Topical Retinoids in the Treatment of Acne Vulgaris

Topical Retinoids in the Treatment of Acne Vulgaris
Andrea L. Zaenglein, MD
Topical retinoids are highly effective in the treatment of both comedonal and inflammatory
lesions of acne and are a vital part of almost any acne regimen. A better understanding of
the structure and function of this class of medications has led to better outcomes in
treatments of patients with acne. In this article, the structure and function of retinoids is
first reviewed. Then, the clinical effectiveness and tolerability of each of the available
topical retinoid formulations is summarized.
Semin Cutan Med Surg 27:177-182 © 2008 Elsevier Inc. All rights reserved.
T
he effects of topical tretinoin (all-trans retinoic acid)
were first realized by the German researchers Stuttgen
and Beer in 1962. They were studying the effects that the
retinoid had on epidermal differentiation and keratinization,
focusing the clinical application toward the treatment of the
ichthyoses. By the late 1960s, however, Kligman et al had
realized the potential of tretinoin in the treatment of acne.1 As
a result of their efforts, the first topical retinoid was introduced for the treatment of acne in 1972.
Retinoid Metabolism
The retinoids are classically described as a group of compounds with similar chemical structures exerting similar biologic effects. That said, many synthetic retinoids have dissimilar structures but still have retinoid activity. Therefore,
function, the ability to bind retinoid receptors and activate
the retinoid pathway, truly dictates what a retinoid is. The
naturally occurring retinoids all work along the vitamin A
pathway. They are considered vitamins in that they are necessary in small amounts for the body to function properly.
However, the body does not intrinsically produce these substances; they therefore must be acquired from the diet. The
primary dietary source of vitamin A is from foods of animal
origin, usually in the form of retinylpalmitate, which is subsequently converted by the small intestine to the alcohol
form, retinol (vitamin A). Retinol is the main transport and
storage form in the body with cytosolic binding protein
(CRBP)-facilitating enzymatic functions. Intracellular transport and functioning is mediated by the cytosolic retinoic
Departments of Dermatology and Pediatrics, Penn State/ M.S. Hershey Medical Center, Hershey, PA.
Address reprint requests to: Andrea L. Zaenglein, MD, Associate Professor of
Dermatology and Pediatrics, Department of Dermatology, HU14, Penn
State/ M.S. Hershey Medical Center, 500 University Drive, Hershey, PA
17033. E-mail: [email protected]
1085-5629/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.sder.2008.06.001
acid binding proteins (CRABP-1, CRABP-2). Once absorbed,
retinol is reversibly converted to retinaldehyde (retinal),
which then can be irreversibly metabolized to all-trans retinoic acid (tretinoin), the alcohol form (Fig. 1). The carotenoid, ␤-carotene is a highly lipophilic, plant-derived retinoid that is considered a previtamin because it can be
converted into retinaldehyde, entering the vitamin A pathway at that step. Inside the cell, all-trans retinoic acid is the
primary form seen. However, the isomers, 9-cis retinoic acid
(alitretinoin) and to a lesser extent, 13-cis retinoic acid
(isotretinoin) are also found.
Retinoid Receptors
The metabolites of vitamin A work as hormones. They bind
to specific receptors, exert their effects, and are subsequently
metabolized to inactive forms. There are 2 distinct types of
retinoid receptors in the human body: RAR (retinoic acid
receptors) and RXR (retinoid X receptors).2,3 RAR is composed of 3 isoforms, RAR␣, RAR␤, and RAR␥, each encoded
by separate genes.4 These receptors are ligand-dependent
transcriptional factors that belong to the steroid-thyroid hormone family.5 The concentration and activity of each type of
retinoid receptor varies by tissue type throughout the body.
RAR␥ is the most abundant type seen in cutaneous epithelium, whereas RAR␤ is not found in the skin.6 Different retinoid isomers also exhibit different binding affinities for these
retinoid receptors. 9-cis retinoic acid is a ligand for both RAR
and RXR, whereas all-trans retinoic acid (tretinoin) has binding affinity only for RAR.2,7 13-cis retinoic acid (isotretinoin)
does not bind retinoid receptors directly, making its mechanism of action still unclear.8 These possible combinations
make the effects of retinoids vital and varied throughout the
entire body.
Retinoid receptors work together in specific pairs to function (Fig. 1). RAR must combine as a heterodimer with RXR
177
A.L. Zaenglein
178
retinyl esters
retinol
β-carotene
retinaldehyde
retinaldehyde
all trans
retinoic acid
Coactivators
All trans RA
9-cis RA
RXR
RAR
RARE
Nucleus
DNA
Polymerase
Gene
Transcription
Cytoplasm
Figure 1 Metabolism and mechanism of action.
(RAR–RXR).9 RXR, however, can function as a homodimer
(RXR–RXR) or bind with several other members of the steroid–thyroid superfamily, including thyroid hormone, vitamin D3, and peroxisome proliferator-activated receptors.10
Once coupled, the retinoid receptordimers localize to the cell
nucleus and bind specific DNA regulatory sites, called retinoic acid response elements (RAREs).11 In doing so, depending on the conformation and ligand pairings, a variety of
transcription activators and repressors are induced. Through
other mechanisms not involving RAREs, retinoids also exert
indirect effects on transcription through antagonism of other
transcription factors, such as the proinflammatory and proliferative mediators like AP1.12-14 These mechanisms are
thought to contribute to the antiproliferative and antiiflammatory properties of retinoids.
sponses; and (4) inflammation.16 Although retinoids have no
direct effect on decreasing sebum production, the other three
factors are closely linked. Modulation of one will often have a
direct or indirect effect on another.
The first step in controlling acne is to normalize keratinization. Hyperproliferation of the basal keratinocytes has long
been recognized as a major step in the pathogenesis of acne.17
Retinoids, in turn, have been established as the treatment of
choice for comedonal lesions. Additionally, they have recently been shown to work preventatively in suppressing
new comedone formation through inhibition of
the microscopic precursor lesion, the microcomedone.18,19
The effects of retinoids on keratinization at the cellular level
are just being identified, including regulation of keratinocyte
proliferation through RAR–RXR-mediated gene transcription, increased expression of CRABP1, and through indirect
effects on cellular signaling.20,21
Of late, retinoids also have been recognized for their inherent antiinflammatory properties. Inflammation occurs
very early in the onset of acne lesions.22 Proinflammatory
cytokines, including interleukin (IL)-1␣, leukotriene B4, tumor necrosis factor-␣, IL-␤, IL-12, and IL-8, are all up-regulated in lesions of acne.23-26 Retinoids work to decrease inflammation by several pathways. One mechanism is through
the toll-like receptor pathway. Propionibacterium acnes has
recently been recognized to induce toll-like receptors (TLR2,
TLR4) as a part of the body’s innate immune function.27,28
These receptors are located on monocytes in the perifollicular
region and, on activation by P. acnes, induce proinflammatory mediators such as tumor necrosis factor-␣, IL-␤, IL-12,
and IL-8.27,29 Both all-trans retinoic acid and adapalene have
been shown to down-regulate TLR2 through both a direct
and indirect means.30,31 Retinoids also regulate AP-1, a controller of several genes that regulate cellular proliferation and
inflammation.32
Functions of Retinoids
Formulations
There are 4 main physiologic functions of retinoids in the
body.15 The first is to ensure normal embryonic development, the importance of which is evidenced by the welldescribed effects of an excessive retinoid state during pregnancy, isotretinoin-induced embryopathy. The second role
of retinoids in the body is to normalize epithelial differentiation in varying tissue types, including the skin. This effect is
used in the treatment of acne as well as the ichthyoses. Third,
retinoids maintain healthy vision through the production of
rhodopsin, an 11-cis-retinaldehyde-containing eye pigment
that enables night vision. Finally, retinoids are required for
adequate immune function and lymphocyte survival.
The cellular interplay of the retinoids with their receptors
and the downstream effects of their transcription regulation
are seen clinically in the example of acne. Topical retinoids
perform many functions that directly affect the 4 major
pathogenic steps in the production of acne: (1) increased
sebum production; (2) abnormal keratinization of the follicular infundibulum; (3) Propionibacterium acnes-mediated re-
There are 3 generations of retinoids based on their chemical
structure. The first generation includes retinol, tretinoin, and
isotretinoin. The second-generation retinoids are etretinate
and its metabolite acitretin. The synthetically produced tazarotene, adapalene and bexarotene make up the third generation of retinoids (Fig. 2). A list of currently available topical
retinoid formulations is listed in Table 1.
Tretinoin
Tretinoin was the first retinoid used for the treatment of acne.
The efficacy of the early preparations of tretinoin were somewhat limited by cutaneous irritation. However, newer formulations afford much greater tolerability than the early prototypes. Advances in drug-delivery systems have also yielded
good results with less irritation.
Tretinoin is the only topical retinoid available in generic
formulations, often making it the drug of choice for patients
with limited financial means or highly restrictive formularies.
Topical retinoids in the treatment of acne vulgaris
179
Table 2 Comparative Cost of Select Retinoids*
Tretinoin
Adapalene
Tazarotene
Tretinoin/
clindamycin
Tretinoin 0.025% cream
Avita® 0.025% gel
Retin-A Micro® 0.1% gel
Atralin™ 0.05% gel
Differin® 0.1% gel
Tazorac® 0.1% cream
Ziana™ 0.025%/1.2% gel
45
45
45
45
45
30
30
g
g
g
g
g
g
g
$59.80
$85.77
$149.42
$175.89
$168.79
$287.35
$170.44
Average price without insurance from CVS and Walmart (5/3/08).
Figure 2 Structure of topical retinoids used in the treatment of acne:
the chemical structure of the retinoid determines its ability to bind
retinoic acid receptors.
Avita®, like Retin-A Micro®, takes advantage of new vehicle technology, making improvements on the original tretinoin formulations. In this product, the tretinoin is enmeshed
within a polyoylprepolymer, creating a delayed, controlled
release of the medication. Avita is available as a 0.025%
cream and gel.
Atralin™ is a newer branded retinoid formulated to have
less irritation. It is available as a 0.05% aqueous gel containing the moisturizers, soluble collagen and sodium hyaluronate, as well a humectant, glycerin. It should be noted that
the collagen in Atralin™ contains soluble fish proteins and
should not be used in any patients who have a known fish
allergy.
Adapalene
A list of average prices of topical retinoid formulations is
listed in Table 2. Generic tretinoin is available in 0.025%,
0.05% and 0.1% cream, and a 0.01% and 0.025% alcoholbased gel. Generic tretinoin 0.05% liquid is currently the
only available topical retinoid in a liquid form.
Retin-A Micro® was the first formulation with a modified
vehicle developed to combat the inherent irritancy of tretinion. Inert microspheres embedded with tretinoin rest on the
cutaneous surface and slowly release the retinoid. It is available in a 0.04% and 0.1% nonalcohol gel formulation. It is
also the only retinoid that comes in a pump dispenser.
Adapalene (Differin®) was the first synthetic retinoid used in
the treatment of acne vulgaris. It is a highly lipophilic compound, derived from naphthoic acid, which is easily taken up
by the pilosebaceous unit. Because of its lipophilic nature,
systemic absorption is minimal and no evidence of teratogenicity has been reported. Once in the cell, adapalene can
directly bind RAR␤/␥ and exert its effects, but does not bind
the CRABPs.33,34 This retinoid has been shown to regulate
keratinization and has antiinflammatory properties as well.
Adapalene is available as a 0.1% aqueous based non irritating gel formulation. Recently, adapalene has become avail-
Table 1 Topical Retinoids Available in the United States
Generic
Single-agent products
Tretinoin
Trade
Retin-A®
Retin-A Micro®
Avita®
Atralin™
Generic
Adapalene
Differin®
Tazarotene
Tazorac®
Combination products
Tretinoin/clindamycin
Ziana™
Vehicle
Concentration
Size
Cream
Gel
Liquid
Gel with microsponge
Cream
Gel
Gel
Cream
Gel
Cream
Gel
Cream
Gel
0.025%, 0.05%, 0.1%
0.01%, 0.025%
0.05%
0.04%, 0.1%
0.025%
0.025%
0.05%
0.025%, 0.05%, 0.1%
0.025%, 0.1%
0.1%
0.1%, 0.3%
0.1%
0.1%
20 g, 45 g
15 g, 45 g
28 mL
20 g, 45 g, 50-g pump
20 g, 45 g
20 g, 45 g
45 g
20 g, 45 g
15 g, 45 g
45 g
45 g
30 g, 60 g
30 g, 100 g
Gel
0.025%/1.2%
30 g, 60 g
A.L. Zaenglein
180
able in a higher concentration of 0.3% gel as well. In clinical
trials, adapalene 0.3% gel has shown greater efficacy than
adaplene 0.1% gel and vehicle.35
The mainstay of adapalene’s marketing is its superior tolerability. Numerous studies, including head-to-head comparisons with its competitors, have been performed by the
manufacturer. Although the frequency and type of cutaneous
adverse events can be fairly high even with adapalene, they
are generally milder in severity than with the other retinoids.36
Tazarotene
Tazarotene (Tazorac®) is another synthetically produced retinoid commonly used in the treatment of acne. It is quickly
hydrolyzed to its active metabolite, tazarotenic acid and is
able to bind all 3 RAR␣/␤/␥. Although its affinity is for
RAR␤/␥, its primary effects include regulation of cell differentiation and down-regulation of proinflammatory mediators (IL-6, migration inhibition factor-related protein).12
Taking advantage of its antiproliferative properties through
AP1 and the down-regulation of ornithine decarboxylase and
keratins 6/16, tazarotene is also used topically in the treatment of psoriasis.12,37
It is formulated as a 0.05% and 0.01% gel and cream. Both
concentrations are approved by the Food and Drug Administration for psoriasis, but only the 0.1% gel or cream is
approved for acne. Irritation is not uncommon with tazarotene use. Approximately, 10 to 30% of patients experience
peeling, dryness, irritation and burning with its use, mostly
during the early weeks of therapy.
cal antibiotics may increase the risk of bacterial transfer of
resistance factors.38 The package insert states that clindamycin also has neuromuscular blocking properties of its own
that may enhance the effects of neuromuscular blocking
agents. This should be noted in any patients receiving concomitant botulinum toxin injections.
Efficacy
Comparing efficacies of the 3 major commercially available
retinoids is difficult because there are no head-to-head, placebo-controlled trials matching all 3 medications against
each other. Each have proven efficacy in treating both comedonal and inflammatory acne. The only 3-way comparison
noted was a retrospective, investigator blinded, photographic
review documenting the efficacy of tazarotene 0.1% gel, adapalene 0.1% gel, tretinoin 0.1% microsponge, tretinoin
0.025% gel in the treatment of inflammatory acne.39 All retinoid formulations resulted in significant clinical improvement with tazarotene 0.1% gel edging out the others. A prospective study would be needed to fully document relative
efficacies of the 4 retinoids.
A listing of select clinical trials comparing 2 of the 3 available retinoids is given in Table 3. In general, adapalene 0.1%
gel and tretinoin 0.1% microsphere formulations are comparable in efficacy. Tazarotene 0.1% cream was shown most
effective but overall was the most irritating. In most studies
involving adapalene, it was shown to have the least severity of
adverse cutaneous reactions.
Other Retinoids
Compatibility and Stability
Motretinide, isotretinoin and retinoyl ␤-glucuronide are additional topical retinoid formulations used in the treatment of
acne. Although used widely in the European Union, they are
currently not available in the U.S. market.
It is well established that combination therapy works faster
and is more effective than monotherapy with any single
agent. In patients with mild-to-moderate mixed inflammatory and comedonal acne, a combination of a topical antimicrobial, either benzoyl peroxide or antibiotic, is considered
optimal.16 It is important then to consider the compatibility
of all the individual agents together when choosing a retinoid.
By far, one of the most common combinations is the use of
benzoyl peroxide with a retinoid. Tretinoin is significantly
degraded, up to 89%, by the coadministration of benzoyl
peroxide.40,41 To combat this interaction, prescribers have
long recommended using benzoyl peroxide in the morning
Combination Products
Ziana™ (clindamycin phosphate 1.2% and tretinoin 0.025%) is
the first tretinoin-containing combination product available.
It is formulated in an aqueous, glycerin-containing gel. This
product should not be used with any erythromycin-containing products, and the two have in vitro antagonism of questionable significance. In addition, combining different topi-
Table 3 Select Studies Comparing Efficacy of Topical Retinoids
Adapalene
Tretinoin
Study Comparisons
n
Eff.
Tol.
Eff.
Tol.
Adapalene 0.1% gel vs Tretinoin 0.05% cream
Adapalene 0.1% gel vs Tretinoin 0.1% microsphere gel
Adapalene 0.1% gel vs Tretinoin 0.05% cream
Adapalene 0.1% gel vs Tazarotene 0.1% gel
Tazarotene 0.1% cream vs Adapalene 0.1% gel
Tazarotene 0.1% cream vs Tretinoin 0.1% microsponge gel
Tazarotene 0.1% cream vs Tretinoin 0.025% gel
409
40
25
173
145
169
143
ⴝ
ⴝ
ⴚ
ⴚ
ⴚ
ⴙ
ⴙ
ⴝ
ⴙ
ⴙ
ⴝ
ⴝ
ⴙ
ⴚ
ⴚ
ⴝ
ⴚ
ⴚ
ⴝ
ⴙ
ⴙ, has shown greater tolerability or efficacy; ⴚ, has shown less tolerability or efficacy; ⴝ, no difference noted.
Tazarotene
Eff.
Tol.
ⴙ
ⴙ
ⴙ
ⴙ
ⴚ
ⴝ
ⴚ
Topical retinoids in the treatment of acne vulgaris
and applying tretinon in the evening, easily bypassing the
potential for tretinoin degradation. The modified version of
tretinoin in microsphere formulation, has been shown to be
much more stable in the presence of benzoyl peroxide.40
Studies combining benzoyl peroxide and clindamycin with
tretinoin 0.01% microsphere showed some degradation but
was stable at 6 hours.42 Adapalene is the first retinoid on the
market that a combination formula containing a benzoyl peroxide is currently in trials. The stability of tazarotene in the
presence of benzoyl peroxide cannot be accurately measured
due to its rapid metabolism to it active metabolite, tazarotenic
acid.43
Early formulations of tretinoin also had the problem of
degrading when exposed to ultraviolet light. This has led to
the almost universal recommendation of nightly retinoid application that still holds as dogma today. The newer formulations of tretinoin as well as adapalene have documented
stability in ultraviolet light.44
Side Effects
It is important to provide patients with education on how to
control irritancy and improve tolerability of all of the retinoids. Physicians should inquire about a patient’s cleansing
routine, carefully noting the patient’s preferred cleanser.
True soaps should be avoided. Because of their high pH,
soaps can increase the innate irritancy of the retinoid. An
alkaline soap will strip the natural lipids from the skin’s surface, priming the skin for irritation. Instead a syndet, or synthetic detergent, should be used as they have been formulated with a lower pH to closely mimic the skin’s own pH of
5.5. In general twice daily cleansing is recommended. This
establishes good habits and enforces the routine of applying
medications twice daily as well.
If patients are experiencing erythema and dryness, decreasing the application frequency of the retinoid to every
other night or so can give the patient’s skin time to develop
tolerance. In general, tolerance of the retinoid is achieved
within about 3 weeks. As the irritation subsides, the patient
can then slowly increase the frequency of application to
nightly.
Because retinoids work by increasing the rate of desquamation of the stratum corneum, patients often notice a fine
peeling on the surface of the skin not associated with erythema. This side effect can be controlled by gentle exfoliation
with a washcloth, followed by application of a bland moisturizer. The peeling is generally temporary or sporadic in
nature and is usually self-limited.
Another well-described side effect is a flare of acne within
the first few weeks of starting a topical retinoid. This flare-up
will resolve with continued use of the medicine. By informing
patients of this possible flare at the onset of therapy, knowing
that it will resolve with continued treatment, goes a long way
to ensure continued compliance.
Although retinoids are not true photosensitizers, some patients experience increased photosensitivity to the sun while
on retinoids. Patients should be warned about this ahead of
time as they are sure to read about it in the package insert or
181
pharmacy information sheets. The mechanism of the photosensitivity is 2-fold. Any irritation of the skin will surely alter
the skin’s natural photoprotection and enhance ultraviolet
damage. Also, because the retinoids work by decreasing the
thickness of the stratum corneum, the photobarrier is reduced as well. Patients should be instructed to use a recommended sunblock liberally, especially when prolonged ultraviolet exposure is anticipated.
The issue of pregnancy and topical tretinoin use is interesting. Neither animal nor human data have shown a significant risk for tretinoin-induced malformations with topical
application.45,46 That said, given the well-known teratogenicity of oral isotretinoin, most dermatologists, erring on the
side of caution, do not recommend the use of any retinoids
while a woman is pregnant or breastfeeding. Most topical
retinoids carry a Food and Drug Administration pregnancy
category of C, with the exception of tazarotene. Because tazarotene is also approved for psoriasis, a condition where the
total body surface area affected can exceed 35%, the risk of
fetal exposure is higher. Thus, it carries a pregnancy category
rating of X. All females of child bearing potential should be
counseled on adequate birth control and instructed to discontinue using tazarotene if they plan to become pregnant.
The manufacturer also recommends confirming a negative
pregnancy test 2 weeks before starting tazarotene.
Conclusions
First introduced to the market more than 30 years ago, the
effects of tretinoin in the treatment of acne were only just
being elucidated. Now, with advances in our understanding
of retinoid metabolism and the pathogenesis of acne, the
clinical relevance of these medications has only grown. Topical retinoids have repeatedly been shown to be an effective,
first line therapy for both comedonal and inflammatory acne.
Combination with antimicrobial agents will enhance their
effects and optimize treatment regimens, resulting in better
outcomes for patients.
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