Contemporary Treatment Approaches to Acne and Psoriasis

12 Pages·2005·0.61 MB·English

SA-Connetics 1/19/05 3:05 PM Page 1
A SUPPLEMENT TO
Skin & Allergy News
®
Contemporary
Treatment Approaches
to Acne and Psoriasis
Managing Acne in Adult Women
New Developments in Therapy
for Acne Vulgaris: A Preview
The Role of Oral Retinoid
Treatment for Psoriasis
in the Age of Biologics
Advances in Combination
Topical Therapy for Psoriasis
FACULTY
Diane S. Berson, MD
Weill Medical College of Cornell University
New York, N.Y.
Produced in
Linda F. Stein Gold, MD
affiliation with the
29th Annual Hawaii Henry Ford Health System
Dermatology Seminar West Bloomfield, Mich.
John Y. M. Koo, MD
Psoriasis Treatment Center
University of California at San Francisco
Lee T. Zane, MD
University of California at San Francisco
SA-Connetics 1/26/05 3:28 PM Page 2
Skin & Allergy News Contemporary Treatment Approaches
®
to Acne and Psoriasis
President, Elsevier/IMNG
Alan J.Imhoff
Vice President, Managing Acne in Adult Women
Medical Education Diane S.Berson,MD 3
& Business Development
Sylvia H.Reitman,MBA New Developments in Therapy for Acne Vulgaris:
A Preview
Program Manager, 5
Lee T.Zane,MD
Medical Education
Margo Ullmann
The Role of Oral Retinoid Treatment for
Clinical Editor Psoriasis in the Age of Biologics
7
Joanne M.Still John Y.M.Koo,MD
National Account Manager Advances in Combination Topical Therapy for Psoriasis
Cheryl J.Gromann Linda F.Stein Gold,MD 9
Graphic Design CME Post-Test and Evaluation 12
Lehner & Whyte,Inc.
Publication Manager FACULTY
Judi Sheffer Diane S.Berson,MD John Y.M.Koo,MD
Assistant Professor of Dermatology Professor and Vice Chairman
The articles contained within this sup- Weill Medical College of Cornell University Department of Dermatology
plement are based on clinical dialogues
New York, N.Y. Psoriasis Treatment Center
held with the faculty. This supplement is
University of California at San Francisco
produced in affiliation with the Skin Linda F.Stein Gold,MD
Disease Education Foundation’s 29th Director of Dermatology Research Lee T.Zane,MD
Annual Hawaii Dermatology Seminar, a
Henry Ford Health System Clinical Instructor
continuing medical education program
West Bloomfield, Mich. Department of Dermatology
held March 18-24 2005, in Maui,
Hawaii. University of California at San Francisco
This educational supplement to CME RECOGNITION LEARNING OBJECTIVES
SKIN & ALLERGY NEWS, designated by The SKIN & ALLERGY NEWS supplement “Contemporary By reading and studying this activity, participants should
the American Academy of Dermatology Treatment Approaches to Acne and Psoriasis” is recog- be able to:
(AAD) for AAD CME credit, was sup- nized by the American Academy of Dermatology for 1 • Discuss the role that oral retinoids play in the treatment
ported by an unrestricted educational hour of AAD Category 1 CME credit and may be used to- of patients with moderate to severe psoriasis.
grant from ward the American Academy of Dermatology’s Continuing • Describe how the range of systemic psoriasis treatment
Medical Education Award. options (eg, cyclosporine, oral retinoids, and the biolog-
This program was developed in accordance with the ic agents) may be used in combination or sequentially to
Accreditation Council for Continuing Medical Education optimize therapeutic response and long-term manage-
guidelines. ment in patients with moderate to severe psoriasis.
• List and describe the new and investigative topical com-
Term of approval:February 2005-January 31, 2006
bination treatments for psoriasis and describe their
Estimated time to complete this educational activity: mechanism of action.
It was produced by the medical educa- 1 hour. • Explain the characteristics of acne in adult women, and
tion department of International list the treatment options that are currently available.
Medical News Group. Neither the
TARGET AUDIENCE • Discuss the treatments for acne vulgaris that are now in
Editor of SKIN & ALLERGY NEWS, the development, including the classes of retinoids,
Editorial Advisory Board, nor the re- This activity has been developed for dermatologists and antibiotic/immunomodulatory agents, combination
porting staff reviewed or contributed to other health care professionals involved in the treatment of agents, and laser/light techniques.
its contents. The opinions expressed in acne in adult women and/or psoriasis.
this supplement are those of the faculty FACULTY AND UNAPPROVED USE DISCLOSURES
and do not necessarily reflect the views EDUCATIONAL NEEDS Faculty/authors must disclose any significant financial in-
of the supporter or the Publisher. Acne in adult women and mild to moderate psoriasis are terest or relationship with proprietary entities that may
common conditions seen in dermatologic practices. In have a direct relationship to the subject matter. They must
Copyright © 2005 Elsevier Inc. All rights acne, clinicians can anticipate advances in technologies also disclose any discussion of investigational or unlabeled
reserved. No part of this publication (such as new photodynamic techniques), new drugs and uses of products.
may be reproduced or transmitted in any drug classes (including retinoic acid metabolism blocking
form, by any means, without prior agents, or RAMBAs), and novel drug delivery systems Dr Berson has served on advisory boards for Allergan,
written permission of the Publisher. (such as foam vehicle for clindamycin). In psoriasis, com- Inc., Connetics Corporation, Dermik Laboratories, Gal-
Elsevier Inc. will not assume responsi- bination therapies offer renewed hope for both patients and derma International, and Medicis Pharmaceuticals Corpora-
bility for damages, loss, or claims of any clinicians: oral retinoids plus other topical and/or systemic tion. Dr Stein Goldis a principal investigator and consul-
kind arising from or related to the infor- treatments for patients with moderate to severe disease, tant to Connetics. Dr Koohas received funding for clinical
mation contained in this publication, grants from Allergan, Biogen, Inc., Fujisawa Healthcare,
and, for those with mild to moderate disease, combinations
including any claims related to the Inc., Valeant Pharmaceuticals International, and Serono
of calcipotriene and tazarotene with corticosteroids offer
products, drugs, or services mentioned S.A. He is also a consultant to Abbott Laboratories, Amgen,
enhanced efficacy in topical treatment. Improved vehicles
herein. Inc., Biogen, Centocor, Inc., Genentech, Inc., Novartis
in the topical category also offer improved efficacy, con-
Pharmaceuticals Corporation, and Fujisawa. Dr Zanehas
venience, and comfort, and, therefore, are likely to improve
Photos on pages 7 and 9 courtesy of the served on advisory boards for Connetics and QLT, Inc.
patient compliance. Clinicians must be informed about
Derm Education Foundation, NFP
these developments that will help them to meet the Dr Koodiscusses the unlabeled use of acitretin in combi-
(www.derm.md).
treatment challenges presented by patients with acne and nation with other agents. Dr Zanediscusses the unlabeled
psoriasis. use of new retinoic acid derivatives of isotretinoin and
alitretinoin; clindamycin in a foam vehicle; dapsone in a
INTERNATIONAL topical formulation; zileuton in an oral formulation; clin-
MEDICAL NEWS damycin/ tretinoin gel combination product; laser and light
GROUP devices and photodynamic therapy using lemuteporfin.
SA-Connetics 1/19/05 3:07 PM Page 3
Managing Acne in Adult Women
Diane S. Berson, MD
Acne is most commonly associ- sebaceous glands, and hair follicles. In Women with regular menses do not
ated with young people of both addition, it is thought—although not yet require a hormonal workup because
genders between puberty and proven—that acne flares in adult acne associated with the menstrual
age 21, but most dermatologists also women can be associated with stress. cycle (“hormonal acne”) may occur
see a number of adult patients with The proposed mechanism is a stress-re- without an underlying hormonal prob-
acne. In men, acne breakouts can be se- lated release of adrenalin and cortisol lem. In such patients, it may be that in-
vere, but men usually respond well to from the adrenal glands, which results creased production of androgens occurs
treatment and chronic recurrences are in a release of androgens. These in- peripherally, at the site of the sebaceous
the exception rather than the rule. In creased circulating levels of androgens glands, or that the receptors on the se-
contrast, women tend to experience may stimulate production of excess baceous glands may be more sensitive
chronic, low-grade acne breakouts, sebum, causing an outbreak of inflam- to the normal level of circulating hor-
even after successful treatment of each matory lesions. mones.
episode. Patients may have had acne as In performing the history and physi-
adolescents and now have a persistent Evaluation cal examination, it is important that
problem; less commonly, patients expe- A thorough history should be taken clinicians take time to reassure the pa-
rience onset of acne in adulthood with on all adult women who present with tient that her concerns are important.
no prior history. persistent acne. This should include a Remember that there is a psychologic
menstrual history as well as a pregnan- aspect for many women who believe
Clinical Presentation cy history. Women who present with that they should have outgrown their
Acne in adult women tends to be acne and hirsutism, alopecia, or men- often-embarrassing adolescent acne.
characterized by lesions on a number of strual irregularities should be evaluated
areas of the skin, including the fore- for adrenal hyperplasia or polycystic Considerations in
head, chest, or back, but usually on the ovarian syndrome. A history of infertil- Treatment
lower part of the face (Figure)—specif- ity is a sign of a possible hormonal ab- In addition to choosing the appro-
ically, the lower cheeks, jaw line, neck, normality. In addition, ask about OC priate medication to treat acne in adult
and especially the chin. These out- use. Patients who stop taking the “Pill” women, it is important to review proper
breaks are characterized by areas of often experience acne outbreaks for skin care and guide them in their
inflamed papules and pustules. (In con- several months; usually these flares are choices of cleansing, moisturizing, and
trast, most teenagers with mild to mod- short-lived and self-limited. makeup products. Whereas teenagers
erate acne tend to present with open and tend to have oily skin, many adult
closed, noninflammatory comedones— Figure. Acne on the Lower Face women have dry or sensitive skin, so
blackheads and whiteheads—in the T the products developed and marketed as
zone.) acne remedies for adolescents often are
Outbreaks in adult women often are inappropriate for adults. Products for
mild and may be cyclic in nature, the re- adult women must be well tolerated,
sult of hormonal fluctuations. In many nonirritating, and applied easily and
women, lesions appear just before the compatibly with makeup.
onset of the menstrual period,1but acne
is also associated with hormonal fluctu- Treatment Strategy
ations resulting from other causes, in- Initially, topical treatment with a
cluding pregnancy, initiation of the use combination of an antimicrobial med-
of oral contraceptives (OCs), and cessa- ication and a retinoid should be used.
tion of OC use. This will be effective for most patients
Excess androgen also may be a cause in clearing the outbreak. For treatment
In adult women,outbreaks of acne tend to
of acne in adult women.2Sources of an- appear as inflamed papules and pustules, of facial acne, cream-, lotion-, or foam-
drogen include the adrenal glands and typically on the lower part of the face, based products may be used, but if the
especially the chin.
ovaries, as well as peripheral sites, the chest or, particularly, the scalp are in-
Contemporary Treatment Approaches to Acne and Psoriasis 3
SA-Connetics 1/19/05 3:07 PM Page 4
volved, patient compliance is more like- perience hormonal flares. If this per- References
ly to be maintained with a foam-based sists for several months, an antiandro- 1. Lucky AW. Quantitative documentation of a
medication. The topical retinoids cur- genic agent such as spironolactone (a premenstrual flare of facial acne in adult
women. Arch Dermatol.2004;140:423-424.
rently available are tretinoin, adapalene, diuretic agent that inhibits androgen
2. Cibula D, Hill M, Vohradnikova O, Kuzel D,
and tazarotene. A combination product biosynthesis and binds androgen recep-
Fanta M, Zivny J. The role of androgens in
containing tretinoin and clindamycin is tors in the sebaceous glands) may be determining acne severity in adult women.
now in clinical trials. administered along with OC therapy.3 Br J Dermatol.2000;143:399-404.
The usual maintenance treatment 3. Shaw JC. Low-dose adjunctive spironolac-
tone in the treatment of acne in women: A
choice for women with chronic, low-
retrospective analysis of 85 consecutively
grade, cyclic acne is a topical retinoid
“In performing treated patients. J Am Acad Dermatol.2000;
to help prevent new lesions plus an OC 43:498-502.
the history
to decrease the influence of hormonal
fluctuations. The estrogen component and physical
of the OC works mainly in two ways to
examination, it is
control acne. First, it decreases produc-
tion of androgens in ovaries so less an- important that
drogen is available to stimulate the se- clinicians take
baceous glands. Second, estrogen in-
time to reassure
creases sex hormone binding globulin,
which binds testosterone, so less testos- the patient that
terone is available to stimulate the seba-
her concerns are
ceous glands.
important.”
Patients with persistent inflammation
or mild acne may continue use of the
topical retinoid along with the topical
antimicrobial.
For patients with severe acne, in Some women with acne flares do
whom topical retinoid/antimicrobial have concomitant hormonal problems.
therapy plus an OC fails to control le- For those with polycystic ovarian syn-
sions, oral antibiotics may be added to drome, the treatment of choice is an
the regimen. When acne is severe and OC. Adrenal hyperplasia is treated
the potential for scarring is present, the mainly with oral corticosteroids.
patient should be evaluated for possi-
ble use of isotretinoin. (Of course, Conclusion
many women with adult acne and hor- Many women continue to suffer from
monal fluctuations are, by definition, acne well into adulthood. In contrast to
of childbearing age, so careful atten- men, acne in adult women tends to be
tion must be paid to appropriate pa- chronic and related to hormonal fluctu-
tient selection and compliance with ations. Although these outbreaks tend
birth control recommendations during to be mild, they often are bothersome
treatment with isotretinoin.) Once the and cause patients great frustration.
course of therapy with isotretinoin is Fortunately, research has shown the
complete, recurrence of acne frequent- likely contributors to acne in adult
ly can be decreased by continuation of women and has resulted in the develop-
OCs and the use of a topical retinoid. ment of topical and hormonal therapies
In some cases, a patient with acne that are effective for both initial and
may improve with the Pill but still ex- long-term maintenance therapy.
4 Contemporary Treatment Approaches to Acne and Psoriasis
SA-Connetics 1/31/05 3:54 PM Page 5
New Developments in Therapy
for Acne Vulgaris: A Preview
Lee T. Zane, MD
The pathogenesis of acne vulgaris troduction of new derivatives of ahead of rapidly changing bacterial re-
includes four important patho- retinoids and modulators of retinoid sistance patterns. New introductions
physiologic factors1: 1) altered metabolism. New topical derivatives of within the antibiotic/immunomodulato-
growth and differentiation of follicular 13-cis-retinoic acid (isotretinoin), and ry class push the limits of antimicrobial
keratinocytes, 2) increased sebaceous 9-cis-retinoic acid (alitretinoin) are in technology and offer different ways of
gland size and activity, 3) follicular development, along with a modified thinking about antibiotic activity. In this
colonization with Propionibacterium tretinoin molecule designed with the class of new therapies, clinicians can
acnes, and 4) an inflammatory and im- goal of being less irritating. anticipate new vehicles of delivery,
mune response. Acne therapies target An exciting new entry into the novel compounds, and innovative ap-
any or all of these factors. This article retinoid group is a novel class of mole- proaches to minimizing bacterial colo-
will offer a preview of some new acne cules called retinoic acid metabolism nization and reducing the inflammatory
treatments that are either recently ap- blocking agents (RAMBAs). These response.
proved or seeking approval by the US agents decrease retinoid metabolism, In the antibiotic subgroup, a clin-
Food and Drug Administration (FDA). thereby maintaining higher therapeutic damycin product delivered in a novel
These treatments may contain novel levels of endogenous retinoic acid. One foam vehicle will offer the ability to
compounds or novel ways to deliver RAMBA has received FDA orphan spread easily and cover large surface
compounds and fall into four major drug status for the treatment of congen- areas. In addition to aiding in the treat-
classes: retinoids, antibiotic/immuno- ital ichthyosis, although its application ment of acne, this product could poten-
modulatory agents, combination prod- in the treatment of acne is inviting. tially be useful in the treatment of folli-
ucts, and laser/light therapy (Table). culitis in non-acne-prone areas as well.
Antibiotic/ A traditionally oral antibiotic, dap-
Retinoids Immunomodulatory Agents sone, will soon be introduced in topical
In addition to new strengths and for- Practitioners and scientists wage a form. Dapsone's antimicrobial and anti-
mulations of existing retinoids, practi- seemingly unending war against antibi- neutrophilic activities are well known.
tioners can also look forward to the in- otic resistance, trying to stay one step This novel formulation introduces an
innovative gel technology that can topi-
Table.New Acne Treatments Anticipated cally deliver highly water-insoluble
compounds that had previously been
Antibiotics Laser and Light
✦ Clindamycin in a foam vehicle ✦ Short-wave-length (400 to 420 nm) relegated to systemic delivery only.
✦ Dapsone in topical form light (highly absorbed by porphyrins in Expanding the way we think about
✦ Antimicrobial cationic peptide P. acnesto produce antimicrobial action) antibiotic therapy is a new class of an-
✦ Synthetic peptide compound derived ✦ Longer-wave-length (870 to 1200 nm) timicrobial peptides. These short pro-
from bactericidal-permeability-increasing light (believed to penetrate deeper to
protein affect sebaceous gland growth and teins often mimic endogenous defense
secretory activity) peptides to elicit their antibacterial ef-
✦ Blue light, 417 nm
Antiinflammatory/ fects. Two highly anticipated agents in
Immunomodulatory Agents ✦ Narrow-band (405 to 420 nm)
✦ Zileuton in oral form ✦ Light-emitting-diode (LED) blue-light this class are a novel antimicrobial
✦ Pyridine carboxylate compound arrays cationic peptide as well as a synthetic
✦ Intense pulsed-light therapy peptide compound derived from bacte-
Combination Therapy ricidal-permeability-increasing protein.
Photodynamic Therapy
✦ Clindamycin 1% plus tretinoin 0.025% In the antiinflammatory/immuno-
gel ✦ Lemuteporfin + visible-light stimulation
modulatory subgroup, the asthma med-
✦ Other clindamycin/retinoid combinations
✦ Tetracycline derivative/retinoid Retinoids ication zileuton is being investigated in
combinations ✦ Topical derivatives of 13-cis-retinoic an oral formulation for the treatment of
acid (isotretinoin) and 9-cis-retinoic
acne. Zileuton is a 5-lipoxygenase in-
acid (alitretinoin)
✦ Modified tretinoin molecule hibitor that blocks the formation of
✦ Retinoic acid metabolism blocking agents leukotrienes from arachidonic acid, thus
(RAMBAs) modulating the inflammatory response.
Contemporary Treatment Approaches to Acne and Psoriasis 5
SA-Connetics 1/19/05 3:08 PM Page 6
In addition, a novel pyridine carboxy- er, ideally targeting the pilosebaceous glands that is specific to skin, 2) antibi-
late that binds zinc in zinc finger pro- unit, is followed by stimulation with otic-independent mechanisms for re-
teins is under development. This agent visible light, leading to selective dam- ducing P. acnes colonization, 3) target-
appears to have both antiviral and im- age to sebaceous glands. While ed antiandrogen therapy for skin, 4) an
munomodulatory activity in addition to aminolevulinic acid (ALA) PDT, the agent with the efficacy of oral
being highly active againstP. acnes. first entry into this market, has demon- isotretinoin but free of its noncutaneous
strated efficacy, it unfortunately ap- effects, and 5) the “single-dose, one-
Combination Agents pears to lack good specificity for folli- time magic bullet” that cures acne for
The predominant theme in the combi- cles, causing damage to interfollicular life. The hope here is that the quest for
nation class is the pairing of antibiotics skin.2 these “ideal agents” will cultivate in-
with retinoids. This combination strate- ventiveness in therapeutic mechanisms,
gy not only offers the convenience of a stimulate innovation in drug design,
“All of these
single application for two active agents, and foster creativity in drug delivery.
it may also improve antibiotic penetra- therapies offer
tion and efficacy through the aid of Conclusion
practitioners new options
retinoid action on keratinocytes. While The emerging therapies discussed
for treating the
several such combination products are here exemplify innovation in acne ther-
anticipated, one of the first entries ex- millions of patients apy in a number of different ways.
pected in this class is a clindamycin 1% Some employ modifications to existing
worldwide with acne
plus tretinoin 0.025% gel. Other entries agents to increase efficacy, enhance
are likely to pair one of the retinoids and underscore the ease of use, or improve methods of de-
with either clindamycin or a tetracy- livery, while others hope to gain thera-
great need for
cline derivative. peutic synergy by combining agents to-
creativity and innovation
gether. New approaches, novel com-
Laser, Light and in shaping the future of pounds, and innovative technologies
Photodynamic Therapy will hopefully push the field of acne
acne treatment.”
In the use of laser and light in the therapeutics in new directions. These
treatment of acne, the proposed mecha- new therapies may offer practitioners
nisms of action include the use of short new options for treating the millions of
wave lengths (400 to 420 nm), which A new photosensitizing agent, lemute- patients worldwide with acne and serve
are highly absorbed by porphyrins in porfin, is currently being investigated to underscore the great need for contin-
P. acnes, to produce antimicrobial ac- for its use in acne. Preliminary, unpub- ued creativity and ingenuity in shaping
tion, and longer wave lengths (870 to lished data from experiments in mice the future of acne therapy.
1200 nm) which are believed to pene- suggest that lemuteporfin may elicit a
trate deeper to affect sebaceous gland PDT response that is more specific to References
growth and secretory activity. sebaceous glands.
1. Gollnick H, Cunliffe W, Berson D, et al.
In addition to the 417-nm blue light Management of acne: A report from a
and 405- to 420- nm narrow-band light Unmet Needs Global Alliance to Improve Outcomes in
products being developed, the intro- As these new therapies are intro- Acne. J Am Acad Dermatol. 2003;49(1
suppl):S1-S37.
duction of light-emitting-diode (LED) duced, clinicians will need to deter-
blue-light arrays and intense pulsed- mine where each one fits into their in- 2. Hongcharu W, Taylor CR, Chang Y, Aghassi
D, Suthamjariya K, Anderson RR. Topical
light therapy is anticipated. There is dividual treatment algorithms for acne.
ALA-photodynamic therapy for the treat-
also speculation that an intense pulsed- However, despite the great benefits of-
ment of acne vulgaris. J Invest Dermatol.
light unit for home use may be under fered by the therapies discussed here, 2000;115:183-192.
development. important needs remain unmet in the
In photodynamic therapy (PDT) for field of acne treatment technology, in-
acne, the application of a photosensitiz- cluding: 1) an inhibitor of sebaceous
6 Contemporary Treatment Approaches to Acne and Psoriasis
SA-Connetics 2/1/05 11:43 AM Page 7
The Role of Oral Retinoid Treatment
for Psoriasis in the Age of Biologics
John Y. M. Koo, MD
The educational programs aimed biologic therapies. Except for concerns dosages have led some clinicians to
at clinicians who treat psoriasis regarding possible hepatotoxicity in abandon oral retinoid use. However, this
are currently—quite appropri- combination with methotrexate, oral does a disservice to patients because
ately—focused on the newest therapies, retinoids are essentially without risk oral retinoid treatment has great value as
the biologic agents. The biologic agents for important drug interactions. a therapeutic enhancer for virtually
represent hope for patients with psoria- Patients who are given higher do- every other psoriasis therapy in use
sis who have suffered for years without sages of acitretin are likely to experi- today, from the phototherapies to the bi-
adequate relief. However, clinicians ence side effects such as dry skin, ologics.
should not draw the conclusion that cracked lips, hair loss, gastrointestinal Oral retinoid treatment plus a biolog-
the prebiologic agents—including complaints (including bloating and di- ic agent is a natural combination.
topical medications, phototherapy, cy- arrhea), and musculoskeletal aches and Although the biologic agents currently
closporine, methotrexate, and oral pains. Although these side effects are approved by the FDA for the treatment
retinoids—have become obsolete. To not serious, they are bothersome and of psoriasis—etanercept, efalizumab,
the contrary, the prebiologic agents are cause additional distress to patients and alefacept—have demonstrated rea-
and will continue to be extremely use- who are already uncomfortable from sonable efficacy in clinical trials, none
ful, and the biologics should take their their psoriasis. works as well as cyclosporine or PUVA.
proper place among these other medica- Many patients on biologic therapy are
tions. Among the prebiologics, the oral Combination Therapy left with residual psoriatic plaques.
retinoids are a safe and effective option Oral retinoid monotherapy is associ- Vitamin A type medications—that is,
for many patients, particularly when ated with a slow and often incomplete the retinoids—improve skin psoriasis
used in combination, sequential, and response. It is highly effective in the by enhancing cell maturation and dif-
maintenance strategies with other resolution of scaling and thick plaques, ferentiation. The result of improved
agents. (Figure) but is less effective for eradi- maturation and differentiation is
cating erythema. The slow onset of ac- desquamation and, consequently, a flat-
Optimal Use of Oral tion, incomplete resolution of erythe- tening of plaques. Most importantly,
Retinoid Therapy ma, and annoying side effects at higher oral retinoids are not immunosuppres-
Oral retinoid treatment should be sive, an important benefit for combina-
given in low doses, either in combina- tion treatment. Because the biologic
Figure.Widespread Erythema
tion, sequential, or maintenance treat- and Scaling agents downregulate the immune sys-
ment regimens. Acitretin (the only oral tem, it is theoretically (and probably
retinoid currently approved for use in clinically) safer to avoid doubling up on
psoriasis by the US Food and Drug immunosuppressants.
Administration [FDA]*) is well tolerat- Oral retinoid treatment also is the
ed by most patients at dosages of 25 best therapy available for enhancing
mg/day or less. (Patients older than 65 phototherapy. Extensive evidence
years of age may better tolerate even shows that UVB and PUVA work about
lower dosages, such as 25 mg every twice as well if a patient is taking
other day or 10 mg/day.) Furthermore, 25 mg/day of acitretin1 simultaneously
oral retinoid therapy can be combined so lower doses of light can be used.
with practically all other psoriasis treat- Anecdotal experience in our center (as
ments—including ultraviolet B (UVB) well as that of many experts) is that
phototherapy, psoralen–ultraviolet-light even topical agents seem to work better
(PUVA) therapy, topical treatments, and in patients taking acitretin. It makes
The large body surface area affected sense that this would be so, because
makes topical therapy impractical in this
*Oral tazarotene has demonstrated efficacy patient with psoriasis.Oral retinoid when acitretin eliminates scales and
in psoriasis, but it has not been approved by therapy—alone or in combination with flattens psoriatic plaques, topical med-
other agents—may be helpful.
the FDA. ications can better penetrate the skin.
Contemporary Treatment Approaches to Acne and Psoriasis 7
SA-Connetics 1/26/05 3:29 PM Page 8
Sequential Therapy Oral retinoid treatment is an impor- to remember that the prebiologic
In patients who are in psoriatic tant element in this model, particularly agents maintain a useful place in that
crisis—experiencing a severe flare of for long-term use. According to an ex- spectrum of options.
their disease, involving rapid spread of tensive 10-year review of the available Oral retinoid monotherapy has two
inflammation and discomfort—sequen- disadvantages: relatively slow onset of
tial therapy should be considered. This action and possibly an incomplete re-
is a strategy involving three overlapping “...although we embrace sponse (chiefly, residual erythema). In
steps: step 1, clearance; step 2, transi- addition, excessive dosing can result in
the importance
tion; and step 3, maintenance. a range of annoying side effects at high
and utility of
An example of such a treatment doses. However, when oral retinoid
regimen is the administration of cy- the biologics, it is therapy is combined with other psoria-
closporine or methotrexate to bring the sis treatments—that is, as a therapeutic
crucial to remember
flare under rapid control. This is fol- enhancer—its value is clear. Oral
lowed by the addition of acitretin, the that the prebiologic retinoid treatment appears to enhance
dosage of which is optimized and maxi- agents maintain a all of the therapies—including pho-
mized before cyclosporine or metho- totherapy, topical agents, and systemic
useful place in
trexate is gradually and slowly tapered treatments such as the biologics.
off. This combination would be contin- that spectrum In the schema described, oral retinoid
ued for 1 to 3 months to prevent recur- therapy is an important “turtle” in the
of options.”
rence of a flare as cyclosporine or turtle-stacking model. Even the biologic
methotrexate administration is tapered agents often are not fully satisfactory to
and discontinued. After this transition the patient as monotherapy, and because
period—and once the patient is com- literature,2acitretin therapy is known to oral retinoid therapy is not immunosup-
pletely off cyclosporine or methotrex- be associated with a significantly pressive, it is a natural partner to en-
ate—treatment with acitretin, alone or in longer remission time than is either cy- hance the action of biologic agents.
combination with UVB and/or PUVA, closporine or methotrexate. Among the Lastly, at least theoretically, the com-
may be continued as maintenance (or an- currently approved biologic agents, ale- bination use of oral retinoid therapy
other safe regimen can be used instead). facept has a long remission time, but and a biologic agent may: (1) reduce the
If phototherapy is not available or only in the minority of patients who possible long-term neoplastic risk that
feasible, another safe, long-term agent, achieve at least a 75% improvement in may be associated with the biologics
such as etanercept, can be used in com- the Psoriasis Area and Severity Index; because of the chemopreventive effects
bination with acitretin. etanercept has a reasonable remission of the retinoid on both cutaneous and
One way to conceptualize the opti- time but one that probably is shorter systemic malignancies, (2) maximize
mum maintenance combination therapy than that of acitretin; and efalizumab the chance for synergy in efficacy be-
is a model I have labeled “turtle stack- has a short remission time, complicated cause these classes of agents have very
ing.” In this model, fast-acting but po- by the risk for rebound. different mechanisms of action, and (3)
tentially toxic agents such as cy- reduce costs by making higher mainte-
closporine are characterized as “rab- Conclusion nance doses of biologics unnecessary.
bits,” whereas the safer agents—includ- The advent of biologic agents has
ing all of the currently approved biolog- provided significant treatment bene- References
ics, acitretin, and UVB phototherapy— fits to many patients, and they repre-
1. Lebwohl M, Menter A, Koo J, Feldman SR.
are described as “turtles.” The idea of tur- sent a welcome addition to the range Combination therapy to treat moderate to
tle stacking is to maximize efficacy while of treatment options the clinician has severe psoriasis. J Am Acad Dermatol.2004;
using only the safer “turtle” agents. to offer those who suffer from moder- 50:416-430.
Thus, two or even three turtles might be ate to severe psoriasis. However, al- 2. Koo J, Lee BS, Lee CS, Lebwohl M. Psor-
stacked to maximize efficacy and still though we embrace the importance iasis. J Am Acad Dermatol.2004;50:613-622.
maintain a safe side effect profile. and utility of the biologics, it is crucial
8 Contemporary Treatment Approaches to Acne and Psoriasis
SA-Connetics 1/19/05 3:09 PM Page 9
Advances in Combination
Topical Therapy for Psoriasis
Linda F. Stein Gold, MD
Psoriasis has a chronic and often (UVB) light exposure, and active noids, which target keratinocytes, act-
unpredictable course. The goal of vitamin D—calcitriol—regulates the ing to modulate the major causes of
therapy is always to use the least body's levels of calcium. In psoriasis, psoriasis. Tazarotene is rapidly metabo-
potent medication to achieve the de- calcitriol inhibits keratinocyte prolifer- lized by esterase to tazarotenic acid;
sired efficacy while minimizing poten- ation and induces terminal differentia- thus, the drug's elimination half-life is
tial toxicity. Topical therapy, although tion in vitro. An individual patient’s short, 1 to 2 hours. Tazarotene is classi-
the cornerstone of treatment for mild response to calcitriol varies with the fied as a pregnancy category X drug,
disease, also has an important place in state of the disease and the number of but it demonstrates no significant tissue
the treatment of patients with moderate vitamin D receptors in psoriatic ker- accumulation.
to severe psoriasis as well (Figure). atinocytes. (Vitamin D receptors are The pivotal trials leading to FDA ap-
Topical therapy adds significant benefit increased in patients with psoriasis.) proval of tazarotene for the treatment of
when incorporated into combination The topical drug calcipotriene, an ana- psoriasis demonstrated good efficacy
regimen with phototherapy or systemic log of calcitriol, acts via the same re- and safety. The side effects observed
agents for more resistant lesions. ceptors as does calcitriol but is 100 with tazarotene—chiefly, pruritus, burn-
Currently, three main topical treat- times less calciotropic. ing, and irritation—were consistent
ments commonly are used for psoriasis: Calcipotriene is as effective as cal- with those expected with topical
corticosteroids, calcipotriene, and taza- citriol in inducing cell differentiation retinoids.2
rotene, agents that are all well known and inhibiting proliferation of ker- In a comparative trial versus fluoci-
to dermatologists. In addition, pime- atinocytes in vitro. Calcipotriene mono- nonide,3 tazarotene demonstrated com-
crolimus and tacrolimus, currently indi- therapy has been shown to be as effec- parable efficacy. The incidence of re-
cated by the US Food and Drug Admin- tive as a high-potency corticosteroid lapse was 55% for 0.05% fluocinonide
istration (FDA) for the treatment of and to maintain efficacy in long-term versus 37% for 0.05% tazarotene and
atopic dermatitis, are being investigated use in patients with chronic plaque 18% for tazarotene 0.1%. (The differ-
for use in psoriasis. psoriasis.1 ence between fluocinonide and the
Tazarotene was the first topical 0.1% concentration of tazarotene was
Modes of Action of retinoid developed for the treatment of significant, P<0.01.)
Traditional Agents psoriasis. It is one of a class known as Topical immunomodulators. Tacro-
Corticosteroids are the most com- retinoic acid receptor-specific reti- limus and pimecrolimus, approved by
monly used topical agents for psoriasis. the FDA for the treatment of atopic der-
These range in potency from mild Figure.Plaque Psoriasis on Elbow matitis, also have been studied in psoria-
(class 7) to superpotent (class 1). Top- sis.4To date, a number of clinical studies
ical corticosteroids work by altering have demonstrated that these agents hold
DNA synthesis and gene transcription, promise for facial and inverse psoriasis.
directly inhibiting inflammatory cells,
and inhibiting mediators of inflamma- The Importance
tion. The potency of topical agents is re- of the Vehicle
lated to skin thickness, hydration, and The vehicle is important in deter-
temperature, as well as to the halogena- mining biologic activity, and numerous
tion of the parent compound and the ve- studies have shown that wide varia-
hicle used to deliver the active agent. tions in drug penetration can occur de-
Despite good efficacy achieved with pending on the vehicle used (Table on
these agents, clinicians tend to avoid Page 10). The drug must be soluble in
prolonged use of potent and superpo- the vehicle to be effective, and increas-
tent corticosteroids because of the risk ing the concentration of the drug may
This patient has a sharply demarcated,
of adverse effects such as skin atrophy. erythematous lesion.Effective topical not increase efficacy. In considering a
Calcipotriene. The skin makes vita- therapy requires adequate penetration of vehicle, the importance of patient ac-
medication through this thick plaque.
min D in response to ultraviolet-B ceptance also cannot be overlooked as
Contemporary Treatment Approaches to Acne and Psoriasis 9
SA-Connetics 1/26/05 3:34 PM Page 10
this is essential for comfort, conve- halobetasol ointment each evening for 2 one of the few drugs that does not in-
nience, and, therefore, compliance. weeks. Those who showed a 50% im- teract with and inactivate calcipotriene.
Under ideal circumstances, compli- provement were randomly assigned to Foam-based clobetasol was compared
ance with topical therapy is, at best, one of two groups: calcipotriene twice with clobetasol solution in randomized
probably about 50%. Over the course daily on weekdays plus halobetasol clinical efficacy trials, vasoconstrictor
of an 8-week study, Carroll and col- twice daily on weekends or placebo assays, and in vitro penetration studies.9
leagues5 found that compliance fell twice daily on weekdays and halobeta- The investigators found that clobetasol
from 85% to 51%, as determined by sol twice daily on weekends. in the foam vehicle yielded higher pen-
electronic monitoring caps. etration, more potent vasoconstriction,
and greater clinical efficacy than did
“In considering a vehicle,
Tazarotene/ clobetasol solution.
Corticosteroid Combination the importance of patient To evaluate the efficacy of 0.005%
The efficacy and safety of tazarotene calcipotriene ointment and 0.05% clo-
acceptance also cannot be
plus corticosteroid therapy was eval- betasol foam, Blum and coworkers10
uated in an investigator-masked, ran- overlooked as this is conducted a 24-week randomized, dou-
domized 12-week study involving the essential for comfort, ble-blind, vehicle-controlled, prospec-
retinoid plus a variety of strengths of tive trial in 86 patients with mild to
convenience, and,
corticosteroid creams.6 In this study, moderate psoriasis on the trunk and
300 patients applied tazarotene 0.1% therefore, compliance.” extremities. The subjects were random-
once each evening. Subjects were ran- ized in a 2:1:1 ratio to one of three
domly assigned to apply one of the groups: clobetasol foam and calcipo-
following each morning: a low-, medi- Out of the original 44 subjects, 40 re- triene ointment combination, clobetasol
um-, or high-potency corticosteroid mained. These patients were random- foam alone, or calcipotriene ointment
cream, or placebo cream. The invest- ized equally to two double-blind treat- alone.
igators concluded that all of the ment groups to continue in the mainte- At the end of 2 weeks, the target
tazarotene/corticosteroid combinations nance phase of the study for 6 months. lesions were evaluated for erythema,
were more effective than was tazarotene At the end of that time, the investigators induration, and scaling, using the
monotherapy. reported that 40% of patients in the Psoriasis Grading Scale, and investiga-
Other studies have confirmed the placebo/halobetasol group remained in tor and subject evaluations were per-
benefits of tazarotene/corticosteroid remission versus 76% of those in the formed using the Global Severity
combination therapy.7 A number of calcipotriene/halobetasol group. Assessment of Psoriasis. The evaluation
studies have demonstrated the efficacy Innovations to enhance the penetra- of trunk lesions at week 2 showed a
of combining tazarotene with pho- tion and, therefore, the efficacy of topi- mean percent reduction in erythema, in-
totherapy, particularly UVB. cal combination agents for psoriasis in- duration, and scaling of 69.3% in the
clude the use of new vehicles, including subjects using combination therapy. In
Calcipotriene/ foam. One particularly interesting com- contrast, those who used clobetasol
Corticosteroid Combination bination is calcipotriene plus clobeta- foam alone had a 48.1% reduction and
In a landmark study evaluating the ef- sol; the high-potency corticosteroid is those who used calcipotriene ointment
ficacy and safety of the combined use
of calcipotriene and the superpotent Table.New Developments in Combination Topical Therapy for Psoriasis
corticosteroid halobetasol, Lebwohl
and colleagues8 demonstrated that the The following combinations are being studied using corticosteroids in foam vehicles:
combination was superior to monother- ✦ Calcipotriene/clobetasol
apy with either agent. In this double- ✦ Pimecrolimus/betamethasone*
blind, placebo-controlled, parallel-
✦ Tacrolimus/betamethasone*
group study, patients applied cal-
* Pimecrolimus and tacrolimus have been studied in but are not yet approved for patients with psoriasis.
cipotriene ointment each morning and
10 Contemporary Treatment Approaches to Acne and Psoriasis