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Retinoids have shown benefits in the treatment of acne (see 15),
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BOX 30-1 Two transciption factors, c-Jun and c-Fos, must combine to produce activator protein-1 (AP-1) AP-1 is able to activate the MMP genes resulting in production of collagenase, gelatinase, and stromelysin All-trans-retinoic acid blocks the UV-induced increase in c-Jun protein Although high levels of c-Jun mRNA are still present, signifying that the c-Jun gene has been activated, the levels of c-Jun protein are decreased Topical retinoic acid likely acts to reduce UV induction of c-Jun protein by stimulating its breakdown through the ubiquitin-proteasome pathway19 (Fig 30-3)
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FIGURE 30-3 Mechanism of inactivation of active protein-1 by retinoids psoriasis, ichthyosis, keratoderma, and several other diseases In fact, there are more than 125 distinct dermatologic disorders for which there is credible evidence of retinoid efficacy5 Multiple studies have examined the use of retinoids for the prevention and treatment of photoaging The first of these clinical trials, using tretinoin, to demonstrate clinical improvement of photoaged skin were published in 1986 and 19883,20 Since then, many other studies and much clinical experience have shown similar results In one randomized single-center study, 100 subjects were divided into three treatment groups21 One group was treated with 01% tretinoin, another with 0025% tretinoin, and the last group with vehicle cream Treatment with either 01% or 0025% tretinoin resulted in statistically significant improvement of photoaged skin compared with vehicle treatment The histologically observed changes with the use of retinoids include abolition of cellular atypia, increased compacting of the stratum corneum, less clumping of melanin in basal cells, and a correction of polarity of keratinocytes, with more orderly differentiation as cells move upward The ultrastructural changes seen with retinoid use include evidence of hyperproliferation of keratinocytes (eg, larger nuclei, increased ribosomes, etc) and a reduction in the size of melanosomes As described in 6, changes in collagen and the ratio of collagen I to collagen III have been found to be important in the photoaging process Retinoids have been shown to increase collagen synthesis in photoaged individuals22 In addition to preventing the breakdown of collagen as described above, topical application of tretinoin 01% to photodamaged skin partially restores levels of collagen type I An increase in anchoring fibrils (collagen VII) is also seen after application of tretinoin 01%22
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Side effects from retinoid use occur when the product binds undesired receptor subtypes not involved in the expected biologic cascade The more specific the binding pattern a retinoid exhibits, the fewer side effects it will elicit The newer generation retinoids destined for dermatologic use have been designed to reduce side effects by making compounds that bind more
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selectively to the RAR receptor subtype However, with these improved molecules, the side effects from topically applied retinoids still persist, likely linked to intrinsic RAR activation The most common side effects of topical retinoids are skin irritation, desquamation, and redness (Fig 30-4) The increased desquamation and resultant flaking of the skin correspond with increased proliferation of keratinocytes, as indicated by a greater number of mitotic figures and enhanced expression of differentiation markers23 These findings seem to be related to the type and dose of the retinoid and usually occur within 2 to 4 days of beginning topical treatment24 New studies have suggested that patients may achieve maximum clinical improvement of photoaged skin without developing retinoid dermatitis In other words, the irritation produced by retinoids is separate from the photoaging benefits of retinoids This is demonstrated in the study that compared two different strengths of tretinoin (01% and 0025%) Although both strengths were equally efficacious in the treatment of photoaging, the degree of irritation differed markedly between the two treatment groups, with the 01% tretinoin-treated group exhibiting approximately a three-fold greater incidence of irritation than the 0025% tretinoin-treated group21 This irritation seems to be receptor mediated as implied by evidence that the topical application of tretinoin to the skin of transgenic mice deficient in RARs does not result in any apparent epidermal hyperplasia or desquamation25 This suggests that the development of newer retinoids with specific receptor and pharmacokinetic profiles and relevant dosing may lead to a lower incidence of irritation, flaking, and desquamation Erythema is another side effect of topical retinoids, one that elicits noncompliance from patients This symptom is caused by a different mechanism that appears not to be receptor mediated26 Patients with rosacea and naturally pink skin tend to be particularly disturbed by this side effect Using the techniques described in Table 30-1 may decrease the incidence of all types of skin irritation A study performed in the late 1990s suggested that after a 48-week regimen of once-daily 005% tretinoin emollient cream, the benefits of tretinoin could be sustained by using the treatment only 3 times weekly for an additional 24 weeks27 The tretinoin should be used at least 3 times a week, however, because the same study showed that once-
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