Topical Retinoids in Clinical Practice: The Treatment of Acne Pathogenesis of Acne Vulgaris

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Topical Retinoids in Clinical Practice: The Treatment of Acne
Pathogenesis of Acne Vulgaris

Acne vulgaris is the most common skin disorder.[10] It is a chronic inflammatory process that results from the formation of a plug composed of skin cells and sebum in sebaceous follicles. The disease affects virtually all adolescents to some degree, as well as many adults. A 1999 community-based study showed that 12% of women over the age of 25 years had clinical acne, and acne prevalence did not significantly decrease until after age 44.[20]

Four events develop within the pilosebaceous unit (Figure 1) to create the pathophysiologic condition of acne vulgaris[2,10]:

1. Excessive sebum production secondary to stimulation by androgens;

2. Abnormal follicular keratinization and desquamation resulting in formation of a follicular plug;

3. Proliferation of the anaerobic microorganism Propionibacterium acnes; and

4. Inflammation.

fig1

Figure 1. Normal pilosebaceous unit. (Courtesy NIH)

The specialized sebaceous follicles affected by acne vulgaris are localized primarily on the face and trunk. Excessive sebum combines with desquamated epithelial cells from the follicle walls to form a bulging, distended mass called a microcomedo -- the first acne lesion (Figure 2). This enclosed, sebum-rich environment is ideal for the proliferation of P acnes, the anaerobic bacterium that produces chemotactic factors and recruits proinflammatory molecules involved in the inflammatory phase of acne. The immune system may also influence the quality of inflammatory acne lesions by introducing lymphocytes, neutrophils, and monocytes.[2]
fig2

Figure 2. Microcomedo. (Courtesy NIH)

Clinically, the lesions of acne vulgaris fall into 2 broad categories: noninflammatory and inflammatory. Noninflammatory comedones may be open or closed (Figures 3 and 4), and are colloquially known as "blackheads" and "whiteheads," respectively. Inflammatory lesions include papules, pustules, nodules, and cysts. The prevalence of each of these may vary from patient to patient. While most patients have a mixture of inflammatory and noninflammatory lesions, some patients present with predominantly one or the other.
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Figure 3. Open comedo. (Courtesy NIH)

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Figure 4. Closed comedo. (Courtesy NIH)

Given the multifactorial nature of acne vulgaris, therapies may be directed at any of the 4 major etiologic events, or therapies may be prescribed in combination. Effective topical treatments for acne include benzoyl peroxide, retinoids, and antibiotics. Systemic acne therapy includes oral antibiotics, hormonal therapy, and the oral retinoid isotretinoin. The role of topical retinoids in treating acne is described below.
Mode of Action of Topical Retinoids in the Treatment of Acne

In general, topical retinoids are effective in the treatment of acne because they help normalize follicular keratinization, thus extruding existing comedones and preventing the formation of new microcomedones (Figures 5a and 5b). Topical retinoids are the most effective comedolytic agents available for the treatment of acne. Because the microcomedo is the primary acne lesion, preventing the formation of new microcomedones and extruding existing comedones also interrupts the progression toward future inflammatory lesions. In addition, the newer topical retinoids tazarotene and adapalene also possess some anti-inflammatory properties.[21] The improved microenvironment in the sebaceous follicle also may reduce the proliferation of P acnes.[15]
fig5a

Figure 5a. Acne patient pretreatment.

fig5b

Figure 5b. Acne patient after 12 weeks of treatment with tazarotene.

In their early clinical history, topical retinoids were used primarily for the treatment of comedonal acne (acne characterized predominantly by open and closed comedones). However, with the introduction of the newer generation of topical retinoids that also have direct and indirect anti-inflammatory effects, their use in inflammatory acne is increasing, and topical retinoids are now recognized as first-line treatment for both comedonal and inflammatory acne. Another use of topical retinoids is maintenance therapy to prevent the formation of new microcomedones after inflammatory lesions and comedones have cleared. Topical retinoids are often used in combination therapy, especially with benzoyl peroxide and topical and/or oral antibiotics.
Effective Use of Topical Retinoids in Clinical Practice

The local side effects associated with topical retinoids can be ameliorated by proper usage. Patient education plays an important role (Table 2). Patients should be instructed to wash their faces gently with tepid water and mild cleansers. Abrasive cleansers, vigorous scrubbing, and the use of astringents should be avoided and can actually exacerbate acne and increase potential retinoid irritation. Noncomedogenic moisturizers can reduce local irritation. Patients should also use sunscreens, avoid excessive sun exposure, and protect their faces from cold, windy weather.
Table 2. Patient Education for Topical Retinoids
Wash face gently with tepid water and a mild cleanser
Avoid abrasive cleansers, vigorous scrubbing, and astringents
Apply a sunscreen daily
Apply noncomedogenic moisturizers to reduce irritation
Avoid excessive sun exposure
Protect the face from cold, windy weather
Wait 20 minutes after washing the face before applying the topical retinoid
Apply a pea-sized dose. More is not better!

Before applying a topical retinoid, patients should first wash their faces and then wait until the skin is thoroughly dry -- 20 minutes is preferable. Patients should apply only a pea-sized dose and be instructed that "more is not better." Patients should understand that because topical retinoids affect the root pathophysiologic processes of acne, clearing takes time. Improvement with the third-generation topical retinoids is generally seen in about 4 weeks. Patients should also be prepared for an early apparent worsening of their acne while existing microcomedones and comedones are extruded. If patients understand that this is a sign that the medication is working, they are less likely to become discouraged.

The choice of vehicle is also an important component of successful topical retinoid therapy. Creams are preferred for patients with more sensitive skin, while gels may be the best choice for patients who have excessively oily skin or who live in hot, humid climates.

Intermittent application, or "pulse therapy," may avoid local irritation and help acclimate the skin to retinoids. Sometimes physicians recommend that patients apply the retinoid every other day until daily application can be tolerated without erythema or irritation. A regimen called "short-contact tazarotene therapy,"[22] in which patients apply tazarotene gel for 30 seconds to 5 minutes per application twice daily and then wash off the drug, also has been used.
Recent Clinical Trials Using Topical Retinoids for the Treatment of Acne Vulgaris

Despite the introduction of more tolerable retinoids several years ago, topical retinoids are still perceived to cause severe irritation and are underused for inflammatory acne both in the United States and Europe.[2] Findings from recent clinical trials show that new compounds and new formulations are highly effective and well tolerated in the majority of patients.

Tazarotene vs tretinoin. Several clinical trials published within the last 3 years have compared tazarotene 0.1% gel with various formulations of tretinoin. These clinical trials were the first to directly compare tazarotene with tretinoin for efficacy and/or tolerability.[23]

In a double-blind, multicenter, randomized, parallel-group trial of tazarotene 0.1% gel and tretinoin 0.025% gel, 143 patients were examined for both efficacy and tolerability through 12 weeks of once-daily treatment of mild-to-moderate facial acne vulgaris.[23] Overall, the results of this study showed consistently better efficacy for tazarotene and roughly equal tolerability for both treatments. Specifically, tazarotene reduced the number of noninflammatory and inflammatory lesions at 4, 8, and 12 weeks -- all timepoints examined during treatment. Although the reduction of inflammatory lesions compared with tretinoin did not achieve statistical significance, the reduction of open comedones at 12 weeks was 65% for tazarotene vs 44% for tretinoin (P = .034). Tazarotene also proved superior in the reduction of noninflammatory lesions at 12 weeks (55% vs 42% for tretinoin, P = .042).

Tolerability was very good for both treatments, with mean levels of peeling, erythema, dryness, and burning peaking at or below trace levels and subsiding to below trace levels by the end of 12 weeks. The authors point out in the discussion that the incidence of participants dropping out early due to adverse events was quite low. Two of the 72 patients in the tazarotene group and 1 of the patients in the tretinoin group discontinued treatment. The study authors suggest that this low level of participant attrition could be the result of specific guidelines given to the patients to wash the face using a gentle nonsoap cleanser, to apply only a pea-sized amount of retinoid to the area, and to use noncomedogenic moisturizers as needed to alleviate dryness.

In a study of 169 patients with facial acne vulgaris, patients were randomized to receive once-daily applications of either tazarotene 0.1% gel or tretinoin 0.1% microsphere gel over 12 weeks.[24] Both treatments resulted in an improvement in mean global response. However, by this measure, tazarotene was significantly more effective at weeks 8 and 12. Tazarotene treatment also reduced overall disease severity more dramatically by week 12 (36% reduction vs 26% reduction with tretinoin, P = .02).

By the end of the 12-week trial, the difference in reduction of inflammatory lesions for tazarotene vs tretinoin microsphere was not significantly different, although the tazarotene reduction was slightly greater. However, tazarotene was significantly more effective in reducing the number of noninflammatory lesions (both open and closed comedones; median reductions 60% with tazarotene vs 38% with tretinoin, P = .02).

Both drugs were well tolerated, with mean levels of all adverse events remaining at or below trace at most, and subsiding to below trace levels by week 8. All adverse events subsided to below trace levels by week 12, including those assessed by the investigators (dryness, peeling, erythema, and perception of oiliness) as well as those assessed by the patients themselves (burning and pruritus).

Another trial, using a split-face study, assessed the tolerability of once-daily treatments with either tazarotene 0.1% gel or another retinoid in healthy volunteers with sensitive skin over a period of 28 days.[25] All 60 women in the study had either a history of atopic disease or a tendency for rosacea; they also tended to experience irritation from detergents and other facial products. While tazarotene 0.1% gel was applied to one side of the face, the other side of the face was treated with either (1) tretinoin 0.025% gel, (2) tretinoin 0.1% gel microsphere, or (3) adapalene 0.1% gel.

The relatively small number of subjects (20) in each of the 2 treatment groups limited the ability to achieve statistical significance, particularly because treatments were modified after the study began for roughly half of the participants in each group (55% for tazarotene and 47% for all other retinoids). Dropout rates were 7% for tazarotene only, 2% for the nontazarotene treatment only, and 15% for irritation on both sides of the face. Moreover, all 4 retinoid formulations induced some level of dryness, erythema, burning, or stinging. These results prompted the study authors to suggest that, rather than different retinoids having an inherent tendency to cause more or less irritation, the level of irritation experienced by individuals is more readily attributed to the patient's own susceptibility.

Adapalene vs tretinoin. In a 2001 controlled clinical trial comparing the safety and efficacy of adapalene gel 0.1% and tretinoin cream 0.05% in patients with mild-to-moderate facial acne vulgaris,[26] 409 patients were randomized to 10 weeks of once-daily treatment with either adapalene gel or tretinoin cream. Adapalene gel was as effective as tretinoin cream but was significantly better tolerated. Adapalene gel produced significantly less erythema, dryness, desquamation, and stinging/burning compared with tretinoin cream.

Adapalene gel 0.1% was compared with tretinoin microsphere gel in a 12-week, multicenter, randomized, controlled, investigator-masked, parallel-group study enrolling 168 patients.[27] The efficacy of adapalene gel and tretinoin microsphere gel was comparable, but there were significantly fewer treatment-related adverse reactions in the adapalene group.

Adapalene gel 0.1% was compared with tretinoin gel microsphere 0.1% in another 12-week double-blind clinical trial.[28] Both drugs demonstrated similar efficacy after 12 weeks of treatment, but tretinoin gel treatment achieved a significantly greater reduction in the number of comedones at week 4, suggesting that treatment with tretinoin microsphere gel might have a faster onset of action. Patients treated with tretinoin had more peeling and dryness compared with patients receiving adapalene, but erythema and burning/stinging were similar in the 2 patient groups.

Tazarotene vs adapalene. A 2001 randomized clinical trial compared alternate-day applications of tazarotene 0.1% gel with daily applications of adapalene 0.1% gel.[29] This double-blind, parallel-group study involved 164 patients with mild-to-moderate facial acne vulgaris. At the end of 15 weeks of treatment, both regimens achieved comparable efficacy, achieving at least a 50% improvement in patients' acne in virtually the same percentage of patients (73% for adapalene and 74% for tazarotene). The percentages of both inflammatory and noninflammatory lesions decreased for both treatments.

Patients from both groups experienced the typical adverse events of peeling, erythema, dryness, burning, and pruritus. Tazarotene treatment led to a statistically significant greater level of all 5 symptoms during the first 3-6 weeks of treatment. However, all symptoms were scored as mild at most. All adverse events associated with tazarotene decreased to the same levels as adapalene by week 6 (burning and pruritus), week 9 (erythema and dryness), or week 12 (peeling).

The success of this alternate-day regimen suggests that, even in patients with suboptimal compliance, tazarotene treatment may be highly efficacious. Additionally, this first head-to-head trial of the receptor-selective retinoids shows adapalene and tazarotene to be quite comparable in efficacy and tolerability in the described formulations and under the described application regimens.

A double-blind, randomized clinical trial compared daily applications of adapalene and tazarotene in 0.1% gel formulations.[30] The study examined 145 patients with mild-to-moderate facial acne vulgaris. At the end of the 12-week treatment period, once-daily treatment with tazarotene was significantly superior to adapalene in reducing overall disease severity (P < .0001), noninflammatory lesion count (P < .0001), and inflammatory lesion count (P < .0002). Overall treatment success, reflected in a > 50% global improvement, was also greater for tazarotene than for adapalene (78% vs 52% respectively, P < .002). Tazarotene was associated with statistically significant greater levels of burning, pruritus, erythema, and peeling at certain timepoints during the study compared with adapalene, but at the end of the 12-week treatment period the proportion of patients who rated their skin "comfortable" or "very comfortable" was not statistically significantly different between the 2 treatment groups.