By far the most important agents in photorejuvenation are the synthetic retinoids. The human body produces low levels of natural retinoids, which are oxidative.
Review
Rethinking the Role of Tretinoin in the Management of Rosacea Suzan Obagi, MD; Sheri Rolewski, RN, CRNP, MS Suzan Obagi, MD; Sheri Rolewski, RN, CRNP, MS While the etiology of rosacea remains unclear, there is an increasing body of evidence to suggest that photodamage has a causative role. Therefore, it becomes imperative that treatment regimens include an agent that effectively treats all aspects of photodamaged skin and rosacea concomitantly. In this article, the role of photodamage in rosacea is described. The rationale for the use of tretinoin as a first-line agent is discussed in detail, as well as specific instructions on how to overcome the initial skin irritation that patients with rosacea may experience.
R
osacea is a relatively common progressive and inflammatory disease of the skin. It can affect individuals of all races,1 but those of Northern European descent tend to be the most commonly afflicted.2 The sequelae of long-lasting rosacea are both physical and emotional. The physical symptoms often lead to embarrassment about appearance and decreased self-esteem, which can have negative effects on personal and professional interactions.3 While the true etiology of rosacea continues to elude us, there are several theories that may explain the pathogenesis of this disorder, including genetic predisposition, infection with Helicobacter pylori4 or Demodex folliculorum mites.5,6 Additionally, the role of environmental damage cannot be overlooked. Although most dermatologists agree that rosacea is a photoaggravated condition, with many patients complaining of increased flushing with heat and sun exposure, there is no clear-cut consensus about the link between rosacea and photodamage. However, the role of photodamage7,8 in the pathogenesis of rosacea is beginning to take on prominence as we better understand the pathologic role of inflammatory cytokines and reactive oxygen species (ROS).9 The causative role of photodamage in the pathogenesis of rosacea is not a new concept, yet it seems to be
gaining renewed interest. Most recently, Millikan10 referred to it and drew on studies dating back to the 1960s that implicate UV rays in the pathogenesis of this disease. A study by Kosmadaki et al11 found that UV rays have a causative role in inducing vascular endothelial growth factor (VEGF). The authors went on to extrapolate their findings to the pathogenesis of UV exposure in rosacea in a September 23, 2002, National Rosacea Society news release.12 The management of rosacea requires the control of trigger factors, use of topical agents, and, on occasion, systemic medications. Numerous topical agents are used to manage rosacea. These include metronidazole, azelaic acid, and sulfur-based agents in various combinations with or without the addition of systemic agents such as metronidazole, antibiotics, or isotretinoin.13 However, rosacea can be recalcitrant to conventional treatment regimens, which in turn leads to frustration for both the patient and the health care provider. Because patients with rosacea historically report very sensitive skin, we are taught to put together a treatment regimen that will not irritate the skin. This makes most physicians hesitant to use topical retinoids because of their potential for irritation. Unfortunately, this may result in the abandonment of a very useful agent that addresses all aspects of rosacea from photodamage to inflammation. On the other hand, topical tretinoin has been shown to minimize the manifestations of papulopustular rosacea within a relatively short time.13,14 In this article, we discuss the role that UV ray damage plays in the pathogenesis of rosacea and the rationale behind the regular use of topical tretinoin for patients with rosacea. We also describe how we approach the
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Dr. Obagi is Assistant Professor of Dermatology and Ms. Rolewski is Instructor of Dermatology, University of Pittsburgh School of Medicine, Pennsylvania. Dr. Obagi is also Director, The Cosmetic Surgery and Skin Health Center, University of Pittsburgh Medical Center. The authors report no actual or potential conflict of interest in relation to this article.
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Management of Rosacea treatment of rosacea in our large university-based practice by using topical tretinoin as the foundation of our treatment regimen.
UV RADIATION DAMAGE UVA and UVB rays affect both the epidermal and dermal components of the skin. Keratinocytes and fibroblasts from the same individual exhibit shorter in vitro life spans when harvested from sun-exposed skin compared with those from sun-protected sites.15,16 Damage to and subsequent loss of epidermal barrier function have been linked to the extreme skin sensitivity that most patients with rosacea complain about.17 Sun exposure accelerates the loss of dermal thickness that usually occurs with age, as evidenced by the thinner dermis found in sun-exposed skin compared with that in sun-protected sites.18,19 Progressive photodamage leads to degeneration of collagen, with subsequent deposition of an abnormal elastotic material (solar elastosis)20 and degradation of the collagenous meshwork by matrix metalloproteinases.21 UV-induced damage of the dermis results in vascular wall damage and leakage, which leads to an inflammatory response.22 Evidence pointing toward inflammation in the pathogenesis of rosacea stems from histopathologic findings that superoxide dismutase activity is lower in patients with severe rosacea than in control patients, while levels of ROS are higher.23
less correlation of photodamage with the papulopustular or rhinophymatous variants of rosacea. However, there are no large studies that correlate the amount of photodamage with severity of disease in patients with rosacea.
RATIONALE FOR THE USE TOPICAL RETINOIDS
OF
By far the most important agents in photorejuvenation are the synthetic retinoids. The human body produces low levels of natural retinoids, which are oxidative metabolites of vitamin A (retinol). The 2 main metabolic derivatives of vitamin A, retinoic acid (all-transretinoic acid and 13-cis-Retinoic acid) and retinaldehyde, are important for the growth, differentiation, and maintenance of epithelial tissues.24 At the epidermal level, these retinoids promote epidermal normalization and proliferation, loss of keratinocyte atypia, and compaction of the stratum corneum.25,26 At the dermal level, retinoids increase collagen deposition in the subepidermal region, decrease collagen breakdown by inhibition of collagenases (matrix metalloproteinases), decrease solar elastosis, and increase glycosaminoglycan production.25 At the level of the dermal vasculature, retinoids have been shown to have inhibitory effects on VEGF.27 VEGF is considered to be a key positive regulator of angiogenesis and vascular permeability.11 Retinoids offer protection from UV radiation. The topical application of all-transretinoic acid has been shown to protect the skin against damage from UVB28 and UVA rays.29 Additionally, retinoids have an antiinflammatory effect by inhibiting the generation of oxygen-free radicals and ROS.30 In terms of safety, the long-term application of a topical retinoid has not shown any risk of malignant degeneration.31
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CLINICAL CORRELATION Because rosacea is predominantly a disease that affects lighter-skinned individuals, it is logical that these same individuals would be more susceptible to the damaging rays of the sun. Most physicians and researchers agree that rosacea is a photoaggravated disorder. Based on the evidence presented in this article on the effects of UV radiation on the skin, the role of UV damage in the pathogenesis of rosacea becomes more appreciated as a multifactorial one. The more fairskinned the individual, the less that person’s skin can protect itself from UV rays. UV damage results in angiogenesis (ie, telangiectasia), vascular leakage with subsequent inflammatory response, and an altered stratum corneum, which may no longer act as an effective barrier to topical irritants (ie, sensitive skin). Indeed, in our office, we routinely see 10 to 20 patients with rosacea per day (about 600 patients per year). We are surprised by the amount of photodamage present in our patients. The degree of photodamage seems to correlate with the severity of rosacea and is more pronounced in fairer-skinned patients. While this seems to be the case for our erythematotelangiectatic patients, there seems to be 506 Cosmetic Dermatology
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APPLICATION The beneficial effects of retinoids on photodamaged skin are numerous. We can extrapolate from the studies to illustrate how the use of retinoids may benefit patients with rosacea. To minimize telangiectasia formation and progression, patients with rosacea would benefit from the inhibitory effects of retinoids on VEGF. Retinoids would help control papulopustular breakouts. Furthermore, retinoids would normalize epidermal function and, with time, restore a compact stratum corneum, which should minimize the skin irritability experienced by patients with rosacea. The anti-inflammatory role of retinoids should help slow disease progression. And lastly, but most importantly, for all patients with cosmetic concerns, retinoids would help regenerate
S. Obagi, S. Rolewski TABLE 1
SUNBLOCK AGENTS
FOR
PATIENTS WITH ROSACEA BASED
ON
PATIENT SKIN TYPE
Sunblock
SPF
Skin Type
Solbar Zinc (zinc oxide 7.5%, homosalate 10%, and octyl methoxycinnamate 7.5%)
38
Extremely dry or sensitive skin
Obagi Healthy Skin Protection (zinc oxide 9% and octyl methoxycinnamate 7.5%)
35
Normal or slightly oily skin
Dermatone Z-Cote (zinc oxide 10%, octyl methoxycinnamate 7.5%, and ensulizole 3%)
36
Oily skin and/or for male patients
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collagen and improve the overall appearance of the skin with continued use. Minimizing disease progression should be the initial goal of therapy, followed by the treatment of the symptoms of rosacea. Patients can play an important role in their treatment by identifying and minimizing the trigger factors that cause flushing and blushing, such as consumption of alcohol or spicy foods and exposure to extreme heat or cold. In addition to avoiding triggers, using a sunblock daily is necessary to protect the skin from both UVA and UVB rays and thus minimize further oxidative damage. We routinely give patients a choice of 3 sunblocks that primarily contain titanium dioxide and/or zinc oxide (Table 1). One is for normal skin, one for oily skin, and one for extremely dry skin. We have found these 3 sunblocks to be well tolerated and nonirritating for most of our patients. By recommending a nonirritating sunblock, we can then focus on getting the patient acclimated to the use of a topical retinoid without worrying about further aggravating their skin. We instruct patients to use this sunblock daily in place of a moisturizer. We give the patients detailed written instructions on the correct application of tretinoin (Table 2). Patients are instructed to wash their face without washcloths or loofah sponges. They are instructed to then apply 1 g of tretinoin cream (usually 0.05%) to the entire face nightly, including the lower eyelids; every 2 to 3 days they can also apply the cream to the upper eyelids, neck, and chest. One gram is roughly equivalent to 1 in of cream squeezed
from the tube onto a finger. If their skin gets too irritated, we instruct patients to discontinue the use of tretinoin for 1 to 2 nights, moisturize the skin, then resume tretinoin after 1 to 2 days. Patients are told to expect 6 to 12 weeks of peeling, redness, and irritation, which usually subside over time. Once the initial reaction phase dissipates, the dose of tretinoin is increased to 0.1% cream. The microgel formulations are not used unless the patient specifically complains of worsening acne breakouts due to the regular cream base. If patients cannot tolerate the 0.05% tretinoin cream, they are switched to the 0.025% cream. Rarely, a patient cannot tolerate any tretinoin whatsoever, and in these instances the traditional topical agents are used. For patients with moderate to severe erythema and telangiectasia, we add treatment with a pulsed dye laser (PDL). The 595-nm PDL targets vascular structures via selective light absorption by oxyhemoglobin. This technology is approved by the US Food and Drug Administration to treat vascular lesions of the skin and has been in use for more than 10 years with a proven track record.32 The PDL is a noninvasive method to treat telangiectasia, minimize the D folliculorum count on the skin, and improve dermal collagen production. The use of tretinoin prior to and after laser therapy helps to minimize the duration of laser-induced purpura.33 Once laser therapy is completed, patients are kept on tretinoin as maintenance therapy. As we tell patients, the goal is to keep reducing the photodamage in their skin while minimizing the inflammatory component of rosacea. Vol. 17 No. 8 • AUGUST 2004 • Cosmetic Dermatology
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Management of Rosacea TABLE 2
INSTRUCTIONS
FOR THE
CORRECT USE
OF
TRETINOIN
FOR
PATIENTS WITH ROSACEA
What to Expect and How to Manage Skin Reactions
Patient Instructions Wash skin and pat dry. Apply 1 g of tretinoin cream to entire face including the lower eyelids.* Avoid the corners of the eyes and lips. Every 2–3 days apply tretinoin to upper eyelids, neck, and chest. Apply sunblock to entire face every morning. Use sunblock daily in place of a moisturizer. Stop tretinoin 1 week prior to waxing skin.
Transition period of 6–12 weeks, during which face will be red, dry, and flaky. Reaction is more severe in skin that is heavily sun damaged. If the reaction is too irritating, take 1–2 nights off from tretinoin and moisturize. After 1–2 nights, resume the tretinoin. Taking more than 1–2 nights off may restart the reaction phase again. The goal of tretinoin treatment is to diminish sun damage, rosacea, and overall aging of skin.
*1 g=1 in of cream (squeezed onto a finger).
FUTURE CONSIDERATIONS To see if the patients with rosacea can tolerate this combination, we began the process of conducting an anonymous patient survey in which we asked patients a number of questions about tolerance and perceived benefits of tretinoin coupled with PDL therapy. Preliminary data have shown considerable promise. By utilizing topical tretinoin along with PDL therapy, most patients with rosacea can tolerate topical tretinoin and gain control of the chronic sequelae of rosacea. Many patients are reporting a decrease in overall skin sensitivity over time, which is suggestive of an improvement in skin barrier function. This combination treatment has shown a pattern of decreased flushing and blushing, improved self-esteem, and increased satisfaction in many patients with rosacea. We urge that more studies be conducted to further elucidate the pathogenesis of rosacea with particular attention to the role of photodamage. There is a paucity of knowledge about this increasingly common disease.
aware of the risks, benefits, reasonable expectations, and availability of such options and guide patients accordingly. Our goal should be to address all aspects of rosacea within our abilities: to treat telangiectasia by laser, use a home topical retinoid therapy for maintenance, and have patients apply sunblock daily to keep their rosacea from worsening. With proper patient education and guidance, those who experience the chronic progressive sequelae of rosacea can discover relief and comfort, knowing that their symptoms and appearance can be greatly improved. Importantly, since we know that rosacea has many psychosocial aspects, it would be interesting to assess if the psychological measures of these patients improve to the same extent as those of patients with photodamage who have been treated with tretinoin.34
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COMMENT Many patients with rosacea utilize the Internet and the National Rosacea Society Web site (www.rosacea.org) for information on the latest treatment options, including intense pulsed light and PDL. Practitioners need to be 508 Cosmetic Dermatology
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S. Obagi, S. Rolewski continued from page 508 6. Bonnar E, Eustace P, Powell FC. The Demodex mite population in rosacea. J Am Acad Dermatol. 1993;28:443-448. 7. Marks R. Concepts in the pathogenesis of rosacea. Br J Dermatol. 1968;80:170-177. 8. Dahl MV. Pathogenesis of rosacea. Adv Dermatol. 2001;17:29-45. 9. Kawaguchi Y, Tanaka H, Okada T, et al. Effect of reactive oxygen species on the elastin mRNA expression in cultured human dermal fibroblasts. Free Radic Biol Med. 1997;23:162-165. 10. Millikan LE. Rosacea as an inflammatory disorder: a unifying theory? Cutis. 2004;73(suppl 1):5-8. 11. Kosmadaki MG, Yaar M, Arble BL, et al. UV induces VEGF through a TNF-alpha independent pathway. FASEB J. 2003;17:446-448. 12. Study shows sunlight may affect blood vessels of rosacea patients [press release]. Barrington, Ill: National Rosacea Society. September 23, 2002. Available at: http://rosacea.org/press/archive/20020923.html. Accessed July 20, 2004. 13. Ertl GA, Levine N, Kligman AM. A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea. Arch Dermatol. 1994;130:19-24. 14. Bergfeld WF. A lifetime of healthy skin: implications for women. Int J Fertil. 1999;44:83-95. 15. Gilchrest BA. Relationship between actinic damage and chronologic aging in keratinocyte cultures of human skin. J Invest Dermatol. 1979;72:219-223. 16. Gilchrest BA. Prior chronic sun exposure decreases the life span of human skin fibroblasts in vitro. J Gerontol. 1980;35:537-541. 17. Lonne-Rahm SB, Fischer T, Berg M. Stinging and rosacea. Acta Derm Venereol. 1999;79:460-461. 18. Moragas A, Garcia-Bonafe M, Sans M, et al. Image analysis of dermal collagen changes during skin aging. Anal Quant Cytol Histol. 1998;20:493-499. 19. de Rigal J, Escoffier C, Querleux B, et al. Assessment of aging of the human skin by in vivo ultrasonic imaging. J Invest Dermatol. 1989;93:621-625. 20. Albrecht S, From L, Kahn HJ. Lysozyme in abnormal dermal elastic fibers of cutaneous aging, solar elastosis and pseudoxanthoma elasticum. J Cutan Pathol. 1991;18:75-80. 21. Saarialho-Kere U, Kerkela E, Jeskanen L, et al. Accumulation of matrilysin (MMP-7) and macrophage metalloelastase (MMP-12) in actinic damage. J Invest Dermatol. 1999;113:664-672.
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