Dispelling the Myths About Using Retinoids

A common perception related to the use of topical retinoid therapy is that initial exacerbation of acne commonly precedes clinical improvement. Market research and informal surveys that I have completed suggest that many dermatologists limit the use of topical retinoids when initiating acne therapy due to concern regarding initial exacerbation. A second observation. likely related to previous availability and usage of formulations associated with a high incidence of irritation, is that clinical results are optimized only if irritation is induced by topical retinoid therapy. The availability of several studies evaluating the use of the topical retinoids — tretinoin, adapalene and tazarotene — formulated in a variety of vehicles, allows for a critical assessment of response patterns, including those occurring early in the course of treatment. Assessments do not appear to support the contention that initial exacerbation of acne is a common finding after initiation of topical retinoid therapy. Efficacy data coupled with the development of less irritating formulations suggest that irritation is not a prerequisite. This article focuses on: 1. efficacy-response patterns over time after initiation of topical retinoid therapy 2. correlations of levels of irritation with clinical efficacy. Topical Retinoid Development Prior to the availability of topical tretinoin in 1971, agents utilized for the treatment of acne vulgaris impacted primarily upon inflammatory lesions, with little effect on comedones. After the introduction of topical tretinoin, promotional and educational efforts emphasized the comedolytic activity of the compound. The combination of a topical retinoid targeted against comedones, with agents that primarily reduce inflammatory lesions, such as benzoyl peroxide, sulfacetamide-sulfur or topical antibiotics, revolutionized the approach to acne therapy. Over time, further understanding of the mechanisms related to the biologic effects of topical retinoids has increased our recognition of the capacity of these agents to reduce inflammatory and comedonal acne lesions, and enhanced our ability to apply these agents clinically. The development of better vehicles has allowed for markedly decreased irritation with preservation of clinical efficacy. In addition, the release of two topical retinoids, adapalene in 1996, and tazarotene in 1997, has expanded our armamentarium for the treatment of acne vulgaris and other cutaneous disorders, such as chronic photoaging and melasma. Modes of Action of Topical Retinoids1-6 Available data supports that topical retinoids induce their therapeutic effects through multiple modes of action. As a result, both inflammatory and noninflammatory (comedonal) lesions are significantly reduced and decreased microcomedone formation is also observed. Decreased Hyperkeratinization. Topical retinoid application reduces follicular hyperkeratinization associated with microcomedone and comedone formation. This interrupts the development of both inflammatory and noninflammatory acne lesions. Reduced Expression of Toll-like Receptor-2. One mechanism whereby Propionibacterium acnes triggers the development of inflammation in acne vulgaris is through binding and stimulation of a specific “pathogen recognition receptor,” called toll-like receptor-2 (TLR-2). Toll-like receptors (TLRs) are located on a variety of cell surfaces including mononuclear cells and dendritic cells involved in antigen recognition; stimulation of TLR-2 by exoproducts of P. acnes signals a cascade that results in the production of pro-inflammatory cytokines. Topical retinoids downregulate the expression of TLR-2. As a result, the ability of P. acnes to stimulate production of inflammation is decreased. This is one mechanism which accounts for the direct anti-inflammatory effect of topical retinoids. Reduced Activation of the AP-1 Transcription Factor Pathway. Topical retinoids inhibit activation of the AP-1 transcription factor pathway involved in the regulation of matrix metalloproteinase genes. This mechanism correlates with decreased inflammation and may possibly reduce the risk of acne scarring. An in vivo human model suggests activation of the AP-1 transcription factor pathway as a component of acne inflammation and scarring. Trends in Utilization of Topical Retinoids for Acne Treatment7-10 Based on an analysis of data collected from 1990 to 1999 by the National Ambulatory Medical Care Survey, topical retinoids are underutilized overall by dermatologists and non-dermatologists for the treatment of acne vulgaris. A topical retinoid was prescribed at 35.3% of the 54.2 million acne visits. Reasons for the underutilization of topical retinoids in acne treatment include the following: a. “pigeon-holing” for the treatment of comedonal acne b. underappreciation of the ability of topical retinoids to reduce inflammatory as well as comedonal acne lesions c. the perception that topical retinoid use produces an initial exacerbation of acne prior to improvement d. concern regarding irritation in patients presenting with a significant number of inflammatory lesions. Nevertheless, the analysis indicated that over the past decade, prescriptions for topical retinoid therapy for acne have increased, predominantly among dermatologists. The value of topical retinoids in treating acne vulgaris and their vital role early in the course of acne treatment has been reemphasized recently in the literature. Often, hesitation to use these agents as part of initial therapy in patients presenting with predominantly inflammatory acne vulgaris appears to relate to unsubstantiated “recycled dogma,” and perceptions related to the use of older, more irritating formulations. Debunking the Myths Related to Topical Retinoid Use MYTH. A common perception among some clinicians and patients is that exacerbation of acne commonly precedes visible improvement after starting topical retinoid therapy. REALITY. There is no evidence that worsening of acne is to be anticipated after starting treatment with a topical retinoid prior to clinical improvement.11-20 A review of multiple studies including adapalene, tazarotene and tretinoin, exhibits an overall consistent trend of progressive improvement with reduction in both inflammatory and comedonal lesions.11-20 Most studies have been completed over a 12-week period. Although individual patients may experience minimal change early in treatment, and in some a modest increase in lesion counts may be observed over the first 4 weeks, the majority follow a pattern of progressive inflammatory and comedonal lesion reduction. Exacerbation prior to visible improvement has not been a commonly or consistently observed trend.11-20 In one multicenter, randomized, investigator-masked, parallel-group trial (n=105), both the group using adapalene 0.1% gel and the group using tretinoin 0.025% gel demonstrated reductions in inflammatory, non-inflammatory and total lesion counts as compared to baseline.13 Lesion reduction was noted as early as week 1, with progressive improvement observed at each subsequent evaluation period through week 12. Although both agents demonstrated effective response early in the course of therapy, adapalene 0.1% gel demonstrated a faster onset of effect in this trial, with a statistically significant greater reduction in inflammatory and total acne lesion counts at week 1 as compared to tretinoin 0.025% gel. The more rapid onset of reduction in inflammatory and non-inflammatory lesion counts with adapalene was also reflected by the improved quality of life scores evaluated during the study. MYTH. Production of irritation is required in order to achieve clinical efficacy with use of a topical retinoid. REALITY. It is not necessary to induce irritation in order to achieve clinical benefit with a topical retinoid. As noted above, the early formulations of topical tretinoin were associated with a high incidence of significant irritation. Over time, it became difficult for clinicians to separate efficacy observed in patients from signs of irritation, such as redness and peeling. Many clinicians and patients perceived that visible exfoliation (“peeling”) was needed to achieve therapeutic benefit from topical tretinoin therapy. This belief was further propagated by the fact that topical tretinoin was the “designated comedolytic” and that a significant number of patients experienced marked irritation with the older vehicle formulations used initially. After the release of adapalene in 1996, and with the development of less irritating formulations of topical tretinoin, it became apparent based on data from controlled trials and clinical experience, that efficacy could be achieved without concomitant irritation. Studies with topical retinoids clearly demonstrate that efficacy may be obtained in the absence of irritation, with the literature supporting that adapalene is associated with the lowest potential for skin irritation.10-12,16-18,20 In addition, individual patients may demonstrate increased “sensitivity” to topical retinoid use, indicating that therapy must be adjusted or titrated in a subset of patients in order to achieve the balance between efficacy and tolerability.21 It is no longer necessary to induce signs of irritation, such as erythema, peeling and skin tenderness. Rational methods of topical retinoid usage, such as proper skin care and moisturizer recommendations, initiation of topical retinoid application every other day at the start of treatment, and staggered combination with other topical agents early in the course of therapy have improved the ability of the clinician to use a topical retinoid early during treatment.22 This has been demonstrated in patients with both comedonal and predominantly inflammatory acne vulgaris.11-20 MYTH. Topical retinoids primarily reduce comedonal lesions with limited effectiveness in reducing inflammatory acne lesions. REALITY. Topical retinoids used as monotherapy significantly reduce both inflammatory and comedonal acne lesions. Multiple studies evaluating adapalene, tazarotene or tretinoin alone for the treatment of acne vulgaris, including efficacy data referred to in product labeling approved by the FDA (U.S. product monographs), clearly support that topical retinoids effectively reduce both inflammatory and comedonal acne lesion counts.2,10-20,23 Most topical retinoid studies have evaluated response over a 12-week duration. Topical retinoids are also commonly and effectively combined with other topical and systemic agents, including benzoyl peroxide, topical antibiotics and oral antibiotics.1,2,10,12,14 The modes of action described above at least partially explain the ability of topical retinoids to decrease both inflammatory and comedonal acne lesions and allow for the combining of therapies that are directed at different points in the pathogenesis of acne. Topical retinoids, both through inhibition of comedogenesis and reduction in inflammation, provide a rational foundation for acne therapy, including use in combination with other agents. Due to their multifaceted ability to inhibit microcomedone formation, reduce comedonal acne lesions, and decrease inflammatory acne lesions, it is recommended that a topical retinoid be prescribed as part of the initial treatment regimen for acne vulgaris, unless specific clinical factors in an individual patient dictate otherwise.