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V o l u m e
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SkinCareGuide
N u m b e r
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A p r i l
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Indexed by the US National Library of Medicine and MEDLINE
Pimecrolimus 1% Cream (Elidel)
For Atopic Dermatitis
L.A. Bernard, MDa, J.N. Bergman, MDa,b, L.F. Eichenfield, MDa,b
a
Pediatric and Adolescent Dermatology, Children’s Hospital and Health Center, San Diego, CA
b
University of California School of Medicine, San Diego, CA
ABSTRACT
Pimecrolimus is an immunomodulating medication that inhibits production of inflammatory cytokines in the skin and this compound
was specifically developed for the treatment of inflammatory skin diseases. Phase II and III clinical trials with the topical formulation of pimecrolimus (Elidel® cream, Novartis) have shown that it is safe and effective for use in patients with atopic dermatitis
(AD). The US FDA recently approved Elidel® for use in patients ≥2 years of age with mild-to-moderate atopic dermatitis (AD).
Key Words: pimecrolimus, immunosuppressant, atopic dermatitis
Pimecrolimus (formerly SDZ ASM 981) is a natural macrolide
product derived from the fungus Streptomyces hygroscopicus var.
ascomyceticus. The topical formulation of pimecrolimus (Elidel®
cream, Novartis) is one of a new class of non-steroidal topical
immunosuppressant medications. When applied topically, it has
cutaneous anti-inflammatory activity and appears to be
minimally absorbed into the circulation. Safety and efficacy of
pimecrolimus 1% cream have been established in several wellcontrolled clinical trials involving children and adults with AD.
This medication was approved by the US FDA for use in adults
and children (≥2 years) with mild-to-moderate AD in December
2001, and is now widely available. The product is currently
undergoing regulatory review in Europe and Canada.
Mechanism of Action
The mechanism of action is closely related to that of
cyclosporine, an immunosuppressant medication useful in some
inflammatory skin disorders refractory to standard therapy. Oral
cyclosporine is quite effective but has significant toxicities.
Unfortunately, it has been found in trials to be ineffective
topically.1 Efforts have been directed toward the development of
new topical compounds with potent anti-inflammatory activity
similar to cyclosporine, but without the systemic side effects.
Topical tacrolimus and later, pimecrolimus, represent the first
generation of this type of product. When applied topically, both
medications selectively target inflammation in the skin without
impairing systemic immune responses. In the early development
phase of pimecrolimus, more than 400 ascomycin derivatives
were synthesized and their characteristics explored in pre-clinical
studies; SDZ ASM-981 was chosen for development because of
its favorable safety profile and cutaneous efficacy.2
Pimecrolimus binds with high affinity to the T-cell receptor
macrophilin 12, which leads to inhibition of calcineurin, a protein
phosphatase required for activation of the T-cell. As a result, Tcell activation is inhibited, and transcription and release of proinflammatory cytokines is prevented. Additionally, pimecrolimus
decreases mast cell production of pro-inflammatory cytokines
(e.g., TNF-alpha) and IgE induced pro-inflammatory mediators
(e.g., histamine).3 The ability of pimecrolimus to inhibit the
activation of multiple cell lines and cytokines may account for its
ability to effectively reduce inflammation.
In animal models, both topical and systemic pimecrolimus are
highly effective against skin inflammation. However, in contrast
to tacrolimus, oral pimecrolimus is a poor systemic immune
suppressant,4 reducing the likelihood of systemic toxicity.
Drug Interactions
Potential interactions between pimecrolimus and other drugs have not
been systematically evaluated. Systemic interactions are unlikely due
to the low levels of pimecrolimus found in the blood after topical
application, but cannot be ruled out based on data gathered to date.
EDITOR-IN-CHIEF: Stuart Maddin ASSOCIATE EDITOR (International): Hugo Degreef, Catholic University, Leuven: ASSOCIATE EDITOR (Canada): Jason Rivers
INTERNET EDITOR: Harvey Lui PUBLICATIONS EDITOR: Penelope Gray-Allan EDITORIAL ADVISORY BOARD: Kenneth A. Arndt, Beth Israel Hospital & Harvard Medical School, Boston;
Wilma Fowler Bergfeld, Cleveland Clinic, Cleveland; Jan D. Bos, University of Amsterdam, Amsterdam; Enno Christophers, Universitäts-Hautklinik, Kiel; Richard L. Dobson, Medical University
of South Carolina, Charleston; Jeffrey S. Dover, Yale Universtiy School of Medicine, New Haven; Boni E. Elewski, University of Alabama, Birmingham; Barbara A. Gilchrest, Boston University
School of Medicine, Boston; W. Andrew D. Griffiths, St. Johns Institute of Dermatology, London; Aditya K. Gupta, University of Toronto, Toronto;Vincent C.Y. Ho, University of British Columbia,
Vancouver; Mark Lebwohl, Mount Sinai Medical Center, New York; James J. Leyden, University of Pennsylvania, Philadelphia; Howard I. Maibach, University of California Hospital, San Francisco;
Larry E. Millikan, Tulane University Medical Center, New Orleans; Takeji Nishikawa, Keio University School of Medicine, Tokyo; Constantin E. Orfanos, Freie Universitäts Berlin,
Universitätsklinikum Benjamin Franklin, Berlin; Stephen L. Sacks, Viridae Clinic Sciences, Vancouver; Alan R. Shalita, SUNY Health Sciences Center, Brooklyn; Richard Thomas, Vancouver
General Hospital, Vancouver; Stephen K. Tyring, University of Texas Medical Branch, Galveston; John Voorhees, University of Michigan, Ann Arbor; Klaus Wolff, University of Vienna, Vienna
Studies with human liver microsomes indicate that pimecrolimus is
metabolized in vitro by the CYP3A family of P450 enzymes. It
appears to be eliminated almost completely in the bile. FDA labeling
suggests that concomitant administration of known CYP3A inhibitors
in patients with widespread disease be undertaken with caution.
Indications
To date, pimecrolimus has primarily been studied for use in AD,
which is a chronic, highly pruritic inflammatory skin disorder and
the most common chronic skin disease in childhood.5 The disease
may be associated with significant morbidity and can have a
significant impact on quality of life for patients and families.
Additionally, research has shown that patients are often not
satisfied with prescribed therapy.6
Until recently, topical treatment of AD has been limited to the use
of corticosteroids. Patients who experienced side-effects from
long-term use of the agents, or patients who were refractory to
therapy had no other effective alternatives for topical treatment.
Pimecrolimus and tacrolimus represent novel treatment options
for this subset of patients.
Phase II and III trials of pimecrolimus have documented its safety
and efficacy for AD treatment (summarized in Table 1). Although
a few preliminary studies have been conducted using
pimecrolimus to treat psoriasis and irritant hand dermatitis, its use
has not yet been studied extensively for other skin conditions.7-9
Oral pimecrolimus showed efficacy and tolerability when studied
for moderate-to-severe plaque psoriasis. Topical pimecrolimus
has also been studied for treatment of psoriasis and has
demonstrated disease improvement when used under occlusion. A
study of pimecrolimus for chronic irritant hand dermatitis found
that the cream safely and effectively ameliorated the signs and
symptoms of the disease after 6 weeks of therapy. Based on the
studies to date, it is likely that pimecrolimus will be studied for a
wide variety of inflammatory skin disorders in the future.
Design
Sample Regimen
Size
AD Clinical Trials
The efficacy and safety of pimecrolimus in patients with AD was
shown in 1998, in a small, randomized, blinded, placebo
controlled trial. In 34 adult patients, pimecrolimus 1% cream
proved to be superior to placebo, and no clinically significant
adverse events were reported.10
Another larger, phase III, multi-center, blinded, randomized
dose-finding trial also suggested efficacy and safety of
pimecrolimus. This study evaluated 260 patients who were
randomized to receive either 0.05%, 0.2%, 0.6%, 1%
pimecrolimus, vehicle or betamethasone valerate 0.1% cream
twice daily for 3 weeks. The 0.2%, 0.6% and 1% pimecrolimus
creams were found to be more effective than vehicle, with 1%
being the most effective. Betamethasone valerate was more
effective than all concentrations of pimecrolimus. Pimecrolimusrelated adverse events included burning and a feeling of warmth
in the 0.6% and 1% groups (42.9% and 48.9%, respectively, vs.
34.9% with vehicle). Based on these findings, the 1% cream was
chosen for further study in phase III trials.11
Subsequently, 2 large, phase III, multi-center, randomized,
controlled trials comparing pimecrolimus to vehicle were
conducted in pediatric patients (aged 2-18 years) with AD. These
two studies were of identical design, allowing for pooling of the
results. Four hundred three patients were enrolled and both groups
received treatment twice daily for 6 weeks. Efficacy was evaluated
primarily by the Investigators Global Assessment (IGA), which
uses a 6-point scale ranging from clear to very severe disease. The
majority of patients studied had moderate disease. Treatment
success was defined as achieving an IGA of 0-1 (clear to almost
clear) during the study. At the first study visit (day 8), 12% of
pimecrolimus patients achieved this, as compared to only 2.2% of
vehicle patients (p<0.05). At the final study evaluation (day 43),
34.8% of pimecrolimus-treated patients were clear to almost clear,
as opposed to only 18.4% of vehicle-treated patients (p<0.05).
Inclusion
Primary
Endpoint
Results
Multicenter, randomized,
blinded, controlled,
dose-finding
Phase II11
n=260
Elidel® 0.05%,
Elidel® 0.2%,
Elidel® 0.6%,
Elidel® 0.6%,
Elidel® 1%,
Vehicle, or
Betamethasone valerate
b.i.d. for 6 weeks
Adult patients,
moderate AD
Hanifin score
(a numeric
score based
on signs and
symptoms of
AD)
Elidel® 0.2%, 0.6% and 1% were more
effective than vehicle, with 1%the most
effective. Betamethasone valerate was
more effective than all concentrations
of Elidel®.
Multicenter, randomized,
blinded, controlled
Phase III (2 identical trials
with pooled results)12
n=403
Elidel® 1% or
Vehicle b.i.d.
for 6 weeks
Patients 1-17
years of age,
mild-tomoderate AD
Physician’s
Global
Evaluation
35% of Elidel® patients were clear or
almost clear at end of study vs. 18%
vehicle (p<0.05).
Multicenter, randomized,
controlled
Phase III13
n=186
Elidel® 1% or
Vehicle b.i.d.
for 6 weeks
Infants 3-23
months of age,
mild-tomoderate AD
Physician’s
Global
Evaluation
By first visit, 17% of Elidel® blinded,
patients were clear or almost clear vs.
9.5% in vehicle (p=0.174). By final visit,
54.5% of Elidel® patients vs. 23.8%
vehicle (p<0.001) achieved this rating.
Table 1: Review of clinical trial data.
2
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 4 • April 2002
Pimecrolimus was also significantly more effective than vehicle at
all visits for all secondary efficacy assessments studied (pruritus
score and Eczema Area and Severity Index Score (EASI)). The
incidence of adverse events was similar in both groups. The
authors concluded that pimecrolimus 1% cream is safe and
effective in children ≥2 years of age with mild-to-moderate AD.12
Another multi-center, randomized, controlled clinical trial was
conducted, which compared pimecrolimus to vehicle in 186
children from 3-23 months of age. The design of this study was
virtually identical to that of the two trials described previously.
Patients applied medication twice daily for 6 weeks. The majority
of the infants had moderate disease at study entry. By day 8, 17%
of pimecrolimus-treated patients were clear or almost clear,
compared with 9.5% in the placebo group (p = 0.174). By day 43
this increased to 54.5% of patients in the pimecrolimus group
who were clear or almost clear and 23.8% of vehicle-treated
patients (p<0.001). For all secondary efficacy parameters,
pimecrolimus was significantly more effective than placebo. The
incidence of adverse events was similar between the two groups.
The authors concluded that pimecrolimus is safe and effective in
infants aged 3-23 months with mild-to-moderate AD.13
Recently, a unique trial was conducted in pediatric patients aged
1-17 years, which suggested that pimecrolimus may be safe and
effective maintenance therapy for preventing AD flares. The
results also suggested a steroid-sparing effect in patients treated
with pimecrolimus.14
Pharmacokinetics
Pharmacokinetic studies of pimecrolimus have been conducted
with both adult and pediatric patients as young as 3 months of age.
Measured blood concentrations of pimecrolimus were consistently
low in both children and adults (99% had <2ng/ml) regardless of
age, extent of body surface area (BSA) treated or duration of
therapy. The majority of the readings were below the limit of
quantification, even in the youngest patients. Over 12 months of
treatment, there was no accumulation of the drug over time.15
Adverse Effects
Pimecrolimus cream is well tolerated when applied topically.
Adverse effects have generally been limited to local irritation
such as warmth, burning and pruritus. Unlike with topical
corticosteroids, there has been no atrophy or adrenal axis
suppression seen with Elidel®.
A significant concern exists related to local immunosuppression
with topical application of tacrolimus and pimecrolimus. These
agents inhibit T-cell activation and could therefore theoretically
put patients at risk for conditions occurring more often in patients
with T-cell suppression, namely skin cancer and viral infections.
Incidence of these infections in completed trials was similar in
the placebo and treated groups, but longer term data is needed to
confirm that no association exists.
Conclusions
In summary, pimecrolimus cream is one of a new class of antiinflammatory medications that have a unique mechanism of action
derived from inhibition of pro-inflammatory cytokines in the skin.
It has been shown to be safe and effective in several randomized,
controlled trials in patients with AD. Long term data is limited to
1 year of use and ongoing studies to assess long term safety are
appropriate. Based on the information gathered to date, it is likely
that in the future, pimecrolimus will be used extensively for AD
and a variety of other inflammatory skin conditions.
References
1. Atakan N, Erdem C. The efficacy, tolerability and safety of a new oral
formulation of Sandimmun-Sandimmun Neoral in severe refractory atopic
dermatitis. J Eur Acad Dermatol Venereol 11(3):240-6 (1998 Nov).
2. Stuetz A, Grassberger M, Meingassner J. Pimecrolimus (Elidel, SDZ ASM
981) ñ preclinical pharmacologic profile and skin selectivity. Semin Cutan
Med Surg 20(4):233-41 (2001 Dec).
3. Neckermann G, Bavandi A, Meingassner JG. Atopic dermatitis-like
symptoms in hypomagnesaemic hairless rats are prevented and inhibited by
systemic or topical SDZ ASM 981. Br J Dermatol 142(4):669-79 (2000 Apr).
4. Grassberger M, Baumruker T, Enz A, et al. A novel anti-inflammatory drug,
SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br
J Dermatol 141(2):264-73 (1999 Aug).
5. Laughter D, Istvan J, Tofte S, Hanifin J. The prevalence of atopic dermatitis
in Oregon schoolchildren. Jl Am Acad Dermatol 43(4):649-55 (2000 Oct).
6. Paller A, McAllister R, Doyle J, et al. Atopic dermatitis in pediatric patients:
perceptions of physicians and parents. At: American Academy of
Dermatology Annual Meeting, (2000 Mar) San Francisco, CA.
7. Greig G, Burtin P, Wolff K, et al. Oral SDZ ASM 981: Clinical safety,
tolerability, and efficacy in patients with moderate to severe chronic plaque
psoriasis. At: American Academy of Dermatology Annual Meeting, (2001,
Mar) Washington D.C.
8. Mrowietz U, Graber M, Brautigam M, et al. The novel ascomycin derivative
SDZ ASM 981 is effective for psoriasis when used topically under occlusion.
Br J Dermatol 139(6):992-6 (1998 Dec).
9. Cherill R, Tofte S, MacNaul R, et al. 1% SDZ ASM 981 cream effective in
treatment of chronic irritant hand dermatitis: a 6 week, randomized, doubleblind, vehicle-controlled, single-center study. J Eur Acad Dermatol Venereol
14(suppl 1):128 (2000).
10. Van Leent E, Graber M, Thurston M, Wagenaar A, Spuls PI, Bos JD.
Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical
treatment of atopic dermatitis. Arch Dermatol 134(7):805-9 (1998 Jul).
11. Luger T, Van Leent E, Graber M, et al. SDZ ASM 981: An emerging safe
and effective treatment for atopic dermatitis. Br J Dermatol 144(4):788-94
(2001 Apr).
12. Eichenfield L, Lucky A, Boguniewicz M, et al. Safety and efficacy of
pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate
atopic dermatitis in children and adolescents. Jl Am Acad Dermatol
46(4):495-504 (2002 Apr).
13. Papp K, Ho V, Halbert A, et al. Pimecrolimus (Elidel®, SDZ ASM 981) cream
1% is effective and safe in infants aged 3-23 months with atopic dermatitis. At:
World Congress of Pediatric Dermatology, (2001 May) Cancun, Mexico.
14. De Prost Y, Wahn U, Bos J et al. Pimecrolimus cream reduces the number of
flares and the need for topical corticosteroids in children with atopic
dermatitis: a 12 month, double-blind, controlled study. At: American
Academy of Dermatology Annual Meeting, (2002 Feb), New Orleans, LA.
15. Wahn U, Praiser D, Gottlieb A, et al. Low blood concentrations of SDZ ASM 981
in infants with extensive atopic dermatitis treated with cream 1%. At: American
Academy of Dermatology Annual Meeting, (2001 Mar), Washington D.C.
WE ’RE ON THE NET! www.skincareguide.com
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 4 • April 2002
3
Topical Treatment of Psoriasis in Children
J. Coffey, MD, I. Landells, MD, FRCPC
Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
ABSTRACT
Psoriasis is a common dermatosis, affecting children in North America. Many papers have stressed the treatments available for adult
psoriasis, but few have dealt with this disorder in children. Topical treatment modalities continue to be the first line therapy for childhood
psoriasis. This paper summarizes the general topical treatments available including their clinical use, benefits, cost, and side-effects.
Key Words: childhood psoriasis, topical treatments
Psoriasis is a common dermatosis affecting 1-3% of the North
American population.1,2 In children it is also very common,
representing 4.1% of all childhood skin conditions, and usually
occurring after 10 years of age; but 10% occur before age 10, and
2% before 2 years.3-5 This disorder causes significant morbidity,
social embarrassment, and financial burden.2
Childhood Psoriasis
In infants, psoriasis often starts in the diaper area, but a confident
diagnosis at this stage is often difficult. Childhood psoriasis tends
to be more extensive and severe than that seen in adults.6
However, systemic antipsoriatic modalities may have devastating
and potentially irreversible side-effects that limit their use in
children.7 Thus topical therapies are generally preferred in the
pediatric population.
It is important to keep in mind that children are not simply
small adults. There is a need for child and parental education,
compliance, and cooperation. This is why, while being treated,
children with psoriasis should be followed closely. Successful
psoriasis treatment is a life-long task requiring major
contributions from the family and physician, and failure to
treat has been shown to have an adverse effect on quality of life
in children.7
There are five forms of psoriasis: plaque psoriasis, guttate
psoriasis, pustular psoriasis, inverse psoriasis and erythrodermic
psoriasis. In children, the most common types of psoriasis are the
guttate and chronic plaque types. Psoriatic arthritis is seen in
approximately 6% of children and adults.7,8
Signs and symptoms of psoriasis include erythema, scaling, skin
thickening, and pruritus. A thorough physical examination should
include assessment of joints, scalp, elbows, knees, nails, palms,
and soles of the feet.1,3,9
Triggers
Triggers of psoriasis include comorbid inflammatory diseases
(e.g., Crohn’s disease, HIV); emotional stress; withdrawal of
systemic corticosteroids; preceding streptococcal infections in
the case of guttate psoriasis; climate (northern regions); drugs
(e.g., lithium, antimalarials, systemic interferon, and betablockers); and physical trauma (e.g., pressure, friction, rubbing
and scratching).1,10,11 Exacerbating triggers are different in
children and adults, with infections and trauma being the most
common triggers in children.7
4
Pathogenesis
Psoriasis is a complex disorder that may undergo periods of waxing
and waning, recurrence and regression, and involves variable body
surface areas. Genetic studies have linked it to several chromosomal
loci (HLA-Cw6, 17q25, 4q), and psoriasis is an immunologic
disorder leading to secondary hyperproliferation of keratinocytes.12
The normal turnover rate of keratinocytes from the basal cell layer
to the stratum corneum is 28-44 days, but in psoriasis it is reduced
to 4 days.2 Abnormal keratinocyte differentiation and infiltration of
inflammatory cells are also typical features.11,13 Treatments
available are designed to counteract one or more of these features.14
Treatment Options
Available treatment modalities target keratinocyte
hyperproliferation, abnormal keratinocyte differentiation, and
infiltration of inflammatory cells. Treatment options for
children include:
1)
Topical treatments, e.g., corticosteroids (mild, mid and high
potency agents), keratolytics, anthralins, coal tars, vitamin
D analogs, retinoids, ureas, and emollients.1,9,11,15 Many of
these are available as ointments (cutaneous plaques), creams
(intertriginous areas) and lotions (scalp) (see Table 1).
2)
Phototherapy (e.g., UVB with topical adjuvant therapy,
topical or systemic PUVA in teenagers). Sunlight and
phototherapy can be beneficial if multiple areas are affected,
but care must be taken to apply sunscreen to all unaffected
areas.
3)
Systemic therapies for severe, or resistant conditions (e.g.,
methotrexate,
cyclosporine,
retinoids,
dapsone,
hydroxyurea).1,3,8,9,11
Topical Treatments
Therapy should start with a combination of emollients, topical
corticosteroids and calcipotriol, with or without the addition of
tar, salicylic acid, and other topical agents.1,3 For severe or
resistant forms systemic modalities should be implemented. The
choice of therapeutic agent should be based upon the location and
extent of the plaques, the resistance to previous modalities, the
various side-effects (see Table 2), and the cost of treatment (see
Table 3).1 As a rule of thumb, ointments are more effective than
creams, which are in turn, better than lotions. Other factors
influencing the decision include the age of the patient, type of
psoriasis, and associated medical disorders.
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 4 • April 2002
Drug
Mechanism of Action/Use
Topical Corticosteroids
Low-Potency – desonide (Desocort®, Tridesilon®),
hydrocortisone agents (Prevex HC®, Cortate®, Emo-Cort®),
hydrocortisone valerate (Westcort®)
Mid-Potency – betamethasone valerate (Celestoderm®, Prevex B®,
Betnovate®), triamcinolone acetonide (Kenalog®), mometasone
furoate (Elocom®)
High-Potency – amcinonide (Cyclocort®), fluocinonide (Lidex®),
desoximetasone (Topicort®), halcinonide (Halog®)
Ultra-Potency – halobetasol propionate (Ultravate®), clobetasol
propionate (Dermovate®), betamethasone dipropionate (Diprolene®)
• anti-inflammatory, immunosuppressive, and antiproliferative properties
• mild potency for delicate skin (face, genitals, and face)
• mid potency for torso and extremities
• high potency for recalcitrant plaques, palms, and soles.
• b.i.d. or daily with other topicals (e.g., Tazorac®, Dovonex®)
Keratolytics - salicylic acid (Keralyt®) or with Vaseline, urea
agents (Uremol®), and lactic acid (Lac-Hydrin®, Epi-Lyt®)
• remove scales or hyperkeratosis
• may be added to topical Corticosteroids (e.g., Nerisalic®, Diprosalic®)
Anthralins such as Anthra-Derm®, Drithocreme®, Dritho-Scalp®,
Micanol®
• inhibit cell growth, restores cell differentiation
Coal Tars - Estar® gel, Balnetar®, Neutrogena® T/Gel, MG271,
DHS Tar, Doak®, LCD, Targel®
•
•
•
•
Vitamin D Analogs – calcipotriol (Dovonex®, Dovobet®)
• inhibit keratinocyte proliferation
• promote keratinocyte differentiation
• available in combination with steroids (Dovobet®)
Retinoids - Tazarotene (Tazorac®), trans-retinoic acid (Retin-A®)
• mediate cell differentiation, cell proliferation
• for longterm improvement and maintenance therapy
Ureas — Uremol® 10, Uremol® 20
• thins stratum corneum, removes scaling
• enhances water binding
• good for adjuvant therapy
Emollients — petrolatum (Vaseline®), Eucerin®, Aveeno®
oilated bath, Lubriderm®, Moisturel®, Aquaphor®
• softens dry skin and relieves itching
• adjunct to most other therapies
antiproliferative, anti-inflammatory
useful in combination with UVB
shampoos effective for scalp lesions
may be added to topical emollients or steroids
Table 1: Mechanisms of Action for Topical Psoriasis Medications 1, 11, 15-17
Topical Corticosteroids
Corticosteroid efficacy is related to potency and absorption into
the skin. There are four potency levels: low, mid-, high and ultra.
A mild potency corticosteroid should be used for delicate skin,
e.g., on the face and genitals. Mid-potency corticosteroids should
be used on the torso and extremities, and high potency
corticosteroids should be used to treat recalcitrant plaques, as
well as the palms and soles. In children, the least potent topical
steroid that is effective should be used, and the strength tapered
as the condition improves. When used chronically, or at high
doses, they can cause skin atrophy, tachyphylaxis, acne, localized
hypertrichosis, striae, telangiectasia, and purpura. The may also
suppress the Hypothalamic-Pituitary-Adrenal axis.1,3,8,11,18,19
Keratolytics
These preparations act by decreasing the cell-to-cell cohesion as
measured by the ease by which layers of cells can be stripped
from the surface of treated skin. Excessive use of salicylic acid in
children can result in salicylates toxicity. The effect of these
ointments in removing scales and relieving the symptoms of
dryness is enhanced when used under an occlusive plastic
dressing (i.e., saran wrap). Children are sensitive to
alphahydroxy acid, and small areas of the skin should be tested
before applying it over wide areas. Salicylic acid is commonly
used in combination with other topical preparations (e.g.,
corticosteroids, tars, anthralins, emollients).1,3,8,11,18,19
Anthralins
Anthralins are effective in inhibiting the hyperproliferative growth
observed in psoriasis. Although it is an effective agent, it is not an
ideal drug because of irritating and staining properties. Regardless
of these shortcomings, it is the treatment of choice (in the US) for
plaque psoriasis. These agents also have the benefit of synergistic
effects when used in combination with UVB therapy, and salicylic
acids. Emollients or suitable corticosteroid may be applied after the
anthralin treatment has been washed off to potentiate the desired
clinical outcome. Common side-effects include brownish staining
of the skin, erythema, irritancy, and contact dermatitis.1,3,8,11,18,19
Coal Tar
Tar products have both anti-inflammatory as well as
antiproliferative effects. Their benefits are synergistic in
combination with steroids, emollients, and especially UVB
treatment. Coal tar can also be used effectively as a shampoo for
psoriatic scalp lesions. Side-effects include folliculitis, contact
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 4 • April 2002
5
Drug
Local and Systemic Side-Effects
Topical Corticosteroids
(at high dose and chronic use)
• skin atrophy, tachyphylaxis, acne, localized hypertrichosis, striae, telangiectasia, purpura
• may suppress the Hypothalamic-Pituitary-Adrenal axis
Keratolytics
• local irritation, salicylate toxicity (if extensive use)
Anthralins
• no systemic effects
• stains hair, nails, and local irritation of the skin
Coal Tars
• folliculitis, contact allergic dermatitis
Vitamin D Analogs
• irritant dermatitis, hypercalcemia (high dose and extensive use)
Retinoids
• local skin irritation, pruritus, photosensitivity
• possibly teratogenic
Ureas
• no major side-effects, local irritation
Emollients
• may be greasy, sticky, difficult to maintain compliance
Table 2: Adverse Effects of Topical Psoriasis Medications 1, 3, 8, 11
allergic dermatitis, aggravation of acne, and photosensitization of
the skin. Patients dislike it because it is messy, stains skin,
clothing, and bathtubs, and has an unpleasant odor.1,3,8,11,18,19
Calcipotriol
Calcipotriol, or Vitamin D analogues, act to inhibit proliferation, and
promote differentiation of keratinocytes. They are slow acting,
however, and results may not be noted for 6-8 weeks. Adverse effects
include irritant dermatitis and hypercalcemia with high doses or
extensive use. In view of the risk of hypercalcemia and high cost,
this preparation is not recommended for patients with extensive
psoriasis. However, the vitamin D analogue does not suppress the
Hypothalamic-pituitary-adrenal axis, making its use in pediatric
patients a good alternative to topical steroids. Calcipotriol has been
commercially combined with topical steroids with success, but is
not stable if compounded by an independent pharmacy. Pulse
topical steroids with maintenance calcipotriol is becoming the
standard therapy for mild-moderate plaque psoriasis.1,3,8,11,18,19
Retinoids
Tazorotene and Retin-A® are actively involved in mediating cell
differentiation, and decreasing cell proliferation. They are
nonsensitizing, nonphototoxic, and nonphotoallergenic.
Application is once daily to affected areas only, with clearing
occuring in 12 weeks. The most common side-effect is local skin
irritation, although pruritis, and photosensitivity may be
observed. These agents used orally are teratogenic, and
potentially have similar effects at high doses
topically.1,3,8,11,18,19
Ureas
Urea is aproteolytic at high concentrations. It is most useful when
applied to thickened nails secondary to psoriasis. It has also been
added to some topical glucocorticoid preparations and is useful in
treating psoriatic plaques and ichthyosis. The most common sideeffect experienced by some patients is local irritation.3,8,18,19
Drug
Cost
Topical Corticosteroids - Cost will vary according to product and strength used
• weak
• moderate
• strong
Keratolytics (Keralyt® gel)
≤$7**
Anthralins (Anthranol®, Micanol®, Anthraforte®)
$7 - $17**
Coal Tars - prices vary according to product and strength used; generic preparations available
• Estar gel/Doak Oil
Vitamin D Analogs (Dovonex®)
≤$17**
$17 - $34**
• Retin-A®
• Tazorac®
Retinoids
$17 - $34**
>$70**
Ureas (Uremol® 10, Uremol® 20)
≤$17**
Emollients (Over the counter)
≤$17**
Table 3: Cost (in USD) of topical psoriasis treatments.20,23
* Cost of 15g of topical steroids (includes drug cost only)
** Cost of 50g or 50ml or 30-day supply — includes drug cost only (excluding topical steroids)
6
≤$7*
≤$14*
$4 - ≥$14*
Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 4 • April 2002
Emollients
Emollients are occlusive agents that make the skin soft and pliable
by increasing hydration of the stratum corneum. They act to soften
dry skin and relieve itching. Petrolatum is probably the most
occlusive and therefore the best emollient available. In terms of
efficacy, the more occlusive a preparation is, the more effective it
is. In order to be most effective, emollients should be applied to
damp skin. There are no reported side-effects, but they may be
greasy and sticky, and patients may find it difficult to maintain
compliance.18,19
Cost of Psoriasis Topical Treatment
Competing therapies for the treatment of psoriasis have
substantially different cost implications. Clearly, assessment of the
cost and benefits of a treatment needs to consider all costs (direct
and indirect) as well as objective measurement of benefit (decrease
in morbidity) from the patient’s perspective. Topical
corticosteroids vary in price from <$7 to >$34USD per month
based on potency (cheaper for low potency) and vehicle (lotions
more expensive than creams and ointment). The newest topical
treatments (retinoids and Vitamin D analogues) can be extremely
expensive with monthly costs exceeding $100. Other topical
treatment options are comparable in price to the low potency
steroids, although combination therapy is commonly used in
resistant plaques and costs may become very high.18,20,21
Conclusion
The treatment of psoriasis in children differs from that in adults. It
is important to emphasize educating the family, dealing with
emotional aspects of the disease, and eliminating triggering
factors. Since psoriasis is a common dermatosis that can adversely
affect the lives of children, these patients’ treatment should be
active and effective. It is important to point out to patients that
psoriasis is not contagious, that the disease can disappear in some
cases, and that the doctor is there to help manage the problem.
There is no cure, and this disease bears an enormous emotional and
financial cost upon children and their families.
References
1.
Fitzpatrick TB, Johnson RA, Wolff K. Color Atlas and Synopsis of Clinical
Dermatology, Common and Serious Diseases. New York:McGraw-Hill (1997)
pp. 76-92.
2.
Federman DG, Froelich CW, Kirsner RS. Topical Psoriasis Therapy. Am Fam
Physician 59(4):957-62, 64 (1999 Feb).
3.
Buxton PK. ABC of Dermatology, 3rd ed. London:BMJ publishing group (1998)
pp. 12-15.
4.
Oranje AP, Marcoux D, Svensson A. Topical calcipotriol in childhood psoriasis.
J Am Acad Dermatol 36(2 Pt 1):203-8 (1997 Feb).
5.
Darley CR, Cunliffe WJ, Green CM, Hutchinson PE, Laber MR, Down N.
Safety and efficacy of calcipotriol ointment (Dovonex) in treating children with
psoriasis vulgaris. Br J Dermatol 135(3):390-3 (1996 Sep).
6.
Salleras M, Sanchez-Regana M, Umbert P. Congenital Erythrodermic Psoriasis:
Case Report and Literature Review. Pediatr Dermatol 12(3):231-4 (1995 Sep).
7.
Burden AD. Management of psoriasis in childhood. Clin Exp Dermatol
24(5):341-5 (1999 Sep).
8.
Sauer GC, Hall JC. Manual of Skin Diseases, 7th ed. Philadephia
(PA):Lipincott-Raven Publishers (1996) pp.138-143.
9.
Bork K, Brauninger W. Diagnosis and Treatment of Common Skin Diseases.
Philadephia (PA):W.B. Saunders Company (1988) pp.120-121.
10. Seyger MM, van de Kerkhof PC, van Vlijmen-Willems IM, de Bakker E, Zwiers
F, de Jong EM. The efficacy of a new topical treatment for psoriasis: Mirak. J
Eur Acad Dermatol Venerol 11(1):13-8 (1998 Jul).
11. Pardasani AG, Feldman SR, Clark AR. Treatment of Psoriasis: An Algorithm
Based Approach for Primary Care Physicians. Am Fam Physician 61(3):725-33
(2000 Feb).
12. Bhalerao J, Bowcock AM. The genetics of psoriasis: A complex disorder of the
skin and immune system. Hum Mol Genet 7(10):1537-45 (1998 Apr).
13. Weinstein GD, Keueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, for
topical thrapy of psoriasis: Vehicle-controlled study of safety, efficacy, and
duration of therapeutic effect. J Am Acad Dermatol 37(1):85-92 (1997 Jul).
14. Hagemann I, Proksch E. Topical treatment by urea reduces epidermal
hyperproliferation and induces differentiation in psoriasis. Acta Derm Venerol
76(5):353-6 (1996 Sep).
15. Bondi EE, Jegasothy BV, Lazarus GS. Dermatology: Diagnosis and Therapy.
Norwalk (CN):Appleton and Lange (1991) pp. 14-20.
16. Baker H, Pegum JS. Clinical Dermatology, 4th ed. London: Bailliere-Tindall
Publishers (1989) pp.104-106.
17. Dezfoulian, B., et al., A new generation of hydrocolloid dressings in
combination with topical corticosteroids in the treatment of psoriasis vulgaris.
J Eur Acad Dermatol Venerol (1997).
18. Freedberg IM, Fitzpatrick TB. Fitzpatrick’s Dermatology in General Medicine,
5th Edition. NY:McGraw-Hill (1999).
19. Roenigk HH, Maibach, HI. Psoriasis, 3rd Edition, Revised and Expanded.
NY:Marcel Decker, Inc. (1998).
20. Marchetti A, LaPensee K, An P. A Pharmacoeconomic analysis of topical
therapies for patients with mild-to-moderate plaque psoriasis: A U.S. study. Clin
Ther 20(4):851-69 (1998 Jul-Aug).
21. Gray J, Gillis AM, editors. Therapeutic Choices, 3rd edition. Ottawa: Canadian
Pharmacists Association (2000).
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Skin Therapy Letter • Editor: Dr. Stuart Maddin • Vol. 7 No. 4 • April 2002
7
Update on Drugs
Class
Name/Company
Antiinflammatory
Agent
Fluocinolone Acetonide,
Hydroquinone, Tretinoin
Tri-Luma®
Hill Dermaceuticals
Pimecrolimus
Atopic
®
Dermatitis Agent Elidel
Novartis
Approval Dates and Comments
The US FDA approved this anti-inflammatory agent in January
2002, for the short-term treatment of moderate-to-severe melasma
of the face, combined with sun avoidance measures that include the
use of sunscreens.
The Danish Medicines Agency approved this non-steroid atopic
dermatitis agent in March 2002, for patients from as young as 3
months of age through to adulthood. Denmark is the first country in
Europe to approve this cream.
Anti-acne Agent
Clindamycin, Zinc
Zindaclin™ Gel
Access Pharmaceuticals
The UK Medicines Control Agency approved this ant-acne agent in
Feb 2002, for the treatment of acne. Zindaclin™ is a clindamycin
zinc complex in a gel formulation that has a prolonged residence in
the skin, thereby reducing systemic absorption and its associated
side-effects. Clinical studies demonstrated that once-daily dosing
was equivalent to the twice per day application required by the
market-leading clindamycin product.
Antifungal
Agent
Voriconazole
Vfend®
Pfizer
The European Commission of the European Union authorized
marketing of both the oral and IV formulations of this antifungal
agent in March 2002, for treatment in immunocompromised patients
with progressive, possible life-threatening infections that include
acute invasive aspergillosis; fluconazole-resistant invasive Candida;
and serious fungal infections caused by Scedosporium spp. and
Fusarium spp.
Antiviral Agent
Imiquimod
Aldara® 5% Cream
3M Pharmaceuticals
The US FDA approved a broader indication for this antiviral agent
in March 2002, to include adolescents 12 years of age and older for
treatment of external genital warts. It was previously approved for
patients 18 years and older.
Drug News
Antifungal
Agents
Ten patients with moccasin tinea pedis, a hard-to-treat chronic foot fungus all recovered following
treatment with Carmol 40® cream (40% urea, Bradley Pharmaceuticals) combined with ciclopirox cream.
A larger study is planned to verify the findings. In vitro studies had shown synergy between Carmol 40®
and ciclopirox, i.e., the two compounds alone significantly reduced fungus counts after three days, but
completely eradicated the fungus within 6 hours when given together.
Human
Papilloma Virus
According to a recent large-scale study of women in western Washington in the US, infection with HPV
can be a serious risk factor for vaginal cancer. Like cervical and other anogenital cancers, vaginal cancer
was found to be strongly associated with prior infection of this virus. The results, published in
Gynecologic Oncology*, suggest that women with genital warts should be monitored for the development
of multiple anogenital cancers.
* Gynecological Oncol 84(2):263-70 (2002 Feb).
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the consequences of any such inaccurate or misleading data, opinion or statement. While every effort is made to ensure that drug doses and other quantities are presented accurately, readers are advised that new methods and
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