Volume 2, Number 1 (Summer 2008)

Advances in Rosacea and Acne Vulgaris

Evans C. Bailey, MD, PhD

University of Michigan Medical Center, Ann Arbor, Michigan

Rosacea and acne vulgaris are common dermatologic conditions. Until recently, there was little progress in understanding the biologic basis of rosacea and its clinical hallmarks of hypertrophy of the sebaceous glands and facial flushing, redness, papules, and pustules. Recent studies demonstrated a role for the antimicrobial peptide cathelicidin in producing a state of chronic inflammation that may lead to these clinical features. These insights may result in new, more effective therapies for treating rosacea. Novel treatments for acne vulgaris address the challenges of antibiotic resistance. Such topical therapies as 5% dapsone gel and retinoid/benzoyl-peroxide combination agents promise to expand the number of agents available for treating acne vulgaris. Several recent publications showed promising results against acne vulgaris using photodynamic therapy and other light-based treatments; however, more research is needed to better define the clinical utility of these novel systems.

Dr. Bailey is Chief Resident, Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan.

Acne vulgaris and rosacea are two of the most common complaints of patients presenting to dermatology offices. The two skin conditions share some clinical features, and they often coexist. However, their etiology and management differ greatly.

Proper diagnosis and treatment of these conditions demand careful physical examination and recognition of cutting-edge findings and dermatologic breakthroughs. This article summarizes lectures given and insights shared at a symposium on acne and rosacea held during the 4th annual Advances in Cosmetic and Medical Dermatology (ACMD) meeting in Wailea, Maui, Hawaii, from February 25 to March 1, 2008. Speakers at this session included Guy Webster, MD, Jefferson Dermatology Associates, Philadelphia, Pa; Alan R. Shalita, MD, Distinguished Teaching Professor and Chairman, Department of Dermatology, SUNY Downstate Medical Center, Brooklyn, NY; James J. Leyden, MD, Emeritus Professor of Dermatology, Department of Dermatology, University of Pennsylvania, Philadelphia; and Richard Rox Anderson, MD, Professor of Dermatology, Harvard Medical School, and Director, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston.

Rosacea

Rosacea is a common dermatologic condition associated with facial flushing, persistent redness, telangiectatic vessels, and inflammatory papules and hypertrophy of sebaceous glands. This condition most often develops in fair-skinned individuals; its prevalence ranges from 1.5%–10%.1

This skin problem represents a clinical diagnosis; until recently, there were no molecular hallmarks identified for this condition. Recent studies by Yamasaki et al2 greatly advanced our understanding of rosacea, providing novel insights into its molecular pathogenesis and new avenues for future therapies.

Molecular Insights

To understand the molecular origin of rosacea’s clinical hallmarks, Yamasaki et al2 evaluated the skin of affected patients for expression of cathelicidin, an endogenous antimicrobial peptide. A member of a family of antimicrobial peptides that fight bacteria, fungi, and viruses, cathelicidin is expressed in keratinocytes, saliva, and sweat, where it exerts its antimicrobial effects.3 In addition to inhibiting infection, cathelicidin also promotes angiogenesis, inflammation, and dermal matrix remodeling, which all may be critical in the pathogenesis of rosacea.3 Synthesized as an inactive precursor, cathelicidin is proteolytically cleaved by serine proteases into smaller, biologically active peptide subunits (Figure 1).2,3 Differences in the location and degree of proteolysis produce an array of peptide fragments of varying activities.4

Figure 1  Processing of cathelicidin to generate active antimicrobial peptides. Cathelicidin is synthesized as an inactive precursor protein with an amino-terminal signal sequence, a central cathelin domain, and an inactive carboxy-terminal antimicrobial peptide (AMP) domain. Serine proteases, including stratum corneum tryptic enzyme (SCTE), cleave the AMP domain to generate the active antimicrobial peptide LL-37. Further cleavage of LL-37 by serine proteases generates a family of biologically active peptides. aa = amino acids. Adapted, with permission, from Izadpanah and Gallo.3

Yamasaki et al2 found cathelicidin expression to be significantly elevated in rosacea skin as compared with normal skin. Stratum corneum tryptic enzyme (SCTE), a major serine protease responsible for processing cathelicidin in the epidermis, was expressed to a greater extent in rosacea skin than in normal skin. Furthermore, rosacea skin exhibited a unique array of cathelicidin peptides when its spectrum of fragments was compared with that of normal skin. Injection of one of these fragments, LL-37, into murine skin promoted both inflammatory cytokine expression in keratinocytes and erythema.

These studies concluded that rosacea may maintain inflammation and erythema via a molecular mechanism involving elevated expression and modified processing of cathelicidin. When chronically activated, these normally protective defenses may damage the host instead, producing the erythema, telangiectasias, and inflammatory pustules that characterize rosacea (Figure 2).5

Figure 2  Model for the role of cathelicidin in the pathogenesis of rosacea. In normal human skin (left), the cathelicidin precursor is processed by serine proteases, such as stratum corneum tryptic enzyme (SCTE), to generate the biologically active antimicrobial peptide LL-37, which then is processed further to smaller peptides with various biologic activities. In rosacea (right), increased levels of cathelicidin precursor and elevated levels of the serine protease SCTE lead to increased levels of LL-37 and other biologically active peptides, resulting in chronic inflammation and the phenotypic features of rosacea. Adapted, with permission, from Bevins and Liu.5

Future Treatments

The discovery of elevated cathelicidin levels in rosacea may lead to more effective therapies for this condition. Oral tetracyclines are a standard therapy for rosacea, even though there is little evidence that the condition has an infectious etiology. The unique actions of this family of antibiotics include inhibition of serine proteases; thus, inhibition of cathelicidin processing may explain the antibiotic’s efficacy against rosacea.2 Unfortunately, increasing rates of antibiotic-resistant bacteria in all fields of medicine and surgery demand strategies to limit the use of antibiotics to prevent worsened resistance.6

Overall, if tetracyclines truly inhibit the processing of cathelicidin, and if derived tetracycline analogs can inhibit cathelicidin processing without exerting antibiotic effects, then a new class of medications may allow safer, more effective rosacea treatment.

Acne Vulgaris

Acne vulgaris is a common dermatologic condition that has multiple etiologic factors. Abnormalities in the shedding of the follicular epithelium, lipid content from sebaceous glands, and overgrowth of Propionibacterium acnes all play major roles in the development of clinical acne lesions.7 The pathogenesis of acne vulgaris has been well described; however, treatment of this sometimes-stubborn skin problem continues to challenge clinicians and patients.

Antibiotics

Oral tetracyclines and topical clindamycin and erythromycin are commonly prescribed to treat acne.8 Emergence of P acnes strains that are resistant to these antibiotics has prompted investigations into strategies to decrease resistance. Unfortunately, with greater use of antibiotics and more reports of drug resistance, there has been a parallel increase in community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections—and tetracyclines often are used as a first-line treatment for these infections.9–11 To avoid excessive use of oral antibiotics and worsening bacterial resistance, clinical investigators are exploring the safety and efficacy of using topical antibiotics alone for mild-to-moderate cases of inflammatory acne.

Over a 16-week study, Cunliffe et al12 demonstrated a 27% reduction in total lesions after treating mild-to-moderate facial acne with topical clindamycin. The combination of benzoyl peroxide and clindamycin was even more effective, producing a 52% reduction in total acne lesions at 16 weeks. Langner et al13 recently confirmed the efficacy of a topical clindamycin/benzoyl-peroxide combination; this formulation was well tolerated over a 12-week course and caused minimal side effects.

Antibiotic/benzoyl-peroxide combinations also reduce the formation of antibiotic-resistant strains of P acnes and coagulase-negative staphylococci on the skin. Cunliffe et al12 demonstrated that use of topical clindamycin alone against acne led to a 1,600% increase in clindamycin-resistant P acnes and a 3,500% increase in clindamycin-resistant coagulase-negative staphylococci on the skin over a 16-week treatment course. This resistance was effectively eliminated when clindamycin was combined with benzoyl peroxide. The levels of clindamycin-resistant bacteria after 16 weeks of therapy were no higher than were baseline values.

These combinations are well tolerated. Recent developments in delivering benzoyl peroxide by encapsulating the medication into microscopic silica spheres will provide extended-release topical products that may decrease its side effects further. Overall, use of topical antibiotic/benzoyl-peroxide combinations is safe and effective for mild-to-moderate acne vulgaris; these products avoid complications of systemic antibiotics as they prevent further emergence of antibiotic-resistant strains of bacteria.

Dapsone

A promising treatment for acne vulgaris that avoids antibiotic use is topical 5% dapsone gel (Aczone™). Oral dapsone is effective for a number of inflammatory dermatoses, including cystic acne; however, its use is limited by the need for regular laboratory evaluations due to potential hematologic toxicity.14,15

Topical dapsone does not appear to cause the same systemic side effects as does the oral form; topical use of this drug may avoid the need for hematologic monitoring.16 Recently published trials of 5% dapsone gel demonstrated it to be safe and somewhat effective against acne vulgaris when compared with the vehicle alone.16 This new formulation could provide another topical agent for treating acne vulgaris.

Retinoids

Retinoids are a critical component of any treatment regimen for acne vulgaris.7 Topical and oral antibiotics have a faster onset of action than do retinoids, yet topical retinoids clearly are effective in reducing all acne lesions, including inflammatory acne.7

Retinoids apparently can reduce inflammatory lesions, because they normalize follicular keratinization and possess an intrinsic anti-inflammatory effect. Retinoids decrease inflammatory mediators and inhibit chemotaxis, providing a rational basis for using them topically against inflammatory acne. Shalita7 provided a review of these and other aspects of topical retinoids against inflammatory acne.

In a recently published set of guidelines for treating acne vulgaris,17 a consensus panel considered topical retinoids to be a standard of care for both comedonal and inflammatory acne. Topical retinoids are most effective when used as part of a multimodality therapy for initial treatment of this skin condition; they often may be used as a long-term monotherapy in patients with well controlled acne.7 Recent retinoid/benzoyl-peroxide formulations have been more effective than has either agent used alone; such combinations also may improve patient compliance as patients use just one topical agent.18

Emerging Therapies for Acne Vulgaris: Light-Based Therapies

Photodynamic therapy (PDT), a new and evolving treatment for acne vulgaris, involves the application of a photosensitizing agent to tissues followed by irradiation with a light source.19

Pottier et al20 were the first to use 5-aminolevulinic acid (ALA), a precursor in the heme biosynthesis pathway, as a topical photosensitizing agent. When applied to the skin, ALA is incorporated into epidermal cells and sebaceous glands; this causes intracellular accumulation of the photoactive heme precursor protoporphyrin IX (ppIX).20–22 Irradiation of photosensitized tissue with light of the appropriate wavelength leads to activation of ppIX and tissue damage via various mechanisms.20–22 The use of blue light in PDT protocols was approved by the US Food and Drug Administration for treating actinic keratoses; it also has been used for superficial basal cell skin cancers.22

In the first reported study of this technique against acne vulgaris, Hongcharu et al23 achieved long-term remission of acne vulgaris on a patient’s back after leaving a 20% ALA solution on the skin for 3 hours and then irradiating the area using a high-intensity broadband light source (500–700 nm). Numerous other groups attempted to reproduce these results using various light sources, including blue light, broad-band intense pulsed light, and various red-light devices.24 Some investigators25,26 demonstrated the efficacy of PDT against acne vulgaris using longer wavelengths of light that were similar to those originally used by Hongcharu et al23; in particular, these researchers used red light in the 635-nm range.25,26

Conclusions on the efficacy of PDT against acne in most cases have been hampered by small patient populations in published studies, frequent lack of controls, and little uniformity in research conditions.24 Further, unlike treatment of actinic keratoses and superficial basal cell carcinomas, which targets the epidermis, acne therapy appears to rely on modulating the effect of the sebaceous glands, a dermal structure. Shorter wavelengths of light, such as that of blue light, are very effective for activating ppIX, but they are unable to penetrate the dermis.19 Red light at 635 nm can activate ppIX and can achieve deeper penetration than can blue light.19

A second major variable in PDT is how long the affected area is incubated with the porphyrin precursor. Multiple protocols using ALA have been proposed; most featured short incubation (ie, 1 hour or less).21 The use of short incubation periods has been promoted as a way to decrease the side effects of erythema and crusting that often occur with longer incubations. However, although side effects may be limited by these shorter incubation times, efficacy also may be sacrificed. Longer incubation times allow greater time for synthesis of ppIX; this may provide more target to be activated by deeply penetrating wavelengths of light and may cause greater damage to the sebaceous gland and, perhaps, more effective treatment of acne vulgaris. Longer incubation times, however, may significantly increase side effects, including pain, erythema, crusting, and hyperpigmentation.24

Several proposed strategies may minimize epidermal accumulation of ppIX and side effects as they maintain accumulation of ppIX in the sebaceous gland. However, it is unclear whether such strategies also will limit the efficacy of PDT. The sebaceous gland clearly is one of the major culprits in acne vulgaris; still, abnormal shedding of corneocytes in the follicular infundibulum also plays a role in acne pathogenesis, and attempts to limit epidermal effects of PDT in acne vulgaris may diminish its efficacy. Future well-designed, large, prospective clinical trials evaluating these variables will guide the use of this therapy in acne.

The photopneumatic system is another device that incorporates light-based therapy for acne vulgaris. This device, marketed as Isolaz™ (Aesthera Corp; Pleasanton, Calif), applies negative pressure to the skin. This system may clear impacted follicular contents mechanically. As it applies negative pressure, the system illuminates the skin with a broadband light source that is similar to an intense pulsed-light device. Unfortunately, no published clinical trials have evaluated the efficacy of this approach, which limits conclusions on whether it will be useful in treating acne vulgaris.

Conclusion

Elucidation of the role of cathelicidin in the chronic inflammatory state of rosacea represents a major advance in understanding the pathogenesis of this common condition. Further studies are needed to better understand how cathelicidin peptides alter the skin flora in rosacea and whether other inflammatory stimuli cooperate with cathelicidin to generate the phenotype of rosacea. These observations likely will lead to more specific therapies for the papules, pustules, and flushing of rosacea.

Acne therapy continues to pose challenges stemming from antibiotic resistance. Fortunately, numerous alternatives to antibiotics are available for treating acne vulgaris. Topical agents consisting of benzoyl peroxide combined with antibiotics or with retinoids are highly effective against acne vulgaris as they prevent bacterial resistance to the anti-infectives. Non-antibiotic therapies, including the use of topical retinoids and 5% topical dapsone, also may treat inflammatory acne effectively, as they avoid the systemic effects of oral antibiotics.

Novel strategies for treating acne vulgaris are being developed. However, the ultimate utility of light-based therapies, including PDT and photopneumatic approaches, is still unclear. Recommendations on the most effective device and protocol for most patients must wait until results from adequately powered trials with appropriate controls are reported. Thus far, the data for PDT and red-light sources that involve long incubations using a porphyrin precursor are promising; ongoing trials are comparing the efficacy of this therapy with isotretinoin, the gold standard for inflammatory acne. Until these studies are published, statements on the efficacy of these approaches must be viewed critically.

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