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Volume 9 • Number 10 • December 2004 - January 2005
Indexed by the US National Library of Medicine and PubMed
EDITOR-IN-CHIEF
Stuart Maddin, MD
University of British Columbia, Vancouver, Canada
ASSOCIATE EDITORS
Etanercept (Enbrel)–An Update
B. Goffe, MD
Hugo Degreef, MD, PhD - Medical Dermatology
Catholic University, Leuven, Belgium
Jason Rivers, MD - Medical Dermatology
Department of Dermatology, University of Washington Medical School, Seattle, WA, USA
University of British Columbia, Vancouver, Canada
Jeffrey S. Dover, MD - Surgical Dermatology
Yale University School of Medicine, New Haven, USA
Dartmouth Medical School, Hanover, USA
ASSISTANT ASSOCIATE EDITOR
Murad Alam, MD - Surgical Dermatology
Northwestern University Medical School, Chicago, USA
EDITORIAL ADVISORY BOARD
Kenneth A. Arndt, MD
Beth Israel Hospital
Harvard Medical School, Boston, USA
Wilma Fowler Bergfeld, MD
ABSTRACT
Etanercept is a tumor necrosis factor antagonist with anti-inflammatory effects. It is
currently approved in the US for psoriasis, psoriatic arthritis, ankylosing spondylitis,
rheumatoid arthritis and juvenile rheumatoid arthritis. Clinical trials have shown this agent
to have an excellent safety profile and to be well tolerated by both adult and pediatric
patients.
Key words: etanercept, Enbrel®, psoriatic arthritis, TNF-alpha, psoriasis
Cleveland Clinic, Cleveland, USA
Jan D. Bos, MD
University of Amsterdam, Amsterdam, Holland
Enno Christophers, MD
Universitäts-Hautklinik, Kiel, Germany
Richard L. Dobson, MD
Medical University of South Carolina, Charleston, USA
Boni E. Elewski, MD
University of Alabama, Birmingham, USA
Barbara A. Gilchrest, MD
Boston University School of Medicine, Boston, USA
W. Andrew Griffiths, MD
St. John’s Institute of Dermatology, London, UK
Aditya K. Gupta, MD, PhD
University of Toronto, Toronto, Canada
Vincent C. Y. Ho, MD
University of British Columbia, Vancouver, Canada
Mark Lebwohl, MD
Mt. Sinai Medical Center, New York, USA
James J. Leydon, MD
University of Pennsylvania, Philadelphia, USA
Harvey Lui, MD
University of British Columbia, Vancouver, Canada
Howard I. Maibach, MD
University of California Hospital, San Francisco, USA
Larry E. Millikan, MD
Tulane University Medical Center, New Orleans, USA
Takeji Nishikawa, MD
Keio University School of Medicine, Tokyo, Japan
Constantin E. Orfanos, MD
Freie Universitäts Berlin
Universitätsklinikum Benjamin Franklin, Berlin, Germany
Alan R. Shalita, MD
SUNY Health Sciences Center, Brooklyn, USA
Richard Thomas, MD
University of British Columbia, Vancouver, Canada
Stephen K. Tyring, MD, PhD, MBA
University of Texas Health Science Center, Houston, USA
John Voorhees, MD
University of Michigan, Ann Arbor, USA
Klaus Wolff, MD
University of Vienna, Vienna, Austria
MANAGING EDITOR
Penelope Gray-Allan
Etanercept (Enbrel®, Amgen) is a recombinant human protein with anti-inflammatory
properties that was the first approved treatment for psoriatic arthritis by the US FDA in
January 2002. It was approved by TPP Canada in January 2004 for the same indication.1-3
In May 2004, the US FDA approved this drug for the treatment of adult patients with
chronic moderate-to-severe plaque psoriasis who are candidates for systemic therapy or
phototherapy. In September 2004, the European Union approved it for the treatment of
adult patients with moderate-to-severe plaque psoriasis who failed to respond to, or have
a contraindication to, or are intolerant of other systemic therapies. Also in September 2004,
the US FDA approved a new dosing form: a 50mg/ml prefilled syringe, which will allow
most patients to take only one injection per week instead of two. Additional indications for
etanercept include the treatment of rheumatoid and polyarticular-course juvenile
rheumatoid arthritis (RA and JA respectively), and ankylosing spondylities. In RA the
clinical responses to etanercept have been maintained for up to 7 years in clinical trials.4
Tumor necrosis factor (TNF) is a proinflammatory cytokine that has been strongly
implicated in the pathogenesis of psoriasis and psoriatic arthritis, and plays a key role in
the activation of innate and acquired immune responses. An inappropriate production of
this cytokine is seen in psoriasis and psoriatic arthritis, which can lead to chronic
inflammation, tissue damage and excessive keratinocyte proliferation. The downstream
effects of excessive TNF production on various cell types and the clinical manifestations
relevant to psoriasis and psoriatic arthritis are summarized in Table 1. Currently there are
three TNF-alpha inhibitors available in the US – one receptor fusion protein (etanercept),
and two monoclonal antibodies (infliximab and adalimumab).
Mechanism of Action
Etanercept inhibits TNF activity by competitively binding to it and preventing interactions
with its cell surface receptors. Elevated levels of TNF have been found in psoriatic skin
lesions, and in synovial explants and fluid from patients with psoriatic arthritis.5-7
Furthermore, TNF levels in the serum of patients with plaque psoriasis,8 and in blister
fluids of involved psoriatic skin9 have also been shown to be higher than in those of
controls. These values were significantly correlated with the psoriasis area and severity
index (PASI) scores, and TNF levels were reduced in association with clinical resolution
after effective treatment.8
Cell Type
Action of TNF
Effect
Macrophage
• Increased proinflammatory cytokine production
• Increased chemokine production
• Increased inflammation
• Swelling of joints
Keratinocyte
• Increased proliferation
• Scale and thickness
Endothelial
• Increased expression of adhesion molecules
• Increased production of VEGF (vascular
endothelial growth factor)
• Increased leukocyte infiltration
into skin and joints
• Increased angiogenesis and erythema
• Auspitz sign
Hepatocyte
• Increased acute phase response
• Increased C-reactive protein
Synoviocyte (fibroblast-like)
• Increased metalloproteinase synthesis
• Articular cartilage degradation
T-lymphocyte
• Increased proinflammatory cytokine production
• Increased nuclear transcription factor activation
• T cell activation
• Increased inflammation
Dendritic cell
• Increased proinflammatory cytokine production
• Dendritic cell maturation
• Increased dendritic cell migration from skin to
lymph nodes
• T-cell activation and differentiation
• Increased inflammation
Table 1: Effects of Excessive TNF Production on Various Cell Types*
*Reprinted with permission from the Journal of the American Academy of Dermatology, V49(2 suppl):S105-S111.
Goffe B, Cather C: “Etanercept: An Overview,” © 2003 American Academy of Dermatology.
The production of chemokines, and the expression of
adhesion molecules by keratinocytes and vascular endothelial
cells can be stimulated by TNF produced within psoriatic
lesions. These signals then cause recruitment of additional
inflammatory cells into the plaque. Krueger suggests that TNF
may function as part of a positive feedback loop, which acts to
amplify and sustain the inflammatory process within psoriatic
plaques.10 Biologic responses that are induced or regulated by
TNF are modulated by etanercept. It may, therefore, serve to
reduce inflammation within plaques by breaking this cycle.
Clinical Studies
A 24-week, multicenter, double-blind, randomized, placebocontrolled, phase III trial studied etanercept as a monotherapy in
moderate-to-severe psoriasis. Six-hundred-fifty-two patients
with chronic, stable plaque psoriasis over ≥10% of their body
surface area who had previously received or been candidates for
phototherapy or systemic psoriasis therapy were enrolled. All
systemic psoriasis therapies were discontinued within 4 weeks
of the first dose of the study drug.11
Patients received 50mg etanercept subcutaneously (SC) twice
weekly (n=164), 25mg etanercept SC twice weekly (n=162),
25mg etanercept SC once weekly (n=160), or placebo SC
twice weekly (n=166). Forty-nine percent of patients in the
50mg etanercept twice weekly group achieved at least a 75%
improvement in the PASI score (PASI 75) at 12 weeks,
compared with 4% of placebo-treated patients (p<0.001).
Efficacy continued to improve with longer treatment: 59% of
2
the etanercept 50mg twice weekly patients reached PASI 75 at
24 weeks of treatment. Statistically significant improvements
in patient global, physician global, and quality of life as
assessed by the Dermatology Life Quality Index (DLQI)
confirmed the efficacy of etanercept therapy. Etanercept was
well tolerated.
In another phase III monotherapy trial,3 46% of patients
receiving etanercept 50mg twice weekly achieved >PASI 75 at
12 weeks, compared with 3% of placebo-treated patients
(p<0.0001). The majority of patients who achieved a PASI 75
in the 50mg biweekly arm continued treatment in an openlabel extension where their etanercept dose was reduced to
25mg biweekly. At week 24, 77% had maintained their PASI
75 response using half of the original dose.
Etanercept in Psoriatic Arthritis
For adults with psoriatic arthritis and/or rheumatoid arthritis,
the recommended dose of etanercept is 50mg administered SC
once weekly using a 50mg/ml single-use pre-filled syringe.3 It
may be used as monotherapy or concomitantly with
methotrexate (MTX).
In a phase II, randomized, double-blind, placebo-controlled
12-week study, the efficacy and safety of 25mg twice-weekly
subcutaneous injections of etanercept or placebo was assessed
in 60 adult patients with psoriatic arthritis.1 The study
endpoints for psoriatic arthritis included the proportion of
patients who met the Psoriatic Arthritis Response Criteria
(PsARC) and American College of Rheumatology 20%
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005
criteria (ACR20) for improvement in the number of tender and
swollen joints, as well as patient and physician assessments.
The endpoints for psoriasis were a 75% improvement in the
PASI score, and improvements in prospectively identified
individual target lesions (≥2cm in diameter). The etanercepttreated group had statistically better outcomes for all clinical
psoriatic arthritis endpoints. At 12 weeks, 87% of the
etanercept-treated patients achieved the PsARC compared
with 23% of patients receiving placebo (p<0.0001). The
ACR20 was achieved by 73% of etanercept and 13% of
placebo treated patients (p<0.0001).1
Etanercept also improved the psoriasis skin lesions in this trial.
The median target lesion response was 50% in the etanercept
group compared with 0% in the placebo group (p=0.0004).
There were 19 patients in each treatment group who met the
criterion of ≥3% of body surface involvement and were
eligible for evaluation for psoriasis using the PASI score. At 12
weeks, 26% of the etanercept, and 0% of the placebo-treated
patients had achieved a 75% improvement in the PASI
(p=0.0154).1
An open label extension of this study demonstrated that
treatment with etanercept allowed statistically significant
reduction of concomitant MTX and/or steroid doses, and
discontinuation of MTX and/or steroids in 25% and 44% of
patients respectively.12
The results of this study were confirmed in a larger, 205 patient,
multicenter, randomized, double-blind, placebo-controlled
phase III trial of the efficacy and safety of etanercept in psoriatic
arthritis.2 Arthritis was significantly improved with etanercept
treatment. ACR 20 was achieved by 59% of the etanercept
group and 15% of the placebo group at 12 weeks (p<0.0001).
Significant improvement in arthritis was maintained with
continued etanercept treatment through the end of the study at
24 weeks. Results from the subset of patients who were
evaluated using PASI showed a median improvement of 47% in
All Treatment Groups at Week-12
Placebo Group
(n=166)
Type of Event
Injection-site reaction
Headache
Upper respiratory infection
Injection-site ecchymosis
Asthenia
Myalgia
Accidental injury
Sinusitis
Nausea
Rash
12 (7)
11 (7)
19 (11)
6 (4)
5 (3)
4 (2)
7 (4)
1 (1)
2 (1)
4 (2)
patients receiving etanercept while a median 0% improvement
was seen in those receiving placebo (p<0.0001).12
Etanercept Administration
Etanercept is supplied as a lyophilized powder (25mg to a vial)
which requires reconstitution with sterile bacteriostatic water,
which is also included. The administration is similar to that of
insulin or SC methotrexate and can be easily taught to patients
in a dermatology office setting. All patients are required to
have regular follow-up visits while taking this medication.
Ethanercept is now also available as a 50mg/ml single-use
prefilled syringe. Prior to therapy, lab work that includes a
baseline HIV, hepatitis panel, tuberculin skin test, ANA,
comprehensive metabolic panel, and a complete blood count
is reccomended. Thereafter, lab work may be done when
deemed necessary. During therapy, patients are not allowed to
be immunized with live virus vaccines. Etanercept may safely
be given to patients who are already receiving MTX, as per the
package insert. The cost for a 4-week supply of medication is
approximately $1,100.00 USD.
Safety
Klareskog, et al. reported results of a long-term safety study of
etanercept in 2,054 patients from North America and Europe.13
In the long-term follow-up group, the rates of infection
requiring hospitalization or intravenous antibiotics were 0.04
events per patient-year, which is comparable to the rates seen in
the placebo-control group during the double-blind portion of
the trials.
However, it should be noted that postmarketing reports have
included accounts of serious infections and sepsis, including
fatalities with the use of etanercept. Even so, in the arthritis
clinical trials, numerous patients were on concomitant
methotrexate and/or prednisone without any increased risk of
infection. Caution should be used when considering
etanercept for patients with a history of recurring infections,
Low-Dose Etanercept Medium-Dose Etanercept High-Dose Etanercept
Group (25mg q.w.)
Group (25mg b.i.w.
Group (50mg b.i.w.)
(n=160)
(n=162)
Number of Patients (Percent)
17 (11)
28 (17)
5 (3)
19 (12)
16 (10)
15 (9)
11 (7)
4 (2)
7 (4)
6 (4)
3 (2)
6 (4)
6 (4)
5 (3)
0
0
5 (3)
4 (2)
4 (3)
4 (2)
(n=164)
22 (13)
11 (7)
9 (5)
8 (5)
3 (2)
3 (2)
7 (4)
0
3 (2)
5 (3)
Table 2: Adverse events occurring in at least 5% of patients in any treatment group.11
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005
3
and etanercept should not be administered to patients with
sepsis or active infections, including chronic or localized
infections.3 Patients who are on concomitant
immunosuppressive therapies, or patients who may be
predisposed to infections may have a greater risk of infection
when they are given etanercept.
Patients who have had a significant exposure to varicella and
have no immunity to this condition should temporarily
discontinue etanercept, and prophylactic varicella zoster
immune globulin should be considered.3
Rare reports of new onset or exacerbation of central nervous
system demyelinating disorders, and pancytopenia in patients
treated with etanercept have been noted by postmarketing
surveillance. Consequently, caution should be exercised when
considering the use of etanercept in patients with preexisting
or recent-onset central demyelinating disorders.
Discontinuation of etanercept therapy should be considered in
patients with confirmed significant hematological
abnormalities.3
Additionally, 11% of patients in clinical trials who were
treated with etanercept developed a new positive ANA titer of
1:40 or greater, compared to 5% of patients who were in the
placebo group. The development of anti-dsDNA antibodies
was also higher in patients treated with etanercept when
compared to those treated with placebo (15% and 4%
respectively). Cases of drug-induced systemic lupus and
subacute cutaneous lupus have been reported in the
literature.14,15 After discontinuation of etanercept these
conditions resolved.
The US FDA pregnancy rating for etanercept is category B.
However this rating was made based on results of
developmental toxicity studies of etanercept performed in rats
and rabbits. There have been no studies in pregnant women
and, therefore, etanercept should be used during pregnancy
only if clearly needed. It is not known if etanercept is excreted
in human milk or absorbed systemically after ingestion. A
decision to discontinue nursing or to discontinue etanercept
should be made by nursing mothers.3
Adverse Events
In controlled trials, the only adverse event that occurred
significantly more frequently in patients treated with
etanercept compared to placebo was mild-to-moderate
injection-site reactions, e.g., erythema and/or itching, pain,
or swelling (see Table 2). These reactions tended to occur in
the first month, subsequently decreased in frequency, and
did not generally result in discontinuation of the drug.11
Application of cool compresses and 1% hydrocortisone
ointment are helpful to alleviate discomfort associated with
injection-site reactions.
Conclusion
Clinical trials have demonstrated consistent efficacy for
etanercept in the treatment of inflammatory diseases such as
psoriasis, psoriatic arthritis, RA, and JRA, and research on the
potential future use of this agent in other inflammatory
diseases is ongoing. The rapid and significant clinical
responses to etanercept highlight the central role of TNF in
contributing to the pathology of these diseases, as well as
etanercept’s potent inhibitory effects. Etanercept is well
tolerated by both adult and pediatric patient populations, and
long-term data on the use of etanercept have demonstrated an
excellent safety profile.
Dr. Goffe has had research funded by Amgen, Biogen,
Genentech and Centocor, and he has performed various paid
consulting and speaking functions.
References
1. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge
DJ. Etanercept in the treatment of psoriatic arthritis and
psoriasis: a randomised trial. Lancet 356(9227):385-90
(2000 Jul).
Continued on page 9
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4
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005
A Review of Prednicarbate (Dermatop)
A. K. Gupta, MD, PhD, FRCPC1,2 and M. Chow, HBSc2
1
Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Centre
(Sunnybrook site) and the University of Toronto, Toronto, Canada.
2
Mediprobe Reseach Inc, London, Ontario, Canada.
ABSTRACT
Prednicarbate is a nonhalogenated corticosteroid that is used in the treatment of inflammatory skin diseases, for example atopic
dermatitis. It has a favorable benefit-risk ratio, with an inflammatory action similar to that of a medium potency corticosteroid,
but with a low potential to cause skin atrophy. Thus, prednicarbate may be a consideration in the treatment of atopic dermatitis
in children, and other inflammatory disorders in children and adults.
Key Words: prednicarbate, corticosteroid, atopic dermatitis, inflammatory skin disease
Prednicarbate is a nonhalogenated, double-ester derivative of
prednisolone. Modification to the prednisolone molecule has
resulted in a molecule that causes the suppression of
inflammation, but maintains low skin atrophy potential.1,2
numerically higher clearing and mean percent improvements of
signs and symptoms at return visits compared to betamethasone
valerate. Prednicarbate had an overall improvement of 76.4%
compared to the vehicle emollient (29.7%) and demonstrated
similar efficacy to betamethasone valerate.9
Mechanism of Action
The anti-inflammation action of corticosteroids is associated
with the inhibition of the Il-1a cytokine within keratinocytes.3,4
Il-1a is also found in fibroblasts, where it is responsible for
proliferation, collagenase induction and Il-6 synthesis, which
are related to skin thickness.4 Fibroblasts are important in
wound healing and tissue repair.5 The primary mechanism of
action of corticosteroids is the suppression of Il-1a , which
subsequently inhibits the cytokine in both keratinocytes and
fibroblasts. The inhibition of Il-1a in keratinocytes results in
anti-inflammatory effects, while in fibroblasts there is an
atrophogenic effect.
Prednicarbate has different effects on keratinocytes and
fibroblasts. In keratinocytes, prednicarbate produces a high
degree of suppression of IL-1a that is almost similar to that
produced by betamethasone-17-valerate.4,6,7 In contrast,
prednicarbate has only a minor effect on IL-1a and IL-6
suppression in fibroblasts; this results in a low potential to cause
atrophy.4,6,7
Clinical Efficacy
Several German and Spanish studies have reported the
effectiveness of prednicarbate in a variety of formulations at a
strength of 0.25%, for the treatment of dermatitis.8
In two multicenter, randomized, double-blind, parallel group
studies (see Table 1), Hanifin et al.9 compared prednicarbate
0.1% emollient cream with both the emollient cream vehicle
and betamethasone valerate 0.1% cream in the treatment of
patients with atopic dermatitis, where males were 12 years or
older and females were 18 years or older. Treatments were
applied twice daily for 21 days. Prednicarbate had significantly
greater efficacy than the vehicle emollient, with greater
improvement ratings of total key signs/symptoms at all return
visits; significant improvement was recorded as early as day 8
(P≤0.05). Prednicarbate demonstrated at least equivalent or
Adverse Events
Prednicarbate has been associated with few adverse events;
these include burning sensation, pruritus, drying, scaling,
cracking, and pain, as well as dizziness, paresthesia, urticaria,
folliculitis and edema/rash.2,9 In a study where prednicarbate
was applied to children (4 months to 12 years) twice daily for
21 days no suppression of the hypothalamic-pituitary-adrenal
(HPA) axis was observed.10 The low atrophogenic potential of
prednicarbate has been supported in several studies.1,4-7
Contact allergies to topical corticosteroids is also a concerning
adverse event, particularly with long-term use. Corticosteroids
have been ranked as the seventh most common allergen.11
Sensitivity to corticosteroids can be difficult to diagnose
because the anti-inflammatory action of the corticosteroid can
camouflage the allergic reaction to the corticosteroid itself.12
Corticosteroids may be classified into 4 groups (A-D) based on
their allergenicity.12,13 Prednicarbate (in Group D) is a prodrug
corticosteroid.12 It rapidly de-esterfies at position C21 to
prednisolone-17-ethylcarbonate, which eventually metabolizes
to prednisolone.12 The metabolites may exhibit allergenicity that
is different from the parent molecule; furthermore,
prednicarbate may cross-react with other corticosteroids.
In a study byHanifin, et al.9 evaluating prednicarbate emollient
cream 0.1% versus vehicle, safety data were available for 211
patients. Adverse effects thought to be related to the study drug
were reported in 12 patients (prednicarbate group: 4, vehicle
group: 8). In the prednicarbate group, the adverse effects
included pruritus, burning sensation of skin, rash, contact
dermatitis, and edema. Skin atrophy was recorded in three and
one patients in the prednicarbate and vehicle groups,
respectively. The presence of atrophy in the vehicle group may
be explained by preexisting atrophy that may have been the
result of previous topical corticosteroid usage. Therefore, it is
difficult to ascertain whether atrophy in a patient is the result of
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005
5
Study 1
Prednicarbate
Vehicle
Prednicarbate
Study 2
Betamethasone Valerate
Number of subjects
98
86
89
92
% Improvement of
total key
signs/symptoms
scores at endpoint
76.4%
29.7%
79.7%
75.8%
Global evaluation
scores of cleared or
excellent
improvement at
endpoint
72%
20%
Adverse events
Pruritus, skin
burning sensation,
contact dermatitis,
edema/rash, skin
atrophy
Pruritus, skin burning
sensation, dry skin,
rash, pain, vasodilation,
application-site
reaction, discoloration,
skin atrophy, striae
Equally effective – scores were:
prednicarbate=1.03
betamethasone valerate=1.00
Dizziness, skin
burning sensation,
paresthesia, rash,
folliculitis
Acne, furunculosis,
rash, pustular rash
Table 1: Summary of the efficacy of prednicarbate emollient cream 0.1% compared with vehicle and betamethasone valerate
cream 0.1%.9
the current application of topical corticosteroid as opposed to
previous topical corticosteroid use.
In the second Hanifin, et al.9 study comparing prednicarbate to
betamethasone valerate, safety data are available for 200
patients. Adverse effects that were thought to be study drug
related were seen in 7 and 5 patients in the prednicarbate and
betamethasone valerate groups, respectively. The adverse
effects in the prednicarbate group were burning sensation of the
skin, rash, folliculitis, paresthesia and dizziness. None of the
patients had skin atrophy.
Indications
In Canada and the United States, prednicarbate (0.1% emollient
cream and 0.1% ointment) has been approved for the treatment
of inflammatory and pruritic manifestations of acute and
chronic corticosteroid-responsive dermatoses.14,15 It can be
applied without occlusion twice daily for 2 weeks.14,15 The
emollient cream has been approved for the use in adults and
children over 1 year old, and the ointment has approval in the US
for use in individuals 10 years and older.14,15 Prednicarbate
should be used cautiously in children around the diaper area
because the diaper and plastic pants may result in occlusion.
Conclusion
Prednicarbate has been demonstrated to be effective, with a high
anti-inflammatory action and low potential for adverse events,
particularly skin atrophy. This topical corticosteroid exhibits
characteristics that may prove beneficial in the treatment of
children and elderly patients, as well as adults who may require
intermittent long-term treatment.
6
References
1. Kerscher MJ, Korting HC. Topical glucocorticoids of the
non-fluorinated double-ester type: lack of atrophogenicity
in normal skin as assessed by high-frequency ultrasound.
Acta Derm Venereol (Stockh) 72(3):214-6 (1992).
2. Cornell RC, Cherill RJ, Abrams BB. Safety of prednicarbate
emollient cream 0.1% and ointment 0.1%, nonhalogenated,
midpotency topical steroid formulations. J Geriatr
Dermatol 2:57-65 (1994).
3. Korting HC, Hulsebus E, Kerscher M, Greber R, SchaferKorting M. Discrimination of the toxic potential of
chemically differing topical glucocorticoids using a neutral
red release assay with human keratinocytes and fibroblasts.
Br J Dermatol 133(1):54-9 (1995 Jul).
4. Lange K, Kleuser B, Gysler A, et al. Cutaneous inflammation
and proliferation in vitro differential effects and mode of
action of topical glucocorticoids. Skin Pharmacol Appl Skin
Physiol 13(2):93-103 (2000 Mar-Apr).
5. Hein R, Mauch C, Hatamochi A, Krieg T. Influence of
corticosteroids on chemotactic response and collagen
metabolism of human skin fibroblasts. Biochem Pharmacol
37(14):2723-9 (1988 Jul).
6. Lange K, Gysler A, Bader M, Kleuser B, Korting HC,
Schafer-Korting M. Prednicarbate versus conventional
topical glucocorticoids: pharmacodynamic characterization
in vitro. Pharm Res 14(12):1744-9 (1997 Dec).
Continued on page 9
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005
ADVANCES IN DERMATOLOGIC SURGERY
Editors: Jeffrey S. Dover, MD and Murad Alam, MD
Treatment of Photoaging with Topical
Aminolevulinic Acid and Light
M. Alam, MD1 and J. S. Dover, MD, FRCPC2,3,4
Section of Cutaneous and Aesthetic Surgery, Department of Dermatology, Northwestern University, Chicago, IL, USA
2
SkinCare Physicians, Chestnut Hill, MA, USA
3
Department of Medicine (Dermatology), Dartmouth Medical School, Hanover, NH, USA
4
Section of Dermatologic Surgery and Cutaneous Oncology, Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA
1
ABSTRACT
Photodynamic therapy (PDT) has been used for several years for the treatment of actinic keratoses and prevention of invasive
nonmelanoma cancers. More recently, increasing physician expertise with the topical sensitizers and light sources employed in
PDT has led to expanded applications, including its use for improvement of the visible signs of photoaging. Aesthetic treatment of
photoaged skin with brief application of topical 5-aminolevulinic acid followed by well-tolerated light sources, such as intense
pulsed light or pulsed-dye laser, can enhance the effectiveness of nonablative laser treatment without increasing adverse effects or
downtime.
Key Words: photodynamic therapy, intense pulsed light, pulsed-dye laser, aminolevulinic acid, photoaging
Nonablative laser and light sources have been widely used for
the reduction of the visible signs of photoaging for several
years. The benefits of nonablative treatment include quicker
patient recovery time due to the absence of marked
postoperative erythema, desquamation, and crusting.
Moreover, the risks of unwanted pigmentary and textural
abnormalities are much reduced in nonablative rejuvenation
compared to ablative treatment.
The benefits of nonablative treatment are partially
counterbalanced by its reduced efficacy relative to laser skin
resurfacing. Among the novel methods for maximizing the
efficacy of nonablative treatment is the concurrent use of a
photosensitizing agent, such as 5-aminolevulinic acid (5-ALA).1
5-ALA and Light: Well-Tolerated Treatment of Actinic
Keratoses and Photoaging
Originally developed to be used with red or blue light to treat
superficial cutaneous malignancies and premalignant lesions
(e.g., actinic keratoses), 5-ALA has recently been applied in
combination with a variety of light sources, such as pulsed-dye
laser and intense pulsed light, to increase the effectiveness of
light treatment. This cosmetic use entails less intense 5-ALA
pretreatment regimens and more well-tolerated light doses for
activating the photosensitizer.
This so-called “photodynamic photorejuvenation” was
discussed in the literature as early as 2002, when RuizRodriguez and colleagues2 treated 17 patients with a
combination of actinic keratoses (AKs) and diffuse
photodamage. They applied 20% 5-ALA mixed in an oil-inwater emulsion and under occlusion for 4 hours prior to
treatment (0.2g/cm2) with the pulsed light device (Epilight®,
Lumenis), using a 615nm cutoff filter, total fluence of 40J/cm2
in double pulse mode of 4.0msec with 20msec interpulse delay.
Approximately 3/4 of the AKs and adjacent photodamaged skin
resolved 1 month after the first treatments, and posttreatment
erythema, edema, and crusting lasted up to 10 days.
These results were extended by Alexiades-Armenakas and
Geronemus,3 who showed that photodynamic treatment of AKs
could be accomplished gently, not only with intense pulsed
light (IPL), but also with 595nm pulsed-dye laser (PDL)
(Vbeam®, Candela). The PDL offered the benefits of rapidity of
treatment as well as the comfort and protective epidermal
effects associated with cryogen spray cooling. The 5-ALA
incubation times were as brief as 3 hours and nonpurpuric PDL
settings (4-7.5J/cm2, pulse duration of 10ms, 10mm spot size,
and 30ms cryogen spray with 30ms delay) were used. Minimal
intraoperative stinging, burning, and pain were reported, and
while there was some postoperative erythema, no purpura,
crusting, or scarring was seen. While Alexiades-Armenakas
and Geronemus were focused on the treatment of AKs, they
demonstrated that laser and 5-ALA could be effectively used
with virtually no downtime.
5-ALA and Light: Treatment of Photoaging Alone
Indeed, anecdotal use of IPL and PDL for improvement of the
visible signs of aging has rapidly spread. Now the first discrete
studies of this application are becoming available. Avram and
Goldman4 retrospectively reviewed 17 patients treated with 5ALA and IPL and found 55% improvement in telangiectasia,
48% improvement in pigmentary abnormalities, and 25%
improvement in coarseness of skin texture, but minimal change
in fine wrinkles. Low doses of 5-ALA and IPL permitted postoperative courses significant for only mild erythema and edema
for 3-5 days. Separate preliminary studies by both Gold5 and
Roe, et al.6 have also indicated treatment efficacy following
short contact (30-60 minutes incubation) full-face incubation
with 20% 5-ALA followed by treatment with IPL.
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005
7
ADVANCES IN DERMATOLOGIC SURGERY
Editors: Jeffrey S. Dover, MD and Murad Alam, MD
Recently, a prospective, randomized, controlled trial comparing
efficacy and tolerability of 5-ALA followed by IPL treatment
with IPL alone was performed by Dover, Bhatia, and Arndt
(unpublished data, October 2004). A total of three split-face
treatments were delivered to each of 20 patients, and these were
followed by two whole-face IPL-only treatments, also 3 weeks
apart. Prior to each of the first three treatments, one side of each
patient’s face was precleansed with acetone and received topical
5-ALA solution for 45 minutes (+15 minutes). The 5-ALA
solution was washed off before treatment was commenced with
a 560-1200nm device (IPL™ Quantum SR, Lumenis Inc.) using
the standard SR head on Program 1 (first pulse of 2.4ms, second
pulse of 4.0ms, 14ms interpulse delay; fluence of 23-28J/cm2;
epidermal cooling chiller tip on maximum). After each
treatment, patients again washed their faces and applied a
moisturizer containing an SPF 30 sunscreen. Assessment of
outcomes was conducted using a comprehensive rating measure
that evaluated global photodamage, fine lines, mottled
pigmentation, tactile roughness, and sallowness, each on a 0-4
scale; measurements were obtained by a blinded rater before
treatment and 4 weeks after the final treatment. The 5-ALA-IPL
sides were associated with 80%-95% improvement on the
various subscales compared to 20%-55% improvement for the
5-ALA-only sides. The greatest relative improvements in the 5ALA-IPL sides were in mottled hyperpigmentation and global
photoaging, and to a lesser extent, in fine lines. Tactile
roughness and sallowness did not appear to show greater
improvement with 5-ALA-IPL treatment vs. IPL alone. Not
only the independent rater, but also patients preferred the
benefits of the combined 5-ALA-IPL treatment. Significantly,
side-effects and tolerability did not differ between the IPL-only
treated areas and the areas treated with 5-ALA-IPL.
General Treatment Guidelines
1. IPL (and other light sources, including PDL) can be used
after pretreatment with 5-ALA to reduce the visible signs of
photoaging.
2. Patients should be instructed that red/brown
dyspigmentation and overall appearance are likely to
improve significantly, and fine lines, to a lesser extent.
3. Pretreatment with acetone or alcohol is followed by short
contact (approximately 1 hour) application of 20% 5-ALA.
This is then thoroughly washed off before IPL treatment.
4. IPL or PDL treatment should be delivered at standard
parameters.
5. After treatment, the treated area should again be washed off,
and moisturizer and sunscreen applied.
6. Patients should be instructed to practice strict sun avoidance
and sun protection for the remainder of the treatment day
and the next day.
7. Additional treatments are delivered at 3-4 week intervals,
with a standard regimen consisting of 3-6 treatments. While
it appears from the Dover study that three combined 5ALA-IPL treatments may produce results as good as or
8
better than five IPL alone treatments, further study is
necessary to confirm this finding.
Management of Undesired Effects6
The 5-ALA-IPL or PDL treatment for photoaging is a safe
treatment associated with patient comfort during treatment and
rapid, uneventful recovery after treatment. There are two
potential problems that can be easily detected and treated.
Phototoxicity occurs when patients disregard instructions
regarding post-treatment sun avoidance. The best treatment is
prevention, including strict sun avoidance for 24 hours after
treatment. If phototoxicity does occur, it presents as welldemarcated erythema and edema at the treated sites.
Application of ice and topical corticosteroid ointments, rest, and
the passing of time will aid in resolution of symptoms. The risk
of superficial infection is very low. Patients with a history of
recurrent cold sores may be given antiviral prophylaxis for
herpes simplex prior to treatment. Superficial bacterial
infections or impetigo may occur at extremely sun-damaged
sites or at locations where the 5-ALA solution has not been
completely washed off before IPL treatment. These are typically
easily treated with topical antibiotics, such as mupirocin.
Conclusion
Topical 5-ALA enhances the efficacy of laser and light
treatment of facial photoaging. While IPL devices have been
used most often in this combination therapy, other lasers and
light sources, including PDL, appear effective as well.
Moreover, combination 5-ALA and light therapy does not add
to recovery time or discomfort. Provided sun avoidance is
practiced for a day following treatment, combination therapy,
like laser or light alone, is associated with mild posttreatment
erythema and edema, but no crusting or erosions. The new
short-contact regimens of 5-ALA require pretreatment for 3060 minutes, no longer than the duration of applications of
topical anesthetics used for various cutaneous procedures.
Finally, prepackaged 20% 5-ALA (Levulan® Kerastick®,
DUSA Pharmaceuticals) does not require time-consuming
preparation prior to application. In short, 5-ALA-light therapy
is a further refinement of nonablative laser therapy that permits
effective treatment of photoaging with minimization of posttreatment effects.
References
1. Alam M, Dover JS, Arndt KA. Energy delivery devices for
cutaneous remodeling: lasers, lights, and radio waves. Arch
Dermatol 139(10):1351-60 (2003 Oct).
2. Ruiz-Rodriguez R, Sanz-Sanchez T, Cordoba S.
Photodynamic photorejuvenation. Dermatol Surg
28(8):742-4 (2002 Aug).
3. Alexiades-Armenakas MR, Geronemus RG. Lasermediated photodynamic therapy of actinic keratoses. Arch
Dermatol 139(10):1313-20 (2003 Oct).
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005
4. Avram DK, Goldman MP. Effectiveness and safety of ALAIPL in treating actinic keratoses and photodamage. J Drugs
Dermatol 3(1 Suppl):S36-9 (2004 Jan-Feb).
5. Gold MH, Goldman MP. 5-aminolevulinic acid
photodynamic therapy: where we have been and where we
are going. Dermatol Surg 30(8):1077-83 (2004 Aug).
6. Rao J, Goldman MP, Gold MH. ALA-PDT
photorejuvenation. In: Goldman MP, ed. ALA Photodynamic
Therapy. In: Dover JS, Alam M, series ed. Procedures in
Cosmetic Dermatology. London: Elsevier; 2005.
Continued from page 4
2. Mease P, Kivitz A, Burch F, Siegel E, Cohen S, Burge D.
Improvement in disease activity in patients with
psoriatic arthritis receiving etanercept (ENBREL):
results of a phase 3 multicenter clinical trial [abstract].
Arthritis Rheum 44(suppl):S90-A 226 (2001).
11. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept
Psoriasis Study Group. Etanercept as monotherapy in
patients with psoriasis. N Engl J Med 349(21):2014-22
(2003 Nov).
12. Mease PJ, Goffe BS, Metz J, VanderStoep A, Burge DJ.
Enbrel (etanercept) in patients with psoriatic arthritis and
psoriasis. Arthritis Rheum 43(suppl):S403 (2000).
13. Klareskog L, Moreland LM, Cohen SB, Sanda M, Burge
DJ. Global safety and efficacy of up to five years of
etanercept (Enbrel®) therapy [abstract]. Arthritis Rheum
44(suppl):S77-Abstract 150 (2001).
14. Shakoor N, Michalska M, Harris CA, Block JA. Druginduced systemic lupus erythematosus associated with
etanercept therapy. Lancet 359(9306):579-80 (2002 Feb).
15. Bleumink GS, ter Borg EJ, Ramselaar CG, Ch Stricker
BH. Etanercept-induced subacute cutaneous lupus
erythematosus. Rheumatology (Oxford) 40(11):1317-9
(2001 Nov).
3. Enbrel® (etanercept) prescribing inforamtion. Immunex
Corporation, Thousand Oaks, CA (2004 Oct).
Continued from page 6
4. Moreland LW, Cohen S, Fleischmann RM, Baumgartner
SW, Schiff MH, Burge DJ. Safety and Efficacy of up to 5
Years of Etanercept (Enbrel) Therapy in Rheumatoid
Arthritis. Presented at: EULAR 2002, Stockholm,
Sweden.
7. Gysler A, Kleuser B, Sippl W, et al. Skin penetration and
metabolism of topical glucocorticoids in reconstructed
epidermis and in excised human skin. Pharm Res 16(9):138691 (1999 Sep).
5. Ritchlin C, Haas-Smith SA, Hicks D, Cappuccio J,
Osterland CK, Looney RJ. Patterns of cytokine production
in psoriatic synovium. J Rheumatol 25(8):1544-52 (1998
Aug).
6. Partsch G, Steiner G, Leeb BF, Dunky A, Broll H, Smolen
JS. Highly increased levels of tumor necrosis factor-alpha
and other proinflammatory cytokines in psoriatic arthritis
synovial fluid. J Rheumatol 24(3):518-23 (1997 Mar).
7. Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD.
Elevated tumour necrosis factor-alpha (TNF-alpha)
biological activity in psoriatic skin lesions. Clin Exp
Immunol 96(1):146-51 (1994 Apr).
8. Mussi A, Bonifati C, Carducci M, et al. Serum TNF-alpha
levels correlate with disease severity and are reduced by
effective therapy in plaque-type psoriasis. J Biol Regul
Homeost Agents 11(3):115-8 (1997 Jul-Sep).
9. Bonifati C, Carducci M, Cordiali FP, et al. Correlated
increases of tumour necrosis factor-alpha, interleukin-6
and granulocyte monocyte-colony stimulating factor levels
in suction blister fluids and sera of psoriatic patients-relationships with disease severity. Clin Exp Dermatol
19(5):383-7 (1994 Sep).
10. Krueger JG. The immunologic basis for the treatment of
psoriasis with new biologic agents. J Am Acad Dermatol
46(1):1-23 (20202 Jan).
8. Spencer CM, Wagstaff AJ. Prednicarbate: A review of its
pharmacological properties and therapeutic use in the treatment
of dermatological disorders. BioDrugs 9:61-86 (1998).
9. Hanifin J, Abrams BB, Cherill RJ. Management of atopic
dermatitis with prednicarbate emollient cream 0.1%, a
nonhalogenated prednisolone derivative. J Geriatr Dermatol
2(4):119-27 (1994).
10. Moshang T. Prednicarbate emollient cream 0.1% in pediatric
patients with atopic dermatitis. Cutis 68(1):63-9 (2001 Jul).
11. Degreef H, Dooms-Goossens A. The new corticosteroids: Are
they effective and safe? Dermatol Clin 11(1):155-60 (1993 Jan).
12. Matura M, Goossens A. Contact allergy to corticosteroids.
Allergy 55(8):698-704 (2000 Aug).
13. Coopman S, Degreef H, Dooms-Goosens A. Identification of
cross-reaction patterns in allergic contact dermatitis from
topical corticosteroids. Br J Dermatol 121(1):27-34 (1989 Jul).
14. Dermatop® E Emollient Cream (prednicarbate emollient
cream) 0.1% and Dermatop® E Emollient Ointment
(prednicarbate ointment) 0.1% U.S. package insert. Dermik
Laboratories Berwyn, PA, USA; June 2002.
15. Dermatop® Ointment (prednicarbate ointment 0.1%) and
Dermatop® Emollient Cream (prednicarbate emollient cream
0.1%) Canadian package insert. Dermik Laboratories
Canada, Inc. Mississauga, ON, Canada; November 15 2000.
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005
9
Update on Drugs
Class
Name/Company
Approval Dates and Comments
Antipsoriatic Agent
Efalizumab
Raptiva®
Serono
The European Medicines Agency (EMEA) approved this
humanized therapeutic antibody in September 2004, for the
treatment of moderate-to-severe chronic plaque psoriasis for
which other systemic treatments or phototherapy have been
inadequate or inappropriate.
Antihistamine
Desloratadine Syrup
CLARINEX®
Schering-Plough
The US FDA approved the use of this antihistamine in August
2004, for the relief of symptoms associated with seasonal allergic
rhinitis in children >2 years of age, and perennial allergic rhinitis
and chronic idiopathic urticaria, or hives of unknown cause in
children as young as 6 months of age. This product is expected to
be available in the US during the first half of 2005.
Antifungal Agent
Posaconazole Oral
Suspension
The US FDA, in July 2004, accepted for review the NDA for this
novel triazole agent for the treatment of invasive fungal infections,
such as aspergillosis, fusariosis, and zygomycosis, in patients with
refractory disease or who are intolerant to other therapy.
Schering-Plough
Antipsoriatic Agent
Etanercept
Enbrel®
Amgen/ Wyeth Pharmaceuticals
The US FDA approved a new dosing form in September 2004, for
this biologic treatment. The new prefilled syringe, available for
patient use in the 4th quarter 2004, will eliminate the need to mix the
drug prior to injecting, and will allow most patients receiving this
drug to take only one injection per week instead of the two 25mg
injections currently used weekly by patients. Also in September, the
EMEA approved this product for the treatment of adults with
moderate-to-severe plaque psoriasis who failed to respond to, or
have a contraindication to, or are intolerant of other systemic therapy.
Drug News
UD FDA
Regulatory
Changes
The US FDA is proposing to change the new and generic drug review processes by replacing
“approvable letters” and “not approvable letters” with “complete response letters” that provide
companies with specific information about what needs to be done before their drugs can be approved
for marketing. This approach has been used by the FDA for biological drugs for some time and would
be formalized for all drugs by this proposal. Under the new proposal, responses to “complete response
letters” for new drug applications would be classified by what needs to be done to obtain marketing
approval. More information is available online at: http://www.fda.gov/OHRMS/DOCKETS/98fr/04n0267-npr0001.pdf.
Research News
According to a recent article published in the journal Cell*, researchers at Howard Hughes Medical Institute
have isolated stem cells from the skin of mice and shown that they have the power to self-renew and
differentiate into skin and functioning hair follicles when grafted onto mice. They conclude that the human
equivalent of these stem cells, which scientists are also trying to isolate, could ultimately be used to
regenerate skin and hair.
*Cell 118(5):635-48 (2004 Sep 3).
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Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 9 No. 10 • December 2004 - January 2005