Topical retinoids – Acne vulgaris Pathophysiology and Therapy


Acne vulgaris is a common dermatological complaint, accounting for over 30% of all visits to dermatologists. It is a multifactorial disease in which genetics and hormonal changes play a role in its development. The clinical lesions of acne develop from several steps, beginning with androgen stimulation of the sebaceous glands at or around puberty (1). This stimulates sebum production; the constituents of sebum are comedogenic and contribute to early changes of the follicle that lead to the microcomedo, the precursor lesion of acne vulgaris.

The microcomedo is a dense and cohesive corneal layer that accumulates along with sebum and occludes the follicle instead of naturally desquamating. Through resultant distention, the follicle may mature into open comedones of noninflammatory acne. This occluded, anaerobic, and lipid-rich environment supports the proliferation of the bacterium Propionibacterium acnes (P. acnes), a resident member of cutaneous flora. P. acnes was discovered to play a role in acne pathogenesis in the mid-1970s when treatment with tetracycline was asso-ciated with a decrease in P. acnes and free fatty acids in the surface lipid film.

P. acnes secretes chemotactic factors, attracting neutrophils to the occluded follicle. After phagocytosing P. acnes, hydrolytic enzymes are released by the neutrophils, activating complement and inflammation and breaks down the follicular wall. This leads to the characteristic inflammatory papules and pustules of acne vulgaris (2).


Topical retinoids play a major role in dermatology for the treatment of acne vulgaris. Retinoids are also used for the treatment of an array of dermatoses including acne and other acneiform disorders, photoaging, preneoplastic and neoplastic lesions, ichthyosiform disorders, psoriasiform disorders, keloids, and pigmentation disorders (3). These disorders all demonstrate an abnormal or dysfunctional epidermis.

Retinoids are a class of biologically active compounds that are structurally and functionally related to vitamin A (4). They have a wide range of biologic functions affecting cellular growth. Retinoids promote the proliferation of basal keratinocytes and prevent terminal stages of epithelial differentiation, instead directing keratinocytes to follow a normal or hyperproliferative state, and thus functions as an anti-keratinization agent (5,6). Reversal of abnormal keratini-zation by retinoids is due in part to the reduction of filaggrin expression and suppression of the proteolysis of keratins 1 and 14 (6). This contributes to the normalization of the epidermis.

The advantage of a topical retinoid over a systemic retinoid is its site specificity. This allows treatment of cutaneous lesions without inducing the various adverse effects of systemic retinoids. There are several topical retinoids available, and thus it is important for the clinician to understand their similarities and differences when choosing agents to manage their patients. The most widely used retinoids include topical tretinoin, adapalene, tazarotene, and oral and topical isotretinoin. Topical retinoids inhibit the formation of noninflammatory microcomedones and inflammatory acne lesions, as well as decrease the number of lesions (7). Recently, evidence has shown that inflammatory events can occur prior to microcomedo formation and that the development of plugs is influenced in part by the inflammation caused by P. acnes (8). Retinoids also exhibit direct anti-inflammatory activity (9).

Alterations of cellular growth, differentiation, and maintenance of epi-dermal tissue by retinoids are mediated by two classes of nuclear receptors: retinoic acid receptors (RARs) and retinoic X receptors (RXRs). RARs are divided into three subtypes: a, R, and y. RAR-a is widely found in embryonic and adult tissues; RAR-R is found only in dermal fibroblasts; and RAR-y is widely found in human epidermis and is thought to be the major receptor reg-ulating the effects of retinoids on keratinocytes (10). Tretinoin, a first-generation retinoid, has shown nearly equal affinity for all three receptors, but it may have the highest affinity for the y-receptor. Adapalene, a third-generation retinoid, has shown to bind strongly to RAR-R and -y; RAR-y is the prominent receptor found in epidermal and epithelial cells, allowing for topical retinoids to specifically affect comedonal proliferation.

The major adverse effect of topical retinoids is local irritation, including dry skin, discomfort, erythema, and scaling. Other elements contributing to irritation include quantity applied, site and frequency of application, irritation from washing, other medications, and skin type (11). With use of topical reti-noids over time, skin irritation subsides. Additionally, several studies have demonstrated that topical tretinoin is neither photoallergic nor a photosensitizer. Furthermore, because of insignificant percutaneous absorption of tretinoin, long-term application of topical tretinoin has not been associated with the teratogenic effects shown with systemic use (12).


Topical tretinoin was the first FDA-approved topical retinoid and has remained a standard for acne therapy since the pioneer study of Kligman et al. in 1969 (13). In this study, Kligman et al. demonstrated that a 0.1% tretinoin solution most significantly reduced acne lesion counts in comparison with benzoyl peroxide, sulfur-resorcinol, and vehicle (13). Kligman et al. also noted spontaneous extrusion of comedonal material, which correlated with the histology of treti-noin-treated skin, including acanthosis, parakeratosis, and thinning and decreased cohesiveness of the stratum corneum (13). By its ability to thin the stratum corneum, topical tretinoin allows improved penetration and efficacy of topical antimicrobial agents such as benzoyl peroxide (14).

Tretinoin binds with equal affinity to all RAR subtypes. It is available as a cream (0.025%, 0.05%, 0.1%, and 0.4%), gel (0.01%, 0.025%, and 0.05%), microsphere gel (0.04% and 0.1%), liquid (0.025%, 0.05%, and 0.1%), lotion (0.1%), ointment (0.05%), compress (0.05%), and polymer cream (0.025%) (15). It is also available in Canada in combination with erythromycin and/or with a sunscreen. Many trials have demonstrated that tretinoin as a single agent sig-nificantly reduces both noninflammatory and inflammatory acne lesions, and global severity for periods of up to 12 weeks (16,17). A reduction in lesions may be noted after two to three weeks, but the greatest improvement is noted after three to four months. Common cutaneous adverse effects include desquamation, erythema, burning, and pruritus. Tretinoin binds and upregulates cellular retinoic acid binding protein II(CRABP II), an intracellular binding protein found widely in the skin. The action that tretinoin exerts on CRABP II is a possible reason for the greater level of irritation caused by tretinoin compared with topical retinoids of later generations (18). Tretinoin is also highly unstable when exposed to oxygen and light. Improved tolerability has been achieved by a microsphere formulation, which gradually releases tretinoin over time (Retin-A Micro). This microsphere formulation also prevents degradation by oxidants such as benzoyl peroxide and ultraviolet light (19).


Topical isotretinoin, the 13-cis-isomer of tretinoin, although not available in the United States, is widely available throughout most of the rest of the world and has an established record of safety and efficacy in the treatment of acne. It is available as a single agent topical formulation and, in some countries, combined with erythromycin.


Tazarotene is a member of the third generation of receptor subtype specific retinoids, which maintain efficacy while offering a reduced adverse effect pro-file. It regulates keratinocytes through the RAR-R and RAR-,y subtypes. It is available in a gel and cream formulation, containing either 0.05% or 0.1% of tazarotene. Both formulations were found to significantly reduce non-inflammatory acne and lesion counts when compared with vehicle at 4 to 8 weeks; the 0.1% formulation continued to reduce inflammatory lesions at 12 weeks (20). In a trial comparing tazarotene 0.1% with tretinoin 0.1% microsponge gel, tazarotene was shown to be more efficacious than tretinoin in reducing noninflammatory lesion count (21). When adapalene was introduced, a trial comparing adapalene 0.1% gel with tazarotene 0.1% gel demonstrated that tazarotene was more effective in decreasing numbers inflammatory and non-inflammatory lesions than adapalene (22). Additionally, topical tazarotene plus oral minocycline showed greater efficacy as a maintenance therapy for acne vulgaris, but did not show statistically significant reductions in lesion count when compared with tazarotene alone (23).

For the treatment of noninflammatory lesions, tazarotene has been shown to work best as monotherapy; several studies comparing the efficacy of tazar-otene with standard acne therapy agents such as benzoyl peroxide gel, eryth-romycin/benzoyl peroxide cream, and clindamycin showed that monotherapy was superior to all combinations for the reduction of noninflammatory lesions (24). In combination, tazarotene plus clindamycin was superior for overall improvement. Additionally, a recent study demonstrated that tazarotene 0.1% cream appeared to be more effective and nearly as well tolerated as adapalene 0.3% gel in reducing lesion count and acne severity, and was more effective than adapalene 0.3% gel in reducing postinflammatory hyperpigmentation (25).


Adapalene is a member of the third generation of receptor subtype specific retinoids, available in 0.1% and 0.3% gel, and 0.1% cream formulations. Adapalene shows the greatest affinity for the RAR-,y and RAR-R subtypes. Topical adapalene is a safe and effective retinoid for the treatment of acne vulgaris (26,27). Compared with tretinoin 0.025% gel, adapalene 0.1% gel showed similar efficacy in reducing inflammatory and noninflammatory lesions, and global severity in several randomized trials (28 32). In a trial comparing adapalene 0.1% gel with tazarotene 0.1% gel, daily tazarotene 0.1% was more effective than daily adapalene 0.1% gel in reducing inflammatory and non-inflammatory lesions (22). However, this study did not include the microsphere formulation of topical tretinoin. When combined with doxycycline, adapalene has been shown to be significantly more effective for the treatment of acne than doxycycline alone (33). Several studies demonstrated that a combination of adapalene 0.1% gel plus clindamycin 1% lotion twice daily was significantly more effective in reducing acne lesions and global severity compared with clindamycin 1% lotion twice daily plus gel vehicle (34).

Adapalene is well tolerated and shows a lower adverse effect profile when compared with other topical retinoids including tretinoin gel and cream at 0.01%, 0.025%, and 0.05%, tretinoin 0.1% and 0.04% microsphere gel, 0.5% and 0.1% tazarotene gel and benzoyl peroxide (35 39).


The current consensus for the treatment of both noninflammatory and inflammatory acne is the use of both topical retinoids and antimicrobial therapy to provide combination therapy, targeting the different pathophysiologies of acne. Recent in vitro studies have shown that the third-generation retinoid adapalene was significantly more stable than the first-generation retinoid tretinoin in the presence of light, clindamycin, and oxidizing agents such as benzoyl peroxide. The unstable, light-sensitive double bonds present in the chemical structure of tretinoin are absent and are replaced by the more stable naphthoic acid aromatic rings in adapalene (40). This is important because benzoyl per-oxide is often given concurrently with retinoids for its safe, effective anti-microbial activity against P. acnes. Additionally, adapalene has demonstrated targeted delivery to the microcomedo. Clinical trials comparing adapalene 0.3% with another third-generation retinoid tazarotene 0.1% have shown these to be therapeutically similar in efficacy for the reduction of inflammatory and non-inflammatory lesions, but adapalene was significantly better tolerated than tazarotene.

Topical retinoids have been shown to permit greater penetration and efficacy of topical antimicrobials because of their effect of thinning of the stratum corneum, as mentioned previously. This allows for a multitude of combination therapies to suppress the proliferation of P. acnes in micro-comedones to treat inflammatory lesions (41). Recently, a fixed-combination therapy containing topical adapalene 0.1% and benzoyl peroxide 2.5% has demonstrated significant efficacy in addressing comedones, P. acnes, and inflammatory lesions of acne vulgaris (42). Adapalene 0.1%/benzoyl peroxide 2.5% fixed-combination therapy offers an advantage over monotherapies, with significant differences in lesion counts observed as early as one week after initiating therapy (43). Adapalene 0.1%/benzoyl peroxide 2.5% fixed-combination therapy is safe and effective for up to 52 weeks of use (44).

Another recent fixed-combination therapy containing topical tretinoin 0.025% and clindamycin 1.2% has been shown in a large randomized control study to significantly reduce inflammatory, noninflammatory, and total acne lesions after 12 weeks of treatment (45). This combination therapy was sig-nificantly more effective than monotherapy or vehicle alone, and demonstrated excellent tolerability and safety after 52 weeks of use (45).

Topical retinoids have been a safe and efficacious treatment of acne vulgaris for decades. Recent advances in retinoid development have allowed for other treatment modalities to be administered in fixed-combination formulations, offering clinicians and their patients increased tolerability and efficacy.


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Jean-Paul Marat

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