
!;?
-
% )

-
-

-

& '
# 0

! !) ' "- ( )
5
<+ /
1

' "%

! () $"%
67;69:?2 6:?6:;?2 6;867;92 :&?))?62 :69&*6&2 7:966

D
'

.
*;
=
A

0 -
6

-

! !) ' "%
$'
/
.
(

'

.

.
(

'
1
3 1

41

,

)-***-87:-&976

______
E &??9 .
#
D ( 3. ;)7&?

= / 5
/ /. );)?)
.
BEMaGS
F
BEMaGS
F
JUNE 2009
546
70-6.&t*446&
COPYRIGHT 2009
ORIGINAL ARTICLES

-FPO),JSDJL.%BBOE+BNFT2%FM3PTTP%0C
B
*OEJBOB6OJWFSTJUZ.FEJDBM$FOUFS *OEJBOBQPMJT *OEJBOB

.FEJDBM%JSFDUPS %FSN3FTFBSDI 1--$ -PVJTWJMMF ,FOUVDLZ
C
%FQBSUNFOUPG%FSNBUPMPHZ 6OJWFSTJUZPG/FWBEB4DIPPMPG.FEJDJOF -BT7FHBT /FWBEB
ABSTRACT
Introduction: Psoriasis is one of several systemic diseases that presents chiey with cutaneous symptoms and has the potential
to negatively impact patients overall health and quality of life. Physicians who treat patients with psoriasis must be cognizant of the
chronic, lifelong character of the disease and of the potential for multisystem pathology. According to the National Institutes of Health
(NIH), between 5.8 and 7.5 million persons in the U.S.approximately 2.2% of the populationhave psoriasis; worldwide, it affects
an estimated 125 million people. The annual cost of treating psoriasis may exceed $3 billion annually. Immunologic mechanisms are
now accepted as the pathophysiologic basis for the development of psoriatic disease. Treatment strategieswhich include topical
treatment, phototherapy, methtrexate, cyclosporine and acitretinalso encompass several biologic agents that target immune mediators associated with the condition.
Discussion: Patients with mild disease may obtain symptomatic relief with topical agents and targeted phototherapy. Patients with
moderate-to-severe disease are likely to benet from systemic therapy. Shortcomings of the traditional agents, particularly their
adverse event proles, have motivated research and development of biologic agents. Currently three anti-TNF agents etanercept,
iniximab and adalimumab are FDA-approved for treatment of psoriasis. Differences exist among study designs and, therefore,
in interpretation of data; however, the improvements observed in the psoriasis study populations participating in clinical trials are
dramatic. Long-term clinical data continue to accumulate and demonstrate sustained benets with anti-TNF agents. Safety data also
continue to be collected over the long-term; key safety considerations are infection, cytopenia, demyelinating disease, lupus-like
syndromes, congestive heart failure and malignancies. Combination therapy should also be considered when managing psoriasis for
such reasons as augmenting an inadequate response to monotherapy or improving tolerability. Combination therapy with an anti-TNF
agent and phototherapy has shown considerably higher rates of response compared with either intervention alone.
Objective: The objective of this paper is to critically examine the anti-TNF studies to assess the efcacy and safety of the agents
in patients with psoriasis and determine applicability of the data in clinical practice. In light of the chronic nature of this disease, the
emphasis will be on the longest-term data available.
Conclusion: The treatment of plaque psoriasis with TNF- antagonists is still a relatively recent addition to the pharmacologic armamentarium available to clinicians. The collection of long-term data is, therefore, small but growing as results from newer studies
emerge. From the data reviewed here, the clinician can attempt to arrive at a satisfactory assessment of the benets and risks of
treatment with these agents.
Do Not Copy,
Penalties Apply
INTRODUCTION
Psoriasis and its effect on patients should not be trivialized; it

soriasis is one of several systemic diseases that presents
is a chronic condition that may be emotionally and physically
2009-Journal
of Drugs
in Dermatology.
All Rights
Reserved.
chiey with cutaneous symptoms
and has the
potential
devastating.
In fact,
an appropriate treatment model for psoriato negatively
impact patients
overall health
and qualsismarks
would
that of
used
in in
diabetes
mellitus.
Blood sugar levels
This document
information,
images and
of be
Journal
Drugs
Dermatology
(JDD).
ity of life.
immediate
concern
of most
is likely
thematerials
are may
not be
followed
for just
3-month
period
but of
are
monitored
NoThe
reproduction
or use
of any portion
of patients
the contents
of these
made without
theaexpress
written
consent
JDD.
prompt resolution of skin involvement;
physicians
across
several
Clinical studies in diabetes emphasize
If you feel you however,
have obtained
this copy illegally,
please
contactyears.
JDD immediately.
who treat patients with psoriasis must be cognizant of the
glycemic control characterized by spot-checking fasting plasma
chronic, lifelong character of the disease and of the potential
glucose but also by assessing glycosylated hemoglobin A1c
for multisystem pathology.1
(HbA1c). Successful treatment is one that lowers HbA1c for a
short period, such as 3 or 6 months, but also maintains desirPsoriasis is a common disease, accounting for 4.3% of ambulaable levels across several years. Similarly, the optimal standard
tory visits to dermatologists in the United States (U.S.) in 2004.2
for psoriasis treatment would span years not months.
According to the National Institutes of Health (NIH), between
5.8 and 7.5 million persons in the U.S.approximately 2.2% of
It had long been thought that the abnormal epidermal differenthe populationhave psoriasis; worldwide, it affects an estitiation that produces psoriatic plaques was the result of keratimated 125 million people. The annual cost of treating psoriasis
nocyte hyperproliferation. However, the frequency with which
may exceed $3 billion annually.3
psoriasis comorbidly occurs with other immunologic diseases
such as rheumatoid arthritis (RA), Crohns disease and inam-
BEMaGS
F
BEMaGS
F
547
+6/&t70-6.&t*446&
-,JSDJL +%FM3PTTP
matory bowel disease suggest a common immunologic and/or

inammatory etiology.
weeks of treatment and 88% completed 24 weeks of treatment,

with equal proportions completing treatment in each group.5
It is now accepted, for example, that epidermal hyperplasia is

a reaction to the activation of the immune system in focal skin
regions.4 Observations that suggest immunologic mechanisms
are involved in psoriatic disease include responsiveness to immunosuppressive agents such as methotrexate, cyclosporine,
and biologics; exacerbation of symptoms in reaction to certain
cytokines such as interferons and interleukin (IL)-2; and resolution of psoriasis linked with decreased inltration of mediators
of inammation and expression of genes for TNF-, interferon
gamma (IFN-), and ILs.1
The proportions of patients achieving PASI 75 were 49%, 34%,

15% and 4% in the etanercept 50 mg twice weekly (BIW), 25 mg
BIW, 25 mg weekly, and placebo groups, respectively (P < 0.001,
all groups vs. placebo). Statistically signicant differences between the 50 mg BIW etanercept and placebo groups were noted as early as Week 4, and between the 25 mg BIW etanercept
and placebo groups at Week 8. The mean percentage improvements from baseline in PASI were statistically signicant for all
three etanercept treatment groups as early as Week 2. By Week
12, the mean level of improvement was 40.9% in the etanercept
25 mg weekly group, 52.6% in the 25 mg BIW group, and 64.2%
in the 50 mg BIW group, compared with 14.0% in the placebo
group. At Week 24, PASI 75 response rates were 25%, 44% and
59% for the etanercept 25 mg weekly, 25 mg BIW, and 50 mg
BIW groups, respectively.5
Treatment Strategies
Treatment strategies for psoriasis include topical treatments,
phototherapy, methotrexate, cyclosporine, acitretin and biologic agents.1 Patients with mild disease may benet from topical agents and targeted phototherapy. The necessity of treating
psoriasis for the long termoften for the lifetime of the patientrequires that the clinician be especially alert for adverse
effects that may emerge with extended periods of treatment.4
As noted in Table 1, the Papp et al. study (2005) evaluated etanercept and included assessment of a step-down dose for the
group originally treated with 50 mg BIW to determine if the
step-down dose (i.e., etanercept 50 mg BIW to 25 mg BIW)
would continue to benet patients. Pre-specied efcacy analyses were performed on all randomized patients who received
at least one dose of study drug, and missing post-baseline efcacy data were imputed using LOCF. Patients with missing data
at a given visit were assumed not to have met the response
criteria for that end point.6
Do Not Copy,
Penalties Apply
Shortcomings in treatment of psoriasis with traditional agents

motivated the quest for better treatment options and focused
clinical attention on biologic agents. These are proteins with the
capacity to inhibit the autoimmune response mediated by one
of the immune mediators such as B cells, T cells, or TNF-. They
may be directly extracted from animal tissue or synthesized
through recombinant deoxyribonucleic acid (DNA) technology. The three agents that block TNF- and are indicated for the
treatment of psoriasisetanercept, iniximab and adalimumabare the focus of this review.
A total of 611 patients were randomized for treatment at 50 sites

in the U.S., Canada, and Western Europe; of these, 583 received
at least one dose of study drug and were included in the primary analyses. The median BSA affected by psoriasis was 23% and
the baseline PASI was 16.4. Of the 583 patients who received
The objective of this paper is to critically examine the anti-TNF
the study drug, 559 (96%) completed the initial 12 weeks of the
studies to assess the efcacy and safety of the agents in pastudy, 557 continued to the second 12 weeks, and 538 complettients with psoriasis and determine applicability of the data in
2009-Journal
of Drugs the
in Dermatology.
Reserved.
ed the All
fullRights
24 weeks
of the study. At Week 12, PASI 75 had been
clinical practice. In light of the chronic
nature of psoriasis,
achieved
49% of
in the etanercept
emphasis will beThis
on document
the longest-term
available.
contains data
proprietary
information, images and
marks ofby
Journal
of patients
(JDD).50 mg BIW group,
34%may
in the
25 mg
BIW group,
and written
3% in the
placebo
group (P <
be made
without
the express
consent
of JDD.
Etanercept: Efcacy in the
Treatment
Psoriasis
0.0001,
all contact
groupsJDD
vs. immediately.
placebo). Mean percentage improvement
If you
feel you haveof
obtained
please
A summary of etanercept study characteristics (e.g., design,
from the baseline PASI at Week 12 was 68% in the etanercept 50
dosing, efcacy variables) is presented in Table 1. In the Leonarmg BIW group, 57% in the 25 mg BIW group, and 0.2% in the
di et al. study (2003), all patients who received at least one dose
placebo group (P < 0.0001, all groups vs. placebo).6
of double-blind study treatment were included in the analyses
At Week 24, the response rates for all three treatment groups
and, in cases of missing data or termination, analyses were
were either sustained or improved. Figure 1 illustrates the PASI
based on last observations carried forward (LOCF). Of the 672
response rates for the three treatment groups during the 24
patients who were randomized, 652 received at least one dose
weeks of the study. A notable observation concerned the 88 paof double-blind study treatment. Demographic characteristics,
tients in the etanercept 50 mg BIW group who had not attained
disease history and severity of disease at baseline were comPASI 75 by Week 12; of these, 32% did so by week 24, despite
parable between the groups. Mean affected body surface area
the dose reduction from 50 mg BIW to 25 mg BIW.6
(BSA) was 28.7%, and mean Psoriasis Area and Severity Index
(PASI) was 18.4. Ninety-four percent of patients completed 12
BEMaGS
F
BEMaGS
F
548
+6/&t70-6.&t*446&
The results of this trial were remarkably consistent with a study

by Leonardi and colleagues detailed above. This trial also demonstrated that patient response rates were maintained, despite the
reduction in the etanercept dose from 50 mg BIW to 25 mg BIW.6
The objective of the Moore et al. (2007) study was to compare
the efcacy and safety of continuous etanercept therapy with
a single round of discontinuation and retreatment. All patients
who received at least one dose of study drug were included in
the modied intent-to-treat (MITT) analysis. Dropouts prior to
Week 12 were imputed to be non-responders and LOCF imputation was used after Week 12. Of 2,555 patients initially randomized, 2,546 entered the study and received at least one dose
of study drug; 1,117 of the 1,272 in the continuous treatment
group; and 1,084 of the 1,274 in the interrupted study group
completed the study. Baseline characteristics were similar between the two groups.7
-,JSDJL +%FM3PTTP
At 12 weeks, the proportion of Physician Global Assessment

(PGA) responders was similar in each group: 71.3% versus 72%.
At Week 24, the proportion of responders was signicantly higher in the continuous treatment group compared with the interrupted treatment group: 71% versus 59.5% (P < 0.0001). Most
patients whose treatment was interrupted at Week 12 regained
responder status once treatment was reinitiated. Mean time to
relapse after discontinuing therapy was 39.6 days; time to regain responder status after retreatment was 35.0 days. Table 2
shows responder status after continuous and interrupted therapies. The authors suggested that although continuous etanercept therapy provided optimal benets, patients who respond
to etanercept may, if circumstances dictate, safely discontinue
and then reinitiate treatment with a high probability of recapturing the initial response.7
In the phase III study by Tyring et al. (2007), 618 patients were
randomized to receive placebo (n = 307) or etanercept (n = 311);
TABLE 1.
Etanercept Clinical Trial Summary
Study
Leonardi, et al (2003)
Papp, et al (2005)
Do Not Copy,
Penalties Apply
Duration and Design*
Dosing
Efcacy Variables
24 weeks; double-blind,
placebo-controlled
Weeks 012 randomized to:

etanercept 25 mg qW;
etanercept 25 mg BIW;
etanercept 50 mg BIW;
Weeks 1224: Placebo switched to
etanercept 25 mg BIW
Primary: PASI 75 response rates at

Week 12
Secondary: PASI 50 and 90
response rates
24 weeks; double-blind,
placebo-controlled
Weeks 012 randomized to:

etanercept 50 mg BIW
etanercept 25 mg BIW; placebo
Week 12: etanercept 25 mg BIW for
all patients
Primary: PASI 75 response rates at

Week 12
Secondary: Improvement from
baseline in Physicians Assessment
of Scalp Psoriasis, BSA
involvement, DLQI response
Primary: Proportion of PGA

24 weeks; randomized,
Weeks 012: etanercept 50 mg
responders
open-label
BIW for all patients Weeks 12 to
Secondary: Improvement
24:Dermatology.
ContinuousAll
group
received
2009-Journal of Drugs in
Rights
Reserved.
from baseline in Physicians
etanercept 50 mg qW; intermittent
Assessment of Scap Psoriasis, BSA
group responders** discontinued
No reproduction or use of any portion of the contents of these
materials
mayatbeweek
made16without
written consent
of JDD.
involvement,
DLQI response
tx until
relapse
or 20 the express
thenillegally,
reinitiated
etanercept
50 mg
If you feel you have obtained this copy
please
contact JDD
immediately.
qW; non-responders received
etanercept 50 mg qW
Moore, et al (2007)
Tyring, et al (2007)
12 weeks; double-blind
followed by 132-week openlabel extension
Weeks 012 randomized to etanercept 50 mg BIW or placebo; Weeks

12132 all received etanercept 50
mg BIW
Primary: PASI 75 response rate at

Week 12
Secondary: PASI, DLQI, PGA
DLQI = Dermatology Life Quality Index

*Inclusion and exclusion criteria for the studies were as follows: Patients were at least 18 years of age, had active but clinically stable plaque psoriasis
involving at least 10% BSA, scored a minimum of 10 on the PASI (indicating moderate to severe psoriasis), and received photothereapy or systemic
psoriasis therapy at least once or had been a candidate for such therapy. Exclusion criteria included previous antibiotics within 1 week of the start of the
study, active skin infections within 4 weeks, skin condition other than psorisis that would interfere with evaluation, and active guttate, erythrodermic or
pustular psoriasis at the time of the screening visit.
** Responders defined as those who had attained scores on the PSA of 2 or lass and demonstrated improvement fromthe baseline.
BEMaGS
F
BEMaGS
549
+6/&t70-6.&t*446&
of these, 591 patients continued treatment into the open-label

phase of the study. At baseline, patient characteristics were
similar between the two treatment groups; baseline BSA involvement was 27.2% and baseline PASI was 18.2. A history of
psoriatic arthritis was present in 34.3%.8
Rapid improvements in percentage of patients attaining PASI 50,
75 and 90 were evident as early as Week 12 in patients initially
treated with etanercept; patients initially treated with placebo
then switched to etanercept at Week 13 experienced improvement in PASI scores by Week 24. Figure 2 shows the response
rates from the start of the trial to Week 96 for PASI 50, 75 and 90
for the two groups of patients.8
PASI 75 response rates peaked at Week 48, with 63% of patients
originally given etanercept and continued on etanercept treatment (etanercept/etanercept) and 61.1% of those switched from
placebo to etanercept (placebo/etanercept) attaining that level
of response. Most patients (74.4%) who attained a PASI 75 at
Week 48 retained this response at Week 96 but 25.6% lost their
PASI 75 at Week 96. Among the patients who lost their PASI 75
responses, the progressive change in scores was from a baseline value of 20.0 for the placebo/etanercept cohort to 6.7 at
Week 96 and from a baseline score of 18.9 for the etanercept/
etanercept cohort to 7.2 at Week 96. A relatively small proportion (17.4%) of the 132 patients who had not achieved a PASI 75
at Week 48 did so by Week 96.8
-,JSDJL +%FM3PTTP
the long-term ndings provide evidence supporting the effectiveness of etanercept for the long-term treatment of psoriasis.8
In a third phase of the study, U.S. patients (n = 201) had their
etanercept dose reduced to 50 mg weekly and were followed
for an additional 48 weeks, ultimately supplying long-term data
for up to 144 weeks. Patients in whom efcacy was not maintained were eligible to have their dose raised to the previous 50
mg BIW level. Among the patients who increased their dose to
50 mg BIW (n = 122), mean PASI scores were 19 at baseline, 4.3
at Week 96, 9 at Week 120 and 7 at Week 144.9
Iniximab: Efcacy in the Treatment of Psoriasis

The Chaudhari et al. (2001) study was a randomized, placebocontrolled, double-blind trial of 10 weeks duration followed
by an open-label phase to 16 weeks in adult patients who had
moderate-to-severe plaque psoriasis involving at least 5% BSA.
Patients had a history of plaque psoriasis for a minimum of 6
months and a history of topical corticosteroid failure. Patients
were excluded if they used topical therapy in the previous 14
days, systemic therapy in the previous 28 days, or had been
treated with a range of biologic agents at any time. Other exclusion criteria included a range of infections, malignancies, clinically signicant laboratory abnormalities, or drug or alcohol
abuse. Patients were randomized to receive placebo or iniximab 5 mg per kilogram (mg/kg) or 10 mg/kg at Weeks 0, 2 and
6. The primary efcacy outcome measure was PGA at Week 10
of the study. A positive response was dened as good, excellent or clear ratings on the PGA, equivalent with 50% to 74%
clearing, 75% to 99% clearing, and 100% clearing of psoriatic
plaques, respectively. The proportion of patients achieving PASI
75 was a secondary end point.10
Do Not Copy,
Penalties Apply
Compliance was considered a potential reason for the loss of efcacy in some patients during the study, as those judged less compliant in terms of the percentage of self-administered doses had
a higher likelihood of worsening PASI scores. The authors speculated, however, whether psoriasis-specic factors might not decrease the TNF dependency of the disease in patients treated with
TNF antagonists. Despite some loss in response rates over time,
At Week 10, patients were classied as either responders or nonresponders, and the study was unblinded. Non-responders in
TABLE 2.
Responder Status After Continuous Or Interrupted Etanercept
responders
No reproduction or use of any portion of the contents of these materials may be made without thePGA
express
written consent of JDD.
Treatment arm
If you feel you have obtainedMean

this copy
PGAillegally,
score please contact JDD immediately.
No. (%)
at baseline (SD)
Week 16 No. (%)
Week 20 No. (%)
Week 24 No. (%)
Continuous
All patients
Week 12 responders
Week 12 non-responders
1272 (100)
907 (71.3)
365 (28.7)
3.17 (0.80)
3.16 (0.72)
3.21 (0.97)
894 (70.3)
804 (88.6)
90 (24.7)
880 (69.2)
769 (84.8)
111 (30.4)
903 (71.0)
766 (84.5)
137 (37.5)
Interrupted
All patients
Week 12 responders
Week 12 non-responders
1274 (100)
917 (72.0)
357 (28.0)
3.15 (0.81)
3.13 (0.73
3.19 (0.98)
650 (51.0)
556 (60.6)
94 (26.3)
648 (50.9)
539 (58.8)
109 (30.5)
758 (59.5)
632 (68.9)
126 (35.3)
PGA = Physicians Global Assessment; SD = Standard deviation

Reprinted from J Am Acad Dermatol. 2007:56(4):600. Moore A, Gordon KB, Kang S, et al. A randomized, open-label trial of continuous versus interrupted
etanercept thereapy in the treatment of psoriasis, with permission from Elsevier.
BEMaGS
F
BEMaGS
550
+6/&t70-6.&t*446&
the placebo group were assigned to receive iniximab 5 mg/kg

or 10 mg/kg at Weeks 10, 12 and 16. Responders in the placebo
group were followed and treated with iniximab in the event of
relapse. Non-responders in the iniximab 5 mg/kg group were
offered a single infusion of iniximab at the 10 mg/kg level, while
non-responders in the iniximab 10 mg/kg group were dropped
from the study (see next study for discussion of the open-label
phase of this trial). Analysis was done on the basis of intention to
treat (ITT); all randomized patients were included.10
-,JSDJL +%FM3PTTP
tients was 20.3. Although not a direct head-to-head comparison

with differences in patient populations and study design, the authors mentioned that iniximab response rates were higher than
FIGURE 2. Improvements in the Psoriasis Area and Severity Index

scores of at least 50% (PASI50), 75% (PASI75), and 90% (PASI90) over
time.
100
The benecial effects of iniximab are observed in this relatively

small study. It is noted that baseline characteristics were not consistent within each treatment group: mean age was 51 years in
the iniximab 5 mg/kg group, 35 years in the 10 mg/kg group,
and 45 years in the placebo group; and less severe disease (mean
PASI 22.1) was present in the 5 mg/kg group than the 10 mg/kg
group (mean PASI 26.6). Baseline PASI scores for the placebo pa-
PASI50
90
Percent of Patients
A total of 33 patients were included, evenly divided between the

three treatment groups. Nine patients (82%) in the iniximab 5
mg/kg group and 10 (91%) in the iniximab 10 mg/kg group
achieved the primary end point of good, excellent, or clear ratings on the PGA compared with 2 (18%) in the placebo group.
Results for PASI 75 were similar: 9 (82%) in the iniximab 5 mg/
kg and 8 (73%) in the 10 mg/kg group reached this level of improvement compared with 2 (18%) in the placebo group. Differences between iniximab and placebo groups were signicant
with P values ranging from 0.0019 to 0.03.10
85
80
74*
70
86
83
Etanercept 25 mg BIW
Placebo
Percent of Patients
60
50
40
85
82
83
82
80
79
50
40
30
Etanercept/Etanercept Group
Placebo/Etanercept Group
20
0
14
100
PASI75
Percent of Patients
90
80
70
60
60
41*
50
60
58
63
61
60
58
55
55
54
54
52
51
48
40
30
20
10
100
PASI90
90
50%
87
85
60
10
Percent of Patients
70
87
76
Do Not Copy,
Penalties Apply
FIGURE 1. Percentage of patients achieving a PASI 75 response

(improvement from baseline of at least 75% in the Psoriasis Area and
Severity Index) over time: sensitivity analysis.
87
80
70 All Rights Reserved.

60
This document contains proprietary information,42%

50
30 No reproduction or use of anyportion of the contents of these materials may be made without the express written consent of JDD.
40
30
If you feel you have obtained this 26%
30
28
26
27
25
30
20
21*
29
28
20
25
*
10
22
21
17
10
0
1
0
0
0
12
16
20
24
Weeks
BL
12
24
36
48
60
72
23
23
84
96
Week
This includes all randomized patients, regardless of whether they received

study drug, and assumes that patients with missing data at a given visit
did not meet the response criteria. BIW, twice weekly. *P<0.0013 vs. placebo; P<0.004 vs. etanercept 25 mg BIW; P<0.001 vs. placebo.
*P<.001, 50 mg of etanercept twice weekly vs placebo at week 12 (2-sided

van Elteren test stratified by previous therapy) based on an intent-to-treat
analysis using last observation carried forward. BL indicated original study
baseline.
Reprinted with permission from Blackwell Publishing. Papp KA, Tyring S,

Lahfa M, et al. A global phase III randomized controlled trial of etanercept
in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol.
2005;152(6):1309.
Source: Tyring S, Gordon KB, Poulin Y, et al. Long-term safety and efficacy
of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol. 2007;143(6):724. Copyright 2007 AmericanMedical Association. All
rights reserved.
BEMaGS
F
BEMaGS
F
551
+6/&t70-6.&t*446&
-,JSDJL +%FM3PTTP
those for etanercept in studies to that point. They suggest that

these differences may be due to differences in study populations
and/or differences in the route of administration, but they also
indicate that the iniximab/TNF- complex may be more stable
than the etanercept/TNF- complex, and that in vitro iniximab
can lyse TNF-expressing cells.10
placebo for the treatment of patients with skin and nail lesions.
Patients in the iniximab group received infusions of 5 mg/kg
at Weeks 0, 2, and 6 and then every 8 weeks through to Week
46. Patients in the placebo group were crossed over to iniximab therapy at Weeks 24, 26, and 30, and then every 8 weeks
through to week 46.12
The Gottlieb et al. study (2003) describes the open-label extension of the previous study through Week 26. Three patients in
each iniximab group received one retreatment infusion and 4
patients in the 5 mg/kg group received two retreatment infusions. As in the rst phase of the study, PASI 75 was employed
to assess symptom improvement from baseline; however, the
PGA was not used in the open-label extension.11
The principal efcacy outcome measure was the proportion of

patients achieving improvement from baseline to PASI 75 at
Week 10; secondary end points included attainment of PASI 75
at Week 24 and the proportion of patients achievement of a PGA
score of cleared (0) or minimal (1) at Week 10. Nail psoriasis was
assessed using the Nail Psoriasis Severity Index (NAPSI). ITT
statistical analysis was used. Data obtained after two missed
infusions or after study infusion discontinuation were excluded.
Patients who discontinued because of lack of efcacy or loss
of response or who started disallowed non-topical medications
were deemed non-responders in the per-protocol analysis.12
A total of 30 patients completed the rst phase of the trial and

continued to the open-label phase. Of these, 29 received either
5 mg/kg or 10 mg/kg of iniximab; 1 responder in the placebo
group remained untreated through the entire duration of the
trial. Of those 29 patients, 25 completed the trial and 4 discontinued. Among the 30 patients, 17 (57%) maintained PASI 50
at Week 26 and 15 (50%) maintained PASI 75. Of the patients
who received the 5 mg/kg dose, 40% maintained PASI 50 and
33% PASI 75. Of those who received the 10 mg/kg dose, 73%
maintained PASI 50 and 67% maintained PASI 75. A total of
nine patients who initially responded to iniximab experienced
a relapse of symptoms and were subsequently retreated. PASI
scores improved with retreatment but not as much as was seen
with the initial treatment.11
Of the 378 enrolled patients, 77 were randomized to placebo

and 301 to iniximab 5 mg/kg. The two treatment groups were
well balanced as to baseline disease characteristics and demographics. Baseline PASI was 22.8 in the placebo group and 22.9
in the iniximab group; approximately 30% in both groups had
psoriatic arthritis.12
Do Not Copy,
Penalties Apply
At Week 10, 80% of iniximab-treated patients had attained

PASI 75 compared with 3% in the placebo group. For PASI 90,
these proportions were 57% and 1%, respectively; for PASI 50,
91% and 8%, respectively (P < 0.0001; all comparisons vs. placebo). Although response rates held steady through Week 24,
by Week 50, PASI 75 responder rates among the original iniximab treatment group declined from 80% to 61%. Of note, 77%
of patients who switched from placebo to iniximab at Week 24
maintained a PASI 75 response at Week 50.12
There was a dose response regarding the duration of clinical

benet. In general, patients who received the 5 mg/kg infusions
of iniximab at Weeks 0, 2, and 6 began to lose response after
Week 14, whereas patients who received the 10 mg/kg infusion
did not lose response until after Week 18. The authors surmise
that these differences may be related to the pharmacokinetics
Samples for analysis of antibodies to iniximab from 264 inixof iniximab or, alternatively, to dose-dependent effects on the
All Rights
Reserved.
imab-treated
patients
revealed 64% of samples were negative
psoriasis disease process.11
formarks
antibodies,
27%
were in
positive,
and 10%
were inconclusive.
of Journal
of Drugs
Dermatology
(JDD).
The open-label
extension
described
in this
provides
valuCorrelation
between
antibodies
maintenance
of response
No reproduction
or use
of any portion
of study
the contents
of these
materials
may be made
without
the expressand
written
consent of JDD.
able data about the duration Ifofyou
response
to iniximab.
With
a illegally,
through
50JDD
wasimmediately.
evident: among PASI 75 responders at
feel you have
obtained this
copy
pleaseWeek
contact
drug that is given by infusion, a desirable characteristic is one
Week 10, 39% of those with positive antibodies to iniximab
that permits the treatments to be widely spaced across time. At
maintained their response at Week 50 compared with 81% of
16 weeks, 82% of patients receiving iniximab 5 mg/kg attained
antibody-negative patients and 96% of patients with inconcluPASI 75; this proportion dropped to 33% at 26 weeks. In pasive results.12
tients receiving iniximab 10 mg/kg, 73% had attained PASI 75
This study, like the previous one, conrmed a high level of efat 16 weeks; it dropped to 67% at 26 weeks, indicating a more
cacy and a rapid response with iniximab for treatment of
prolonged duration of improvement for the higher dose. Part
plaque psoriasis. Some of the decline in response seen at Week
of this response may relate at least partially to the intergroup
50 may have been due to declining plasma concentrations of
baseline differences noted in the previous section.11
iniximab. It is noteworthy that the patients who were switched
The Reich et al. study (2005) was a phase III, multicenter, doufrom placebo to iniximab at Week 24 maintained higher proble-blind, placebo-controlled trial comparing iniximab with
portions of PASI 75 response than those who had been started
BEMaGS
F
BEMaGS
552
+6/&t70-6.&t*446&
on iniximab, perhaps due to receiving loading-dose infusions

later in the course of the study. Although the development of
antibodies to iniximab does not reliably predict those patients
who will respond to treatment, an effect of antibodies was seen
in terms of declining maintenance of response.12
Menter et al. (2007) performed a randomized, double-blind, placebo-controlled, multicenter trial that compared two doses of
iniximab and two schedules of administration: 3 mg/kg and 5
mg/kg given either on a continuous, every 8-week maintenance
schedule or on an as-needed basis. Adult patients with plaque
psoriasis were enrolled by investigators in the U.S., Canada
and Europe. Patients were eligible for phototherapy or systemic therapy; had a baseline PASI of at least 12 with at least 10%
BSA involvement; and no history of serious infection, lymphoproliferative disease, or active tuberculosis. All patients received
induction infusions at Weeks 0, 2, and 6. Patients assigned to
every-8-week maintenance continued to receive original iniximab infusions at Weeks 14, 22, 30, 38, and 46. Patients assigned
to as needed maintenance received their original iniximab infusions only during visits in which the observed improvement
in PASI from baseline was less than 75. A placebo infusion was
administered if PASI improvement was at least 75%.13
-,JSDJL +%FM3PTTP
iniximab 3 mg/kg as needed; 54.5% for iniximab 5 mg/kg

every 8 weeks; 38.1% for iniximab 5 mg/kg as needed. PGA
and DLQI values were consistent with PASI 75 scores; that is,
response rates were greatest among patients who received iniximab 5 mg/kg on an every-8-week basis and lowest among
those in the iniximab 3 mg/kg as needed group.13
As in the Reich study, patients with iniximab antibodies were
less likely to maintain a response at Week 50 than those whose
status was either negative or inconclusive. Patients who were
antibody-positive were also at greater risk for developing infusion reactions than those who were antibody-negative.13
This study, like the others previously noted, provides strong
conrmation of the early efcacy of iniximab for the treatment of plaque psoriasis. The comparison of the 5 mg/kg infusion with the 3 mg/kg infusion conrms that efcacy isto
some degreedose-related. Overall, the results of comparing
the steady, every-8-week infusion schedule with the as-needed
infusion schedule suggest that the former is more effective in
achieving a benecial response.13
Do Not Copy,
Penalties Apply
The primary efcacy end point was the proportion of patients

attaining a PASI 75 at Week 10. Other end points included PGA
and change from baseline in the Dermatology Life Quality Index (DLQI); additional parameters included PASI 50 and PASI
90. ITT analysis was used.13
Adalimumab: Efcacy in the Treatment of Psoriasis

In the Gordon et al. study (2006), patients were 18 years of age
or older with plaque psoriasis of at least one years duration
and involving at least 5% BSA. Patients with lymphoproliferative disease, history of cancer, or central nervous system
demyelinating disease were excluded. The study consisted of
two phases: the rst was a 12-week, double-blind, placebo-controlled, multicenter study in which patients were randomized to
receive subcutaneous (SC) injections of placebo or one of two
adalimumab regimens: (1) 80 mg adalimumab at Week 0 fol-
Percent of Patients Achieving

PASI 75 Improvement from
BaselineThrough Week 10
Of 835 patients enrolled, 313 were randomly assigned to receive iniximab infusions of 3 mg/kg, 314 to iniximab 5 mg/
kg, and 208 to placebo. A total of 252 patients permanently
discontinued the study agent through Week 50. Following the
FIGURE 3. Proportion of patients in the iniximab and placebo groups
second randomization at Week 14, 149 patients were assigned
achieving PASI 75 through Week 10.
to iniximab 3 mg/kg every 8 weeks, 148 to iniximab 3 mg/kg
as needed, 150 to iniximab 5 mg/kg every 8 weeks, and 149
2009-Journal
of Drugswho
in Dermatology. All100
Rights Reserved.
to iniximab 5 mg/kg as needed. The 183
placebo patients
*p<0.001 compared with placebo
crossed over to iniximab
treatment
all assigned
to 5 images
mg/ and marks of Journal
This document
containswere
proprietary
information,
of Drugs
in Dermatology
(JDD).
p=0.001
compared
with placebo
80
kg at Weeks
16, 18, and
every
8 weeks
thereafter.
No reproduction
or22,
useand
of any
portion
of the contents
of 13
these materials may be made without the express written consent of JDD.*
*
The clinical efcacy of iniximab was apparent with a signicantly greater number of patients achieving PASI 75 as early as
Week 2. At Week 10, the proportion of subjects attaining PASI
75 status was 75.5% in the iniximab 5 mg/kg group, 70.3% in
the 3 mg/kg group, and 1.9% of those in the placebo group (P <
0.001) (Figure 3). PASI 90 status was attained by 45.2% of those
in the 5 mg/kg group and 37.1% in the 3 mg/kg group, compared with 0.5% in the placebo group (P < 0.001).13
The proportion of patients in each of the four treatment groups
randomized at Week 14 that attained PASI 75 through Week 50
were 43.8% for iniximab 3 mg/kg every 8 weeks; 25.4% for
60
*
40
Placebo
3 mg/kg iniximab
5 mg/kg iniximab
20
*
0
0
10
Weeks
Reprinted from J Am Acad Dermatol. 2007;56(1):31e1-e15. Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs.
intermittent infliximab maintenance regimens over 1 year in the treatment
of moderate-to-severe-plaque psoriasis, with permission from Elsevier.
BEMaGS
F
BEMaGS
F
553
+6/&t70-6.&t*446&
lowed by 40 mg every other week (EOW) starting with Week 1;

or (2) 80 mg adalimumab at Weeks 0 and 1 followed by 40 mg
weekly beginning at Week 2. Patients who completed this 12week trial were eligible to continue an extension study. Patients
who received adalimumab during the rst 12 weeks continued
their assigned dosages. Placebo patients were switched to 80
mg adalimumab at Week 12, then 40 mg EOW beginning at
Week 13. Patients receiving adalimumab 40 mg EOW who did
not attain PASI 50 were eligible for dosage escalation to 40 mg
weekly. The primary efcacy end points were the proportions
of patients attaining PASI 75 at Week 12 for the initial blinded
trial and at Week 24 for the extension. Efcacy evaluations were
performed on a MITT (Modied Intent-To-Treat) principle and
all patients with missing data were counted as non-responders.
A PGA was also performed at the time of patient evaluation.14
A total of 148 patients were randomized and 147 received at least
one dose of study drug; of these, 140 completed the rst 12-week
phase, 132 completed 24 weeks, and 106 completed the full 60
weeks of treatment. At Week 12, the proportion of patients receiving adalimumab 40 mg EOW who attained PASI 75 was 53%;
of those receiving adalimumab 40 mg weekly, this proportion
was 80% compared with 4% of those in the placebo group (P <
0.001). The proportion of PASI 75 responders at Week 24 among
the patients who were switched from placebo to adalimumab
40 mg EOW was similar to that achieved by patients initially on
adalimumab 40 mg EOW at Week 12. PASI 75 response rates at
Week 60 were 64% for those in the adalimumab 40 mg weekly
group and 58% in the adalimumab 40 mg EOW group.14
-,JSDJL +%FM3PTTP
50 following 12 weeks of adalimumab treatment. Patient inclusion and exclusion criteria in this study were identical to those
in the previous study. The primary efcacy analysis was the
time to relapse after randomization at Week 12 to Week 24 for
patients who had been classied as responders at Week 12.15
A total of 148 patients were entered in the open-label phase
of the study in which all patients received an initial 80 mg SC
injection of adalimumab at Weeks 0 and 1, followed by adalimumab 40 mg weekly. In the second part of the study, responders at Week 12 were randomized to receive either adalimumab
40 mg EOW or placebo. As in the previous study, response was
rapid: 28% of patients attained PASI 50 by Week 2 and 91.9%
achieved this level of improvement by Week 12. During the placebo-controlled period, Weeks 12 to 24, the majority of patients
in both groups maintained PASI 50 or better compared with
baseline; therefore, the median time to relapse during this period (i.e., the primary end point) could not be calculated. In addition, nearly all (98.5%) of the patients in both the adalimumab
40 mg EOW group and the placebo group discontinued treatment after Week 24 due to poor response, making it impossible
to calculate time to relapse during the follow-up period.15
Do Not Copy,
Penalties Apply
The authors suggested that there was a lower risk of relapse for
patients continuing on adalimumab 40 mg EOW than for those
receiving placebo, based on the estimate of the hazard ratio
of risk for relapse, which was 0.7 for patients on adalimumab.
However, the 95% condence interval for this calculation was
too wide for statistical signicance (0.37 to 1.34).15
A minority of patients11% of those receiving adalimumab 40

mg EOW and 26% of those receiving adalimumab 40 mg weeklyattained PASI 100, representing 100% improvement. Conversely, 26 patients failed to attain PASI 50 between Weeks 24
and 60. Twenty patients had their dosage increased from 40 mg
EOW to 40 mg weekly, which resulted in 40% of these patients
attaining PASI 50 and 20% achieving a PASI 75.14
The Menter et al. trial (2008) was a 52-week, randomized, doubleblind, placebo-controlled, phase III study in patients with moderate-to-severe chronic plaque psoriasis. Patients were eligible
for the study if they were 18 years of age or older, had a clinical
diagnosis of psoriasis for at least 6 months, and stable plaque
psoriasis for at least 2 months prior to screening. Moderate-tosevere plaque psoriasis was dened as BSA involvement of 10%
All and
Rights
or more
a Reserved.
baseline PASI score of 12 or greater. Exclusion
This study demonstrated
rapid
efcacy
with adalimumab
and and
criteria
the same
as for
the previously
discussed studies.16
This document
contains
proprietary
information, images
markswere
of Journal
of Drugs
in Dermatology
(JDD).
sustained
uportouse
60 of
weeks
of treatment.
Response
wasmaterials may be made without the express written consent of JDD.
No response
reproduction
any portion
of the contents
of these
The please
study contact
designJDD
called
for three treatment periods (A, B, and
strongly dose-related; patients
received
weekly
rather
If who
you feel
you have
obtained
thisthan
copy illegally,
immediately.
C), as shown in Figure 4. The primary efcacy end points of the
BIW injections demonstrated a higher likelihood of improvestudy were PASI 75 responder rate at Week 16 relative to basement on PASI. Almost one-quarter (26 of 106) of the patients
line and the proportion of patients who lose adequate response
who completed the extension phase failed to attain PASI 50 bebetween Weeks 33 and 52.16
tween Weeks 24 and 60. The authors speculated that possible
reasons for this lack of response might include incomplete TNF
A total of 1212 patients were randomized, 814 to adalimumab and
inhibition or lack of responsiveness to TNF inhibition in some
398 to placebo. At Week 16, all responders who had attained PASI
patients with psoriasis.14
75580 adalimumab patients and 26 placebo patientsentered
The objective of a later Gordon et al. study (2007) was to investiopen-label period B. At the conclusion of period B, 490 PASI 75
gate the time to relapse after either withdrawal of adalimumab
responders were then re-randomized to adalimumab or placebo
or dose reduction from 40 mg weekly to 40 mg EOW among pain period C. Patient characteristics were similar between the adalitients with moderate-to-severe psoriasis who achieved a PASI
mumab and placebo cohorts: mean BSA affected was 26%, base-
BEMaGS
F
BEMaGS
554
+6/&t70-6.&t*446&
line PASI was approximately 19, more than one-half had moderate
psoriasis, and approximately 40% had severe psoriasis.16
After 16 weeks of treatment, 71% of adalimumab-treated patients attained PASI 75 compared with 7% of placebo patients
(P < 0.001). Patients both in the treatment and placebo groups
with PASI 75 scores then entered open-label period B. The
mean improvement in PASI scores from baseline at Week 16 in
patients who attained PASI 75 was 92%. During period B, the
improvement from baseline in these patients remained almost
constant, calculated as 89% at Week 33.16
During period C, the rate at which patients randomized to placebo lost response, dened as less than PASI 50, was higher than
that for patients receiving adalimumab. Twenty-eight percent of
placebo patients lost adequate response by Week 52 compared
with 5% of those continuing to receive adalimumab.16
This study showed similar short-term efcacy for adalimumab
in treating moderate-to-severe plaque psoriasis, as did the
previous study; it also demonstrated a good sustained level of
response to 33 weeks. In addition, it demonstrated what the
-,JSDJL +%FM3PTTP
previous study failed to show: withdrawal of adalimumab was

more likely to be associated with failure of adequate response
than was continuation of treatment.16
Gordon et al. (2008) presents the latest data from the openlabel extension period of the study discussed directly above.
One-half of the adalimumab patients who had attained PASI
75 response at 52 weeks, a total of 233 patients, were included
in the ITT population of this extension. At the end of the previous 52-week study, PASI 75, 90, and 100 response rates were
85%, 59% and 35%, respectively. The results of an additional
6-month treatment period (i.e., 18 months total of continuous
adalimumab treatment) were 87%, 63% and 34%, respectively,
thereby illustrating good sustained response.17
TNF- inhibitors have been used successfully for more than 10
years for the treatment of several conditions including psoriasis, psoriatic arthritis, RA, juvenile rheumatoid arthritis (JRA),
ankylosing spondylitis and Crohns disease. As exposure time
in terms of number of patient-years grows, so does the accumulation of safety data.
Do Not Copy,
Penalties Apply
FIGURE 4. Study design describing 3 treatment periods. DBPC, double-blind, placebo-controlled; eow, every other week; OLE, open label extension; PASI, Psoriasis Area and Severity Index.
Period B
SUSTAINED RESPONSE
17-week open label
Period A
INITIAL RESPONSE
16-week DBPC
< 28 days
40 mg adalimumab eow*
(n=814)
Period C
LOSS OF ADEQUATE RESPONSE
19-week DBPC
1:1 Randomization
Screening
40 mg adalimumab eow
(n=580)
N=1,212
(n=250)
Placebo eow
(n=240)
2009-Journal
of Drugs in Dermatology. All>Rights Reserved.
>
PASI75 response
PASI75 response

information,
and marks
of Journal
Drugs in
continue
to periodimages
B
continue
toofperiod
C Dermatology (JDD).
No reproduction or use of any portion of the contents of these materials may be made
written consent
of JDD.
without the
40 express
mg adalimumab
eow
Placebo eow
If you
feel you have obtained this copy illegally,
(n=398)
(n=26)please contact JDD immediately. (n=22)
Patients with <PASI75
response enter OLE
OLE: 40 mg adalimumab eow
2:1 Randomization
Week
0
Baseline
Patients with PASI responses >50

and <75 enter OLE
16
33
52
*After 80 mg at week 0 and 40 mg at week 1. After 80 mg at week 16 and 40 mg at week 17.

Reprinted from J Am Acad Dermatol. 2008;58(1):108. Menter A, Tyring K, Gordon K, et al. Adalimumab therapy for moderate-to-severe psoriasis: a randomized, controlled phase III trial, with permission from Elsevier.
BEMaGS
F
BEMaGS
F
555
+6/&t70-6.&t*446&
-,JSDJL +%FM3PTTP
Key Safety Considerations

The key safety considerations with TNF- antagonists include
infection, cytopenia, demyelinating disease, lupus-like syndromes, congestive heart failure and malignancies, particularly lymphoma. Serious complications, such as infection and
malignancy, are suspected as consequences of the immunosuppressive nature of TNF- antagonists.18 Regarding malignancies other than lymphoma and nonmelanoma skin cancer, rates
in iniximab clinical trials for all indications were 0.52 per 100
patient-years for iniximab-treated patients and 0.11 per 100
patient-years for control subjects. The control subject rate was
lower than expected, while the rate for the iniximab-treated
patients was similar to that expected in the general population.
The most common malignancies observed were breast, colorectal, and melanoma.19 Similarly, rates in adalimumab clinical trials
were 0.6 per 100 patient-years for adalimumab-treated patients
and 0.4 per 100 patient-years for controls. Malignancies that occurred most frequently were breast, colon, prostate, lung, and
melanoma; rates were similar to those expected in the general
population.20 Malignancy rates among etanercept-treated patients with psoriasis are discussed in the next section. Much of
the accumulated, pooled safety data for these serious adverse
events (AEs) are from RA patient populations, not psoriasis patients. RA may confound the accuracy of some results. For example, patients with RA, whether receiving treatment or not, have
a higher incidence of lymphoma than that of the general population. Similar data for the psoriasis population are not currently
available, although there are indications that patients with psoriasis are at elevated risk for developing lymphoma. A study of
more than 2,700 patients followed for nearly 4 years showed an
almost 3-fold elevated risk for developing lymphoma compared
to age- and gender-matched controls.1 Therefore, it remains uncertain whether the use of TNF- inhibitors also increases risk of
lymphoma. Table 3 provides a summary for two of the key safety
issues, tuberculosis and lymphoma.
individuals who are chronic carriers of the virus are at risk of reactivation with TNF-blocker use, most reported cases occurred
in patients also taking other immunosuppressive agents. Hepatitis B virus carriers may still be candidates for anti-TNF therapy,
but caution should be used when prescribing the agents. Atrisk patients require close monitoring for signs and symptoms
of active hepatitis infection with laboratory work and clinical
evaluations performed regularly.19-21
Recently, a few reports of progressive multifocal leukoencephalopathy (PML) developing among patients treated with biologics have emerged. PML, which is caused by the polyomavirus
JC, named for John Cunningham the patient from whose brain
the rst isolates were obtained, is the only known human viral
demyelinating disorder. AIDS is the underlying illness for 85%
of PML cases; however, in 2005 two patients with multiple sclerosis and one with Crohns disease treated with natalizumab
developed PML. It must be stressed that cases are extremely
rare, particularly when an underlying immunosuppressive disease, such as Hodgkins lymphoma is not present. Still, clinicians are cautioned that, due to the immunosuppresive nature
of the agents, PML may become associated with etanercept
and iniximab.22,23
Do Not Copy,
Penalties Apply
Etanercept Safety Data
An analysis of the incidence of AEs in three randomized, placebo-controlled etanercept studies reported 471 of 1,263 patients
experienced an AE during the rst 12 weeks of the studies. The
incidence of AEs was almost exactly equal in the four treatment
groups, with the distribution of AEs in placebo, etanercept 50
mg BIW, 50 mg weekly and 25 mg weekly groups as 51%, 46%,
56%, and 48%, respectively. The most common AEs were headaches and injection site ecchymoses. Serious AEs (SAEs) occurred with comparable frequency in patients taking etanercept
(1.2% of all patients) and placebo (1.0% of all patients). The most
common infections were upper respiratory infections, sinusitis
and inuenza.24
A warning for hepatitis B virus reactivation is included in the

2009-Journal
of Although
Drugs in Dermatology. All Rights Reserved.
prescribing information for the three anti-TNF
agents.
TABLE 3.
Tuberculosis and Lymphoma Data in Patients Treated With TNF- Antagonists
Serious AE
Etanercept1*
Iniximab2
Adalimumab2
M. tuberculosis
2 (non-US patients)
SIR = 1.083
7 pre-screen (non-US)
14 post-screen (3 in US)
Lymphoma
SIR = 2.93
SIR = 6.4
SIR = 4.35
*Includes patients in Amgen or Wyeth clinical trials of etanercept for approval indication (RA, JRA, ankylosing spondylitis, PsA, psoriasis as of May 2006.
Forty-nine trials analyzed; 18,386 patient years of etanercept exposure included in analyses.
Includes data from 1298 patients in RA trials (2,458 patient-years exposure)
Includes data from 9,460 patients in RA trials
SIR=Standardized incidence ration

Source: 1. Gordon KB, Gottlieb AB, Gianni EH, et al. Clinical trial safety data of events of interest in patients receiving etanercept (Enbrel) across approved
indications. Poster presented at: American Aademy of Dermatology 66th Annual Meeting, February 1-5, 2008; San Antonio, TX, Poster P2610.
2.
Keystone EC. Safety of biologic therapies-an update. J Rheumatol. 2005;32(74):8-12.
BEMaGS
F
BEMaGS
F
556
+6/&t70-6.&t*446&
Safety data for 5,423 patients with moderate-to-severe psoriasis included in six short- and long-term etanercept studies
(4,090 patient-years of exposure) were generated.
Analyses determined that AE rates were comparable between
all treatment groups, including placebo-treated patients. In the
short-term studies (n = 1,245), the four most common noninfectious AEs were headache, injection site hemorrhage, fatigue,
and arthralgia. Upper respiratory tract infection was the most
common infectious AE. Rates, which were reported as events
per 100 patient-years, for injection-site reaction ranged from
42 to 45 among the four treatment groups. Although headaches were most common in the etanercept 25 mg BIW group
(68.28), the rate in the 25 mg weekly group was 14.59. The longterm analyses divided patients into three etanercept treatment
groups; included was a group of patients who received continuous 50 mg BIW therapy, some of whom remained on etanercept treatment for up to 3 years. Results for noninfectious and
infectious AEs and SAEs were similar between the treatment
groups, did not show dose-related toxicity, and were stable
across time. Specic to malignancies, 27 cases were recorded
among etanercept-treated patients. The expected number of
events was 21.9, generating a standardized incidence ratio (SIR)
of 1.2. The four most common noninfectious AEs in the longterm groups were headache, injection site hemorrhage, arthralgia, and back pain. Again, upper respiratory tract infection was
the most common infectious AE.25
Iniximab Safety Data
-,JSDJL +%FM3PTTP
regimens study (n = 589 patients treated long term) revealed

comparable AEs, SAEs, and infections among the four treatment groups during the 50-week study. Infusion reactions were
most common in the as-needed groups for each dose, with
the 3 mg/kg as-needed dose experiencing the most reactions
overall. Two cases of tuberculosis and 12 malignancies were reported in the iniximab cohort. Of the other AEs, only headache,
sinusitis, and rhinitis were notably higher in iniximab-treated
patients than in the placebo group at Week 14, the end of the
double-blind period. Antibodies to iniximab developed in 237
of the 589 patients rerandomized to iniximab at Week 14. These
patients were less likely to maintain response to treatment than
those with negative or inconclusive tests for antibodies. Antibody-positive patients were also at higher risk of experiencing
infusion reactions than antibody-negative patients.13
Adalimumab Safety Data

Safety data is available for patients in the adalimumab studies
described in the previous article of this supplement. During the
12-week, double-blind phase of a long-term adalimumab trial,
AE rates ranged from 67.3% in the placebo group to 78% in the
adalimumab 40 mg weekly group. The extension phase (Weeks
12 to 50) revealed comparable AE rates of 78% between the
placebo/adalimumab group and the adalimumab/adalimumab
group. SAEs occurred in 14% of the adalimumab/adalimumab
group compared with 2.2% in the placebo/adalimumab group.
The most common AEs were nasopharyngitis and upper respiratory tract infections.14
Do Not Copy,
Penalties Apply
Safety data is available for 1,246 patients in the iniximab studIn a 24-week study in which 12 weeks of open-label treatment
ies discussed in the previous article of this supplement. In the
with adalimumab was followed by a 12-week, placebo-consmall, 10-week study that enrolled 33 patients and included a
trolled extension, an AE occurred in 105 patients (70.9%) treated
16-week, open-label extension, there were no reported SAEs.
with adalimumab 40 mg weekly during the open-label period,
During the double-blind phase, the only AE that occurred with
in 36 placebo-treated patients (52.9%), and in 46 adalimumabmore frequency in iniximab-treated than in placebo-treated
EOW-treated patients (67.6%) during the double-blind period.
patients was headache. Two patients developed antinuclear anOverall, there were four SAEs: two occurring in patients taking
tibodies to iniximab but no relevant clinical symptoms related
adalimumab 40 mg EOW and two in patients taking adalimum 2009-Journal
of Drugs inexDermatology.
All Rights
Reserved.
to this development was observed. During
the open-label
ab 40 mg
weekly.
Two infectious AEs were reported in patients
tension, 3 patients
infusion
reactions
to iniximab
and
2 and
taking
40 mg EOW
dose
and one was
reported in a patient
Thishad
document
contains
proprietary
information,
images
marksthe
of Journal
of Drugs
in Dermatology
(JDD).
15
had AEsNothat
were described
severe.
patient
developed
taking
40 mgwithout
weekly
reproduction
or use ofas
any
portionOne
of the
contents
of these materials
maythe
be made
thedose.
express
itchy feet that resolved with discontinuation
of iniximab
and
a illegally, please contact JDD immediately.
obtained this
copy
In a 52-week study in which 1,212 patients were originally enplacebo-treated patient reported arthritic knee pain.10,11
rolled, 429 completed the 52 weeks of the study. The only inIn a 50-week study of 378 patients comparing iniximab 5 mg/
fectious AEs occurring in more than 2% of patients were upkg at Weeks 1, 2, and 6, and then every 8 weeks with placebo,
per respiratory tract infection, nasopharyngeal infection, and
6% of the iniximab-treated patients experienced a SAE comsinusitis. SAEs were reported in 33 patients taking adalimumab
pared with 3% of the placebo-treated patients. The percentages
and in 7 patients taking placebo, computed to be an identiof patients reporting any AE were approximately comparable:
cal rate of 0.06 events per patient-year. There was one case of
82% of those on iniximab compared with 71% of those on platuberculosis, no lymphoma, no lupus-like syndrome and no
cebo. Three iniximab patients experienced skin malignancies:
demyelinating disorder.16 During a 6-month extension of this
study in which 233 patients participated, adalimumab patients
two squamous cell carcinomas and one basal cell carcinoma.12
experienced six SAEs and two serious infections.17
The continuous versus intermittent iniximab maintenance
BEMaGS
F
BEMaGS
557
Combined Therapy for the Treatment of Plaque

Psoriasis
Combined therapy offers the potential to improve upon the
response provided by therapy with a single intervention and
to employ drugs at less than their maximum dose, expecting
a reduction in the incidence of dose-related AEs. A recently
published study by Kircik et al. (2008) evaluated narrowband
(310312 nm wavelength) ultraviolet light B (NB-UVB) thrice
weekly (TIW) in combination with etanercept 50 mg BIW in 86
patients with stable plaque psoriasis. Previous studies with NBUVB demonstrated signicant clearing of skin lesions and, in
one study, 62% of patients achieved PASI 75 after 12 weeks of
UVB therapy. In the study under discussion, mean affected BSA
was 28% and the baseline PASI was 22.9. A total of 84% of the
patients were assessed as having moderate, marked, or severe
disease at baseline.26
Considerable proportions of the patients had prior systemic
treatments, including methotrexate, steroids and oral retinoids.
Most patients (70.9%) previously received treatment with topical steroids and many were treated with vitamin D analogues
and tar compounds.26
-,JSDJL +%FM3PTTP
FIGURE 5. Psoriasis Area and Severity Index (PASI) response over

time (CI=condence interval; wk=week).
100
Mean Percentage of
Patients (95% CI)

+6/&t70-6.&t*446&
80
PASI75
PASI90
PASI100
60
40
20
4 Wk
8 Wk
12 Wk
Source: Kircik L, Bagel J, Korman N, et al. Utilization of narrow-band

ultraviolet light B therapy and etanercept for the treatment of psoriasis
(UNITE): Efficacy, safety, and patient-reported outcomes. J Drugs Dermatol. 2008;7(3):249.
ate combination adalimumab and UVB therapy in patients with

psoriasis is currently recruiting patients (as of March 2008). The
study will include patients on adalimumab therapy for at least 6
weeks who have not experienced a 75% or greater reduction in
PASI. Adalimumab will be continued, while UVB phototherapy
is added to the regimen. Estimated completion date is February
of 2010.28
Do Not Copy,
Penalties Apply
Of the 86 patients enrolled, 83 completed the 12-week study. At

12 weeks, 84.9% of patients attained PASI 75, 58.1% attained PASI
90 and 26.0% attained PASI 100. Most patients (69.8%) reached
PASI 75 at Week 8. As shown in Figure 5, improvement in PASI
response was still increasing at the conclusion of the study.26
CONCLUSION
The chronicity of psoriasis means treatments must be availMean BSA affected by psoriasis improved by 83.6% from baseable, effective, and safe over the long term. The database for
line. Almost three-quarters (74.4%) of patients had a PGA score
long-term analyses of biologic agents is still somewhat limited
of 0 or 1, equivalent to clear or almost clear of psoriasis. Patient
but continues to grow as data are accumulated over time. Curglobal assessment and the DLQI scores improved consistently
rent long-term results are promising, providing patients with
with the improvements in the efcacy outcome measures. With
safe and effective options to manage their symptoms. Moreregard to safety, the most common AEs were UVB-induced skin
over, the growing use of combination therapy provides several
injuries experienced by 62.8% of patients and injection-site repromising options that may enhance efcacy while minimizing
actions experienced by 16.3%.There were two SAEs: one case
2009-Journal
Allevent
Rightspotential.
Reserved.
adverse
of angina pectoris that was not considered
to be treatment-related and one case
cellulitis,
which proprietary
occurred information,
after the study
Thisof
document
contains
26
Short-term
PASIwithout
75 responses
arewritten
important;
early
positive reperiod and
was considered
possibly
No reproduction
or useas
of any
portiontreatment-related.
of the contents of these
materials
may be made
the express
consent
of JDD.
sponses
likelyJDD
to be
highly encouraging to the patient as well
pleaseare
contact
immediately.
A 12-week study in 14 patients with severe psoriasis evaluatas to the clinician. It is well-known that early response to treated the effects of psoralen and ultraviolet light A (PUVA) comment reinforces compliance, and when the deleterious effects
bined with etanercept. Patients received PUVA treatment TIW
of psoriasis symptoms on quality of life are considered, early
and etanercept 25 mg BIW SC. Ten of the 14 subjects (71.4%)
restoration of quality of life is a signal of achievement in treatachieved PASI 75 by Week 8; the proportion of patients attaining
ment of any disease. However, with some agents, maintenance
PASI 50 was 85.7% at Week 8. Patients who achieved PASI 75
of response may be problematic. For example, we note that in
or 50 maintained their improvement through Week 12 but the
the clinical trials discussed above, the proportion of patients
remaining patients who did not achieve PASI 50 or 75 were not
who attained PASI 75 with iniximab at 10 to 16 weeks ranged
able to do so by Week 12.27
between about 70% and 80%.12,13 This gure was considerably higher than the proportion of patients on etanercept that
According to information from the clinicaltrials.gov Web site
attained that level of response; in different trials, that proporfrom the US NIH, an interventional study designed to evalution ranged between about 50% and 60%.5,6,8 However, in a trial
BEMaGS
F
BEMaGS
F
558
+6/&t70-6.&t*446&
of iniximab, the proportion of PASI 75 responders dropped

from 80% at Week 10 to 61% at Week 4612; whereas, in a trial
of etanercept, the proportion of PASI 75 responders increased
from approximately 50% at Week 24 to 63% at Week 48.8
Comparison of efcacy data for the TNF- inhibitors is made difcult by numerous factors, principal among which is the absence of
head-to-head studies. In addition, a factor that may often be overlooked is that efcacy analyses may not be carried out using the
same statistical standards. Figure 6 illustrates this difference.29
-,JSDJL +%FM3PTTP
The Value of Combination Therapy

Clinicians may wish to consider combined therapy for a variety
of reasons, including inadequate response to monotherapy or
problems involving tolerability. As previously discussed, the
combination of a biologic agent with phototherapy, either NBUVB or PUVA, may offer a considerably higher rate of response
as compared to either intervention alone. It should be noted that
there is only one combined therapy study employing NB-UVB in
which more than a quarter of patients attained PASI 100.26
Effective Treatment Options

The chart shows the proportion of patients in an open-label extension of adalimumab that attained PASI 75 at Week 120. The
upper line represents the as treated population with the N
values varying from 89 at Week 10 to 49 at Week 120, while the
lower line represents the ITT population of 92. As the denominator declined, the proportion of patients attaining PASI 75 in
the as treated analysis remained consistently high, ending at
78% at Week 120. In contrast, the proportion of PASI 75 responders of the entire ITT population in this study declined to 41%.
Thus, as accurately as able to gauge from the available data,
the efcacies of the three TNF- inhibitors are roughly comparable. As demonstrated, data for etanercept and iniximab suggest PASI 75 response in approximately 60% of patients at the
1-year mark, while the response rate for adalimumab may be
somewhat lower.29
The treatment of plaque psoriasis with TNF- antagonists is still

a relatively recent addition to the pharmacologic armamentarium available to clinicians. The collection of long-term trial data
is, therefore, small but growing as results from newer studies
emerge. From the data reviewed here, the clinician can attempt
to arrive at a satisfactory assessment of the benets and risks
of treatment with these agents. What should be evident is that
the present opportunity to confer positive systemic results and
relief from symptoms is a major step forward in the treatment
of psoriasis.
DISCLOSURES
Do Not Copy,
Penalties Apply
In light of the similar long-term efcacies demonstrated by the

three TNF- inhibitors and in consideration of the likely need
to continue therapy for many years, a focus on safety issues
becomes paramount. The three antiTNF- agents all carry
prominent warnings in the prescribing information with different verbiage but similar implications. All warn against infection, singling out tuberculosis as a risk and stating that patients
should be screened and tested for latent tuberculosis before
starting therapy.19-21
Dr. Kircik has disclosed that he has received funding as an investigator, consultant or speaker from Amgen.
Dr. Del Rosso has disclosed that he has received grant/research

support from Coria Laboratories, Ltd.; Glaxo Dermatology;
Medicis Pharmaceutical Corporation; and OrthoNeutrogena.
He is a consultant to QLT Inc.; Ranbaxy Pharmaceuticals Inc;
SkinMedica, Inc.; and Stiefel Laboratories, Inc. He is a scientic
advisor to Allergan Inc.; Obagi Medical Products, Inc.; Unilever;
and Warner Chilcott. He is also a member of the speakers bureau for each of the aforementioned companies.
REFERENCES
1.
Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the

management
of psoriasis and psoriatic arthritis: Section 1. Overview
FIGURE 6. Adalimumab and long-term data.
of psoriasis
andof
guidelines
care for the (JDD).
treatment of psoriasis with
This document contains proprietary information, images and marks
of Journal
Drugs inof
Dermatology
100
Percent of Patients
with PASI75
biologics.
J Am
Acad Dermatol.
2008;58(5):826-850.
be made
without
the express
90
(n=60)
2. please
Thiers BH,
Lang
PG immediately.
Jr. Year Book of Dermatology and Dermatologic
contact
JDD
(n=75)
80
70
(n=53)
(n=49)
73
76
78
41
43
41
(n=52)
82
75
3.
(n=89)
60
56
50
61
54
53
40
30
4.
As treated (n varies)
ITT (n=92)
20
5.
10
6.
(n=92)
0
0
10
20
30
40
50
60
70
80
90
10
110 120
Poster presented at American Academy of Dermatology Annual Meeting,

February 2-6, 2007. Washington DC. Poster P 2777.
7.
Surgery 2007. St Louis, MO: Elsevier Mosby; 2007:49.

About psoriasis: Statistics. National Psoriasis Foundation Web site.
Available at: http://www.psoriasis.org/about/stats/index.php. Accessed
May 19, 2008.
Krueger JG. The immunologic basis for the treatment of psoriasis with
new biologic agents. J Am Acad Dermatol. 2002;46(1):1-23.
Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014-2022.
Papp KA, Tyring S, Lahfa M, et al. A global phase 3 randomized controlled trial of etanercept in psoriasis: Safety, efcacy, and effect of
dose reduction. Br J Dermatol. 2005;152(6):1304-1312.
Moore A, Gordon KB, Kang S, et al. A randomized, open-label trial of
BEMaGS
F
BEMaGS
F
559
+6/&t70-6.&t*446&
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
-,JSDJL +%FM3PTTP
continuous versus interrupted etanercept therapy in the treatment of

an integrated, multistudy analysis. Poster presented at: Summer 2007
psoriasis. J Am Acad Dermatol. 2007;56(4):598-603.
American Academy of Dermatology Meeting; August 2-5, 2007; New
Tyring S, Gordon KB, Poulin Y, et al. Long-term safety and efcacy of 50
York, NY. Poster P1817.
mg of etanercept twice weekly in patients with psoriasis. Arch Derma26. Kircik L, Bagel J, Korman N, et al. Utilization of narrow-band ultraviolet
tol. 2007;143(6):719-726.
light B therapy and etanercept for the treatment of psoriasis (UNITE):
Tyring S, Langley R, Gordon KB, Poulin Y. Efcacy and safety proles of
Efcacy, safety, and patient-reported outcomes. J Drugs Dermatol.
etanercept 50 mg twice weekly for up to 144 weeks in patients with
2008;7(3):245-253.
moderate-to-severe plaque psoriasis. Poster presented at: American
27. Woodson J, Kircik L, Kricorian G. PUVA therapy combined with lowAcademy of Dermatology 65th Annual Meeting; February 2-6 2007;
dose etanercept in the management of severe psoriasis. Poster preWashington, DC. Poster P2731.
sented at: Summer 2005 American Academy of Dermatology MeetChaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB.
ing; July 20-24, 2005; Chicago, IL.
Efcacy and safety of iniximab monotherapy for plaque-type psoria28. US National Institutes of Health. UVB-311 after initial slow response to
sis: a randomised trial. Lancet. 2001;357(9271):1842-1847.
adalimumab in psoriasis. Available at: http://www.clinicaltrial.gov/ct2/
Gottlieb AB, Chaudhari U, Mulcahy LD, Li S, Dooley LT, Baker DG. Infshow/NCT00638469? cond=psoriasis&intr=%22adalimumab%22&ra
_______________________________________
liximab monotherapy provides rapid and sustained benet for plaquenk=14. Accessed June 12, 2008.
____
type psoriasis. J Am Acad Dermatol. 2003;48(6):829-835.
29. Papp K, Leonardi C, Gordon K, Frevert L. Efcacy and safety of adaliReich K, Nestle FO, Papp K, et al. Iniximab induction and maintenance
mumab in a 12-week open-label extension study in patients with
therapy for moderate-to-severe psoriasis: A phase 3, multicentre, doumoderate-to-severe chronic plaque psoriasis. J Am Acad Dermatol.
ble-blind trial. Lancet. 2005;366(9494):1367-1374.
2007;56(2):AB193
Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison
of continuous vs. intermittent iniximab maintenance regimens over
1 year in the treatment of moderate-to-severe plaque psoriasis. J Am
Acad Dermatol. 2007;56(1):31.e1-e15.
Gordon KB, Langley RG, Leonardi C, et al. Clinical response to adalimumab treatment in patients with moderate-to-severe psoriasis: DouLeon H. Kircik, MD
ble-blind, randomized controlled trial and open-label extension study. J
Department of Dermatology
Am Acad Dermatol. 2006;55(4):598-606.
Indiana University Medical Center
Gordon KB, Blum RR, Papp KA, et al. Efcacy and safety of adalimum1169 Eastern Pkwy 2310
ab treatment in patients with moderate-to-severe psoriasis: A doubleLouisville, KY 40217
blind, randomized clinical trial. Psoriasis Forum. 2007;13(1):4-11.
Phone .................................................................... (502) 451-9000
Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderFax ......................................................................... (502) 456-2728
ate-to-severe psoriasis: A randomized, controlled phase 3 trial. J Am
E-mail.................................................. wedoderma@bellsouth.net
________________
Acad Dermatol. 2008;58(1):106-115.
Gordon K, Tyring S, Gu Y, Okun M. Psoriasis patients treated continuously with adalimumab: Efcacy and safety results from months 12 to
18 [abstract]. J Am Acad Dermatol. 2008;58(2):AB129.
Keystone EC. Safety of biologic therapiesan update. J Rheumatol
Suppl. 2005;74:8-12.
Do Not Copy,
Penalties Apply
19. Remicade [package

insert]. Malvern,
PA:proprietary
Centocor, Inc;
2009.
This document
contains
information,
20. Humira
[package insert].
North
Chicago,IL:
2009.materials may be made without the express written consent of JDD.
No reproduction
or use
of any
portionAbbott
of the Laboratories;
contents of these
21. Enbrel [package insert]. Thousand
Oaks,
Amgen
andthis
Wyeth;
If you feel
youCA:
have
obtained
2009.
22. Weber T. Progressive multifocal leukoencphalopathy. Neurol Clin.
2008;26:833-854.
23. Yamamoto M, Takahashi H, Wakasugi H, et al. Leukoencephalopathy
during administration of etanercept for refractory rheumatoid arthritis.
Mod Rheumatol. 2007;17:72-74.
24. Gottlieb AB, Leonardi CL, Goffe BS, et al. Etanercept monotherapy in
patients with psoriasis: A summary of safety, based on an integrated
multistudy database. J Am Acad Dermatol. 2006;54(3 suppl 2):S92S100.
25. Gordon K, Leonardi CL, Gottlieb AB, et al. Safety of long-term etanercept treatment in patients with moderate-to-severe plaque psoriasis:
BEMaGS
F
BEMaGS
F
Theres a lot of Flexibility in Topicort
(Desoximetasone)
Multiple Potencies1,2
Choice of 3 Vehicles
t Propylene Glycol-Free
t Preservative-Free
t Class C Corticosteroid3
Do Not Copy,
Penalties Apply
Topicort belongs to the class of hypoallergenic corticosteroid3 due to its reduced frequency of cross reactivity to
other corticosteroids and has the further benet of being propylene glycol and preservative free. Topicort treats a
broad range of corticosteriod responsive dermatoses.
Topicort
Class II
Class II
(Desoximetasone)
2009-Journal
of Drugs Class
in Dermatology.
Class II
IV
document
proprietary
contains
information,
images
and marks of Journal of Drugs in Dermatology (JDD).
TopicortThis
Topicort
Topicort
Topicort
LP Cream 0.05%, Gel 0.05%, and Cream and Ointment 0.25%
Multiple Choices, One Solution
Ointment
0.25%
Cream
0.05%
LP Cream
0.05%may be made without the express written consent of JDD.
No reproduction
or use
of0.25%
any portion ofGel
the
contents of these
materials
The most common adverse reactions include burning, itching, irritation, dryness,
folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis,
allergic contact dermatitis, maceration of the skin, secondary infection, skin atrophy,
striae and miliaria. When used in large areas or under occlusive dressing, patients
should be evaluated for HPA axis suppression. Before prescribing, please see
complete prescribing information.
Topicort is a registered trademark of Taro Pharmaceuticals North America, Inc.
1. Stoughton RB. Percutaneous Absorption of Drugs. Annu Rev Pharmacol Toxicol. 1989;29:55-69.
2. Gilman AG, Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics. 10th ed.
McGraw-Hill, 2001, pg. 1799.
3. Rietschel RL, Fowler JF, Jr. Fishers Contact Dermatitis, Fifth Edition. Lippencott Williams & Wilkins, 2001, pp. 203-7.
For More Information About

Topicort and/or For Free
Samples, Call: 1-866-399-3124
2007 Taro Pharmaceuticals U.S.A., Inc. All rights reserved.
February 2007 AD100-0002-R2
BEMaGS
F
BEMaGS
Do Not Copy,
Penalties Apply
________
AD 100-0002-R1
BEMaGS
F
BEMaGS
F
JUNE 2009
562
70-6.&t*446&
COPYRIGHT 2009
ORIGINAL ARTICLES
Photodynamic Therapy With Low-Strength ALA,

Repeated Applications and Short Contact Periods
(40-60 Minutes) in Acne, Photoaging and Vitiligo
(BCSJFM4FSSBOP.%B .BUJMEF-PSFOUF.%B .BEHB3FZFT.%B 'FSOBOEP.JMMO.%B
"ESJO-MPSFU.%C +PBRVO.FMFOEF[D .BSJB/BWBSSPD .JHVFM/BWBSSP.%B
B
$MOJDB%FSNBUPMHJDB4FSSBOP 7BMFODJB 4QBJO
)PTQJUBM(FOFSBMEF7BMFODJB %FQBSUNFOUPG%FSNBUPMPHZ
D
3FTFBSDIBOE%FWFMPQNFOU%FQBSUNFOU 4F4%FSNB-BCPSBUPSJPT 7BMFODJB 4QBJO
C
ABSTRACT
Topical aminolevulinic acid (ALA) photodynamic therapy (PDT) is currently being used for the treatment of actinic keratosis of the
face and scalp. This study reports the results obtained after three to four treatments with ALA-PDT in patients with acne (n=12),
photoaging (n=8) and vitiligo (n=6). ALA was applied on large areas (e.g., full face) and at very low strengths (1-2%). Side effects
were minimal and self-limited.
INTRODUCTION
hotodynamic therapy (PDT) has been used since 1900.1,2,3

The use of PDT for cutaneous and non-cutaneous malignancies was widely investigated by Dougherty and collaborators.3,4 In 1999, the FDA approved the use of 20% aminolevulnic
acid (ALA) for the treatment of multiple solar keratoses of the face
and scalp.5,6 PDT has been also used to treat some instances of
supercial basal cell carcinomas and Bowen disease.5
ammatory lesions (papules, pustules and cysts). Patients were

advised to wash their face with a soapless cream (Hidraven,
SeSDerma, Valencia, Spain) twice a day during the whole study.
All the patients received one treatment every 34 weeks up to a
maximum of three treatments. An evaluation was carried out 16
weeks after the last treatment session. ALA activation was usually performed with yellow (550 nm) or red light (630 nm, Biophoton, France) for 12 minutes in yellow red (P2). In two cases an
intense pulse light (IPL) system was used (Epsilon 25).
Do Not Copy,
Penalties Apply
Recent studies highlight the effectiveness of ALA-PDT in cases

of photoaging711 and moderate-to-severe acne.1215 PDT has
Photoaging group. Eight patients (6 women, 2 men) with lightalso been used to treat actinic cheilitis,17 hidradenitis suppuratito-moderate photoaging signs on the face, neck, and hands
va,18 molluscum contagiosum,19 rosacea,20 perioral dermatitis,21
were included. The patients aged 42 to 73 (mean age 55) had
melasma, cutaneous leishmaniasis,22 localized scleroderma,23
ne wrinkles, skin thinning, hyperpigmentations/dyschromia
extragenital lichen sclerosus,24 sebaceous hyperplasia25 and to
(solar lentigines, freckles), erythrosis and telangiectasias, withenhance wound healing.26 For the last two years the authors
out evidence of solar keratoses. Each patient received three
have been employing low-strength ALA (1-2%) to treat various
treatment sessions, each spaced 34 weeks apart. Two patients
2009-Journal
All irradiation
Rights Reserved.
skin conditions such as acne, photoaging
and vitiligo.
received
with IPL (Quanta, Eterna Giovinezza).
Objectives
Vitiligo
group.
patients,
agedwritten
1236consent
years (mean
may be
madeSix
without
the express
of JDD. age, 23)
To evaluate the effectiveness and
safety
of low-strength
exhibiting
patches
of immediately.
vitiligo on face, hands or trunk were inIf you
feel you
have obtainedALA-PDT
please contact
JDD
(1-2% Levuderm ALA) in various skin conditions such as acne,
cluded. The selected patients had less than 20% of body inphotoaging, and vitiligo, through repeated applications (every
volvement and had not received treatment for the last 12 weeks.
10 to 15 minutes), short incubation periods (30 to 60 minutes)
Photographs were taken after each treatment session and 4
and three-to-four treatments sessions, spaced 34 weeks apart.
months after the last session; the degree and extension of repigmentation was estimated by photographic comparison.
METHODS
The overall patient group consisted of 26 patients diagnosed
with inammatory acne,12 vitiligo,6 or photoaging.8
Acne group. Twelve patients (9 women, 3 men) with moderateto-severe facial inammatory acne were included. Patients aged
16 to 32 years (mean age, 26 years) had a minimum of 25 in-
Products
Levuderm-ALA (Mediderma, Valencia, Spain) 1% and 2% was
used. Levuderm-ALA Gel is a system consisting of a glass ask
(containing a gel), covered by a white cap (containing the ALA
powder) and an orange applicator. The ask includes 7.5 mL of
a hydroalcoholic gel vehicle. The white cap contains variable
BEMaGS
F
BEMaGS
F
563
+6/&t70-6.&t*446&
amounts of ALA HCl as a dry solid. The various topical gels were
prepared just before their use by breaking the membrane inside
the white cap, allowing the powdered ALA to be released into the
glass container; once in contact, both components were mixed
by shaking. ALA penetration in the skin is enhanced by the presence in the gel vehicle of 5% diethylene glycol monoethyl ether
(Transcutol, Gattefosse, France) which increases transdermal
absorption from hydrophilic gel formulations. The authors are
currently carrying out chromatographic studies to determine for
how long ALA remains stable once in contact with the gel. The
manufacturer recommends product use immediately after preparation and application within 2 hours.
(4FSSBOP .-PSFOUF .3FZFT FUBM
FIGURE 1. Highintensity light source

emitting in the yellow
and orange spectrum.
Light source: Several light sources were used. Triwings (Biophoton, Saint Alban, France) was the source predominantly used.
Irradiation was carried out in the yellow-red spectrum (550-630
nm) for 4-12 minutes (P2) at 100 mW/cm2 (Figure 1). During the
procedure most of the patients used protective goggles, except
those subjects with eyelid vitiligo (Figure 1).
Intense pulsed light:
t &QTJMPO &WMBTFS $BTOJHP *UBMZ
IBOE QJFDF PG
nm, uences of 12 J/cm2, pulse width of 25 ms, and spot size
of 20x50 mm. This source was employed in two cases of photorejuvenation and in two cases of acne. In both, two passes
at uences of 6 J/cm2 were applied.
t &UFSOBM(JPWJOF[[B 2VBOUBTZTUFN .JMBO *UBMZ
IBOEQJFDF
of 570 nm (570-1200 nm). Spot size was 5 cm, uence 20 J/
cm2 and pulse duration 17 ms. Two passes were applied (10
J/Cm2 each), with a single pulse of 17 ms. Treatment sessions
were carried out at intervals of 34 weeks between sessions;
the total number of sessions was four. This source was employed in two cases of skin photoaging.
Do Not Copy,
Penalties Apply
Post-treatment: All treated patients were advised to avoid sun

exposure for a minimum of 12 hours post-treatment and to use
a sunscreen (Suny-SeS Sunscreen SPF 35, SeSDerma), blocking UVB and UVA, for 30 days after each treatment session.
Likewise, the application of a moisturizing cream was recommended (Hidraloe Face Cream, SeSDerma) 23 times a day during the week after each treatment session.
Criteria: Patients with a history of photosensitivity (porphyria,

photodermatoses, photosensitizing drugs), clotting defects
and pregnant or nursing women were excluded from the study.
Participants were asked not to use any topical or systemic
Protocol
treatments (isotretinoin, antibiotics, phenylalanine, steroids,
Before treatment, the skin was degreased (degreasing solution,
tacrolimus and pimecrolimus) for at least 1 month before the
Mediderma), to remove excess oil. Then, 12 layers of a salicylic
beginning of the PDT; the same applied to laser, IPL, chemi 2009-Journal
of Drugs inVaDermatology.
All Rights
acid peel were applied (SaliPeel, MediDerma
Laboratories,
cal peels,
PUVA,Reserved.
UVB narrow-band or any other treatment that
lencia, Spain); after
formation
of a proprietary
white mask
the skin was
could
affect
the results
of in
the
study.
Thisthe
document
contains
information,
images and
marks
of Journal
of Drugs
Dermatology
(JDD).
washedNo
with
abundantorwater.
After
drying
thecontents
skin, Levudermreproduction
use of any
portion
of the
of these materials may be made without the express written consent of JDD.
RESULTS
ALA was prepared and appliedIf every
10you
minutes
46 times.
you feel
have obtained
thisAfter
The treatment with ALA-PDT showed a 50% reduction in the
the last application, the product was left for 10 additional minutes
number of lesions (counts) of inammatory acne after the rst
before the skin was washed with soap and water. Finally the entire
treatment session, 75% after the second session and 92% after
skin was irradiated. In cases of acne and photoaging, 1% Levudthe third session (Figure 2A). Four months after the last treaterm was used; 2% Levuderm was used in patients with vitiligo. In
ment session the patients showed no signs of acne lesions and
one patient, a microdermabrasion pre-treatment was done.
acne scars had also improved. There were also no relapses at
the end of the follow-up period (16 weeks). In two of the paDuring the rst patient visit, baseline photographs were taken.
tients the treatment induced mild phototoxic reactions (erytheThe patients were controlled with serial pictures and clinical
ma and scaling), which cleared completely after 1 week (Figure
exams. The evidence of improvement was checked at each visit.
2B), leaving isolated areas of hyperpigmentation. Patients did
Digital photographs were taken after each treatment session
not report tingling sensations, burning or any discomfort durand 16 weeks after the last treatment.
ing or after irradiation (Figures 3 and 4).
BEMaGS
F
BEMaGS
F
564
+6/&t70-6.&t*446&
Number of Lesions
Mean and Standard Deviation

30
2.04
25
26.83
20
1.06
15
13.42
10
0.60
6.50
5
0
0.75
2.25
Initial
First
Treatment
Second
Treatment
Third
Treatment
FIGURE 2a. ALA-PDT showed 50% reduction in the number of lesions

(counts) of inammatory acne after the rst treatment session,
75% after the second session, and 92% after the third session, Four
months after the last treatment session the patients showed no signs
of acne lesions and acne scars had also improved.
Do Not Copy,
Penalties Apply
In the cases of photoaging, hyperpigmented lesions attenuated

in 90% of the cases, to wit:
tPGUIFDBTFTBGUFSUIFmSTUUSFBUNFOU
tPGUIFDBTFTBGUFSUIFTFDPOEUSFBUNFOUBOE
tPGUIFDBTFTBGUFSUIFUIJSEUSFBUNFOU
FIGURE 2b. Phototoxic reaction 24 hour after activation of 1% Levuderm-ALA, which completely cleared after 1 week.
DISCUSSION
Traditional photodynamic therapy (PDT) has some limitations:

requires long contact periods (3-12 h), produces severe pain
during irradiation, induces phototoxic reactions which last several days, and its indications are limited to solar keratoses and
certain cutaneous neoplasias. In the last 5 years, PDT has become more practical and its side effects have decreased signicantly. The long contact periods have been reduced from several hours (3-12 h) to 30-60 minutes and it is now used not only
Rights
Reserved.areas (e.g., the whole face). In addition,
focallyAll
but
on extended
light
sources
to activate
have also(JDD).
improved and diversiThe following side
were
observed:
one information,
case of persisThiseffects
document
contains
proprietary
images and
marks
of Journal
of DrugsALA
in Dermatology
ed.may
Theberelevant
factors
appropriate
PDT include:
tent localized
rednessorthat
lasted
72 hours
one ofcase
No reproduction
use of
any portion
of theand
contents
theseofmaterials
made without
thefor
express
written consent
of JDD.strength
of ALA,
preparation
the skin, contact period, mode of applitransitory hyperpigmentationIfthat
disappeared
spontaneously.
you feel
you have obtained
please
contact JDDofimmediately.
cation and light source.
The study included 6 patients with vitiligo, one of them with
segmental vitiligo (Figures 6 and 7) in chest and back; these
In this study, repeated (every 10 minutes) application on large
patients received 4 PDT sessions with 2% ALA applied on the
areas with ALA were carried out, (not focalized) with brief inculesions at intervals of 30 days. The degree of repigmentation
bation periods (30 to 60 minutes).
was assessed by photographic comparison. Perifollicular repigmentation began after the rst session; after the second sesALA is a precursor of protoporphyrin IX and, when the skin is
sion almost double repigmentation was observed. At the end
exposed to light, produces a photodynamic reaction, a cytotoxof the therapy, a partial repigmentation of the lesions (25 and
ic process dependent of the simultaneous presence of light and
40%) was observed in 4 of 6 patients (66.6%). A repigmentaoxygen. ALA does not show uorescence, while PpIX is very
tion of more than 55% was observed in another two patients
uorescent. The uorescence can be evaluated in the skin us(33.3%). Best responses were observed for the face, chest and
ing Woods light; this property has been used to determine the
neck. No side effects were appreciated.
The cutaneous hyperemias and small telangiectasias diminished in a partial, but satisfactory, manner in most of cases
(85%) after the third treatment. Skin surface (smoothing) and
elasticity improved in all cases (Figures 4 and 5). Patient satisfaction was assessed through a questionnaire participants
were asked to complete: 88% of the patients were completely
satised, 10% almost completely satised and 2% moderately
satised. The follow up period was 6 months.
BEMaGS
F
BEMaGS
F
565
+6/&t70-6.&t*446&
FIGURE 3. Inammatory acne before treatment with 1% ALA-PDT

(Levuderm-ALA).
The preparation of the skin by means of a salicylic acid chemical peel or with microdermabrasion allows shortening the incubation period of ALA (minutes vs. hours). These peels accentuate ALA penetration and contribute to improve the results in
both acne and photoaging.28,29 The peels should be carried out
immediately before PDT application to remove the horny layer
and to allow an even and deeper penetration of ALA.28 A thick
horny layer can be a restrictive factor for the clinical response,
as it has been described in psoriasis where hyperkeratotic sites
show a very low uorescence in comparison with other sites
where the horny layer was thin and the uorescence higher.29
Products used in this study contain Transcutol, a penetration
enhancer. Transcutol is a powerful solubilizing agent with capacity to solubilize hydrophilic and hydrophobic compounds.
Transcutol forms intracutaneous deposits of the applied drugs,
reducing its systemic absorption. In the presence of Transcutol the intercellular spaces expand, allowing the diffusion of
Transcutol and the ingredient, inside them transporting the ingredient and easing the generation of intracutaneous deposits.
Transcutol does not seem to interact with the horny layer and it
does not modify the lipid structure and cutaneous proteins.
Do Not Copy,
Penalties Apply
The light source is another factor to keep in mind in PDT. As

the skin is very accessible to light, any source providing light
of wavelengths in the absorption spectrum of the PpIX can be
used. For porphyrins, wavelengths of 505, 540, 580 and 630 nm
(Q bands) and 410 nm (Soret band) are used. The advantage
of the longer wavelengths, especially those in the yellow (550)
and red (630 nm) range or orange range, is its dermal penetration depth (2 mm). In particular, we tested a high intensity light
source (100 mW/ Cm2) with excellent results and very short
exposure times. Blue light has a very limited penetration (less
than 0.5 mm) and may not reach the dermis and a lesion located
at this level. At this wavelength (410 nm), penetration is 0.5 to
1 mm, at best. Very deep penetration is not necessary if lesions
are intraepidermal. The activation of ALA is usually done using
red light, blue light, vascular lasers and intense pulse light. All
All light
Rightssources
Reserved.
of these
have their advantages and disadvantages,marks
and everything
depend
on the clinicians
readiness and
of Journal ofwill
Drugs
in Dermatology
(JDD).
knowledge.
Certainly
may activate
endogenous
may be made
withoutthis
the express
written consent
of JDD.PpIX produced
by Propionibacterium
acnes, but the authors believe that
If you feel
you have
obtained
thistreatcopy illegally,
please
FIGURE 4. Improvement of acne lesions
2 months
after
the third
longer wavelengths are preferable to target the photodynamic
ment session with ALA-PDT.
reaction at the level of the sebaceous glands.
moment of the accumulation of PpIX after ALA application and
its clearing of the skin after interrupting the application. When
ALA concentration is also an important factor. It seems evident
using low concentrations (1-2%), and repeated applications (evthat the use of high ALA concentrations (20%) is indicated in
ery 10 minutes), the uorescence in the skin can be detected
solar keratoses and supercial basal cell carcinomas and other
between the fourth and the sixth application. The uorescence
neoplasias of the skin. However, further studies are needed to
begins to decrease approximately 15 minutes after the applicadetermine the ideal strengths and contact periods for the differtion of the gel, indicating that the application should be carried
ent conditions to treat, including SK. At present, commercially
out up to 10 minutes before exposure to light as long as the
available ALA products in Spain range from 1, 5, 10 and 20%.
incubation time of 1 hour has lapsed (Figure 9).
The use of low concentrations of ALA has many advantages. In
the rst place, virtually no side effects (phototoxic reactions)
BEMaGS
F
BEMaGS
F
566
+6/&t70-6.&t*446&
fuse solar keratoses on the face and scalp exhibiting signs of

photodamage would benet with PDT.7,8 Ruiz-Rodrguez et al.9
reported the use of ALA-PDT to treat solar keratoses of the face
and scalp as a part of a unique photorejuvenation procedure. In
their study, 20% ALA was applied for 4 h and the skin was irradiated with intense pulsed light (590-1200 nm) at uences of 40
J/cm2; two treatment sessions were done, spaced by 1 month.
The results showed the removal of 34 from 38 solar keratoses
in 17 patients in 3 months. Cosmetic results were favorable and
the procedure was well tolerated.
FIGURE 5. Photoaging signs on the chest (solar lentigines, dyschromia).
Studies by the authors show that ALA-PDT, at low concentrations, improves ne wrinkles, the texture (roughness) and
elasticity of the skin, the small telangiectasias, even the skin
color, decreases erythrosis and fades hyperpigmentations and
dyschromia in patients with photoaging, with virtually no side
effects. It is important to consider the psychological aspects of
the treatment together with the cosmetic results observed in
all patients. In patients showing signs of photoaging, as well as
solar keratoses, a combination treatment could be used: application of low-strength ALA on the whole face and focalized applications of higher strengths of ALA on specic lesions. Lubart
et al.32 has proposed that PDT would produce high amounts
of ROS (reactive oxygen species), which destroy collagen bers, encouraging the formation of new ones. But when at inner depths of the tissue, low amounts of ROS are formed, they
would stimulate broblasts and collagen metabolism, resulting
in an improvement of photoaging signs.
Do Not Copy,
Penalties Apply
In acne cases, the authors results conrm the positive results

obtained by Goldman,15 Taub,13 and other authors16 with ALAPDT applied on the whole face for short contact periods (3060
FIGURE 6. Fading of the solar lentigines and dyschromia after 3 treatments sessions with 1% Levuderm-ALA activated by intense pulse
minutes and 1530 minutes, respectively). In these cases, there
light (570-1200 nm).
is no doubt that low strengths of ALA are effective and safe,
making PDT an excellent therapeutic option for the treatment
of acne. The improvements seem to be long-lasting, as reported
are observed compared to the use of high concentrations and
elsewhere14 and appear to be related to destruction of P. acnes,
2009-Journal
Reserved. glands or both.
larger contact periods. In this study,
only
two mild of
phototoxic
effectsAll
onRights
the sebaceous
reactions, whichThis
cleared
rapidly
and proprietary
spontaneously,
wereimages
ob- and marks of Journal of Drugs in Dermatology (JDD).
document
contains
information,
served No
(Figure
8). In or
addition,
these
low
concentrations
andmaterials
Vitiligo
disorder
that
isexpress
difcultwritten
to treat,
one which
reproduction
use of any
portion
of the
contents of these
may is
beamade
without
the
consent
of JDD.has been
short periods of contact haveIf reduced
completely
the this
paincopy
re- illegally,
described
as an JDD
autoimmune
disease. The partial results obyou feel you
have obtained
please contact
immediately.
lated to the treatment which, in the past, was a restrictive factor
tained with just 4 treatments are very encouraging. It is possible
in the use of PDT. Lower strengths of ALA and short incubation
that the ALA-PDT helps modulate the immune response in the
periods will popularize the use of PDT and will allow a greater
skin of the patients with vitiligo, as described in other autoimnumber of treatments and the use of PDT in cosmetic applicamune diseases such as extragenital lichen sclerosus.24 Recently
we treated a 29-year-old woman with a long lasting genital litions, enlarging the use of procedures employing LED lamps,
chen sclerosus with ALA-PDT and achieved great success. An inlasers and intense pulse light sources emitting radiation in the
hibition of the formation of antibodies against melanocytes may
absorption spectrum of PpIX.
be also postulated as a result of PDT damage. In this instance, it
may be possible that light in the blue range could be the most
The authors predict that these procedures will be more effecappropriate. PDT could also be used in combination treatment
tive, they will shorten the number of treatment sessions and
with PUVA. A synergistic antitumoral effect has been described
can also potentially prevent the development of solar kerain vitro in HUT-78 cellular lines of Sezary syndrome combining
toses and related skin cancers. In addition, patients with dif-
BEMaGS
F
BEMaGS
F
567
+6/&t70-6.&t*446&
Do Not Copy,
Penalties Apply
FIGURE 7. Segmental vitiligo in a 12-year-old patient.
FIGURE 8. Segmental vitiligo showing perifollicular partial repigmentation after 4 treatments sessions with 2% ALA-PDT (Levuderm-ALA).
PDT and PUVA.29 PDT may also induce an immunosuppressive

effect in a way similar to that of UV phototherapy; it has been
observed in mice that the population of Langerhans cells falls
1-5 days after the procedure.30 Finally, PDT may induce hyperpigmentation in normal volunteers accompanied by an absolute
increase of the number of melanocytes with histological signs
of activation. This melanocyte activation may play a role in the
treatment of hypopigmentation diseases.31
FIGURE 9. Fluorescence of the

skin after 4 applications of 1%
Levuderm-ALA, spaced every 10
minutes (Woods light).
DISCLOSURES
Dr. Gabriel Serrano is medical director of SeSDerma Laboratories, Valencia, Spain.
Dr. Joaqun Melendez

and Dr.contains
Maria Navarro
belong
to theimages
re- and marks of Journal of Drugs in Dermatology (JDD).
This document
proprietary
information,
search and
development
department
of SeSDerma
Laboratories.
No reproduction
or use
of any portion
of the contents
REFERENCES
1.
2.
3.
4.
5.
J Drugs Dermatol. 2004;3(1 Suppl):S8-S25.
Kalka K, Merk H, Mukhtar H. Photodynamic therapy in dermatology. J

Am Acad Dermatol. 2000;42(3):389-413.
Pass Hl. Photodynamic therapy in oncology: Mechanisms and clinical
use. J Natl Cancer Inst. 1993;85(6):443-456.
Dougherty TJ, Grindey GB, Fiel R, et al. Photoradiation therapy. II. Cure
of animal tumours with hematoporphyrin and light. J Natl Cancer Inst.
1975;55(1):115-121.
Dougherty TJ, Kaufman JE, Goldfarb A, et al. Photoradiation therapy
for the treatment of malignant tumours. Cancer Res. 1978;38(8):26822635.
Taub AF. Photodynamic therapy in dermatology: History and horizons.
6.
7.
8.
9.
10.
Bissonette R, Bergeron A, Liu Y. Large surface photodynamic therapy

with aminolevulinic acid treatment of actinic keratoses and beyond. J
Drugs Dermatol. 2004;3(1 Suppl):S26-S31.
Avram DK and Goldman MP. Effectiveness and safety of ALA-IPL
in treating actinic keratoses and photodamage. J Drugs Dermatol.
2204;3(1 Suppl):S32-S39.
Gold MH. The evolving role of aminolevulinic acid hydrochloride with
photodynamic therapy in photoaging. Cutis. 2002; 69(6 Suppl):8-13.
Ruiz-Rodriguez R, Sanz-Sanchez T, Cordoba S. Photodynamic photorejuvenation. Dermatol Surg. 2002;28(8):742-744.
Sadick NS, Weiss R, Kilmer S, Bitter P. Photorejuvenation with in-
BEMaGS
F
BEMaGS
F
568
+6/&t70-6.&t*446&
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
tense pulse light: Results of a multicenter study. J Drugs Dermatol.

traviolet A in vitro in HUT-78 enhances by 5-aminolevulinic acid. Photo2004;3(1):41-49.
dermatol Photoimmunol Photomed. 2007;23(2-3):95-97.
Zane C, Capezzera R, Sala R, et al. Clinical and echographic analysis
30. Hayami J, Okamoto H, Sugihara A, Horio T. Immunosuppressive efof photodynamic therapy using methylaminolevulinate as sensitizer
fects of photodynamic therapy by topical aminolevulinic acid. J Dermain the treatment of photodamaged facial skin. Lasers Surg Med.
tol. 2007;34(5):320-327.
2007;39(3):203-209.
31. Monfrecola G, Procaccini EM, DOnofrio D, et al. Hyperpigmentation
Gold MH, Boring MN, Bridges TN, Biron JA. The use of a novel intense
induced by topical 5-aminolaevulinic acid plus visible light. J Photopulse light and heat source and ALA-PDT in the treatment of acne
chem Photobiol B. 2002;68(2-3):147-155.
vulgaris. J Drugs Dermatol. 2004;3(6):S15-S19.
32. Lubart R, Friedmann H, Lavie R, et al. A reasonable mechanism for
Taub AF. Phtodynamic Therapy for the treatment of acne: A pilot study.
visible light-induced skin rejuvenation. Laser Med Sci. 2007;22(1):1-3.
J Drugs Dermatol. 2004;3(6):S10-S14.
Hongcharu W, Taylor CR, Chang Y, et al. Topical ALA-photodynamADDRESS FOR CORRESPONDENCE
ic therapy for the treatment of acne vulgaris. J Invest Dermatol.
200;115(2):183-192.
Gabriel Serrano, MD
Goldman MP, Boyce SM. A single-center study of aminolevulinic acid
Clnica Dermatolgica Serrano
and 417 nm photodynamic therapy in the treatment of moderate to
Grabador Esteve 3
severe acne vulgaris. J Drugs Dermatol. 2003;2(4):293-396.
46004 Valencia, Spain
Rojanamatin J, Choawawanich P. Treatment of inammatory facial acne
E-mail:..................................................... ______________
gabriels@sesderma.com
vulgaris with intense pulsed light and short contact of topical 5-aminolevulinic acid: A pilot study. Dermatol Surg. 2006;32(8):991-996.
Alexiades-Armenakas M. Laser-mediated photodynamic therapy of actinic cheilitis. J Drugs Dermatol. 2004;3(5):548-551.
Gold MH, Bridges TN, Bradshaw V, Boring MM. Light therapy for
hidradenitis suppurativa. J Drugs Dermatol. 2004;3:S32-S39.
Gold MH, Boring MM, Bridges TM, Bradshaw VL.The successful use
of ALA-PDT in the treatment of recalcitrant molluscum contagiosum.
J Drugs Dermatol. 2004;3(2):187-190.
Katz B, Patel V. Photodynamic therapy for the treatment of erythema,
papules, pustules, and severe ushing consistent with rosacea. J
Drugs Dermatol. 2006; 5(2 Suppl):6-8.
Richey DF, Hopson B. Photodynamic therapy for perioral dermatitis. J
Drugs Dermatol. 2006;5(2 Suppl):12-16.
Gardlo K, Horska Z, Enk CD, Rauch L, et al. Treatment of cutaneous leishmaniasis by photodynamic therapy. J Am Acad Dermatol.
2003;48(6):893-896.
Taub AF. Photodynamic therapy: Other uses. Dermatol Clin. 2007;
25(1):101-109.
2009-Journal
Drugs of
in Dermatology.
Alexiades-Armenakas M. Laser-mediated
photodynamicoftherapy
lichen sclerosus.
J Drugs
Dermatol.
2004;3(6):S25-S27
.
This
document
contains
proprietary information,
Gold
BradshaworV,use
Boring
MM,
et al.ofTreatment
of sebaceous
NoMH,
reproduction
of any
portion
the contents
gland hyperplasia by photodynamic
5-aminolevulinic
acid illegally, please contact JDD immediately.
If you therapy
feel youwith
have
obtained this copy
and a blue light source or intense pulse light source. J Drugs Dermatol.
204;3(6):S6-S9.
Jayasree RS, Gupta AK, Rathinam K, et al. The inuence of photodynamic therapy on the wound healing process in rats. J Biomater Appl.
2001;15(3):176-186.
Katz BE, Truong S, Maiwald DC, et al. Efcacy of microdermabrasion
preceding ALA application in reducing the incubation time of ALA in
laser PDT. J Drugs Dermatol. 2007;6(2):140-142.
Kleinpenning MM, Smits T, Ewalds E, et al. Heterogeneity of uorescence in psoriasis after application of 5-aminolaevulinic acid: An immunohistochemical study. Br J Dermatol. 2006;155(3):539-545.
Akita Y, Watanabe D, Yanagishita T, et al. The effect of psoralen plus ul-
Do Not Copy,
Penalties Apply
BEMaGS
F
BEMaGS
The Dermatology Board Exam is in August...
Are You Prepared?

Now Perf
orming
Faster
than Ev
er!
Do Not Copy,
Penalties
ApplyIn-Review
Were Here to Help: Dermatology
Online Practice Exam & Study System
Thousands of questions
Interactive study tools
Timed, Board simulated exam
And for a LIMITED TIME, Online Boot Camp
Cram for the exam with the Online Boot Camp, which includes high-yield,
bulleted information, a diagnostic exam, and a mnemonics database.
Be prepared on exam day:
Stiefel.com/professional
Provided through an educational grant from Stiefel Laboratories
BEMaGS
F
BEMaGS
F
JUNE 2009
570
70-6.&t*446&
COPYRIGHT 2009
ORIGINAL ARTICLES
Are Ointments Better Than Other Vehicles for

Corticosteroid Treatment of Psoriasis?
"OOB);JWLPWJDIBBOE4UFWFO3'FMENBO.%1I%C
B
8FTU7JSHJOJB6OJWFSTJUZ4DIPPMPG.FEJDJOF .PSHBOUPXO 8FTU7JSHJOJB
$FOUFSGPS%FSNBUPMPHZ3FTFBSDI %FQBSUNFOUTPG%FSNBUPMPHZ 1BUIPMPHZBOE1VCMJD)FBMUI4DJFODFT
8BLF'PSFTU6OJWFSTJUZ4DIPPMPG.FEJDJOF8JOTUPO4BMFN /PSUI$BSPMJOB
ABSTRACT
Topical corticosteroids are the most common treatment agent for psoriasis in the United States (U.S.). Conventional dermatologic
wisdom holds that ointment preparations provide the highest potency (due to their occlusive nature and moisturizing ability) and are
best suited for psoriasis. This article presents evidence challenging the conventional belief that ointment vehicles are necessarily best
for psoriasis. A previous systematic review of the efcacy of clinical trials of potent topical corticosteroids did not support greater efcacy or greater delivery of potent topical corticosteroids with ointment vehicles compared to other topical preparations. Moreover,
preference studies demonstrate that psoriasis patients often nd application of ointment to be messy, raising concerns about both
short-term and long-term adherence to treatment. Recent compliance studies demonstrate that poor compliance to topical treatment
is common among psoriasis patients and contributes to poor psoriasis treatment outcomes. Non-ointment topical corticosteroid
products exhibit excellent efcacy in clinical practice. Much of the poor outcomes in psoriasis, even tachyphylaxis, likely relate less to
actual medication failure and more to failure to apply the medication. Topical psoriasis treatment is likely to be more successful when
physicians and patients discuss what type of vehicle the patient will use and plan treatment accordingly.
INTRODUCTION
Do Not Copy,
Penalties Apply
ost people with psoriasis have limited disease that

should be amenable to topical treatment.1 Potent topical corticosteroids are the primary treatment for psoriasis in the U.S.2 Conventional dermatologic wisdom holds that
ointment preparations are best for treating psoriatic plaque.3-5
One reason ointments are preferred for psoriasis is that they
are thought to be more powerful than alternative preparations;
also, since psoriasis is a dry, scaly process an ointment vehicle is
used to help moisturize and repair barrier function. Nevertheless,
the traditional approach of using topical corticosteroid ointment
preparations for psoriasis is often frustrating because of treatment difculty and poor results.6
the patient is most likely to comply. This article presents a challenge to the conventional wisdom that ointments are the best
vehicles for psoriasis.
Ointments: Not Necessarily More Effective
Warino et al7 reviewed the efcacy of clobetasol propionate formulations for psoriasis as determined by published clinical trials.
The analysis was limited by changes in what psoriasis outcome
measures were used over time. Using clobetasol propionate ointment for 2 weeks resulted in 70% of subjects achieving at least 75%
improvement in lesions. Other clobetasol propionate preparations
were also very effective: clear or almost-clear status was achieved
by up to 80% with a lotion formulation at 4 weeks, 68% with a
foam preparation
at 2 weeks and 82% with a spray formulation at 4
The disappointing
results
are surprising
considering
the high
ef- and
weeks.
The
authorsofconcluded
that clobetasol
propionate is a very
This
document
information,
images
marks
of Journal
(JDD).
cacy potent
corticosteroid
exhibit
clinical
trials.7materials
effective
treatment
for psoriasis
and
that other
preparations
may
No reproduction
or use ointments
of any portion
of the in
contents
of these
may be
made without
the express
written
consent
of JDD.
Poor compliance may explain
why
topical
corticosteroid
haveplease
efcacy
similar
toimmediately.
that of ointments in clinical trial settings.
If you
feel
you have
obtained this ointcopy illegally,
contact
JDD
ments are less effective in clinical practice than in clinical trials.
Some 30 to 40 percent of medications taken for chronic condiThese clobetasol data are from different trials, and the comparitions are not taken as prescribed.8 One of the most bothersome
sons could be confounded by multiple factors. Understanding
aspects of psoriasis is the messiness of treatment.9 Poor tolerof the relative efcacy of ointments versus other vehicles might
ability of sloppy ointment vehicles, and the resulting poor adherbe strengthened by a trial that compared the same corticosterence, may make ointments an unattractive choice of treatment
oid medication in different vehicles. However, clinical trial refor many patients with psoriasis.
sults are not necessarily indicative of clinical practice. Research
subjects adherence to treatment is better than clinic patients
To the extent that non-compliance is caused by the perceived
adherence. Thus, while ointment vehicles may be as effective
messiness of ointments, these products may not be best suitas other vehicles in clinical trials, ointments have the potential
ed, then, for the treatment of psoriasis. Instead, treatment for
to be less effective among actual clinic patients if patients nd
psoriasis should focus on nding treatment options with which
the ointment vehicle less tolerable.
BEMaGS
F
BEMaGS
F
571
+6/&t70-6.&t*446&
Many Patients Dislike Ointments

Quantitative measures of patient preferences for different vehicles have been developed and used to assess patients preference for different topical vehicles. Messy vehicles may adversely affect patients quality of life.10 Less messy preparations are
preferred by some patients over ointment preparations.10,11
Patients found a foam vehicles characteristics of no residue,
stain-free, quick-drying, and fragrance-free as excellent or good
by at least 95% of patients.11 This vehicle was ranked as superior
to other formulations based on impact of quality of life, including ease of use, ability to continue daily tasks directly following
application, ability to feel free of medication after application
and the ability to apply to any body area. Those subjects receiving clobetasol foam rated the foam characteristics 61% superior
to ointment, and 98% that they would be likely to comply with
twice-daily dosing for 28 days with the foam as compared to
56% compliance with ointments.
Poor Compliance to Topical Treatment

The association between patient adherence practices and
changes in psoriasis severity have been assessed using quantitative electronic monitors.12-14 These monitors were used to
assess adherence to twice daily application of salicylic acid in
a controlled trial of salicylic acid plus topical tacrolimus ointment versus salicylic acid plus placebo. Poor adherence was
common in the study.12,13 Moreover, poor adherence was a signicant predictor of change in total disease severity, positively
correlated with poor outcomes.12 Poor adherence is worse in
clinical practice and a major factor limiting the effectiveness of
topical corticosteroid ointments.
";JWLPWJDI 4'FMENBO
The effectiveness of Skin Cap was likely a matter of compliance. Patients were more compliant with a spray of Skin Cap
than they were with the more intrusive, greasy corticosteroid
ointment. Another reason for good compliance with Skin Cap
was that patients were not afraid of the potential for corticosteroids side effects, as they thought they were just using zinc
pyrithione. Skin Cap, a spray clobetasol propionate that was
more potent in clinical practice than any clobetasol propionate
ointment, demonstrated that a greasy, occlusive preparation is
not necessarily more potent than a non-moisturizing clobetasol
propionate formulation, particularly in real-life clinical practice.
DISCUSSION
Across all medical disciplines, poor outcomes are frequently due
to poor adherence and not to poor absorption or non-response.20
Many poor outcomes in psoriasis probably relate less to actual
medication failure and more to failure to apply the medication.
Not only are psoriatic lesions frustrating but treatment with the
continued application of messy topical preparations for years is
also frustrating. The potency of topical corticosteroids is determined not only by how potent the active drug is at activating corticosteroid receptors and how well the vehicle delivers the drug
into the skin, but also by whether the topical corticosteroid is actually applied.21 Some 40% of patients with psoriasis report non-adherence to their medication.8 Many of the remaining 60% are also
non-adherent. The well observed phenomenon of tachyphylaxis
may represent the steady decrease in adherence to topical treatment rather than any loss of corticosteroid receptor function.22,23
Do Not Copy,
Penalties Apply
Patients often report that they nd ointments messy and difcult

to use.4,9 Patient preference studies using validated measures
conrm that some patients report that they do not like applying
Clobetasol Spray: An Effective Treatment
ointments.10 Many psoriasis patients dont even bother to ll their
In their treatment diary, Shelley and Shelley describe an overprescriptions,23 probably at least in part because of past frustrathe-counter (OTC) medication for the treatment of psoriasis,
tion with greasy topical preparations. There are now topical corSkin Cap.15 The product was presumed to be steroid-free, conticosteroid vehicles that are less messy than ointments and that
taining zinc pyrithione and sodium lauryl sulfate as its active
are effective for delivering the active drug through the stratum
2009-Journal
of Drugs
Dermatology.
All Rights
Reserved.
ingredients. The diary stated, No longer
do patients
need in
stecorneum.
Moisturizing
the plaque is not a necessary condition
roids inuncted, ingested
or injected,
and
no moreinformation,
methotrexate
formarks
clearing
psoriasis
plaques.
Methotrexate,
This document
contains
proprietary
images and
of Journal
of Drugs
in Dermatology
(JDD). cyclosporine and
or PUVA
The authors
previously
unTNFmay
(tunor
necrosis
factor)
inhibitors
are
highlyof effective
psoNovisits.
reproduction
or use ofdescribed
any portionpatients
of the contents
of these
materials
be made
without
the express
written
consent
JDD.
responsive psoriatic plaques vanishing
after
only
days of
using
riasis
treatments,
but immediately.
they are not moisturizers. While moisturIf you feel you
have
obtained
this
copy illegally,
please
contact JDD
a one-second spray. Another study found histological improveizing may be of some benet by itself, measures that effectively
ments in psoriasis occurring within hours of initiating Skin Cap
reduce the inammation in psoriasis clear the plaques. Potent
treatment. Ultimately, however, Skin Cap was found to contain
topical corticosteroids, applied directly to the site of inammaclobetasol propionate.17 Skin Cap illustrated the importance
tion and to skin with poor barrier function, are highly effective at
of patient compliance and treatment outcome. This OTC remreducing the inammation and clearing psoriasis lesions.
edy, seemingly more effective than clobetasol ointments and
creams, was heralded as a miracle. It wasnt the zinc; a clinical
Topical psoriasis treatment is likely to be more successful when
trial found that topical zinc pyrithione added nothing to the efphysicians and patients discuss what type of vehicle the patient
cacy of topical clobetasol propionate in the treatment of psoriawill use and plan treatment accordingly. The tendency for dermasis.18 The high efcacy of Skin Cap was not due to a difference
tologists to recommend corticosteroid ointments for psoriasis is
in the bioavailability of clobetasol propionate with Skin Cap
an anachronism, dating to an early time in vehicle development
compared to approved clobetasol propionate preparations.19
when corticosteroid ointments may have been more potent and
BEMaGS
F
BEMaGS
F
572
+6/&t70-6.&t*446&
";JWLPWJDI 4'FMENBO
when patients adherence to treatment wasnt recognized as a

major factor driving the outcome of psoriasis treatment. Less
messy corticosteroid preparations are now available that effectively deliver the active corticosteroid through the epidermal barrier. While some psoriasis patients do prefer ointments and can
be effectively treated with ointment preparations, a less messy
vehicle may be preferable for other patients. The best vehicle to
use for psoriasis treatment may not be an ointment; the best vehicle is likely to be the one the particular patient will best use.
clobetasol propionate foam 0.05% in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions. J Cutan Med Surg.
2003;7(3):185-192.
12. Balkrishnan R, Carroll CL, Camacho FT, Feldman SR. Electronic monitoring of medication adherence in skin disease: Results of a pilot study.
J Am Acad Dermatol. 2003;49(4):651-654.
13. Carroll CL, Feldman SR, Camacho FT, et al. Adherence to topical therapy decreases during the course of an 8-week psoriasis clinical trial:
Commonly used methods of measuring adherence to topical therapy
overestimate actual use. J Am Acad Dermatol. 2004;51(2):212-216.
DISCLOSURES
14. Carroll CL, Feldman SR, Camacho FT, Balkrishnan R. Better medication
The Center for Dermatology Research is supported by a grant
adherence results in greater improvement in severity of psoriasis. Br J
Dermatol. 2004;151(4):895-897.
from Galderma Laboratories, L.P. Dr. Feldman has received re15. Shelley WB and Shelley ED. A dermatologic diary: Portrait of a practice.
search, consulting and speaking support from Galderma, ConCutis. 1997;59:181-182.
netics/Stiefel, Warner Chilcott, Amgen, Astellas, Abbott, Cento16. Rowlands CG and Danby FW. Histopathology of psoriasis treated with
cor, and Coria. Ms. Zivkovich has no conicts to declare.
zinc pyrithione. Am J Dermatopathol. 2000;22(3):272-276.
ACKNOWLEDGEMENTS
17. Swanson DL, Pittelkow MR, Benson LM, et al. Deja vu all over again:
A poster version of this work was presented at the 2007 Annual
Skin cap still contains a high-potency glucocorticosteroid. Arch Dermatol. 2005;141(6):801-803.
Meeting of the American Academy of Dermatology.
18. Housman TS, Keil KA, Mellen BG, et al. The use of 0.25% zinc pyriREFERENCES
thione spray does not enhance the efcacy of clobetasol propionate
1.
Stern RS, Nijsten T, Feldman SR, et al. Psoriasis is common, carries a
0.05% foam in the treatment of psoriasis. J Am Acad Dermatol.
substantial burden even when not extensive, and is associated with
2003;49(1):79-82.
widespread treatment dissatisfaction. J Investig Dermatol Symp Proc.
19. Franz TJ, Lehman PA, Feldman SR, Spellman MC. Bioavailability of
2004;9(2):136-139.
clobetasol propionate in different vehicles. Skin Pharmacol Appl Skin
2. Pearce DJ, Stealey KH, Balkrishnan R, et al. Psoriasis treatment
Physiol. 2003;16(4):212-216.
in the United States at the end of the 20th century. Int J Dermatol.
20. Urquhart J. The odds of the three nons when an aptly prescribed medi2006;45(4):370-374.
cine isnt working: Non-compliance, non-absorption, non-response. Br
3. Wolff K, Johnson RA, Suurmond D, (eds). Management of Psoriasis.
J Clin Pharmacol. 2002;54(2):212-220.
Fitzpatricks Color Atlas and Synopsis of Clinical Dermatology. 5th edi21. Kirkland R, Pearce DJ, Balkrishnan R, Feldman SR. Critical factors detion. McGraw-Hill Companies, New York, NY; 2005:68-71.
termining the potency of topical corticosteroids. J Dermatolog Treat.
4. Valencia IC, Kerdel FA. Topical Glucocorticoids. In: Freedberg IM,
2006;17(3):133-135.
Eisen AZ, Wolff K, Austen KF, et al. Fitzpatricks Dermatology in Gen22. Miller JJ, Roling D, Margolis D, Guzzo C. Failure to demonstrate theraeral Medicine. 6th edition. McGraw-Hill Companies, New York, NY;
peutic tachyphylaxis to topically applied steroids in patients with pso2003:2324-2328.
riasis. J Am Acad Dermatol. 1999;41(4):546-549.
5. Van de Kerkhof, PCM. Psoriasis. In: Bolognia JL, Jorizzo J, Rapini RP
23. Feldman SR. Tachyphylaxis to topical corticosteroids: The more you
2009-Journal
Allthem,
Rights
(eds). Dermatology, Mosby New York, NY,
2003:125-149.of Drugs in Dermatology.
use
theReserved.
less they work? Clin Dermatol. 2006;24(3):229-230.
6. Krueger G, Koo
J, Lebwohl
M,contains
et al. Theproprietary
impact of psoriasis
on quality
24.marks
Storm
Andersen
SE, Benfeldt
E, Serup J.
One in 3 prescriptions are
This
document
information,
images and
of A,
Journal
of Drugs
in Dermatology
(JDD).
of life:
of a 1998
National
patient-memnever
Primary
nonadherence
an outpatient
clinic. J Am
No Results
reproduction
or use
of any Psoriasis
portion ofFoundation
the contents
of these materials may
beredeemed:
made without
the express
writteninconsent
of JDD.
bership survey. Arch Dermatol.
2001;137(3):280-284.
Acad Dermatol.
2008;59(1):27-33.
If you
feel you have obtained this copy illegally, please
contact JDD
immediately.
7.
Warino L, Balkrishnan R, Feldman SR. Clobetasol propionate for
psoriasis: are ointments really more potent? J Drugs Dermatol.
2006;5(6):527-532.
Steven R. Feldman, MD, PhD
8. Richards HL, Fortune DG, OSullivan TM, et al. Patients with psoDepartment of Dermatology,
Wake Forest University School of Medicine
riasis and their compliance with medication. J Am Acad Dermatol.
Medical Center Boulevard
1999;41(4):581-583.
Winston-Salem, NC 27157-1071
9. Rapp SR, Exum ML, Reboussin DM, et al. The physical, psychological
Phone: ......................................................................336-716-7740
and social impact of psoriasis. J Health Psychol. 1997:2:525-537.
Fax: .......................................................................... 336-716-7732
10. Housman TS, Mellen BG, Rapp SR, et al. Patients with psoriasis prefer
E-mail:...................................................... sfeldman@wfubmc.edu
______________
solution and foam vehicles: A quantitative assessment of vehicle preference. Cutis. 2002;70(3 Pt 1):327-332.
11. Gottlieb AB, Ford RO, Spellman MC. The efcacy and tolerability of
Do Not Copy,
Penalties Apply
BEMaGS
F
BEMaGS
F
JUNE 2009
573
70-6.&t*446&
COPYRIGHT 2009
CASE REPORTS
Localized Dyskeratotic Plaque With

Milia Associated With Sorafenib
+FBOFFO"$IBQQFMM.% /JDPMF.#VSLFNQFS.% /BUBMJF4FNDIZTIZO.%
%FQBSUNFOUPG%FSNBUPMPHZ 4BJOU-PVJT6OJWFSTJUZ4DIPPMPG.FEJDJOF 4BJOU-PVJT .JTTPVSJ
"#453"$5
Sorafenib, a multitargeted kinase inhibitor used for the treatment of unresectable hepatocellular carcinoma and advanced renal cell
carcinomas, received FDA approval in 2005. Since its introduction to the market, there have been various dermatologic side effects
reported in the literature, the most well known being hand-foot skin reaction. This article presents a case of an atypical localized
cutaneous eruption with an unusual course and protracted resolution time associated with sorafenib therapy.
*/530%6$5*0/
he association between kinase inhibitors and the risk

of developing cutaneous side effects is a well reported
phenomenon in the literature. The most common and
well-studied cutaneous side effect of sorafenib is the hand-foot
skin reaction. However sorafenib induces many other cutaneous side effects that tend to get reported under the broad, and
nondescript, umbrella of rash.
The rash had been previously diagnosed as folliculitis and herpes zoster for which he received acyclovir without improvement. He continued chemotherapy for another month before
sorafenib was discontinued secondary to the unresolved skin
eruption. Upon discontinuation of sorafenib, the hematologist
noted some improvement of the lesion. When the patient presented, he had been off sorafenib for three weeks.
Do Not Copy,
Penalties Apply
As sorafenib continues to gain popularity in the treatment of

end-stage renal and hepatocellular carcinomas, the incidence
of both typical and atypical cutaneous side effects will increase.
Since medications like sorafenib have a prolonged treatment
course, their side effects, especially those which are cutaneous
and visible, are likely to affect medication compliance and patient self-esteem. It therefore remains important for physicians
to recognize and treat these cutaneous manifestations promptly. This article presents a patient with an atypical cutaneous
side effect associated with sorafenib therapy.
On physical examination, there was a 4 cm by 3 cm hyperkeratotic, erythematous and somewhat sclerotic plaque located
on his left upper cutaneous and mucosal lip (Figure 1). Within
the plaque, there were multiple yellowish papules which resembled milia. The intra-oral cavity was moist and pink with no
abnormal ndings.
$"4&3&1035
A 55-year-old Asian male with a past medical history of multifocal hepatocellular carcinoma, hepatitis B and diabetes mellitus
an
2009-Journal
Drugs in Dermatology. All Rights Reserved.
presented with a two-month history of
enlarging,ofverrucous
plaque located on
hisdocument
left upper
lip. The
lesion was
neither images
pru- and marks of Journal of Drugs in Dermatology (JDD).
This
contains
proprietary
information,
ritic norNo
painful.
Thereorwere
noany
other
lesions
othermaterials may be made without the express written consent of JDD.
reproduction
use of
portion
of the present
contents on
of these
areas of his body or any previous
a similar
The illegally, please contact JDD immediately.
If you history
feel you of
have
obtainedrash.
this copy
patient had been receiving sorafenib 400g, twice daily, for eight
months when this skin eruption occurred. At the time he was
also taking lamivudine, metformin and glipizide.
FIGURE 1. 4 cm x 3 cm
hyperkeratotic,
erythematous and somewhat sclerotic plaque with
multiple yellowish papules
resembling milia.
FIGURE 2. Focal acantholytic dyskeratosis of the epidermis (Hemotoxylin-eosin stain; original magnication: X100).
BEMaGS
F
BEMaGS
F
574
+6/&t70-6.&t*446&
+$IBQQFMM /#VSLFNQFS /4FNDIZTIZO
Punch biopsies were performed on the left upper cutaneous

lip which showed focal acantholytic dyskeratosis (Figure 2)
with hyperkeratotic and dilated follicular infundibula (Figure
3). There was also a lymphocytic inltrate consisting of histiocytes and multinucleated giant cells surrounding the follicles
(Figure 4). Gomori methenamine silver (GMS) and acid-fast bacilli (AFB) stains were negative for fungi and mycobacterium,
respectively. Biopsy sent for direct immunouorescence was
negative.
The bacterial, fungal and acid-fast bacilli smears and cultures
performed on biopsied tissue from the left upper lip were
negative. The bacterial, fungal and acid-fast bacilli cultures of
the thick, white, milia-like contents expressed from the small
papules was also negative. The patient was given the diagnosis of localized cutaneous drug eruption most likely related to
sorafenib therapy.
The patient applied tazarotene 0.05% gel every night and triamcinolone 0.1% ointment every morning to the lesion. After four
weeks, the lesion improved but did not resolve on this regimen. At this time the patient resumed sorafenib at a lower dose
of 200 mg daily. Intralesional triamcinolone 5 mg/cc injections
were added to the treatment regimen with the hope of achieving more rapid resolution. During the next four weeks, a total of
0.3 cc of intralesional triamcinolone was given using two separate injections, which dramatically improved the appearance of
the lesion (Figure 5). Subsequently, sorafenib was increased to
200 mg twice daily; he later received one more 0.2 cc injection
of triamcinolone 5 mg/cc with additional improvement. Topical
therapy was continued.
Do Not Copy,
Penalties Apply
FIGURE 3. Hyperkeratotic and dilated follicular infundibula and milia
(Hemotoxylin-eosin stain; original magnication: X40).
One week prior to the time of nal injection, sorafenib was

discontinued by his hematologist/oncologist secondary to
poor tumor response of the hepatocellular carcinoma. Three
months following the discontinuation of both sorafenib and intralesional triamcinolone, the patients cutaneous lesion almost
All Rights
Reserved.
resolved
completely
except for a minor amount of residual
erythema
desquamation
(Figure 6);(JDD).
topical therapies were
marks of and
Journal
discontinued
at this
time.
may be made
without
the express written consent of JDD.
%*4$644*0/
FIGURE 4. Granulomatous inammation surrounding a ruptured follicle (Hemotoxylin-eosin stain; original magnication: X100).
Sorafenib is a multikinase inhibitor which is FDA approved for

the treatment of unresectable hepatocelluar carcinoma and advanced renal cell carcinoma. It works by inhibiting tumor cell
replication and angiogenesis at multiple intra- and extracellular
levels.1 In addition to inhibiting the receptor tyrosine kinases
VEGFR 2 and 3 (Vascular Endothelial Growth Factor Receptor),
PDGFR-B (Platelet Derived Growth Factor Receptor Beta), FMSlike tyrosine kinase-3 (Flt-3) and c-KIT, it also inhibits RAF serine/threonine kinases C and B, which play important roles in the
RAS/RAF/MEK/ERK pathway.1,2 Blocking VEGFR, c-KIT, Flt-3 and
PDGFR-B effectively inhibits tumor angiogenesis while block-
BEMaGS
F
BEMaGS
F
575
+6/&t70-6.&t*446&
FIGURE 6. Patient after all

treatments were stopped.
culitis, hair depigmentation, alopecia, melanocytic lesions and

squamous cell carcinoma of the skin.1,2,5
FIGURE 5. Improvement of the skin lesion with topical and intralesional

therapies.
ing RAF kinases inhibits tumor cell growth. Since its advent,
patients with advanced renal cell carcinoma have experienced
longer periods of progression-free survival. In addition, multiple studies have found that cutaneous side effects are a positive predictor of better treatment outcomes.3,4 However, this
does not appear to be the case in this patient.
These complications typically occur during the rst 15 weeks of

treatment and partial-to-complete resolution is usually achieved
with either discontinuation or reduced-dose therapy.1 Cystic lesions are one of the rarer side effects of sorafenib. Previous
reports of cystic lesions, including milia, have occurred after
six to 11 weeks of sorafenib dosed at 400 mg twice daily. However, these reports did not provide detailed descriptions of the
lesion, its location, suggested treatment or expected resolution
time.4 In our case, the patients cutaneous side effect was late
in onset (32 weeks) and only achieved minimal improvement
upon discontinuation of sorafenib alone. Although the plaque
responded best to intralesional triamcinolone, there was more
improvement with topical therapy than with discontinuation
of sorafenib alone. Hence, it is not clear if discontinuation of
sorafenib alone would have led to complete resolution of the
eruption or how long this would have taken. The combination
of topical and intralesional treatments helped the lesion improve in seven months despite the patient resuming sorafenib
during that time.
Do Not Copy,
Penalties Apply
When sorafenib was initially studied in large-scale phase 3

clinical trials, the cutaneous side effects of the drug were not
thoroughly characterized and were usually given generalized
descriptions such as rash. However, as more patients gain access to sorafenib and the incidence of cutaneous side effects is
now known to be very common, the need for studies directed
specically at carefully reporting the various cutaneous presentations is important. This is especially true since eruption
severity and the extent to which these symptoms impact daily
The mechanism of the cutaneous side effects to sorafenib
activities are guidelines in governing both the dosage and/or
remains unknown. One report hypothesizes that they may
discontinuation of the medication. One randomized, doublebe related to tirosyl-kinase inhibition.3 Another theory links
pathogenesis to lesion location by highlighting the tendency
blinded, placebo-controlled phase 3 clinical trial which enrolled
2009-Journal
of Drugsside
in Dermatology.
All Rights
Reserved.
of various
cutaneous
side effects to occur in areas subjected
a total of 85 patients found the incidence
of dermatologic
4
to marks
repeatofmicro-trauma
and
pressure such
as the scalp, mouth,
effects to be as high
91% in the
group
treated with
sorafenib.
Thisas
document
contains
proprietary
information,
images
and
Journal of Drugs
in Dermatology
(JDD).
In two larger
studies, anywhere
between
1940%
of patients
onmaterials
nails,
hands
andwithout
feet. Due
to blockade
VEGFRofand
No reproduction
or use of any
portion of
the contents
of these
may
be made
the express
writtenofconsent
JDD.PDGFR-B
sorafenib experienced dermatologic
effects
whichthis
includthere
is a theoretical
that minute vasculature in those areas
If you feelside
you have
obtained
copy illegally,
please
contact JDDrisk
immediately.
ed rash and/or desquamation and 2130% developed hand-foot
would become vulnerable to micro-trauma due to inhibition of
skin reaction.1
components needed for repair resulting in a skin lesion.4 Side
effects may also be dose dependent as they tend to resolve
The most common dermatologic side effect of sorafenib therapy,
with dose reduction or discontinuation. However, there are
and the most well-described in the literature, is hand-foot skin
studies which report spontaneous resolution of cutaneous lereaction. This has recently been regarded as a separate entity
sions without dose reduction and recurrence of lesions despite
than the hand-foot syndrome which occurs with other types of
resumption of therapy at a lower dose.3,4
2
chemotherapy. Other less commonly reported cutaneous side
effects are erythema, exfoliative dermatitis, scalp dysesthesia,
Although VEGFR is not found at the surface of keratinocytes,
bullae, subungual splinter hemorrhages, stomatitis, hyperkerathis case supports the evidence that sorafenib may indeed alter
tosis of the skin or nipples, epidermoid cysts, acne, folliculitis,
keratinocyte differentiation and/or proliferation because muleczema/xerosis, erythema multiforme, keratoacanthomas, vastiple side effects associated with sorafenib (such as keratoacan-
BEMaGS
F
BEMaGS
F
576
+6/&t70-6.&t*446&
thomas, hyperkeratosis, and milia) can all be related to keratinocyte and keratin dysfunction.4,6 More studies on the mechanism,
treatment and expected resolution time of the cutaneous side
effects associated with sorafenib therapy need to be conducted
in order to help better direct treatment. In addition, gaining a
better understanding of how sorafenib causes these cutaneous
side effects will provide further insights into the pathogenesis
of hair, skin and nail disease.
5.
6.
7.
Kong HH, Sibaud V, Chanco Turner ML, et al. Sorafenib-induced

eruptive melanocytic lesions. Arch Dermatol. 2008;144(6):820822.
Beldner M, Jacobson M, Burges GE, et al. Localized palmar-plantar
epidermal hyperplasia: a previously undened dermatologic toxicity to sorafenib. Oncologist. 2007;12(10):1178-1182.
Joncas V, Sammour R, Krasny M, et al. A distinct cutaneous reaction to sorafenib and a multikinase inhibitor. Int J Dermatol.
2008;47(7):767-769.
3&'&3&/$&4
1.
2.
3.
4.
Bayer HealthCare Pharmaceuticals Inc. and Onyx Pharmaceuticals, Inc. Nexavar (sorafenib) tablets. Available at: http://berlex.
bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf. Accessed
August 1, 2008.
Lountzis NI, Maroon MS. Sorafenib-induced palmoplantar hyperkeratosis. J Drugs Dermatol. 2008;7(6):588-589.
Richetta AG, Maiani E, Carboni V, et al. Sorafenib: Atypical cutaneous side effects. Eur J Dermatol. 2007;17(6):549-550.
Autier J, Escudier B, Wechsler J, et al. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor.
Arch Dermatol. 2008;144(7):886-892.

Natalie Semchyshyn, MD
Saint Louis University School of Medicine
1402 South Grand Blvd.
St. Louis, MO 63104
Phone: ..................................................................... (314) 256-3430
Fax: .......................................................................... (314) 256-3431
E-mail: ................................................................nsemchys@slu.edu
___________
Do Not Copy,
Join the
Penalties
Apply
Complim
e
Membersntary
h
for 2009 ip
Graduate
s!
ALUMNI CLUB
Members receive:
Exclusive Exam Cram Pack

Annually updated Study
Guide CD-ROMs If you feel you have obtained this copy illegally, please contact JDD immediately.
Continued access to the
Online Practice Exam &
Study System
Join TODAY at Stiefel.com/professional

For more information, e-mail us at info-ETAS@pceny.com
____________________
Provided through an educational grant from Stiefel Laboratories
BEMaGS
F
BEMaGS
F
JUNE 2009
577
70-6.&t*446&
COPYRIGHT 2009
CASE REPORTS
Painful Parotid Hypertrophy With Bulimia:

A Report of Medical Management
,FMMZ,1BSL.%B 3FCFDDB$5VOH.%C "SMFOF3VJ[EF-V[VSJBHB.%.1)C
B
/PSUIFBTUFSO0IJP6OJWFSTJUJFT$PMMFHFPG.FEJDJOF 3PPUTUPXO 0IJP

C
%FQBSUNFOUPG%FSNBUPMPHZ $MFWFMBOE$MJOJD #FBDIXPPE 0IJP
"#453"$5
In eating disorders, such as bulimia nervosa, body image disturbance often extends beyond the realm of weight and shape into the
dermatologic spectrum. While commonly associated conditions due to binging and self-induced vomiting include cutaneous entities
(e.g.,Russells sign, acne, alopecia and hypertrichosis) and oral pathologies (e.g.,enamel erosion, caries and mild parotid hypertrophy),
a rare but troubling manifestation is disguring parotid enlargement (sialoadenomegaly). This article presents a case of painful sialoadenomegaly associated with hyperamylasemia in a bulimic patient successfully managed with pilocarpine.
$"4&3&1035
%*4$644*0/
36-year-old Caucasian female presented with cosmetic

Bulimia nervosa (BN) is an eating disorder characterized by recomplaints of sun damage and wrinkles. Physical examcurrent binge eating that is followed by a compensatory behavination demonstrated scattered facial lentigines and ne
ior (e.g., self-induced vomiting) in order to avoid weight gain. It
forehead rhytides. In addition, her bilateral cheeks overlying the
is often associated with concomitant affective disordersmost
parotid glands were markedly enlarged, rm and tender to palcommonly depression and body-image distortion issues inpation. The patient stated that her dentist attributed her swollen
cluding low self-esteem and self-criticism.1,2 Gupta and Gupta3
found a signicant association between eating disorders and
cheeks to temporomandibular joint syndrome, which was being
dermatologic complaints. Compared to unaffected controls,
managed with a bite guard. Inspection of the oral cavity revealed
81% of individuals with eating disorders reported dissatisfacexcellent dentition (Figure 1). She also had faint scars on her dortion with their skin appearance with respect to dryness, irregular
sal right hand, consistent with Russells sign. Her current medicapigmentation, ne rhytides, roughness and dark circles under
tions included calcium and vitamin D supplementation, estradiol
the eyes.3 The most common cutaneous manifestations of BN
and an etonogestrel/ethinyl estradiol vaginal ring. Upon further
are xerosis and acne, while the pathognomonic Russells sign
questioning, the patient admitted to having a 10-year history of
(abrasions on the dorsal hand caused by the upper teeth from
active bulimia and secondary osteoporosis. Her eating disorder
stimulation of the gag reex) occurs in 30% of cases. Carotewas currently being managed by her primary care physician and
noderma, alopecia, hypertrichosis, tooth decay with erosions,
therapist. Laboratory tests revealed increased serum amylase
dentin hypersensitivity, xerostomia, periodontal disease and
level of 413 U/L (normal 0-137) accompanied by normal or negaconjunctival suffusion or hemorrhage may also be seen4. This
tive values for comprehensive metabolic panel, complete blood
group of patients may seek treatment for minimal dermatologcount with differential, anti-nuclear antibodies, anti-SSA and
ic disease due to altered self-perception and may also possess
SSB and angiotensin-converting enzyme (ACE) studies. Com 2009-Journal
All Rights
Reserved.of what treatment can accomplish.3
unrealistic
expectations
puted tomography (CT) scan of the head
and neck demonstrated
bilateral massively
parotid
glands with
Thisenlarged
documenthomogeneous
information,
While
benign
parotid
hypertrophy
and
no masses
as well asordiffusely
enlarged
sublingual
No reproduction
use of any
portion ofbilaterally
the contents
of these materials
maythe
be association
made withoutbetween
the express
written
consent
of JDD.
bulimia
was
rst described
in 1969,5 the etiology of the process
glands (Figure 2). There was Ifno
evidence
ofthis
lymphyouradiologic
feel you have
obtained
copy illegally,
please
contact
JDD immediately.
is still unknown. Proposed theories include abnormal parotid
adenopathy. The patient declined ne needle aspiration.
sympathetic innervation, cholinergic stimuli, malnutrition, exOn the basis of her clinical history, physical examination, laboratory and imaging studies, a diagnosis of sialoadenomegaly
FIGURE 1. Massive
due to bulimia was made. Symptomatic treatment with oral
parotid hypertrophy
pilocarpine hydrochloride tablets was initiated at a dosage of
in a patient who
presented with
5.0 mg a day and was titrated to 5.0 mg three times daily. Alswollen cheeks.
though the patient continues binge-purge behaviors despite
multi-disciplinary intervention, maintenance on pilocarpine
therapy over the past 9 months has resolved her parotid pain
without side effects. In addition, modest reduction in the parotid gland size was achieved (Figure 3).
Do Not Copy,
Penalties Apply
BEMaGS
F
BEMaGS
F
578
+6/&t70-6.&t*446&
,1BSL 35VOH "3VJ[EF-V[VSJBHB
sarcoidosis; allergic reactions; and drug reactions to radioactive

iodine I131 or anesthesia. Metabolic and endocrine disorders (diabetes mellitus, hypothyroidism, hyperlipidemia, liver disease,
pituitary-adrenal axis disorders, gout, nutritional disorders and
menopause) have also been associated with parotid enlargement. Malignant diseases, including lymphomas and parotid
neoplasia, may present as bilateral parotid enlargement.6
Ultrasonography can be used to rule out parotid hypertrophy,
stones, tumors, and infection. Computed tomography (CT) scan
of the head and neck usually shows only parotid enlargement
with no masses. Fine-needle aspiration shows normal tissue
with no inammation, granule depletion, lymphocytic inltrate
or fatty change. Sialograms are usually normal, showing normal ducts and tributaries.
FIGURE 2. Computed tomography (CT) scan of the head and neck

showing bilateral signicantly enlarged parotid and salivary glands.
When present in bulimics, parotid hypertrophy may manifest

as unilateral or bilateral painless enlargement of the glands.
Parotid swelling usually occurs 2 to 6 days after a binge-purge
episode. It may regress or persist, depending on the status of
binge-purge activity and the pattern of gland enlargement.6 The
course is often variable. While intermittent hypertrophy most
often occurs in those who vomit at least once daily,9 chronic bulimia can lead to irreversible parotid enlargement. Abstinence
from binge-purge behaviors can lead to normalization of parotid gland size; however, the change in appearance is not often
immediate. Morbidity stems from cosmetic deformity and the
risk of permanent enlargement, both of which can exacerbate
the body image and psychiatric issues in bulimic patients. The
lack of complete regression of parotid hypertrophy in this patient may be explained by the fact that the she has been unable
to refrain from binge-purge behaviors despite intervention.
Do Not Copy,
Penalties Apply
Electrolyte abnormalities often accompany parotid hypertrophy in people with bulimia. Most frequent alterations include
hypokalemic, hypochloremic metabolic alkalosis due to vomitFIGURE 3. Treatment with maintenance pilocarpine resulting in
ing.
Amylase values may also be elevated. In one series, hyperreduction of parotid gland size.
All Rights
Reserved.
amylasemia
was
seen in 61% of binge-purge type patients with
The degree
of hyperamylasemia
bulimia,
in ourofpatient.
marks ofasJournal
Drugs in10Dermatology
(JDD).
cessiveNo
starch
ingestion,
metabolic
disorders
and work
hyperwasmay
shown
to bewithout
proportional
to the
frequency
binge eating
reproduction
or use
of any portion
of the contents
of these
materials
be made
the express
written
consent of JDD.
10
et al. also found that the degree of patrophythe enlargement of Ifparotid
due illegally,
andplease
vomiting.
you feelcellular
you havecomponents
obtained this copy
contactPhilipp
JDD immediately.
rotid enlargement correlated with the severity of dental enamel
to chronic autonomic stimulation.6, 7 Salivary secretion studies
have shown that people with bulimia have a reduced resting
erosions.11 Gwirtsman at al. observed a relationship between
parotid hypertrophy and hyperamylasemia.12 In their study,
ow rate compared to normal control patients. While the inboth parotid swelling and amylase values decreased during the
cidence of parotid hypertrophy and adjunctive salivary gland
abstinence phase for hospitalized bulimic patients. They found
swelling in bulimia nervosa and has been documented in 10
that a serum amylase value of 75 U/L or greater when accom25% of individuals, persistent disguring parotid enlargement
panied by parotid enlargement can help identify and monitor
(sialoadenomegaly), as seen in this young woman, is extremely
binge-purge activity.
rare, occurring in less than 0.5% of these patients.1,8
Benign parotid hypertrophy is observed in a variety of other conditions: inammatory disorders such as bacterial or viral infection; autoimmune diseases including Sjgrens syndrome and
The most effective overall treatment of bulimia-associated parotid hypertrophy is a multi-disciplinary approach toward management of the underlying eating disorder. In the interim, con-
BEMaGS
F
BEMaGS
F
579
+6/&t70-6.&t*446&
servative treatment of parotid hypertrophy includes application

of heat, salivary substitutes and sialogogues (including tart
candies). Two extreme cases of massive parotid enlargement
were surgically treated with bilateral supercial parotidectomy.
While immediate post-operative results yielded early patient
satisfaction and cosmetic improvement, longer term follow-up
for these same parameters were not available.6
Non-invasive intervention may be advantageous because potential complications of surgery (facial nerve injury and permanent
facial disgurement) can be avoided. Pilocarpine has been reported to be a successful medical intervention in two refractory
cases.7,9 Pilocarpine is a parasympathetic muscarinic receptor
agonist that increases secretions from glands. Primary indications are for treatment of glaucoma and xerostomia. Total dosage of pilocarpine is limited by adverse effects, which include
ushing, profuse sweating and salivation, diarrhea, bradycardia,
hypotension and bronchospasm. While the exact mechanism of
improvement is unknown, it is presumed that the increased ow
of saliva may serve to decompress the glands.
Mehler et al. described treatment of two hospitalized patients
with refractory bulimia-associated parotid hypertrophy who
abstained from purging and were treated with ophthalmic pilocarpine given orally.7 Improvement was noted within two days.
In their rst patient, dosing began at 5 mg daily and was tapered to 2.5 mg daily for total treatment duration of two weeks.
During treatment, the patient experienced increased sweating,
ushing and increased salivation. The second patient was given
a dose of 1.5 mg daily for one week, which was associated with
only minimal ushing.7 In patients who are unable to cease
purging activities, as in our case, pilocarpine at higher doses (5
mg three times daily) offers safe, symptomatic improvement.
,1BSL 35VOH "3VJ[EF-V[VSJBHB
3&'&3&/$&4
1.
Mitchell JE, Hatsukami D, Eckert ED, Pyle RL. Characteristics of

275 patients with bulimia. Am J Psychiatry. 1985;142(4):482-485.
2. Hudson JI, Hiripi E, Pope HG, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2007;61(3):348-358.
3. Gupta MA, Gupta AK. Dissatisfaction with skin appearance among
patients with eating disorder and non-clinical controls. Brit J Derm.
2001;145(1):110-113.
4. Glorio R, Allevato M, De Pablo A, et al. Prevalence of cutaneous
manifestations in 200 patients with eating disorders. Int J Dermatol. 2000;39(5):348-353.
5. Lavender S. Vomiting and parotid enlargement. Lancet.
1969;1(7591):426.
6. Berke GS, Calcaterra TC. Parotid hypertrophy with bulimia: A report
of surgical management. Laryngoscope. 1985;95(5):597-598.
7.
Mehler PS, Wallace JA. Sialadenosis in bulimia. A new treatment.
Arch Otolaryngol Head Neck Surg. 1993;119(7):787-788.
8. Riad M, Barton JR, Wilson JA, et al. Parotid salivary secretory pattern in bulimia nervosa. Acta Otolaryngol. 1991;111(2):392-395.
9. Rauch SD, Herzog DB. Parotidectomy for bulimia: A dissenting
view. Am J Otolaryngol. 1987;8(6):376-380.
10. Kinzl J, Biebl W, Herold M. Hyperamylasemia and salivary gland
enlargements in patients with eating disorders. J Clin Psychiatry.
1991;52(3):139-140.
11. Philipp E, Zonnchen B, Hamm GI, Pirk KM. Oral and dental complications in bulimic patients. Int J Eating Disord. 1991;10:423-431.
12. Gwirtsman HE, Kaye WH, George DT, et al. Hyperamylasemia and
its relationship to binge-purge episodes: Development of a clinically relevant laboratory test. J Clin Psychiatry. 1989;50(6):196-204.
Do Not Copy,
Penalties Apply

Rebecca C. Tung, MD
While bulimia is an eating disorder that may have numerous
26900 Cedar Rd.
associated dermatologic ndings, massive parotid hypertroCleveland Clinic Beachwood
phy is among the most cosmetically disguring and psychoBeachwood,
OHReserved.
44122
2009-Journal
Drugs the
in Dermatology.
All Rights
logically devastating related conditions.
With this isofmind,
Phone:
.......................................................................
dermatologist should
be certain
to inquire
further
regarding
a and marks of Journal of Drugs in Dermatology (JDD). 216-444-5489
This document
contains
proprietary
information,
images
Fax: ............................................................................ 216-839-3879
patients
habits or
and
if mild
parotid
swelling
Noeating
reproduction
usebehaviors
of any portion
of the
contents
of theseismaterials may be made without the express written consent of JDD.
E-mail:.........................................................becki_tung@yahoo.com
______________
encountered on physical examination.
In this
of patients,
If you feel you
havegroup
obtained
identifying and addressing an occult eating disorder early on
may prevent progression to refractory sialodenomegaly. To
conrm the diagnosis of bulimia-associated parotid hypertrophy, suggested work-up includes serum electrolyte and amylase levels as well as imaging studies (ultrasound or CT scan).
Primary management of this entity aims to treat the underlying
eating disorder. Concomitant medical therapy with oral pilocarpine can be employed to alleviate discomfort and modestly
reduce gland size.
%*4$-0463&
None of the authors have any conicts of interest to disclose.
BEMaGS
F
BEMaGS
F
JUNE 2009
580
70-6.&t*446&
COPYRIGHT 2009
CASE REPORTS
Intramuscular Triamcinolone: A Safe, Effective and

Underutilized Dermatologic Therapy
%PVHMBT/3PCJOT.%
/PSUI'MPSJEB%FSNBUPMPHZ"TTPDJBUFT +BDLTPOWJMMF '-
"#453"$5
Although intramuscular triamcinolone acetonide has been available as a dermatologic therapy for many years, it is used sparingly or
not at all by many dermatologists because of concern about its safety, as well as a lack of understanding of its specic therapeutic
benets. This case report discusses the efcacy and safety of intramuscular triamcinolone acetonide, along with description of the
specic technique employed by the author, as well as the clinical indications and side effects seen by the author in his practice over
time. The report describes the positive results attained in the treatment of many chronic, recalcitrant dermatologic conditions that
cannot be adequately controlled by topical therapy alone. Because of its strong safety prole and unique therapeutic efcacy, intramuscular triamcinolone should be considered as a primary therapy for many chronic, steroid responsive, dermatologic conditions
requiring a systemic approach.
*/530%6$5*0/
ntramuscular triamcinolone acetonide has been available

since 1962 but, primarily because of safety concerns, its
use in dermatologic therapy has always been controversial.
Dermatologists who oppose its use usually cite several concerns, namely:
muscle. It is necessary to avoid any leakage of the medication

into the subcutaneous tissue in order to prevent localized atrophy or a sterile abscess from occurring.
Do Not Copy,
Penalties Apply
1. Since it is given as a depot injection deep into the muscle,

and is then slowly released, it may lead to irregular absorption and unpredictable results.
2. The slow, prolonged release of the medication makes its
use primarily for the treatment of chronic conditions and,
therefore, in order to be effective, its side effect prole will
be similar to the well-documented side effects seen with
long term oral corticosteroids. In contrast to a depot injection, the use of oral corticosteroids allows the treating
physician to adjust the dosage or discontinue it altogether
depending on the clinical circumstances.
Indication for Intramuscular Triamcinolone

Intramuscular triamcinolone is indicated in adults with chronic
symptomatic recalcitrant steroid-responsive dermatologic conditions that cannot be adequately treated with topical medication or other simple measures alone. This author has not used
this therapy for children under the age of 16 primarily because
of concerns about its effect on bone growth. There are few other patients for whom this treatment modality would be contraindicated, and this author uses it routinely to treat elderly
patients as well as those with diabetes and hypertension.
Frequency and Dosing
There are no well-controlled studies in the literature to indicate a preferred frequency and dosing schedule and, therefore,
dermatologists who use intramuscular triamcinolone regularly
All Rights
Reserved.
may have
different
preferences. When the author rst learned
While these concerns may appear to be2009-Journal
legitimate,ofatDrugs
least inonDermatology.
to marks
use this
technique,
and in
for
many years
thereafter, the author
an intuitive basis,
are unique
ofinformation,
intramuscular
Thisthere
document
containsfeatures
proprietary
images and
of Journal
of Drugs
Dermatology
(JDD).
injected
60made
mg at
least the
six express
weeks apart.
this
proved to be
triamcinolone
that allow
it of
to any
be portion
used quite
effecNo reproduction
or use
of the safely
contentsand
of these
materials
may be
without
writtenWhile
consent
of JDD.
safeplease
and effective,
there
were times that 80 mg was somewhat
tively in treating many chronic
dermatologic
conditions.
If you
feel you have
obtained this copy illegally,
contact JDD
immediately.
more effective and did not lead to increased short-term side effects. At the same time, stretching the duration of the injections
This author has treated thousands of patients over the past 30
to at least seven to eight weeks apart improved the potential
years with this medication and currently continues to use it evmargin of safety. Depending on the specic condition being
ery day in his ofce practice. The article presents the specic
treated, there could be an early recurrence of symptoms one to
technique which has allowed it to be used effectively in the
two weeks prior to the next scheduled injection but using topitreatment of a wide variety of chronic, challenging, dermatocal medication aggressively has minimized this problem.
logic conditions while at the same time being (intramuscular)
safer than long-term oral corticosteroids.
Clinical Indications
.&5)0%4
Prutitus
It is very important to use a 3 cc syringe and a 1.5-inch IM needle and to inject into the upper outer quadrant of the gluteal
Intramuscular triamcinolone is an extremely effective antipruritic, and its clinical effects will last for six to eight weeks or
BEMaGS
F
BEMaGS
F
581
+6/&t70-6.&t*446&
even longer. This feature allows it to be extremely important in

treating a large number of dermatologic conditions with intractable pruritus (Table 1).
%3PCJOT
TABLE 1.
Pruritic Conditions
Idiopathic pruritus
Idiopathic pruritus in the elderly usually responds quite well as do

a wide variety of localized (Figure 1) and generalized conditions in
which the itch/scratch mechanism is difcult to control with topical
medication alone (Figure 2). On the other hand,Table 2 lists pruritic
conditions that do not respond to intramuscular triamcinolone. In
fact, response or lack of response to intramuscular triamcinolone
may, in many cases, help to reach a specic diagnosis.
Of course, this author also prescribes topical corticosteroids,
since they also have antipruritic and other anti-inammatory
effects but, unless the overall pruritus is controlled with the intramuscular triamcinolone, these conditions may remain resistant to treatment.
Generalized eczematous conditions

Localized neurodermatitis (genital areas, scalp, lower legs)
Prurigo nodularis
Pityriasis rosea
Polycythemia vera
TABLE 2.
Pruritic Conditions Not Relieved by Intramuscular
Triamcinolone
Burning conditions (scalp and genitalia)
Neurologic conditions (stocking and glove, notalgia
paresthetica)
Hand and Foot Conditions

Table 3 lists the four major types of chronic eruptions seen on
the hands and feet. The thickness of the palms and soles, as well
as other factors, may contribute to the relative ineffectiveness
of topical medications in severe cases. Just as with other similar eruptions, the profound anti-inammatory and antipruritic
effects of intramuscular triamcinolone will have a six-to-eight
week duration and allow topical measures to be more effective.
Psoriasis
Prurigo simplex/generalized neurodermatitis
Obsessive compulsive disorders

Scabies
Do Not Copy,
Penalties Apply
Hodgkins disease, as well as other underlying malignancies.

Pruritus secondary to early CTCL may partially respond.
Dermatitis herpetiformis
TABLE 3.
Hand and Foot Conditions

While this author does not use intramuscular triamcinolone
Vesicobullous
to treat generalized psoriasis, it is used to help control certain
treatment-resistant localized forms of the disease (Table 4).
Hyperkeratotic
With the introduction of numerous biologic agents over the
Occupational
past few years we now have many therapeutic options to treat
Acropustulosis
more severe generalized psoriatic disease. However, even with
those agents mild ares can occur, and there can be transition
TABLE 4.
periods when disease control is not ideal, and the booster effect from intramuscular triamcinolone used temporarily can be
Psoriasis: Treatment-Resistant, Localized Forms
benecial in those circumstances.
Palms and soles (hyperkeratotic and acropustulosis)
Scalp
Lichen Planus
Nails
Table 5 lists those forms of lichen
planus
which
not respond
If you
feel you
havemay
obtained
Booster
to topical therapy alone and, because the condition is often
chronic, intramuscular triamcinolone can be very benecial in
achieving adequate control. This author has been able to obtain
TABLE 5.
partial, but not complete, resolution of erosive oral lichen planus,
Lichen Planus: Forms That May Not Respond To Topical
but even partial resolution can allow other topical and intraleTherapy Alone
sional therapy to be used more successfully.
Chronic, symptomatic and widespread
Alopecia
Hypertrophic
Table 6 lists the three forms of alopecia that may respond to

intramuscular triamcinolone. Localized alopecia areata can almost always be treated successfully with intralesional triamcinolone. In widespread cases, including alopecia totalis, intral-
Nails
Lichen plano-pilaris
Oral and genital
BEMaGS
F
BEMaGS
F
582
+6/&t70-6.&t*446&
%3PCJOT
FIGURE 2. Generalized neurodermatitis. FTN: The patient is a 67-yearold male with a 5-month history of a generalized extremely pruritic,
excoriated eruption, and several biopsies were read as spongiotic
dermatitis. An extensive work-up had failed to reveal an underlying
etiology, and several courses of oral corticosteroids had given only
temporary relief of his pruritus. After one triamcinolone injection,
he had received a 6 to 7 week remission of his pruritus and most of
his cutaneous changes had disappeared. A second injection gave
him permanent relief of pruritus and resolution of all his cutaneous
ndings.
Do Not Copy,
Penalties Apply
grooming practices, that theory is no longer considered valid.

The condition usually progresses over several years and often
leads to extensive scarring and permanent hair loss. The progress of the condition can be halted promptly by use of bi-monthly triamcinolone injections which may have to be continued for
FIGURE 1. Localized neurodermatitis. FTN: The patient had a two-year
six-to-twelve months before tapering off. The scarred follicles
history of severe pruritus involving her eyelids and periorbital areas of
will no longer grow hair but, since it is a dynamic process, hair
her face, and she had developed tissue hypertrophy and lichenicamay
fall out before the follicles are completely destroyed, and
tion secondary to rubbing a). Several courses or oral corticosteroids
a
small
amount of hair regrowth is often seen after initiation
had given temporary relief only, and numerous topical medications
of the bi-monthly injections. Just as with widespread alopecia
had been ineffective. Eight weeks after one triamcinolone injection
b), she still has residual pigmentation, but the tissue hypertrophy and
areata, the use of intralesional triamcinolone on a monthly balichenication have gone and the pruritus has not recurred.
sis would not achieve any better results and would have more
All Rights
Reserved.
associated
morbidity.
esional therapy is
usually
impractical
ofinformation,
the associated
This
document
containsbecause
proprietary
Miscellaneous
pain of No
thereproduction
extensive injections
required
tothe
treat
the condition.
or use of any
portion of
contents
of these materials
may be madeConditions
without the express written consent of JDD.
Table
7 lists
a number
of conditions which may be successfully
Intramuscular triamcinolone injections
avoid
the
impracticality
If you feel you
have
obtained
please
contact
JDD immediately.
treated with intramuscular triamcinolone. All are relatively unof the intralesional technique and are successful in a signicant
common except for chronic urticaria which responds quite well,
number of cases. Treatment can usually be tapered off after sixin most cases, to intramuscular triamcinolone. This author will
to-twelve months, and results are long lasting, but there is a
usually prescribe one or two non-sedating antihistamines, rst,
substantial recurrence rate. Alopecia universalis responds less
and then add intramuscular triamcinolone if adequate control
frequently to intramuscular triamcinolone than do other forms
is not achieved.
of the disease, but it is still worth trying since some cases do
respond and there are few other effective alternatives.
Intramuscular triamcinolone will be a crucial factor in achieving
control in the vast majority of patients with the conditions listCentral centrifugal cicatricial alopecia is a chronic progressive
ed above and, of course, patients are always encouraged to use
condition occurring primarily in African-American women (Figappropriate topical therapy along with other local measures.
ure 3). The etiology is not clear and, although it was at one time
Even one or two injections may induce a long-term remission
thought to be caused by the use of hot combs and other hair
BEMaGS
F
BEMaGS
F
583
+6/&t70-6.&t*446&
%3PCJOT
in some of the more severe and persistent cases while, in others, bimonthly injections may have to be continued for a year
or more while always attempting to gradually increase the duration between injections. Many of the patients may eventually
return once or twice a year or even less often on an as-needed
basis. The goal is always to use the least amount of medication
required to achieve the desired outcome.
was gone by the end of the third week.1 While this report does
not explain why the anti-inammatory effects of triamcinolone
acetonide last long after its disappearance from the plasma, it
does help to rebut the common misconception that has lead to
much of the controversy about this therapy. That is, the clinical effects roughly parallel the persistence of the medication
in the circulation which, if true, would lead to long-term side
Side Effects
TABLE 6.
Table 8 lists side effects seen with intramuscular triamcinolone.

Petechiae and purpura occur more frequently in older individuals with signicant actinic damage. Menstrual irregularities also occur, and premenopausal women should be warned
about this in advance and may need to use hormonal therapy
to prevent this problem. Women who are attempting to become pregnant should not be treated with this therapy except
in unusual circumstances. Facial hirsutism in women occurs
rarely, and sterile abscess formation should also be quite rare
if careful injection technique is followed. Localized lipoatrophy
at the injection site can also occur if all the medication is not
completely delivered into the muscle. Except for appearance,
it is not symptomatic and will usually resolve gradually over a
few months. Serum glucose may increase 5-10 dL/mg three to
ve days following each injection and then returns to pretreatment levels. This author does not, therefore, hesitate to treat
patients with diabetes.
Alopecia: Three Forms That May Respond to Intramuscular

Triamcinolone
t"MPQFDJBBSFBUBUPUBMJTVOJWFSTBMJT
t$FOUSBMDFOUSJGVHBMDJDBUSJDJBMBMPQFDJB
t-JDIFOQMBOPQJMBSJT
TABLE 7.
Conditions That May Be Successfully Treated With
Intramuscular Triamcinolone
Chronic urticaria
Small plaque parapsoriasis
Do Not Copy,
Penalties Apply
PLEVA
Pityriasis lichenoides chronica
Cutaneous lymphoid hyperplasia

Generalized granuloma annulare
In contrast, Table 9 shows side effects commonly seen with a

short course of oral corticosteroids that are not seen with intramuscular triamcinolone if used seven to eight weeks apart.
These side effects will, of course, worsen over time the longer
the oral corticosteroids are used. In the authors opinion, to
achieve adequate control of the numerous chronic dermatologic conditions for which intramuscular triamcinolone is effective,
it would require prolonged use of oral corticosteroids which
would lead to signicant morbidity.
Sclerodema
TABLE 8.
Intramuscular Triamcinolone Side Effects
Petechiae and purpura
Menstrual irregularlitis
Mild hyperglycemia (3-5 days)
Localized lipoatrophy
2009-Journal
of Drugswith
in Dermatology.
All Rights
Bone-related side effects are among the
major concerns
Hirsutism
(veryReserved.
rare)
the long term use
systemic
corticosteroids.
Based on images
the andSterile
Thisof
document
contains
marksAbscess
of Journal(very
of Drugs
rare)in Dermatology (JDD).
authorsNoexperience
the
useportion
of intramuscular
reproductionwith
or use
of any
of the contentstriamcinoof these materials may be made without the express written consent of JDD.
lone as described in this report,
these
are extremely
If you
feelside
you effects
have obtained
TABLE 9.
rare if they even occur at all. There are several studies in the
literature which help explain why. Kusama et al. treated ve
Side Effects Commonly Seen With a Short Course of Oral
patients with radioactively tagged triamcinolone acetonide and
Corticosteroids That Are Not Seen With Intramuscular
measured the plasma levels and urinary excretion. They found
Corticosteroids
that the peak plasma level of triamcinolone acetonide occurred
Increased appetite
in the rst one-to-two days and then fell rapidly over the next
Weight gain and uid retention
ve-to-six days to about one-third of its peak level and stayed
steady for the next six to seven days. It was felt that this peBloating and other GI symptoms
riod represented an equilibrium between the slow continued
Moon face and centripetal fat distribution
release from the intramuscular depot and the slow excretion
Insomnia, hyperactivity and psychiatric symptoms
because of triamcinolone acetonides low renal clearance rate.
Muscle weakness
During the next week, the plasma level decreased steadily and
BEMaGS
F
BEMaGS
F
584
+6/&t70-6.&t*446&
%3PCJOT
in this report, the relatively small amount of steroid used should

make the risk for this side effect extremely small.
FIGURE 3. A 38-year-old African-American woman who rst noticed

excess hair shedding six months previously and the clinical ndings
and biopsy results were consistent with the diagnosis of central centrifugal cicatricial alopecia. FTN: Within a week after receiving her
rst triamcinolone injection, the excessive shedding had stopped.
The injections were continued for a year without any progression of
her alopecia.
The package insert for triamcinolone acetonide states that adrenal suppression lasts for 3040 days following an intramuscular
injection5 and this has been conrmed by other studies.6 However, since many of the dermatologic conditions treated by this
modality may require prolonged therapy, there is a question of
whether repeated injections every seven-to-eight weeks may
induce prolonged adrenal suppression. The only study in the
literature to look at this issue was by Droszcz et al. who found
that, in a series of asthma patients treated with long-term (average 3.5 years) intramuscular triamcinolone six weeks apart,
42 of 48 patients had normal adrenocorticosteroid function six
weeks after their last injection.7 The study was reassuring since
it showed that most patients treated on a long-term basis, at
least six weeks apart, did not develop prolonged adrenal suppression. Six of the 48 patients did develop adrenal suppression six weeks after their last injection, at least based on the
adrenal stimulation test that was used, but there was no discussion about whether any of those six patients had any clinical evidence of adrenal suppression, nor was there any follow
up given. If continued clinical adrenal suppression is a concern
and, in my experience it would be quite rare, there are several
safeguards which can be used when following patients undergoing long-term therapy, including review of systems looking
for clinical signs of adrenal suppression such as fatigue, depression, nausea and anorexia; and obtaining a morning cortisol level several days before the patient is scheduled to return
for the next injectionif the level is low, then further testing
can be done.
Do Not Copy,
Penalties Apply
effects. The fact that triamcinolone acetonide is gone from the

circulation by the end of the third week with a subsequent fourto-ve week break before another injection would likely mitigate against many of the side effects seen with long term oral
corticosteroids. An example of one of the side effects would be
bone loss leading to an increased potential for fracture. Oral
corticosteroids may inhibit osteoblast formation and promote
apoptosis of osteocytes. In a study of 244,000 patients treated
with long term oral corticosteroids, Van Staa et al. showed that
those treated with 2.5 mg/day of prednisone or less (80 mg of
%*4$-0463&4
triamcinolone acetonide is equivalent to 1.8 mg of prednisone
The author does not have any conicts of interest to disclose.
a day over an eight week period) do have a slightly higher risk
of fracture compared to controls, but the risk of fracture is cor$0/$-64*0/
respondingly higher with a higher dosage. One nding that
In the authors experience, intramuscular triamcinolone has
this study showed was that there is a rapid onset of fracture risk
2009-Journal
Drugs inof
Dermatology.
Reserved.
provenAlltoRights
be a reliably
effective and safe therapeutic modality.
after starting oral corticosteroids, as well
as a rapidofdecline
2
This
fact suggests
Although
specic
underlying
mechanism
that risk after stopping
oral corticosteroids.
This document
information,
images and
marks ofthe
Journal
of Drugs
in Dermatology
(JDD). is not well underthat theNoepisodic
exposure
from
corticosteroids,
when
givenmaterials
stood,
key towithout
its usethe
is express
its ability
to suppress
the
underlying
reproduction
or use of
any portion
of the contents
of these
maythe
be made
written
consent of
JDD.
in an intramuscular injectionIf eight
weeks
apart,
may this
be less
inammatory
response
long after the medications disappearyou feel
you have
obtained
copy illegally,
please contact
JDD immediately.
harmful than continuous low-dose oral corticosteroid therapy.
ance from the circulation, thereby minimizing side effects that
are normally seen with long-term oral corticosteroids.
Another potential side effect of long term (and rarely even short
term) oral corticosteroids is avascular necrosis which, in most
3&'&3&/$&4
1.
Kusama M, Sakauchi N, Kumaoka. Studies of plasma levels and
cases, involves the femoral head but may involve other bones
urinary excretion after intramuscular injection of triamcinolone acas well. The underlying cause is ischemia due to occlusion of
etonide. Metabolism. 1971;20(6):590-596.
the small vessels which supply the ends of the affected bones.
2. VanStaa T, Leufkens H, Abenhaim L, Zhang B, Cooper C. Use
More than a third of the cases are idiopathic, but oral corticosof oral corticosteroids and risk of fractures. J Bone Miner Res.
teroids have been linked to a substantial number of others.3
2000;15(6):993-1000.
There is only one report in the literature linking intramuscular
3. Richard R. Short term corticosteroids and avascular necrosis: Medtriamcinolone with avascular necrosis,4 and details of that case
ical and legal realities. Cutis. 2007;80:343-348.
make the association somewhat dubious. If used as described
BEMaGS
F
BEMaGS
F
585
+6/&t70-6.&t*446&
4.
5.
6.
7.
%3PCJOT
Nasser SM, Ewan P. Depot corticosteroid treatment for

hay fever causing aseptic necrosis of both hips. Br Med J.
2001;322(7302):1589-1592.
Kenalog-40 (package insert). Princeton, New Jersey: Bristol-Myers
Squibb; 2006.
Mikhail G, Sweet L, Mellinger R. Parenteral long-acting corticosteroids: Effect on hypothalamic-pituitary adrenal function. Ann All.
1973;31(7):337-343.
Droszcz W, Malunowicz E, Lech B, et al. Assessment of adrenocortical function in asthmatic patients on long-term triamcinolone
acetonide treatment. Thorax. 1979;42(1):41-43.

Douglas N. Robins, MD
North Florida Dermatology Associates
836 Prudential Drive #1507
Jacksonville, FL 32207
Phone: ....................................................................... 904-354-4488
Fax: ............................................................................ 904-396-0428
E-mail: ............................................................... ____________
DNRMD1@aol.com
Do Not Copy,
Penalties Apply
raisin is a grape that didnt have the sense to get out of the sun. And if the giant
orb in the sky can do that to a little piece of fruit, imagine what its
doing to your skin. Not to be prejudiced, but we humbly submit that
human beings should have more sense than dumb grapes.
Nothing looks better on you than the glowing, radiant
shine youThis
were
born contains
with. Because
being
document
proprietarytoday,
information,
healthy truly healthy

feel
is whats
sexy.
If you
you have
obtained this copy illegally, please contact JDD immediately.
Go with your own glow

www.skincancer.org
2008 The Skin Cancer Foundation Campaign created by partners + jeary, www.partnersandjeary.com
BEMaGS
F
BEMaGS
F
JUNE 2009
586
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
NEWS, VIEWS & REVIEWS

News, Views and Reviews provides focused updates, in-depth topic reviews and editorials concerning the latest developments in dermatologic
therapies.
From Bench to Bedside:

The Therapeutic Potential
of Nitric Oxide in
Dermatology
tory cytokines, bacterial polysacchrides and endotoxins, and

neuropeptides.10 A fourth isoform, mitochondrial NOS, has
been proposed but its existence and function is the subject of
some debate.11 For example, the total measured NO may also
be attributable to a non-NOS source of NO.12 All isoforms are
modulated by different signals, such as sex hormones,13 and
may have either cytosolic or particulate localization. Additionally, they are exquisitely regulated by a number of different
modalities, such as the availability of substrates and co-factors,
presence of scavengers, and multi-site phosphorylation.14
Since rst identied in 1986 as the endothelium derived relaxing factor, medical and scientic interest in nitric oxide (NO)
Physiology of NO
has grown exponentially, leading to the discovery of an everNitric oxide initiates multiple cellular signaling cascades, most
widening range of physiologic functions. Encompassing nearly
notably via the soluble guanylyl cyclase (sGC) pathway.14 In this
every physiological system and relevant in many pathological
paradigm, NO binds to sGC leading to an increase in cyclic GMP
processes, NO has a notable inuence in the human body. It
levels and subsequent activation of protein kinase G (pkG). This
specically plays a role in vascular biology,1 skeletal muscle
physiology,2 development, neuroscience3 and immunology.4 In
signaling cascade leads to innumerable downstream events,
many ways, however, NO functions as a double-edged sword,
facilitating both local biologic effects such as the vasodilatowith effects that are both cytoregulatory and cytotoxic. NOs
ry and neurotransmitter actions of NO, and also far-reaching
ability to function as a free radical, for example, can be used
impacts such as NOs ability to act as an anti-depressant15 and
anti-pyretic.16 As a free radical, NO is able to generate potent niadvantageously to combat foreign invading pathogens, but
trosylating agents capable of both signaling and cellular damcan also be cytotoxic to host cells. A better example is found
age, such as with peroxynitrite (ONOO-) in the presence of suin the conicting reports on NOs role in cancer, having been
peroxide. This effect only occurs at higher concentrations since
characterized as both pro- and anti-oncogenic.5 In this regard,
it may be that the effect of NO must be understood with regard
NO is rapidly scavenged in most physiological conditions. Sevto the location and amount of production, as its action is short
eral mechanisms may account for long distance NO transport,
lived (being rapidly scavenged by hemoglobin) and concentrasuch as S-nitrosothiols, S-nitrosylated proteins, nitrosyl-metal
tion dependent. Not surprisingly, NO has many dened funccomplexes, and nitrite,17,18 although the actual NO species once
6,7
liberated from these carriers are short lived in the body. Many
tions in the skin, involving key cells such as keratinocytes and
broblasts.8 It has become increasingly apparent that a solid
clinically relevant physiologic states rely on NO as a critical sigunderstanding of nitric oxides functions will be advantageous
naling component.
2009-Journal
of Drugs in Dermatology. All Rights Reserved.
for understanding and treating dermatologic
diseases.
Do Not Copy,
Penalties Apply
NO
andofVascular
Biology
marks
Journal of Drugs
in Dermatology (JDD).
Biological
Synthesis
of of
NO
Themay
earliest
described
of NO was
itsconsent
regulation
of the vasNo reproduction
or use
any portion of the contents of these materials
be made
without role
the express
written
of JDD.
Nitric oxide is generated endogenously
by obtained
several this
distinct
culature
via
endothelial
cells. In this model, NOS1 constitutively
copy illegally,
please
contact
JDD immediately.
isoforms of the enzyme nitric oxide synthase (NOS).9 All NOS
accounts for normal vascular homeostasis and perturbations of
proteins generate NO through the conversion of L-arginine to
this balance are relevant in a wide array of pathophysiologiL-citrulline, requiring tetrahydrobiopterin (THB), FAD, FMN,
cal conditions, such as hypertension,19,20 sickle cell disease,21
acute respiratory distress syndrome22 and atherosclerosis. InNADPH, heme and oxygen. NOS1 and NOS3 are constitutively
deed, endothelial dysfunction is a primary initiator of atheroexpressed and are known by the cell types in which they were
sclerosis and while impaired NOS1 may be implicated in the
enzymatically identied and subsequently cloned (endothelial
development of this disease process,23 further cellular damage
NOS, NOS1, from endothelial cells and neuronal NOS, NOS3,
in an atherosclerotic lesion may be potentiated by upregulated
from neuronal cells). Both of these enzymes are calcium-deNOS2. NOS2, expressed in endothelial cells and macrophages,
pendent, calmodulin-regulated enzymes. Meanwhile, NOS2, or
is not only capable of generating peroxynitrite, it may oxidize
inducible NOS, is expressed in a wide array of cell types and
THB and in turn uncouple NOS1, further building upon the
generates NO in a non-calcium dependent fashion. The enzyme
damage and adding to cellular stress.24 This once again demis induced by a wide array of stimulants such as proinamma-
BEMaGS
F
BEMaGS
F
JUNE 2009
587
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
onstrates the dual nature of NO and stresses the importance of

proper regulation of its function.
against microorganisms, and UV-induced melanogenesis40 and

development of erythema.41
NO and Immunology
Barrier Function
Nitric oxide is one of the most potent and essential effector

molecules involved in host defense,25 released by macrophages, neutrophils, eosinophils, broblasts, epithelial cells, and
glial cells.4 Of these, the most studied and best-understood effect is the NOS2-mediated NO production in macrophages.26
This source of NO can exert its effects directly as a toxic species
towards foreign pathogens, such as through the generation of
peroxynitrite resulting in bacterial DNA damage and inhibition
of repair/synthesis; as an enzyme inhibitor by disrupting Fe-S
clusters; and through membrane lipid peroxidation. In addition,
several infectious pathogens require arginine for cell survival
and proliferation. NOS activity, via the creation of NO from
arginine, depletes this store, resulting in an indirect inhibition
of pathogen growth.2729 Furthermore, NO is able to upregulate
several antimicrobial pathways, such as interferon gamma30
and neutrophil superoxide release.31 In many instances, NO
is critically important when mounting an immune response
against organisms such as M. tuberculosis, where reactive nitrogen species, not oxidative stress, are the primary anti-mycobacterial defense.32 Interestingly, the increased susceptibility of
illicit drug users towards pulmonary infections33 may be in part
explained by the inability of alveolar macrophages to produce
NO following the smoking of marijuana or the use of cocaine.34
With NO playing such an important role in the normal physiological response towards foreign invasion, it is no surprise that
it has such an important role in the primary barrier for the body
against the outside worldthe skin.
As the skin is the primary barrier between the body and the
external environment, the physical protection afforded by an
intact epidermis is especially important and NO participates in
establishing this essential defense mechanism. NOS expression in dermal endothelial cells allows for tight control of blood
ow. It also promotes angiogenesis through upregulation of
vascular endothelial growth factor (VEGF) via hypoxia inducible factor 1.42
One of the major assailants to the skin is ultraviolet irradiation.
The skin is constantly exposed to this stressor capable of inducing oxidative cellular damage. As one of the skins primary
defense mechanisms, keratinocytes produce sustained concentrations of NO upon exposure to both UVA and UVB irradiation,
which only declines after three days and coincides with the
time course of sun-induced erythema.43 In this regard, NO may
quench free radical damage that can result from UV radiation
exposure if generated photoproducts are allowed to propagate
unhindered. This proposed role of NO is supported by reports
that endothelial cells are protected from UVA-induced apoptosis by NO44 and that UV-induced lesions in cutaneous lupus
erythematosus demonstrate reduced expression of NOS2.43
More recently, a non-enzymatic pathway of NO production was
elucidated, where NO is derived from biologically relevant NOrelated products in the human epidermis, supercial vascular
dermis and sweat. In the setting of acute UVA exposure, these
products are quickly mobilized within 30 minutes to generate
NO, resulting in keratinocyte cytoprotection from UVR-induced
apoptosis.45 This study suggests that intake of external sources
of NO precursors, such as dark, leafy greens, may inuence the
innate and acute cutaneous response to UVR.
Do Not Copy,
Penalties Apply
NO and Skin Biology

Physiological Localization and Function
Practically every cutaneous relevant cell type expresses some

isoform of NOS and is therefore able to generate and release NO
for a broad spectrum of physiologic processes. Keratinocytes,
Similarly, NO is able to regulate skin ora through this non-NOS
the major constituent of the epidermis, express both NOS1 and
dependent synthetic pathway. Nitrite is a known constituent of
peroxide
2009-Journal
of Drugs into
Dermatology.
All Rights
Reserved.
in response
NOS235 and produce NO and hydrogen
both blood
and sweat,
and in the case of sweat, the acidity of the
inammatory stimuli.
This maycontains
act as one
of the information,
cardinal broad
skin
surface
allowsoffor
theinreduction
of nitrite
This document
proprietary
images and
marks
of Journal
Drugs
Dermatology
(JDD).to NO.44 The acidiedmay
nitrite
as a
moat,
so to
speak,
of protective
protective
mechanisms
of the
skin,
as the
epidermis
con-materials
No reproduction
or use
of any
portion
of the
contents ofisthese
be functions
made without
the
express
written
consent
of JDD. antimicrobial
NO,contact
preventing
pathogen access to the body. Therefore,
stantly exposed to foreign matter
andyou
organisms.
In addition,
If you feel
have obtained
please
JDD immediately.
this mechanism of protection is likely heightened during UVA
nely regulated responses are also exhibited by NOS species,
exposure because of the synergistic roles of the NOS-mediated
such as in wound healing. Fibroblasts, found in the dermis, regand non-NOS-mediated NO production pathways.
ulate the structural framework of the skin by synthesizing extracellular matrix, collagen, and brin, while orchestrating the
Regulation of Inammation and Immune Function
complex steps of wound healing. Fibroblasts demonstrate both
The effects of nitric oxide with respect to inammation and
NOS2 and NOS3 expression,8 but this expression is inconsistent across different cells, possibly dependent on cell maturaimmune response are especially relevant in the skin and partion.36 Additionally, eccrine glands express NOS3, melanocytes
allel its functions systemically. NO is a nonspecic product of
have shown NOS3 and NOS2 expression,37,38 and Langerhans
inammation via activation of NOS2 in a wide variety of cell
cells exhibit NOS2.39 Due to its widespread distribution, NO is
types, that has been implicated in sepsis, arthritis, SLE and
able to participate in basic physiological roles such as estabpsoriasis.46 Additionally, NO has immunoregulatory functions
via lymphocyte activation and proliferation and numerous
lishing and maintaining circulation, forming a protective barrier
BEMaGS
F
BEMaGS
F
JUNE 2009
588
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
cytokine pathways, including TNF, TGF, p56, and NF-B. To

control these signaling events, many regulatory systems exist whereby feedback and modications affect NOS expression
and NO production, such as the NO-induced nitrosylation of
NF-B, which prevents further activation of NOS2,47 and TGFinduced inhibition of NOS2.48 With that in mind, NO serves as
a rst line of defense against microbial invasion both as a direct, general microbiocidal, by modulating regulatory functions
through the aforementioned pathways, and by interacting with
other inammatory mediators, such as IFN-.
Innate Antimicrobial Activity
collagen. The subsequent aggregation and clotting cascade

results in a brin clot to seal the wound area while platelets
initiate a series of events through cytokines and growth factors, such as platelet derived growth factor (PDGF) and TGF, to
recruit other mediators of wound healing. During this period,
NO production peaks due to widespread activation of NOS2 in
many cell types, including immune cells (most importantly macrophages), keratinocytes and broblasts. By helping vasodilate
the blood supply near the wound area, NO ensures that wound
healing mediators and nutrients are able to gain access to the
site. NO recruits monocytes and neutrophils and promotes the
expression of IL- 8 and TGF . Furthermore, NO positively inuences wound broblasts, collagen synthesis, VEGF expression,
and keratinocyte migration.6163 This peak NO synthesis begins
to decline after 36 days as the proliferative phase follows,
likely in part due to wound macrophage generation of TGF ,
which downregulates NO synthesis.
NO is not only an important effector molecule involved in facilitating an immune response to invading organisms, but it
can also function as a cytotoxic agent against these pathogens.
Susceptibilty of epidermotropic viruses, bacteria, protozoa, helminths and fungi to NO has been demonstrated. Early evidence
that NO functions as an antimicrobial agent is derived from in
During the proliferative phase of wound healing, the most
vitro wound healing experiments showing that inammatory
important task is to generate and occupy the wounded area
stimuli induce keratinocytes to produce NO through NOS2 to
with a scaffolding matrix for regenerating tissue. NO, now at
eradicate intracellular pathogens such as Mycobacterium tua lower concentration and dependent upon NOS1 production,
berculosis, M. leprae, Leishmania species, Trypanosoma cruzi
promotes keratinocyte and broblast proliferation and funcand Plasmodium falciparum and also to block viral replication. Neovascularization of the wound area, as the provisional
tion.5052 However, the organisms themselves can induce NOS2
overexpression, producing severe inammation that can result
matrix is eroded, becomes important and NO-mediated VEGF
in epidermal and dermal damage,53 likely seen in disease states
activation furthers and aids this process. Admittedly, conicting
such as HSV-induced erythema multiforme. Regardless, both
studies have found variable effects of NO on cultured keratinonon-enzymatic and NOS produced NO are critical as the rst
cytes and broblasts; however, this data serves to highlight the
line of defense in preventing and ghting host infection. Anidichotomy of NO function, whereas high levels of NO inhibit
mal models with reduced or absent NOS2 activity demonstrate
broblasts and keratinocytes and are cytostatic, lower concensignicantly increased susceptibility to bacterial infection as
trations are stimulatory.64 Overall, there is widespread agree26
ment that perturbation of NO production uniformly results in
compared to normal wild type mice capable of producing NO.
Extensive research has highlighted the antimicrobial potential
delayed wound healing, decreased collagen content, and imof NO as a reactive free radical to battle infection. Using small
paired wound tensile strength.65,66
molecule NO donors, broad-spectrum antibacterial properties
Finally, remodeling and differentiation occurs over the next
against both gram-positive and gram-negative bacteria was
several months to re-establish normal tissue structure and
demonstrated.54 These results now include multi-drug resistant
organisms such as methicillin-resistant S. aureus (MRSA)55 as
function. During this time, the collagen deposited in the de 2009-Journal of Drugs in Dermatology.
All Rights
well as biolm-fortied species.56
veloping
matrixReserved.
forms crosslinks and the short, unorganized
bers
mature
intoofstronger,
organized structures.
Aiding in the
marks
of Journal
(JDD).
WoundNoHealing
replacement
of the
old the
matrix
are written
severalconsent
matrixofmetalloproteireproduction or use of any portion of the contents of these materials
may be made
without
express
JDD.
The process of recovery fromIf you
a cutaneous
wound
is complex
nases
(MMP),
theJDD
activity
of which are regulated by broblast
feel you have
obtained
please
contact
immediately.
and requires the collective action of a great number of factors
derived tissue inhibitor of metalloproteinase. This balance of
acting in concert with respect to time and location. Wound
MMP activity, and the ultimate wound strength, is also reliant
healing is greatly dependent on precise concentrations of NO
on appropriate NO production.
generated to prevent delayed and improper healing of an acute
Regulation of Pigmentation
wound. There are many reports on the wound healing process
NO is known to be closely related to skin pigmentation, speciwith specic reference to NO.5760 NOs role in wound healing
can be best understood by its inuence on the three distinct
cally following UVR exposure. Melanocytes express NOS and
phases: the inammatory phase, the proliferative phase and
UVB-induced and paracrine-regulated melanogenesis is dethe differentiation/remodeling phase.
pendent on NO.38,40 Cyclic GMP upregulation resulting from NO
generation stimulates tyrosinase acitivity, resulting in melanin
production. Additionally, dendritic branching of melanocytes,
The inammatory phase of wound healing begins immediately
aggregation of melanosomes by melatonin, and the eumelanin/
after wounding, when platelets come into contact with exposed
Do Not Copy,
Penalties Apply
BEMaGS
F
BEMaGS
F
JUNE 2009
589
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
pheomelanin ratio are inuenced by NO.67,68 However, as with so

many other disease states, dysregulation of this system may be
involved in hypo- or hypermelanosis found in hereditary, endocrine, and post-inammatory conditions. In one study, animals
treated with a topical, nonselective NOS inhibitor demonstrated
decreased skin pigmentation following UVB exposure.69
NO and Skin Pathophysiology

Because of the dened roles of NO in cutaneous biology discussed above it is clear how perturbation of NO production
and signaling might lead to the manifestation of pathologic
states. The dysregulation of NOS2 expression in inammatory
skin disease is well established. In cutaneous lupus erythematosus, NOS2 expression is present throughout the epidermis70 and high levels of NOS2 are also found in patients with
Sjogrens syndrome with photosensitivity.71 Psoriasis,72,73 atopic
dermatitis,74 Steven-Johnsons/toxic epidermolytic necrolysis,75
keloid formation,76 morphea/scleroderma77 and pitryriasis lichenoides78 all have known associations with NO dysregulation. More recently, the role of NO in both carcinogenesis and
chemoprevention has received a great deal of attention. This
duality is currently the subject of great debate and therefore
merits further examination.
NO and Skin Cancer
lation of VEGF and basic broblastic growth factor.82,83 Even

more recently, it has been demonstrated that NO is involved in
lymphatic vessel permeability and ow,84 and that NOS2 activity often correlates with lymphangiogenesis and lymph node
metastasis in head and neck squamous cell carcinoma.85 Furthermore, it is reported that there is higher NOS2 expression
in primary and metastatic melanomas as compared to levels
observed in melanocytic nevi.86 In fact, the increased density of
lymphatic vessels in both melanoma at peritumoral and intratumoral locations is associated with increased NOS2 staining
in tumor cells, supporting the hypothesis that NO is involved in
blood and lymphatic vascular formation in tumor tissues.
However, NO may function in an anti-carcinogenic role via the
induced apoptosis of mutated cells or through modulation of
growth responses and gene expression patterns. Dong et al.87
demonstrated the potential anti-carcinogenic features seen with
increased expression of NOS2. In a comparative study between
several nonmetastatic and highly metastatic melanoma clones,
it was demonstrated that the nonmetastatic clones expressed
much higher levels of endogenous NO. Since then, a multitude
of projects designed to generate high intra-tumoral levels of
NO have been pursued, including the use of NO donor drugs
and the transfection of a functional NOS2 gene.88 Additionally,
NO is able to further exert its anti-carcinogenic effects through
the regulation of MMP levels.89 and by increasing the release
of cytochrome c, which activates caspases and induces the release of massive quantities of cellular calcium both of which
result in apoptosis.
Do Not Copy,
Penalties Apply
Our understanding of NOs role in the progression of skin cancer is continually evolving. Over the past two decades, its precise role in tumor pathophysiology has been a matter of great
debate. There is extensive evidence that tumor expressed NOS
and subsequent NO production can be both pro- and anti-carcinogenic, depending on the concentration of NO produced.
It is clear that NO is involved in a multitude of signaling pathways that vary based on cell type and the level of NO produced.
As a pro-carcinogenic factor, elevated NOS expression during
Therefore, it is not surprising that a myriad of effects have been
chronic inammation is known to play an active role in the poobserved following the modication of NO levels in different
tential progression to malignant transformation.10 Two examtumor cell lines. It appears that at modest concentrations, the
ples of this potential role include the association of chronic cueffects of NO could be characterized as pro-malignant, wheretaneous wounds or destructive inammatory processes, such
as, at highly elevated concentrations, NO acts as a potent anti 2009-Journal
Rightspromoting
Reserved. apoptosis and inhibiting metastasis.
as lichen sclerosis et atrophicus and squamous
cell of
carcinoma,
cancerAll
agent,
and the linkage This
between
largecontains
plaqueproprietary
parapsoriasis
and cutaFurthermore,
it is of
clear
that
NO has a dened
document
information,
images and
marks of Journal
Drugs
in Dermatology
(JDD). role in immune
neous T-cell
lymphoma.
It has
been
shown
that
NOS2ofexpressurveillance,
epidermal
protection,
No reproduction
or use
of any
portion
of the
contents
these materials
may be made
without thebarrier
expressmaintenance
written consentand
of JDD.
sion may directly reect the degree
of proliferation/malignancy
andplease
in wound
healing.
Even though the full extent whereby NO
If you feel
you have obtained this copy illegally,
contact
JDD immediately.
of a tumor. A progression in NOS2 immunoreactivity was obcontributes to these key cutaneous processes has yet to be fully
served ranging from Bowens disease (75% positive, mild inidentied, investigations thus far support a role for NO modulatensity), to squamous cell carcinoma (75% positive, increased
tion and manipulation as a therapeutic strategy.
intensity), to metastatic carcinoma (80% positive).79 It could be
Therapeutic Translation: Past, Present and Future
that the local increase in concentration of nitrosamines, which
The extensive role of NO in a wide spectrum of disease states is
are well-known carcinogens, and NO-induced DNA damage80,81
are ultimately the culprits.
well recognized and has therefore stimulated attempts to modulate NO production for therapeutic translation; FDA approved
medical therapy such as Sildenal for erectile dysfunction and
Tumor expressed NOS2 is a proposed mediator of tumor angaseous NO for pulmonary hypertension are just a few examgiogenesis and metastasis formation because of NOs ability
ples. In addition, clinicians are now using Sildenal in combinato directly induce vessel dilation, perfusion and vascular pertion with other medications for the treatment of systemic sclemeability, and endothelial cell proliferation through upregu-
BEMaGS
F
BEMaGS
F
JUNE 2009
590
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
rosis and Raynauds disease and nd they alleviate symptoms

and help to heal ulcers associated with these conditions.90,91
ery of NO for the treatment of numerous diseases, with the NIH

reporting 386 clinical trials involving NO as of April 2009. Many
are related to potential systemic effects and outcomes regarding
nitric oxide, such as cardiovascular and pulmonary disease, but
a considerable number of projects have dermatologic applications. While some, such as a trial of topical glyceryl trinitrate for
extensor tendinosis,103 seek to use a transdermal application approach to deliver NO to an an underlying target area, many of
these trials are directed at the treatment of skin disease.
This review will focus on NO delivery as a therapeutic avenue,

rather then inhibition of NO production because it represents a
burgeoning area of research with wide sweeping applications in
the treatment of cutaneous disease. Developing approaches to
topical delivery of nitric oxide has been a challenge. NO-releasing drugs such as sodium nitroprusside and nitroglycerin have
been used for over a century to enhance coronary vasodilation,
Several corporations are dedicated to the development of NO
although the rate of NO release and the delivered concentradelivery vehicles for the skin. One company, NIOXX, lists Dr.
tion is poorly controlled. More recent modalities that have been
Ferid Murad (co-winner of the 1998 Nobel Prize for his work on
evaluated and developed include continuous horizontal-ow
the role of NO in physiology) as a research director. Their proddelivery of gaseous NO,58 a chemical system utilizing sodium
nitrite and ascorbate,92 as well as an array of NO releasing oruct, a topical gel consisting of nitrite and ascorbic acid in a petganic molecules including: polyethyleneimine cellulose diazrolatum base, is designed to release NO at a local wound site to
eniumdiolate (NONOate) polymer, an insoluble, nontoxic, polytreat burns, diabetic ulcers or eczema. While successful experimer-based NO donor; hydrogel dressing made by crosslinking
ments with animal models have been completed, there are no
poly vinyl alcohol (PVA) with an NO donor; SNAP (S-Nitrosoreports of human clinical trials. A second company, NICOX, has
N-acetyl-D,L-penicillamine), an NO donor; and the NO donor
developed multiple NO releasing products, several of which are
molsidomine (N-ethoxycarbomyl-3- morpholinyl-sidnonimine).
in clinical trials. One in particular, NCX 1047, is formulated for
There are many benets to all these systems, as the applicadermal applicationand is in the preclinical phase. NCX 1047 is
tions of NO are widespread. However, despite the reported suca NO-donating ointment targeted towards skin disorders such
cesses,9399 the currently available NO delivery systems have
as atopic dermatitis, psoriasis and seborrheic dermatitis. Taksignicant limitations and drawbacks. The use of gaseous NO is
ing a different approach, Nitric Bio is seeking to apply direct
not practical given the cost, difculty in administering the gas
gaseous NO to acute and chronic wounds. They report phase
for prolonged periods, and the need for specic ow modula2 trials which are evaluating anti-bacterial (MRSA), anti-fungal
tion techniques. The NO releasing materials also suffer limita(tinea pedis) and wound care applications. It remains to be seen
tions to varying degrees. The use of nitrite with ascorbic acid
whether these attempts to commercialize NO therapy towards
requires a barrier to prevent skin and wound irritation and it
dermatological applications will be fruitful, as many of these
has limited sustained release capabilities. Many of the NO recompounds can be difcult to generate and maintain. One clinileasing polymers utilize complex reactions with organic molcal study of a controlled NO releasing patch for the treatment
ecules, raising concerns as to toxicity, and these polymers do
cutaneous leishmaniasis reported by the Cardiovascular Founnot lend themselves to rapid deployment and administration
dation of Colombia104 was terminated because the treatment
was deemed not effective enough. Confounding factors such as
which is essential for the management of wounds. Of these NO
ancillary effects from other components in the formulation and
donor species, N-diazeniumdiolates100 have emerged as attractive candidates because their chemistry allows for the design
cost of application will need to be addressed, but there is great
2009-Journal
of Drugs
Dermatology.
All if
Rights
Reserved.
of more biocompatible coatings andthey
have the
abilityinto
promise
a nitric
oxide releasing platform can be effectively
generate NO spontaneously
under physiological
conditions.
applied
skin. in Dermatology (JDD).
This document contains
images and
marks towards
of Journalthe
of Drugs
The rateNoofreproduction
release of NO
depends
upon pH,
and/materials may be made without the express written consent of JDD.
or use
of any portion
of thetemperature,
contents of these
Conclusion
or the structure of the amine.IfEven
more
a composite
you feel
yourecently,
have obtained
This review sought to demonstrate that NO is an extraordinarihydrogel/sugar-glass matrix nanotechnology platform was dely powerful and important signaling molecule integral to the
veloped that relies on a sugar-based thermal reduction mechaproper regulation of normal physiology commonly implicated
nism for the generation of NO (converting nitrite to NO) rather
in many pathophysiologic events. It is therefore no surprise
than NO-donor molecules, thereby circumventing a good numthat NO received the prestigious award, Molecule of the Year
ber of the previously described limitations.101 Exposure of these
nanoparticles to moisture initiates the sustained release of the
by Science in 1992 and was the focus of the 1998 Nobel Prize
trapped NO over extended time periods. Topical application of
in Physiology. Our understanding of the physiologic properties
these nanoparticles on MRSA infected murine wound models
of NO has grown exponentially over the past two decades, yet
demonstrated accelerated wound closure and clearance of bacwe have barely breached the surface with respect to NOs exact
terial burden.102
role in inammation, immune response and cell growth/death.
Even more so, we have only begun to elucidate the mechanisms
Currently, there are many clinical studies investigating the delivthrough which NO exerts its extensive physiologic impact on
Do Not Copy,
Penalties Apply
BEMaGS
F
BEMaGS
F
JUNE 2009
591
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
the skin and its likely association with numerous pathologic

processes such as psoriasis and skin cancer. Therefore, it is important to continue to investigate the role of NO in cutaneous
disease, not only to further our understaning of cutaneous biology, but also to establish a framework through which novel and
creative therapeutics can be developed for acute and chronic
skin disease.
14. Schmidt HH, Lohmann SM, Walter U. The nitric oxide and cGMP
signal transduction system: regulation and mechanism of action.
Biochim Biophys Acta. 1993;1178(2):153175.
15. Kaster MP, Rosa AO, Santos AR, Rodrigues AL. Involvement of
nitric oxide-cGMP pathway in the antidepressant-like effects of
adenosine in the forced swimming test. Internatl J Neuropsychopharmacol. 2005;8(4):601-606.
16. Steiner AA, Antunes-Rodrigues J, McCann SM, Branco LG. Antipyretic role of the NO-cGMP pathway in the anteroventral preoptic
George Han, BSa
Jonathan Hale Zippin, MD, PhDb
region of the rat brain. Am J Physiol Regul Integr Comp Physiol.
2002;282(2):R584-R593.
Adam Friedman, MDc
17. Gaston B and Stamler JS. Biochemistry of nitric oxide. In: Nitric
a
Department of Physiology and Biophysics,
Oxide and Infection (ed. Fang FC) 1999:37-55.
18. Gladwin MT, Raat NJ, Shiva S, et al. Nitrite as a vascular endoAlbert Einstein College of Medicine
b
Department of Dermatology, New York-Presbyterian
crine nitric oxide reservoir that contributes to hypoxic signaling,
cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol.
Hospital-Weill Cornell Medical Center
c
Division of Dermatology, Albert Einstein College of Medicine
2006;291(5):H2026-H2035.
19. Huang PL, Huang Z, Mashimo H, et al. Hypertension in mice
References
lacking the gene for endothelial nitric oxide synthase. Nature.
1.
Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts
1995;377(6546):239-242.
for the biological activity of endothelium-derived relaxing factor.
20. Treasure CB, Klein JL, Vita JA, et al. Hypertension and left ventricuNature. 1987;327(6122):524-526.
lar hypertrophy are associated with impaired endothelium-mediat2. Stamler JS and Meissner G. Physiology of nitric oxide in skeletal
ed relaxation in human coronary resistance vessels. Circulation.
muscle. Physiol Rev. 2001;81(1):209-237.
1993;87(1):86-93.
3. Bredt DS, Hwang PM, Snyder SH. Localization of nitric ox21. Reiter CD, Gladwin MT. An emerging role for nitric oxide in sickle
ide synthase indicating a neural role for nitric oxide. Nature.
cell disease vascular homeostasis and therapy. Curr Opin Hematol.
1990;347(6295):768-770.
2003;10(2):99-107.
4. Bogdan C. Nitric oxide and the immune response. Nat Immunol.
22. Kollef MH, Schuster DP. The acute respiratory distress syndrome.
2001;2(1):907-916.
New Engl J Med. 1995;332(1):27-37.
5. Coulter JA, McCarthy HO, Xiang J, et al. Nitric oxideA novel ther23. Kojda G, Kottenberg K, Hacker A, Noack E. Alterations of the vascuapeutic for cancer. Nitric Oxide. 2008;19(2):192-198.
lar and the myocardial guanylate cyclase/cGMP-system induced by
6. Heck DE, Laskin DL, Gardner CR, Laskin JD. Epidermal growth
long-term hypertension in rats. Pharm Acta Helv. 1998;73(1):27-35.
factor suppresses nitric oxide and hydrogen peroxide production
24. Xu J, Xie Z, Reece R, Pimental D, Zou MH. Uncoupling of endotheby keratinocytes. J Biol Chem. 1992;267(30):21277-21280.
lial nitric oxidase synthase by hypochlorous acid: Role of NAD(P)H
7.
Baudouin JE, Tachon P. Constitutive nitric oxide synthase is present
oxidase-derived superoxide and peroxynitrite. Arterioscler Thromb
in normal human keratinocytes. J Invest Dermatol. 1996;106(3):428Vasc Biol. 2006;26(12):2688-2695.
431.
25. Fang FC. Antimicrobial reactive oxygen and nitrogen species: con 2009-Journal
of Drugs proin Dermatology.
All Rights
Reserved. Nat Rev Microbiol. 2004;2(10):820-832.
8. Wang R, Ghahary A, Shen YJ, et al. Human
dermal broblasts
cepts
and controversies.
duce nitric oxide
expresscontains
both constitutive
and
inducible nitric
26.marks
MacMicking
J, ofXie
QW,inNathan
C. Nitric
oxide and macrophage
Thisand
document
proprietary
information,
images and
of Journal
Drugs
Dermatology
(JDD).
oxide
isoforms.
Invest
Dermatol.
1996;106(3):419-427
function.
Annu
Rev Immunol.
1997;15:323-350.
Nosynthase
reproduction
or useJ of
any portion
of the
contents of these. materials may
be made
without
the express
9. Alderton WK, Cooper CE, Knowles
oxide synthases:
27. please
Olds GR,
Ellner
Kearse LA, et al. Role of arginase in killIf you feelRG.
you Nitric
have obtained
contact
JDDJJ,
immediately.
Structure, function and inhibition. Biochem J. 2001;357(Pt 3):593ing of schistosomula of Schistosoma mansoni. J Exp Med.
615.
1980;151(6):1557-1562.
10. Nathan C and Xie QW. Nitric oxide synthases: Roles, tolls, and con28. Eckmann L, Laurent F, Langford TD, et al. Nitric oxide production
trols. Cell. 1994;78(6):915-918.
by human intestinal epithelial cells and competition for arginine as
11. Brookes PS. Mitochondrial nitric oxide synthase. Mitochondrion.
potential determinants of host defense against the lumen-dwelling
2004;3(4):187-204.
pathogen Giardia lamblia. J Immunol. 2000;164(3):1478-1487.
12. Lacza Z, Pankotaia E, Csordasa A, et al. Mitochondrial NO and reac29. Piacenza L, Peluffo G, Radi R. L-arginine-dependent suppression of
tive nitrogen species production: Does mtNOS exist? Nitric Oxide.
apoptosis in Trypanosoma cruzi: Contribution of the nitric oxide and
2006;14(2):162-168.
polyamine pathways. Proc Natl Acad Sci U S A. 2001;98(13):730113. Weiner CP, Lizasoain I, Baylis SA, Knowles RG, Charles IG, Mon7306.
cada S. Induction of calcium-dependent nitric oxide synthases by
30. Diefenbach A, Schindler H, Rllinghoff M, et al. Requirement for
sex hormones. Proc Natl Acad Sci U S A. 1994;91(11):5212-5216.
type 2 NO-synthase for IL-12 responsiveness in innate immunity.
Do Not Copy,
Penalties Apply
BEMaGS
F
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
BEMaGS
F
JUNE 2009
592
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
Science. 1999;284(5416):951-955.
47. delaTorre A, Schroeder RA, Punzalan C, Kuo PC. EndotoxinAndonegui G, Trevani AS, Gamberale R, et al. Effect of nitric oxide
mediated S-nitrosylation of p50 alters NF-kappa B-dependent
donors on oxygen-dependent cytotoxic responses by neutrophils.
gene transcription in ANA-1 murine macrophages. J Immunol.
J Immunol. 1999;162(5):2922-2930.
1999;162(7):4101-4108.
Chan J, Xing Y, Magliozzo RS, Bloom BR. Killing of virulent Mycobac48. Mills C. Macrophage arginine metabolism to ornithine/urea or
terium tuberculosis by reactive nitrogen intermediates produced
nitric oxide/citrulline: A life or death issue. Crit Rev Immunol.
by activated murine macrophages. J Exp Med. 1992;175(4):11112001;21:399-426.
1122.
49. Krncke KD, Suschek CV. Adulterated effects of nitric oxide-generODonnell AE, Selig J, Aravamuthan M, Richardson MS. Pulmonary
ating donors. J Invest Dermatol. 2008;128(2):258-260.
complications associated with illicit drug use. An update. Chest.
50. Bruch-Gerharz D, Ruzicka T, Kolb-Bachofen V. Nitric oxide in hu1995;108(2):460-463.
man skin: Current status and future prospects. J Invest Dermatol.
Shay AH, Choi R, Whittaker K, et al. Impairment of antimicrobial
1998;110(1):1-7.
activity and nitric oxide production in alveolar macrophages from
51. Liew FY, Cox FEG. Nonspecic defense mechanism: The role of
smokers of marijuana and cocaine. J Infect Dis. 2003;187(4):700nitric oxide. Immunol Today. 1991;12:1721.
704.
52. Stenger S, Donhauser N, Thring H, et al. Reactivation of latent
Shimizu Y, Sakai M, Umemura Y, Ueda H. Immunohistochemical
leishmaniasis by inhibition of nitric oxide synthase. J Exp Med.
localization of nitric oxide synthase in normal human skin: Expres1996;183(4):1501-1512.
sion of endothelial-type and inducible-type nitric oxide synthase in
53. Adler H, Beland JL, Del-Pan NC, et al. Suppression of herpes simkeratinocytes. J Dermatol. 1997;24(2):80-87.
plex virus type 1 (HSV-1)-induced pneumonia in mice by inhibition
Lavnikova N, Laskin DL. Unique patterns of regulation of nitric oxof inducible nitric oxide synthase. J Exp Med. 1997;185(9):1533ide production in broblasts. J Leukoc Biol. 1995;58(4):451-458.
1540.
Rocha IM, Guillo LA. Lipopolysaccharide and cytokines induce ni54. Raulli R, McElhaney-Feser G, Hrabie JA, Cihlar RL. Antimicrobial
tric oxide synthase and produce nitric oxide in cultured normal huproperties of nitric oxide using diazeniumdiolates as the nitric oxide
man melanocytes. Arch Dermatol Res. 2001;293(5):245-248.
donor. Rec Res Devel Microbiol. 2002;6:177-183.
Romro-Graillet C, Aberdam E, Biagoli N, et al. Ultraviolet B ra55. Ghaffari A, Miller CC, McMullin B, Ghahary A. Potential application
diation acts through the nitric oxide and cGMP signal transduction
of gaseous nitric oxide as a topical antimicrobial agent. Nitric Oxpathway to stimulate melanogenesis in human melanocytes. J Biol
ide. 2006;14(1):21-29.
Chem. 1996;271(45):28052-28056.
56. Barraud N, Hassett DJ, Hwang SH, et al. Involvement of nitric oxQureshi AA, Hosoi J, Xu S, et al. Langerhans cells express inducide in biolm dispersal of Pseudomonas aeruginosa. J Bacteriol.
ible nitric oxide synthase and produce nitric oxide. J Invest Derma2006;188(21):7344-7353.
tol. 1996;107(6):815-821.
57. Rizk M, Witte MB, Barbul A. Nitric oxide and wound healing. World
Romro-Graillet C, Aberdam E, Clement M, et al. Nitric oxide proJ Surg. 2004;28(3):301-306.
duced by ultraviolet-irradiated keratinocytes stimulates melano58. Frank S, Kmpfer H, Wetzler C, Pfeilschifter J. Nitric oxide drives
genesis. J Clin Invest. 1997;99(4):635-642.
skin repair: Novel functions of an established mediator. Kidney InRhodes LE, Belgi G, Parslew R, McLoughlin L, Clough GF, Friedternatl. 2002;61(3):882-888.
mann PS. Ultraviolet-B-induced erythema is mediated by nitric
59. Diegelmann RF, Evans MC. Wound healing: An overview of acute,
oxide and prostaglandin E2 in combination. J Invest Dermatol.
brotic and delayed healing. Front Biosci. 2004;9:283-289.
All Rights
2001;117(4):880-885.
60. Childress
BBReserved.
and Stechmiller JK. Role of nitric oxide in wound healKimura H, Esumi
Reciprocal
regulation
between
nitric oxideimages
and
ing. Biol
Res Nurs.
2002;4(1):5-15.
ThisH.
document
contains
proprietary
information,
and marks
of Journal
of Drugs
in Dermatology (JDD).
vascular
endothelial or
growth
in angiogenesis.
ActaofBiochim
61. may
Singer
AJ, Clark
RA.the
Cutaneous
woundconsent
healing.ofNJDD.
Engl J Med.
No reproduction
use offactor
any portion
of the contents
these materials
be made
without
express written
Pol. 2003;50(1):49-59.
1999;341(10):738-746.
If you feel you have obtained this copy illegally, please
Kuhn A, Fehsel K, Lehmann P, et al. Aberrant timing in epidermal ex62. Witte MB, Thornton FJ, Efron DT, Barbul A. Enhancement of bropression of inducible nitric oxide synthase after UV irradiation in cublast collagen synthesis by nitric oxide. Nitric Oxide. 2000;4(6):572taneous lupus erythematosus. J Invest Dermatol. 1998;111(1):149582.
153.
63. Wetzler C, Kampfer H, Pfeilschifter J, Frank S. Keratinocyte-derived
Suschek CV, Schroeder P, Aust O, et al. The presence of nichemotactic cytokines: Expressional modulation by nitric oxide in
trite during UVA irradiation protects from apoptosis. FASEB J.
vitro and during cutaneous wound repair in vivo. Biochem Biophys
2003;17(15):2342-2344.
Res Commun. 2000;274(3):689-696.
Mowbray M, McLintock S, Weerakoon R, et al. Enzyme-indepen64. Krischel V, Bruch-Gerharz D, Suschek C, et al. Biphasic effect of
dent NO stores in human skin: Quantication and inuence of UV
exogenous nitric oxide on proliferation and differentiation in skin
radiation. J Invest Dermatol. 2009;129(4):834-842.
derived keratinocytes but not broblasts. J Invest Dermatol.
Clancy RM, Amin AR, Abramson SB. The role of nitric oxide in in1998;111(2):286-291.
ammation and immunity. Arthritis Rheum. 1998;41(7):1141-1151.
65. Schaffer MR, Tantry U, Gross SS, et al. Nitric oxide regulates wound
Do Not Copy,
Penalties Apply
BEMaGS
F
BEMaGS
F
JUNE 2009
593
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
healing. J Surg Res. 1996;63(1):237-240.

metastases formation. Melanoma Res. 1996;6(2):121-126.
66. Schffer MR, Tantry U, Thornton FJ, Barbul A. Inhibition of nitric
83. Fukumura D, Jain RK. Role of nitric oxide in angiogenesis and mioxide synthesis in wounds: Pharmacology and effect on accumucrocirculation in tumors. Cancer Metastasis Rev. 1998;17(1):77lation of collagen in wounds in mice. Eur J Surg. 1999;165(3):26289.
267.
84. Ohhashi T, Mizuno R, Ikomi F, Kawai Y. Current topics of physiol67. Nilsson HM, Karlsson AM, Loitto VM, et al. Nitric oxide modulates
ogy and pharmacology in the lymphatic system. Pharmacol Ther.
intracellular translocation of pigment organelles in Xenopus laevis
2005;105(2):165-188.
melanophores. Cell Motil Cytoskel. 2000;47(3):209-218.
85. Franchi A, Massi D, Santucci M, et al. Inducible nitric oxide syn68. Lassalle MW, Igarashi S, Sasaki M, et al. Effects of melanogenesisthase activity correlates with lymphangiogenesis and vascular eninducing nitric oxide and histamine on the production of eumelanin
dothelial growth factor-C expression in head and neck squamous
and pheomelanin in cultured human melanocytes. Pigment Cell
cell carcinoma. J Pathol. 2006;208(3):439-445.
Res. 2003;16(1):81-84.
86. Massi D, Franchi A, Sardi I, et al. Inducible nitric oxide synthase ex69. Horikoshi T, Nakahara M, Kaminaga H, et al. Involvement of nitric
pression in benign and malignant cutaneous melanocytic lesions.
oxide in UVB-induced pigmentation in guinea pig skin. Pigment
J Pathol. 2001;194(2):194-200.
Cell Res. 2000;13(5):358-363.
87. Dong AH, Staroselsky X, Qi X, et al. Inverse correlation between
70. Warren JB. Nitric oxide and human skin blood ow responses to
expression of inducible nitric oxide synthase activity and producacetylcholine and ultraviolet light. FASEB J. 1994;8(2):247-251.
tion of metastasis in K-1735 murine melanoma cells. Cancer Res.
71. Tsukazaki N, Watanabe M, Shimizu K, et al. Photoprovocation test
1994;54: 789-793.
and immunohistochemical analysis of inducible nitric oxide syn88. Xie K, Fidler IJ. Therapy of cancer metastasis by activation of
thase expression in patients with Sjogrens syndrome associated
the inducible nitric oxide synthase. Cancer Metastasis Rev.
with photosensitivity. Br J Dermatol. 2002;147(6):1102-1108.
1998;17(1):55-75.
72. Ormerod AD, Weller R, Copeland P, et al. Detection of nitric ox89. Phillips PG, Birnby LM. Nitric oxide modulates caveolin-1 and maide and nitric oxide synthases in psoriasis. Arch Dermatol Res.
trix metalloproteinase-9 expression and distribution at the endothe1998;290(1-2):3-8.
lial cell/tumor cell interface. Am J Physiol Lung Cell Mol Physiol.
73. Kolb-Bachofen V, Fehsel K, Michel G, Ruzicka T. Epidermal keratino2004;286(5):L1055-L1065.
cyte expression of inducible nitric oxide synthase in skin lesions of
90. Bergstrom KG, Perelman RO. Treatment of Raynauds: Beyond calpsoriasis vulgaris. Lancet. 1994;344(8915):139.
cium channel blockers. J Drugs Dermatol. 2008;7(5):497-500.
74. Dugas B, Mossalayi MD, Damais C, Kolb JP. Nitric oxide produc91. Ambach A, Seo W, Bonnekoh B, Gollnick H. Low-dose combination by human monocytes: Evidence for a role of CD23. Immunol
tion therapy of severe digital ulcers in diffuse progressive systemic
Today. 1995;16(12):574-580.
sclerosis with the endothelin-1 receptor antagonist bosentan and
75. Lerner L, Qureshi A, Reddy B. Nitric oxide synthase in toxic epithe phosphodiesterase V inhibitor sildenal. J Dtsch Dermatol Ges.
dermal necrolysis and Stevens-Johnson Syndrome. J Invest Derm.
2009 Mar 17, Epub ahead of print.
2000;114(1):196-199.
92. Hardwick JB, Tucker AT, Wilks M, et al. A novel method for the de76. Hsu YC, Hsiao M, Wang LF, et al. Nitric oxide produced by iNOS is
livery of nitric oxide therapy to the skin of human subjects using a
associated with collagen synthesis in keloid scar formation. Nitric
semi-permeable membrane. Clin Sci. 2001;100(4):395-400.
Oxide. 2006;14(4):327-334.
93. Hrabie JA, Klose JR, Wink DA, Keefer LK. New nitric oxide releasing
77. Dooley A, Low SY, Holmes A, et al. Nitric oxide synthase expreszwitterions derived from polyamines. J. Org Chem. 1993;58:1472 2009-Journal
of Drugs
in Dermatology.
sion and activity in the tight skin model
mouse of brosis.
Rheu1476.
Do Not Copy,
Penalties Apply
matolgy. 2008;47(3):272-280.
94.marks
Marxer
SM, Rothrock
AR,inNablo
BJ, Robbins
ME, Schoensch MH.
of Journal
of Drugs
Dermatology
(JDD).
78. Di Giunta
G, da Silvaor
AM,
MN.
Inducible
nitric
oxide of
synthase
Preparation
nitric the
oxide
(NO)-releasing
sol-gels.
Chem Mater.
No reproduction
useSotto
of any
portion
of the
contents
these materials may
be madeof
without
express
written consent
of JDD.
in pityriasis lichenoides lesions.
J Cutaneous
Path.
2009;36(3):3252003;15:4193-4199.
If you
feel you have
obtained
this copy illegally, please
330.
95. Nablo BJ, Prichard HL, Butler RD, Klitzman B, Schoensch MH.
79. Kagoura M, Matsui C, Toyoda M, Morohashi M. ImmunohisInhibition of implant-associated infections via nitric oxide release.
tochemical study of inducible nitric oxide synthase in skin cancers.
Biomaterials 2005;26:6984-6990.
J Cutaneous Pathol. 2001;28(9):476-481.
96. Phillips R, Adjei O, Lucas S, et al. Pilot randomized double-blind
80. Nguyen T, Brunson D, Crespi CL, et al. DNA damage and mutation
trial of treatment of Mycobacterium ulcerans disease (Buruli ulin human cells exposed to nitric oxide in vitro. Proc Natl Acad Sci.
cer) with topical nitrogen oxides. Antimicrob Agents Chemother.
1992;89(7):3030-3034.
2004;48(8):2866-2870.
81. Oshima H, Bartsch H. Chronic infections and inammatory pro97. Shabani M, Pulfer SK, Bulgrin JP, Smith DJ. Enhancement of
cesses as cancer risk factors: possible role of nitric oxide in carwound repair with a topically applied nitric oxide-releasing polymer.
cinogenesis. Mutat Res. 1994;30(2)5:253-264.
Wound Repair Regen. 1996;4(3):353-362.
82. Joshi M, Strandhoy J, White WL. Nitric oxide synthase activity is
98. Masters KS, Leibovich SJ, Belem P, et al. Effects of nitric oxide
up-regulated in melanoma cell lines: A potential mechanism for
releasing poly(vinyl alcohol) hydrogel dressings on dermal wound
BEMaGS
F
99.
100.
101.
102.
103.
104.
BEMaGS
F
JUNE 2009
594
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
healing in diabetic mice. Wound Repair Regen. 2002;10(5):286294.

Muscara MN, McKnight W, Asfaha S, Wallace JL. Wound collagen
deposition in rats: effects of an NO-NSAID and a selective COX-2
inhibitor. Br J Pharmacol. 2000;129(4):681-686.
Parzuchowski PG, Frost MC, Meyerhoff ME. Synthesis and characterization of polymethacrylate-based nitric oxide donors. J Amer
Chem Soc. 2002;124(41):12182-12191.
Friedman A, Han G, Navati MS, et al. Sustained release nitric oxide
releasing nanoparticles: Characterization of a novel platform based
on nitrite containing hydrogel/glass composites. Nitric Oxide.
2008;19(1):12-20.
Martinez L, Han G, Chacko M, et al. Antimicrobial and healing efcacy of sustained release nitric oxide nanoparticles against Staphylococcus aureus skin infections. J Invest Derm. 2009 [Epub ahead
of print].
Paoloni JA, Appleyard RC, Nelson J, Murrell GA. Topical Nitric Oxide
Application in the Treatment of Chronic Extensor Tendinosis at the
Elbow A Randomized, Double-Blinded, Placebo-Controlled Clinical
Trial. Am J Sports Med. 2003;31(6):915-920.
Clinical
Trials.gov, US National Institutes of Health. Available at
__________
http://clinicaltrials.gov/ct2/show/study/NCT00317629. Accessed April
13, 2009
Do Not Copy,
Penalties Apply
New CME
Opportunity
"4611-&.
&/550

June 2009 Supplement:
Natural Prod
ts in have
If you feelucyou
obtained
Skin Car
e
Natural Products in Skin Care
*44/

+VOFt
7PMVNFt
*TTVF SUPPL
EMENT)
Look for this supplement with your June issue of JDD, or download it from our CME library at JDDonline.com.
This supplement to the Journal of Drugs in Dermatology is supported by a medical education grant from Johnson & Johnson
BEMaGS
F
BEMaGS
F
JUNE 2009
595
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
PIPELINE PREVIEWS
Pipeline Previews brings to you information on the newest drugs and medical products as they become available to the dermatological
community. These departments may include additional information from the manufacturers, plus reports from physicians who wish to share
their clinical experience with these new products. In addition, we will inform our readers about the latest drugs receiving Food and Drug
Administration (FDA) approval. We trust you will nd this information benecial to your practice and research.
Acellular Matrix Skin Graft for Diabetic

Foot Ulcers
A new study published recently shows that treating diabetic foot ulcers with an acellular matrix (AM) skin graft led to faster healing than
standard treatment. The results of this randomized controlled trial
were published in the International Wound Journal.
The study enrolled 46 patients who were randomly assigned to AM
therapy and 39 patients who were randomly assigned to standard
therapy. The aim was evaluate the healing of ulcers at 12 weeks in patients each type of therapy. In addition, the study evaluated mean time
to healing with complete re-epithelialization between the 2 groups.
Imiquimod for Infantile Hemangioma

A recent phase 2, open-label study examined the efcacy and safety
of imiquimod in the treatment of supercial and mixed infantile hemangiomas. The study enrolled a total of 16 healthy infants up to 8.8
months of age with untreated, nonulcerated, proliferative supercial
or mixed infantile hemangiomas. Criteria excluded hemangiomas
that were periorbital, perineal, or >100 cm2 in size. Two patients discontinued the study, one for an adverse event (crying upon application) and one for lack of compliance.
Topical imiquimod was applied three to seven times per week for 16
weeks to the hemangiomas. After four months post-treatment, 11
of 14 patients had improvement in erythema. The authors conclude
that topical imiquimod was well tolerated and that improvement was
noted in lesion color but not in lesion size. They surmise that this may
indicate that effects were limited to the supercial component. The
full report can be found in Pediatric Dermatology, March/April 2009,
26(2):203-212.
Do Not Copy,
Penalties Apply
Patients treated with AM received one application of a human acellular dermal regenerative tissue graft (4x4 cm Graftjacket Regenerative Tissue Matrix-Ulcer Repair, Wright Medical Technology, Inc.) that
was sutured in place and covered with a silver-based nonadherent
dressing (Silverlon, Argentum Medical, LLC). Patients in the standard
therapy group received moist-wound therapy with alginates, foams,
hydrocolloids or hydrogels with daily dressing changes.
Results revealed complete healing in 69.6% of the patients in the AM

group and in 46.2% of the patients in the standard treatment group.
The mean time to healing was 5 to 7 weeks in the AM group and 6 to
8 weeks in the standard treatment group.
Photodynamic Therapy for Herpes

Simplex Labialis
A recent report in Photomedicine and Laser Surgery examines photodynamic therapy (PDT) as an adjuvant therapy for the treatment of
herpes labialis. The study enrolled four patients who had 0.01% (m/V)
of methylene blue solution applied to the vesicular stage of their her 2009-Journal of Drugs in Dermatology.
All Rights
pes disease.
The Reserved.
lesions were then irradiated by a laser (660 nm, 120
J/cm2,
40mW).
Twenty-four
after treatment,
marks
of Journal
of Drugs inhours
Dermatology
(JDD). the patients had
A recentNo
report
published
in April
2009
in the
Journal
of Cosmetic
repeated
phototherapy
with
J/cm2written
and 15mW.
The
was
reproduction
or use
of any
portion
of the
contents
of these materials
may be
made without
the3.8
express
consent
ofprocedure
JDD.
and Laser Therapy evaluated hair
removal
with
a novel,
low this
uence,
repeated
72contact
hours and
week later.
If you
feel you
have
obtained
copy illegally,
please
JDD1immediately.
home-use intense pulsed light device. The aim of the study was to
evaluate the efcacy and safety of this home-use treatment for the
Results showed a decrease in the frequency of vesicle recurrence and
general public. In this study, 29 patients with Fitzpatrick skin types
an increase in the healing process. No signicant side effects were
IIII were treated with three weekly therapies with an intense pulsed
noted. The full report can be found at Photomedicine and Laser Surlight device. A total of 31 cutaneous areas were treated, including the
gery, April 2009, 27(2): 357-363.
axilla, bikini area, abdomen, neck, chin and upper lip.
Home-Use Intense Pulsed Light Device
Results indicated that the mean reduction in terminal hair counts was
47% after 4 week of follow-up and 41% after 6 months of follow-up. In
total, 84% of patients had a signicant percentage of hair reduction,
with a mean of 51%. The only noted side effect was mild erythema
post-treatment.
FDA Boxed Warning for Botulinum

Toxin Products
The FDA recently announced that the manufacturers of botulinum
toxin products will need to add a boxed warning regarding risks of
BEMaGS
F
BEMaGS
F
JUNE 2009
596
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
adverse events, specically those that can occur when the effects of
the toxin spread outside of the intended treatment area. In addition,
the manufacturers will need to have a risk evaluation and mitigation
strategy to ensure that benets outweigh the risks.
The affected products are Botox and Botox Cosmetic (botulinum
toxin type A, Allergan) and Myobloc (botulinum toxin type B, Solstice
Neurosciences) that are approved by the FDA for use in the glabella,
treatment of strabismus, blepharospasm, cervical dystonia and primary axillary hyperhidrosis. This new warning stems from reports of
systemic adverse reactions, including respiratory difculty and death
after use of these products for approved and unapproved uses. The
most serious cases occurred predominantly in children treated for cerebral palsy-associated limb spasticity. In adults, most reports of distant spread of toxin effects were noted when the products were used
to treat spasticity or cervical dystonia.
Notably, no denitive serious adverse-event reports of this effect were
associated with the use of Botox at the labeled dose of 20 units for
glabellar lines or 100 units for severe primary axillary hyperhidrosis.
The FDA recommends that healthcare professionals who use botulinum toxin products understand that the dosage strength differs
among the products, be aware of the potential adverse events due
to distant spread of toxin effects and understand that adverse effects
can occur from several hours after injection up to several weeks after
injection. Finally, they should advise patients to seek medical treatment if they develop unexpected loss of strength or muscle weakness,
dysphonia, dysarthria, loss of bladder control, trouble breathing or
swallowing, blurred or double vision or drooping eyelids.
Do Not Copy,
Penalties Apply
BEMaGS
F
BEMaGS
F
JUNE 2009
597
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
CLINICAL TRIAL REVIEW

Clinical Trial Review is a JDD department designed to provide physicians with information on drugs undergoing clinical testing. It is our goal to inform the reader
of the status of select drug trials relevant to the practice of dermatology before this information is available through standard channels. To participate in or learn
more about these and additional trials, visit www.clinicaltrials.gov.
ACNE
A Comparative Study of the Tolerability of Two
Combination Therapies for the Treatment of Acne
Sponsored by Stiefel Laboratories. The purpose of this study is to
compare the tolerability of topical combination therapies in the
treatment of facial acne. Those included in the study will meet the
following criteria: male or female subjects at least 21 years of age,
in good general health with documented diagnosis of acne vulgaris; inammatory (papules and pustules) and non-inammatory
(open and closed comedones) facial lesions; the ability and willingness to follow all study procedures, attend all scheduled visits,
and successfully complete the study; capable of understanding
and willing to provide signed and dated written voluntary informed consent (and any local or national authorization requirements) before any protocol specic procedures are performed.
Dapsone Gel 5% and Tazarotene Cream 0.1% Versus

Tazarotene Cream 0.1% Monotherapy for Facial Acne
Vulgaris
Sponsored by Allergan. This is a 12-week evaluation of the
safety and efcacy of dapsone gel 5% when used with tazarotene cream 0.1% compared with tazarotene cream 0.1% monotherapy in treating moderate to severe facial acne vulgaris.
Those included in the study will have facial acne vulgaris characterized by the following: 30100 facial inammatory lesions;
and 25100 facial non-inammatory lesions; stable disease,
non-rapidly regressing facial acne vulgaris; and, three or more
nodules and/or cysts (diameter of 1cm or greater). Female subjects of childbearing potential must have a negative pregnancy
test at baseline and practice reliable method of contraception
throughout the study.
Do Not Copy,
Penalties Apply
Condition
Intervention
Phase
Acne Vulgaris
Drug: Benzoyl Peroxide/

Clindamycin
Drug: Benzoyl Peroxide/
Adapaleme
Phase 4
Condition
Intervention
Phase
Acne Vulgaris
Drug: Dapsone
Drug: Tazarotene
Phase 4
Study ID Numbers: MA-ACZ0802

ClinicalTrials.gov Identier: NCT00834210
Study ID Numbers: C0000-401

ROSACEA
Photodynamic Therapy (PDT) With Methyl Aminolevulinate (MAL) Cream in Patients With Skin Type V
or IV With Acne Vulgaris
Safety and Efcay Study of Clindamycin Phosphate

1.2% and Tretinoin 0.025% Gel to Treat Rosacea
Sponsored by Massachusetts General Hospital; Medicis Pharmaceutical Corporation. The purpose of this study is to de 2009-Journal
of Drugs
in Dermatology.
All whether
Rights Reserved.
Sponsored by PhotoCure. In this multicenter
study,
patients
termine
Clindamycin Phosphate 1.2% And Tretinoin
with dark skin and
vulgaris
will be
included.
The patients
0.025%
are effective
safe in the
treatment of papuloThisacne
document
contains
proprietary
information,
images and
marks Gel
of Journal
of Drugs and
in Dermatology
(JDD).
will receive
treatment or
with
PDT
andofplacebo
PDT. of
Primary
pustular
Primary
outcome
measures
include the
No reproduction
useMAL
of any
portion
the contents
these materials
may berosacea.
made without
the express
written
consentwill
of JDD.
outcome measures will include:
hypopigmentation
andthis
hyperabsolute
in inammatory
If you
feel you have obtained
copy illegally,
pleasechange
contact JDD
immediately. lesion counts (papules and
pigmentation score assessed after treatment. Secondary outpustules) from baseline to week 12 (end of treatment). Secondcome measures will include: erythema score and other local
ary outcome measures will include reduction in transient eryand non-local adverse events; the reduction in inammatory
thema (ushing) at week 12.
lesion counts from baseline; the reduction in noninammatory
lesion counts from baseline.
Condition
Intervention
Phase
Rosacea
Condition
Intervention
Phase
Acne Vulgaris
Drug: Methyl aminolevulinate

(MAL) PDT
Phase 2
Study ID Numbers: PC TA203/08

Drug: Clindamycin Phosphate 1.2%

and Tretinoin 0.025% Gel
Drug: Placebo
Phase 2
Phase 3
Study ID Numbers: 2008-P-001828

BEMaGS
F
BEMaGS
JUNE 2009
598
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
Efcacy of Topical Azelaic Acid 15% Gel Plus AntiInammatory Dose Doxycycline or Metronidazole
Gel 1% Plus Anti-Inammatory Dose Doxycycline in
Moderate Papulopustular Rosacea
Sponsored by Intendis GmbH. In this study, subjects with moderate papulopustular rosacea will be treated either with azelaic
acid 15% gel topically plus an anti-inammatory dose of doxycyline (40mg)daily or with metronidazole 1% gel topically once
daily plus an anti-inammatory dose of doxycycline (40mg)
over at total of twelve weeks to determine the rapidity of improvement, and the length of time to reach 25%, 50% and 75%
clearing compared to baseline. The change in inammatory lesion count will be assessed at each post-baseline visit by an
analysis of variance model (ANOVA) with factors treatment and
center, but not including treatment-by-center interaction.
Condition
Intervention
Phase
Rosacea
Drug: Azelaic acid gel plus 40 mg

doxycycline
Drug: Metronidazole plus
doxycycline
Phase 4
Study ID Numbers: 1402604, Project number: 256-0024

Safety Study of AMG 157 in Healthy Subjects and

Subjects With Atopic Dermatitis
Sponsored by Amgen. This study is a phase 1 single dose escalation study of AMG 157 in healthy subjects and subjects with
moderate to severe atopic dermatitis. The purpose of the study
is to evaluate the safety, tolerability and pharmacokinetics of
AMG 157. Inclusion criteria is as follows: subject must sign an
Institutional Review Board (IRB) approved informed consent
form before any study specic procedures; subjects must be
aged between 18 and 45 years, inclusive; female subjects must
be of non-reproductive potential; male subjects with partners of
childbearing potential should inform their partner of their participation in this clinical study and use highly effective methods
of birth control during the study; healthy subjects must have a
body mass index (BMI) between 18 to 32 kg/m2, inclusive; subject must have normal or clinically acceptable physical examination, clinical laboratory tests and electrocardiogram (ECG)
results; and for Part B, Subject must have active AD affecting
10% body surface area; and BMI between 18 and 35 kg/m2,
inclusive.
Condition
Intervention
Phase
Atopic
Dermatitis
Healthy
Volunteers
Drug: AMG 157
Phase 1
Do Not Copy,
Penalties Apply
ATOPIC DERMATITIS
Efcacy Study of Montelukast in Atopic Dermatitis

Induced by Food Allergens
Sponsored by 1st Allergy & Clinical Research Center. Atopic

Dermatitis is a disease found in children; the focus of the study
is the mechanisms associated in children with AD induced by
food allergies. This study will be a randomized, double-blind,
placebo-controlled, parallel group trial conducted in participants diagnosed with atopic dermatitis and food allergies.
The study duration for participants will be approximately nine
weeks. A total of 20 participants will be recruited for the entire
study.
Study ID Numbers: 20070620

Management of Pruritus With Xyzal in Atopic

Dermatitis
Sponsored by Derm Research, PLLC. It is historically well known

that the management of pruritus in atopic dermatitis is very difcult. Most of the patients are not controlled with traditional
antihistamines such as Clarinex, Claritin, and Allegra. It will be
a welcome addition to our treatment armamentarium if a drug
such as Xyzal can control pruritus associated with atopic der 2009-Journal of Drugs in Dermatology.
Rights Reserved.
matitis.AllOutpatient,
male or female subjects of any race, at least
18 marks
yearsofofJournal
age may
be included
in this (JDD).
study. Female subjects
Each arm will consist
of 10 participants.The
study
will enrollimages
20 and
This document
information,
of Drugs
in Dermatology
of childbearing
have
a negative
pregnancy
children,
or female,
18
of age
atopic dermatiNomale
reproduction
or use
of years
any portion
of with
the contents
of these materials
may be madepotential
without themust
express
written
consenturine
of JDD.
test please
result contact
at Baseline
and practice a reliable method of contratis (AD) associated with food allergens,
previously
documented
If you feel you
have obtained
JDD immediately.
ception throughout the study.
by skin or RAST test, before enrollment. Atopic dermatitis and
gastrointestinal (GI) symptoms will be scored and followed
throughout the study.
Condition
Intervention
Phase
Condition
Intervention
Phase
Atopic
Dermatitis
Drug: Montelukast
Drug: Placebo
Phase 4
Atopic
Dermatitis
Drug: Levocetirizine
dihydrochloride (Xyzal)
Phase 4
Study ID Numbers: XYZ0801


BEMaGS
F
BEMaGS
F
JUNE 2009
599
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
IMMUNOBULLOUS DISORDERS
Randomized Trial of IVIg With or Without Cyclophosphamide in Pemphigus
Sponsored by the Food and Drug Administration (FDA). The
purpose of this study is to compare two standard treatments
for pemphigus to determine which more effectively improves
the clinical manifestations of the disease and decreases serum
level of the autoantibodies that cause the disease.
The trial is being conducted in patients with pemphigus that
are not responding to, or have developed complications from,
standard treatment. All patients will be treated with IVIg administered using a standard protocol. The IVIg will be given daily
for 4 days, and this cycle will be repeated every other week for a
total of 4 cycles. In addition, half of the patients will be selected
by chance to also be treated with cyclophosphamide, an immunosuppressive drug often used to treat other autoimmune
diseases including pemphigus. The cyclophosphamide is a pill
that is taken 3 times a day. A total of 12 patients will be treated
in each arm of the trial. The trial is being conducted by Dr. JeanClaude Bystryn at the New York University Medical Center.
The extent and activity of the disease, as well as the blood levels of pemphigus antibodies, will be measured at baseline prior
to entry into the trial and periodically during the trial.
There will be a total of 9 study visits until Week 26: screening,

study entry, week 2, and every 4 weeks thereafter. Each study
visit will include a physical exam, vital signs measurement,
medical and medication history, a review of the disease activity log and adverse events experienced since the last visit, skin
assessments and blood collection; patients will also be asked
to complete a tuberculosis (TB) questionnaire. Patients will be
asked to complete quality of life questionnaires at study entry
and weeks 10, 18 and 26. Skin biopsies of unaffected skin will
be done at study entry and weeks 10, 18 and 26; if patients have
PV-associated lesions, additional skin biopsies of affected skin
will be done at study entry and week 18.
Condition
Intervention
Phase
Pemphigus
Drug: Iniximab
Drug: Prednisone
Drug: Placebo
Phase 2
Study ID Numbers: DAIT APV01

Rituximab in the Treatment of Patients With Bullous

Pemphigoid
Do Not Copy,
Penalties Apply
The goal of the study is to determine whether there is a difference between the two treatments in the rate at which: 1) the
activity and extent of the disease improves, 2) the dose of corticosteroids required to treat the disease can be reduced, and
3) the blood level of pemphigus antibodies decrease. This trial
will test this hypothesis by examining whether IVIg treatment
given with cyclophosphamide results in a more rapid decline in
circulating pemphigus antibodies than when given alone.
Sponsored by Duke University. This study will determine the

safety of treatment of bullous pemphigoid in patients resistant to therapy with systemic corticosteroids, with rituximab
plus systemic corticosteroids. Bullous pemphigoid (BP) is an
autoimmune blistering disease characterized clinically by the
presence of severely itchy, tense blisters located over the trunk
and extremities. BP is the most common of the autoimmune
blistering diseases with an incidence of approximately 10 per
1,000,000 population.
In addition, BP occurs more frequently in the elderly. Routine

histopathology reveals a sub-epidermal blister most often with
large numbers of eosinophils. Direct immunouorescence of
Condition
Intervention
Phase
the skin of patients with BP reveals a linear band of C3 and
Pemphigus
Drug: IVIG, cyclophosphamide
Phase 2
IgG at the basement membrane zone. Examination of the sera
Vulgaris
All Rights
Reserved.
of patients
shows
the presence of a circulating anti-basement
membrane
zone autoantibody.
This antibody
marks of Journal
(JDD).has been found to
be directed
against
a 180
protein
of theconsent
basement
membrane
may be made
without
thekdexpress
written
of JDD.
zoneplease
type contact
XVII collagen
(BPAg2) and against a 230 kd protein
JDD immediately.
Use of Iniximab for the Treatment of Pemphigus
(BPAg1) found in the epidermal hemi-desmosome.
Vulgaris
Sponsored by the National Institute of Allergy and Infectious
Diseases (NIAID). Pemphigus vulgaris (PV) is a rare skin disorder that causes blistering of the skin and mucous membranes.
Iniximab is a man-made antibody used to treat certain types of
immune system disorders, including rheumatoid arthritis and
Crohns disease. This study will determine if iniximab given in
combination with prednisone is a safe and effective treatment
for adults with PV.
Condition
Intervention
Phase
Bullous
Pemphigold
Drug: Rituximab
Phase 1
Study ID Numbers: 6641-05-2R0

BEMaGS
F
BEMaGS
F
JUNE 2009
600
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
Efcacy and Safety of Omalizumab in Bullous

Pemphigoid
Sponsored by University of Iowa. The primary objective is to
test the safety and efcacy of Xolair in the treatment of the autoimmune blistering disease, bullous pemphigoid (BP). This is a
pilot, open label case-control study. Patients treated with Xolair
will be compared to patients receiving standard treatment with
prednisone. The enrollment period for the study is 24 weeks: 16
weeks active treatment and 8 additional weeks of observation.
The current treatment for BP is non-specic immunosuppression, causing great morbidity in these patients. Recently, pathogenic IgE class autoantibodies have been identied in these patients. Development of a more targeted approach to treatment
may reduce morbidity.
Condition
Intervention
Phase
Bullous
Pemphigoid
Drug: Omalizumab
Phase 4

Clinical Trial Evaluating Rituximab in Ocular

Cicatricial Pemphigoid
sessment of famciclovir single 1500 mg dose. Inclusion criteria

is as follows: Outpatient males or females 12 to 18 years of age,
with general good health with a documented history typical for
recurrent herpes labialis, as well as prodromal symptoms or active lesions suggestive of a recurrent episode of herpes labialis
(i.e. having had cold sores in the past), with onset not exceeding 24 hours until the time of study drug administration
Adolescents participating in PK part of the study may be enrolled without an active herpes labialis recurrence or with onset
of signs/symptoms of a recurrent herpes labialis episode longer than 24 hours before study drug administration, All adolescents participating in the pharmacokinetics assessments must
fast for at least 8 hours prior to Visit 1 and be willing to fast for
an additional 2 hours after study drug administration.
Condition
Intervention
Phase
Herpes
Labialis
Drug: Famciclovir
Phase 2
Study ID Numbers: CFAM810B2305

Do Not Copy,
Penalties Apply
Sponsored by University of Alabama at Birmingham; Genetech;

Biogen Idec. Cicatricial pemphigoid is an autoimmune blistering disease which affects the skin, mucous membranes, and, in
a small subset of patients, the eye.
Progressive ocular disease can lead to irreversible damage and

blindness. Conventional treatments include systemic steroids,
dapsone, and immunosuppressive agents. These treatments,
however, are not successful with all patients. Ritumimab has
been very effective in the treatment of other autoimmune disorders, and has recently been shown to be effective for autoimmune blistering pemphigus. We propose that it will also be
effective in the treatment of cicatricial pemphigoid.
Zinc for the Treatment of Herpes Simplex Labialis

(HSL)
Sponsors and collaborators: Integrative Medicine Institute;
Womens Health Services, Santa Fe, NM; Southwest College
of Naturopathic Medicine; Beth Israel Continuum Center for
Health and Healing, New York, NY; and Matrixx Initiatives, Inc.
Evaluate the effectiveness of a topical preparation of zinc to
treat cold sores.
Zinc salts irreversibly inhibit herpes virus replication in vitro

and are effective in treating herpes infections in vivo and have
been shown in a clinical trial to be a effective topical treatment
for HSL. Zinc salt solutions applied to herpetic lesions decrease
viral load and markedly improve healing rates, relieving the
symptoms of herpes as healing occurs. Zinc swabs contain 33
mmol/lAll
ofRights
ionic Reserved.
Zinc in an emulsication of Benzalkonium chloCondition
Intervention
Phase
ride,
glycerin,
hydroxyethylcellulose,
sodium
marks
of Journal
(JDD). chloride, and soOcular
Drug: Rituximab
Phase 1
dium
hydroxide
(ph
7.2).
Zinc
gluconate
is
monographed
No
reproduction
or
use
of
any
portion
of
the
contents
of
these
materials
may
be
made
without
the
express
written
consent
of JDD. in the
Cicatricial
Homeopathic
Pharmacopoeia
of the United States (HPUS) and
please contact
JDD immediately.
Pemphipoid
one of OTC indications for Zinc and its salts is for the treatment
Study ID Numbers: U3441S
of cold sores.
DERMATOMYOSITIS
Safety and Pharmacokinetics of Famciclovir Single
1500 mg Dose in Adolescents With Recurrent
Herpes Labialis
Sponsored by Novartis Pharmaceuticals. This study will assess
the safety, tolerability of a single 1500 mg dose of famciclovir in
50 adolescents with recurrent herpes labialis. Eight of the 50 adolescents will also participate in the pharmacokinetics (PK) as-
Condition
Intervention
Phase
Herpes
Simplex
Labialis
Drug: Zicam (Ionic zinc)
Phase 3
Study ID Numbers: IMIZnc2008

BEMaGS
F
BEMaGS
JUNE 2009
601
VOLUME 8 t*446&
COPYRIGHT 2009
DEPARTMENTS
Safety, Potential Efcacy, and Pharmacokinetics of

PZ-601 in the Treatment of Complicated Skin and
Skin Structure Infection
Sponsored by Protez Pharmaceuticals, Inc. The purpose of this
study is to evaluate the potential effect and safety of two different doses of PZ-601 and to compare this with another antibiotic that is approved by the U.S. Food and Drug Administration
(FDA) to treat adults with skin and skin structure infections.
PZ-601 is a novel investigational carbapenem antibiotic with an
antimicrobial spectrum of activity that includes pathogens responsible for community-acquired bacterial infections as well
as multidrug-resistant Gram-positive pathogens and vancomycin-resistant enterococci. PZ-601 also has activity against Gramnegative organisms including cephalosporin and quinolone resistant Enterobacteriaceae as well as Bacteriodes fragilis and
peptostreptococci. Based on the antimicrobial prole, PZ-601 is
a potentially promising agent for the treatment of complicated
skin and skin structure infections.
Condition
Intervention
Phase
Skin Infections
Drug: PZ-601
Drug: PZ-601
Drug: Standard of Care
Phase 2
Sponsored by Johns Hopkins University; Bristol-Myers Squibb.

This study is being done to nd out if a drug called Abatacept
(Orencia ) is safe and effective in treating people with chronic
urticaria (persistent hives).
Participants will have one of the following three conditions:
1) previous or ongoing requirement for corticosteroids for
symptom control OR; 2) prior steroid treatment with steroid
discontinuation due to unacceptable morbidity; or 3) previous
or current use (without symptom control or with unacceptable
morbidity: e.g., hypertension from cyclosporine, hemolysis
from dapsone) of immunomodulatory treatment for urticaria
(e.g., hydroxychloroquine, methotrexate, sulfasalazine, dapsone, cyclosporine, IVIg, mycophenylate, azathioprine, etc).
Condition
Intervention
Phase
Urticaria
Drug: Abatacept (Orencia)
Phase 1
Study ID Numbers: Tahoe-001

Do Not Copy,
Penalties Apply
Study ID Numbers: PZ-601-02

URTICARIA
Study to Evaluate The Safety and Efcacy of

Abatacept in Subjects With Chronic Urticaria
Who Have Had an Inadequate Response to AntiHistamine Therapy
A Study of Xolair (Omalizumab) in Patients With

Chronic Idiopathic Urticaria (CIU) Who Remain
Symptomatic With Antihistamine Treatment (H1)
The Efcacy and Safety of Desloratadine With

Levocetirizine in Treatment of Chronic Idiopathic
Urticaria
Sponsored by Lotus Pharmaceutical. The objective of this study
is to compare the efcacy of desloratadine 5mg (Denosin)
and levocetirizine 5mg (Xyzal) once daily in the treatment of
patients with CIU over 6 weeks. This is a randomized, doubleblind, active-controlled, parallel-group study.
Sponsored by Genetech. The study is a Phase II, dose-ranging,

multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the efcacy and safety of a single subcutaneously administered omalizumab dose as add-on therapy for
the treatment of adolescent and adult patients 12-75 years old
who have been diagnosed with CIU and remain symptomatic
despite treatment with therapeutic doses of an H1 antihistamine. The study will enroll approximately 76 patients at approximately 45 study centers in the United States and Germany.
The primary endpoint

of thiscontains
study proprietary
will be toinformation,
evaluate images
the and
Inclusion
follows:
participants
will have a CIU diagThis document
marks ofcriteria
Journalisofas
Drugs
in Dermatology
(JDD).
change No
in reproduction
average AM/PM
pruritus
from
base-materials
nosis
ofbe
more
3 months
(by history),
as well
as no underor usereective
of any portion
of thescore
contents
of these
may
madethan
without
the express
written consent
of JDD.
line recorded in the subjects Ifdiaries
during
theobtained
rst twothis
weeks
lying
etiology
clearly
dened for urticaria (main manifestation
you feel
you have
copy illegally,
please
contact
JDD immediately.
of the treatment. Secondary Objectives: To assess the efcacy
cannot be physical urticaria).
and safety of desloratadine 5mg (Denosin) and levocetirizine
5mg (Xyzal) once daily in the treatment of subjects with CIU
Condition
Intervention
Phase
over 6 weeks.
Condition
Intervention
Phase
Chronic
Idiopathic
Urticaria
Urticaria Drug: Denosin and

Xyzal
Phase 4
Chronic
Idiopathic
Urticaria
Drug: Omalizumab
Drug: Placebo
Phase 2
Study ID Numbers: Q4577g

Study ID Numbers: 187CL1

BEMaGS
F
BEMaGS
F
602
INSTRUCTIONS TO AUTHORS
(may be downloaded at www.JDDonline.com/submit.php)
All submissions must be clearly marked as articles (recommended: 2000-4000

words, including references and tables), case reports (750-1500 words plus gures),
or letters (700 words max, no gures or references). You may submit either by e-mail
or regular mail.
Mailed hard copies should be double-spaced on 1 side of 8.5 x 11 inch white paper
with adequate margins. All hard copies must be accompanied by an identical
digital copy on CD labeled with the lead authors last name and formatted in
Microsoft Word (DOC) or rich text format (RTF). Figures and photographs may not
be embedded in the text document. See below for requirements. Handwritten or
typed, noncomputer generated submissions will not be accepted. Manuscripts may
be mailed to:
JDD Manuscript Submissions
377 Park Avenue South
6th Floor
New York, NY 10016
Manuscripts may be e-mailed to: submissions@jddonline.com
______________ with all gures and
photographs as separate les according to the guidelines below.
A title page is to be provided and should include the title of the article, author
names, and author afliations. The afliation should comprised of the department,
institution (usually university or company), and city and state (or nation). For
administrative purposes, the title page should include the complete mailing address
and telephone number of the corresponding author designated to review proofs
or conrm revisions, if necessary. The title page must also disclose any relevant
conicts of interest, nancial or otherwise.
An abstract is to be provided, preferably no longer than 150 words. Please use only
1 space after periods at the ends of all sentences. Headers should either be bold or
bold italics, not in all capitals.
Illustrations (photographs, drawings, diagrams, tables, and charts) are each to be
numbered in 1 consecutive series of Arabic numerals (eg, Figure 1, Figure 2; Table 1,
Table 2). The captions for illustrations should be listed sequentially at the end of the
main document. All illustrations must be complete and nal (ie, publication-ready).
Please disclose all relevant conicts of interest at the end of the article.
References
Do Not Copy,
Penalties Apply
Figures, Photographs, & Tables
All gures and photographs must be submitted as separate les in their

source application; do not embed them in a text document.
Graphs/gures/drawings: Illustrator EPS, version CS3 or older; CMYK or grayscale
color spacedo not use spot (PMS) colors; do not convert fonts to outlines.
Photographs: Photoshop TIFF or JPEG; resolution 300 dpi or higher; CMYK or
grayscale color space; image size at least 3.5 wide. Original photographs of high
quality are acceptable but not preferred. If original photographs are submitted,
identify the gure number on the back with lead authors name. If you wish to have
photographs returned, please indicate. Leave photos unaltered; JDD will format
appropriately to keep patient identity condential.
Tables: Created in Microsoft Word, not embedded as an image. PowerPoint slides
are not accepted.
Following the AMA Manual of Style, each reference should be cited in the text with
a superscripted Arabic numeral corresponding to the numeral listed sequentially
in the reference list at the end of the article (eg, as shown in the prior study.1).
If there are more than 4 authors for a reference, list the rst 3 followed by et al
in accordance with the punctuation below. Do not use the automatic footnotes
function in Microsoft Word.
Journal Article
Ito T, Moore JI, Koss MC. Topical application of CO2 increases skin blood ow.
J Invest Dermatol. 1989;93:259-262.
Book
Goodman A, Goodman L, Gilman A. The Pharmacologic Basis of Therapeutics.
6th ed. New York: Macmillan; 1980.
Chapter in a Book
Rights T.
Reserved.
Pathak M,AllFitzpatrick
Preventative treatment of sunburn, dermatoheliosis, and skin
This Agreement
document contains proprietary information, images and
marks
Journal ofagents.
Drugs
Dermatology
Publication
cancer
with of
sun-protective
In: in
Fitzpatrick
T, Eisen A,(JDD).
Wolffe K, eds. Dermatology
Prior to
all authors
required
to of
sign
a publication
agreement
in General
ed. Newthe
York,express
NY: McGraw-Hill;
Nopublication,
reproduction
or usewill
of be
any
portion
the
contents of
these materials
may Medicine.
be made4thwithout
written1993:1689-1717.
consent of JDD.
stating that the manuscript content (including
allyou
gures,
photographs,
If you feel
have
obtainedand
thistables)
Website
is not currently under consideration for publication elsewhere or been previously
National Psoriasis Foundation. Statistics. Available at:
published. The publication agreement also transfers ownership of the copyright for
http://www.psoriasis.org/about/stats/. Accessed July 17, 2006.
the manuscript to the Journal of Drugs in Dermatology.
Package Insert
Lamasil [package insert]. East Hanover, NJ: Sandoz Pharmaceuticals Corp; 1993.
Style
Please consult the latest editions of the American Medical Association (AMA)
Manual of Style, Merriam-Webster Dictionary, and Stedmans Medical Dictionary
for the proper expression of numbers, punctuation, spelling, referencing, and all
other matters of style.
Note: Use of the aforementioned style guides does not signify an endorsement of
said products.
BEMaGS
F
BEMaGS
F
&/5&3508*/
A set of surgical
instruments by
Anmuth Medical
International
$23
value5
!
Want more information on a
product youve seen or read
about in the JDD?
Its easy: check the box(es) and
provide your contact details.
Information on the products
selected will be sent to you via
e-mail and/or mail.
#VZFST3FTPVSDF
COMPANY NAME
PRODUCT NAME
Amgen
Enbrel
Eclipse Medical
Smark Xide Dot
ETAS
Dermatology-In-Review
Galderma
Epiduo
Galderma
Epiduo
Galderma
Differin
Graceway
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.
CONTRAINDICATIONS
Naftin Cream, 1% is contraindicated in individuals who
have shown hypersensitivity to any of its components.
WARNINGS
Naftin Cream, 1% is for topical use only and not for
ophthalmic use.
PRECAUTIONS
General: Naftin Cream, 1% is for external use only. If irritation
or sensitivity develops with the use of Naftin Cream, 1%,
treatment should be discontinued and appropriate therapy
instituted. Diagnosis of the disease should be confirmed
either by direct microscopic examination of a mounting of
infected tissue in a solution of potassium hydroxide or by
culture on an appropriate medium.
Information for patients: The patient should be told to:
1. Avoid the use of occlusive dressings or wrappings unless
otherwise directed by the physician.
2. Keep Naftin Cream, 1% away from the eyes, nose, mouth
and other mucous membranes.
Do Not Copy,
Penalties Apply
Atopiclair
Johnson and Johnson
Aveeno
Merz
Naftin
NexTech
BRIEF SUMMARY
Rx ONLY
NexTech Practice 2009
ODAC
ODAC 2010 Conference
OrthoNeutrogena
Retin-A Micro
Carcinogenesis, mutagenesis, impairment of fertility:

Long-term animal studies to evaluate the carcinogenic
potential of Naftin Cream, 1% have not been performed.
In vitro and animal studies have not demonstrated any
mutagenic effect or effect on fertility.
Pregnancy: Teratogenic Effects: Pregnancy Category B:

Reproduction studies have been performed in rats and rabbits
(via oral administration) at doses 150 times or more the topical
human dose and have revealed no evidence
Taro Pharmaceuticals
Topicort
of impaired fertility or harm to the fetus due to
naftifine. There are, however, no adequate and well controlled
Triax Pharmaceuticals
Locoid Lipocream
studies in pregnant women. Because animal reproduction
studies are not always predictive of human response,
Other________________________________________
this drug should be used during pregnancy only if clearly
needed.
Contact Details:
Nursing
mothers:
It in
is Dermatology
not known whether
This document contains proprietary information, images and marks
of Journal
of Drugs
(JDD). this drug is
excreted in human milk. Because many drugs are excreted
Name/Title........................................................................................................
mademilk,
without
the express
consentwhen
of JDD.
in be
human
caution
should written
be exercised
Naftin
Address.............................................................................................................
Cream,
1% isJDD
administered
to a nursing woman.
If you feel you have obtained this copy illegally, please
contact
immediately.
City.................................................. State .................... Zip..............................
Country .............................................................................................................
Telephone .........................................................................................................
Fax.....................................................................................................................
E-mail ................................................................................................................
YES! I would like to be entered in the rafe to win a set of

surgical instruments by Anmuth Medical International. The drawing
will be held on July 6th, 2009--the winner will be notied by e-mail.
Submit:
Pediatric use: Safety and effectiveness in pediatric patients

have not been established.
ADVERSE REACTIONS
During clinical trials with Naftin Cream, 1%, the incidence
of adverse reactions was as follows: burning/stinging (6%),
dryness (3%), erythema (2%), itching (2%), local irritation
(2%).
Manufactured for: Merz Pharmaceuticals
Greensboro, NC 27410
2008 Merz Pharmaceuticals
Rev. 11/08
Fax: 949.760.0522 Online: JDDonline.com/buyersresource.php

Mail: 1321 N. Lamer Street, Burbank, CA 91506
BEMaGS
F
BEMaGS
F
&I
ES
GA R S T
LA

BL L C A N
E
R
EA DO
IN
3
0g M N

A
ND I N L Y
A
9
0g P
SIZ U M
P
&UNGICIDAL0OWERINA
AI
UN
#ONVENIENT0UMP
!V
TIF
AN
).42/$5#).'
4HEBRANDED
PRESCRIPTIONTOPICAL
ANTIFUNGALCREAM
4ARGETEDPOWER
AGAINST4INEA0EDIS
#RURISAND#ORPORIS
NOWOFFERSCONTROLLED
APPLICATIONINAPUMP
Do Not Copy,
Penalties Apply
&UNGICIDAL0OWER9OU#AN4RUST
www.naftin.com
Naftin (naftine HCl 1%) Cream and Gel, 1% are contraindicated in individuals who have shown hypersensitivity to any of
their components and are for topical use only. During clinical trials with Naftin Cream, 1%, the following adverse reactions
were reported: burning/stinging, dryness, erythema, itching, local irritation. During clinical trials with Naftin Gel, 1%, the
following adverse reactions were reported: burning/stinging, itching, erythema, rash, skin tenderness. See brief summary of
prescribing information on the previous page.
References: 1. IMS NPA Data, December 2008.

2009 Merz Pharmaceuticals. All rights reserved.
BEMaGS
F

Journal of Drugs in Dermatology - June 2009 PDF

Загружено:

Сведения о документе

Исходное описание:

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Journal of Drugs in Dermatology - June 2009 PDF

Загружено:

Авторское право:

Доступные форматы

Contents | Zoom in | Zoom out

For navigation instructions please click here

Search Issue | Next Page

Anti-TNF Agents for the Treatment of Psoriasis

/FXT 7JFXT BOE3FWJFXT

Contents | Zoom in | Zoom out

For navigation instructions please click here

Search Issue | Next Page

Introducing the rst and only once-daily combination

Please see brief summary of Prescribing Information on next page.

   "# %&  &"   0

Journal of Drugs in Dermatology (JDD)

PERMISSIONS: Contact James J. Gormley at 646-736-4328;

International Society for

INTERNATIONAL EDITORIAL BOARD

Dee Anna Glaser MD

Macrene AlexiadesArmenakas MD PhD

Maurizio Podda MD PhD

Luigi Rusciani Scorza MD

Aditya K. Gupta MD PhD

44 Years in Dermatologic Surgery: A Retrospective

Treatment of Poikiloderma of Civatte With Ablative

FIGURE 1. Left to right: Theodore

Treatment of Pruritus in Mild-to-Moderate Atopic

Stefano Veraldi MD PhD, Paolo De Micheli MSc,

Anti-TNF Agents for the Treatment of Psoriasis

Photodynamic Therapy With Low-Strength ALA,

Are Ointments Better Than Other Vehicles for

FIGURE 1. High-intensity light source

(SBDFXBZ1IBSNBDFVUJDBMT UIFNBLFSPG"MEBSB JTQSPVEUP

Localized Dyskeratotic Plaque With

Painful Parotid Hypertrophy With

Kelly K. Park MD, Rebecca C. Tung MD,

American Soc ium Proceedings,

*44/: 1545 9616

Genomics of Skin Aging:

Look for this supplement with

Distributed by: OrthoNeutrogena

Theres no such thing as

when it comes to babys skin.

+ fragrance free, natural colloidal oatmeal

thats the beauty of

Johnson & Johnson Consumer Companies, Inc. 2009

IN THE MANAGEMENT OF ATOPIC DERMATITIS

G Supports healthy skin-barrier function

2009-Journal of Drugs in Dermatology. All Rights Reserved.

Rx Onlyinformation, images and marks of Journal of Drugs in Dermatology (JDD).

For external use only; avoid contact with eyes.

2009 Graceway Pharmaceuticals, LLC, Bristol, TN

News, Views and Reviews

Clinical Trial Review

JDD Buyers Resource

Indications for Use: Under the supervision of a healthcare professional, Atopiclair

Manufactured under license from

ECLIPSEMED ,TD s TOLLFREE   s ________________

44 Years in Dermatologic Surgery: A Retrospective

Development of Mohs Surgery

FIGURE 1. Left to right: Theodore Tromovitch, Perry Robins,

Dr. Alfred Kopf predicted 25 years ago there would be a Mohs

To my dismay, many of my colleagues were upset because they

In December, 1970 at the annual Mohs Conference, Drs. Ted

"# %& &" 0

ECLIPSEMED,TD s TOLLFREE s ________________